%0 Journal Article %J J Alzheimers Dis %D 2024 %T A Continuous Extension of Gene Set Enrichment Analysis Using the Likelihood Ratio Test Statistics Identifies Vascular Endothelial Growth Factor as a Candidate Pathway for Alzheimer's Disease via ITGA5. %A Mahzarnia, Ali %A Lutz, Michael W %A Badea, Alexandra %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Biomarkers %K Cognitive Dysfunction %K Humans %K Likelihood Functions %K tau Proteins %K Vascular Endothelial Growth Factor A %X

BACKGROUND: Alzheimer's disease (AD) involves brain neuropathologies such as amyloid plaque and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand disease etiology and devise therapies.

OBJECTIVE: Our objective was to identify molecular pathways associated with hallmark AD biomarkers and cognitive status, accounting for variables such as age, sex, education, and APOE genotype.

METHODS: We introduce a pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of the three phenotypes (amyloid-β, tau, cognition) using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved 634 subjects with data available for all three phenotypes, allowing for the identification of common pathways.

RESULTS: We identified 14 pathways significantly associated with amyloid-β; 5 associated with tau; and 174 associated with cognition, which showed a larger number of pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited associations with all three phenotypes. Mediation analysis showed that among the VEGF-RB family genes, ITGA5 mediates the relationship between cognitive scores and pathological biomarkers.

CONCLUSIONS: We presented a new statistical approach linking continuous phenotypes, gene expression across pathways, and covariates like sex, age, and education. Our results reinforced VEGF RB2's role in AD cognition and demonstrated ITGA5's significant role in mediating the AD pathology-cognition connection.

%B J Alzheimers Dis %V 97 %P 635-648 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38160360?dopt=Abstract %R 10.3233/JAD-230934 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer's Disease and Lewy Body Dementia in the Oldest Old: A Case Series. %A Leiby, Anne-Marie C %A Scambray, Kiana A %A Nguyen, Hannah L %A Basith, Farheen %A Fakhraee, Shahrzad %A Melikyan, Zarui A %A Bukhari, Syed A %A Montine, Thomas J %A Corrada, Maria M %A Kawas, Claudia H %A Sajjadi, S Ahmad %K Aged %K Aged, 80 and over %K Alzheimer Disease %K DNA-Binding Proteins %K Humans %K Lewy Body Disease %K Syncope %K Tauopathies %K TDP-43 Proteinopathies %X

BACKGROUND: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals.

OBJECTIVE: Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART).

METHODS: In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART.

RESULTS: Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups.

CONCLUSIONS: Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

%B J Alzheimers Dis %V 96 %P 113-124 %8 2023 %G eng %N 1 %R 10.3233/JAD-230238 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Emerging Roles of Meningeal Lymphatic Vessels in Alzheimer's Disease. %A Guo, Xiaodi %A Zhang, Guoxin %A Peng, Qinyu %A Huang, Liqin %A Zhang, Zhaohui %A Zhang, Zhentao %K Alzheimer Disease %K Apolipoprotein E4 %K Glymphatic System %K Humans %K Lymphatic System %K Lymphatic Vessels %X

Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer's disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD.

%B J Alzheimers Dis %V 94 %P S355-S366 %8 2023 %G eng %N s1 %R 10.3233/JAD-221016 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Etiology and Clinical Significance of Network Hyperexcitability in Alzheimer's Disease: Unanswered Questions and Next Steps. %A Samudra, Niyatee %A Ranasinghe, Kamalini %A Kirsch, Heidi %A Rankin, Katherine %A Miller, Bruce %K Alzheimer Disease %K Causality %K Clinical Relevance %K Electroencephalography %K Humans %K Levetiracetam %K Seizures %X

Cortical network hyperexcitability related to synaptic dysfunction in Alzheimer's disease (AD) is a potential target for therapeutic intervention. In recent years, there has been increased interest in the prevalence of silent seizures and interictal epileptiform discharges (IEDs, or seizure tendency), with both entities collectively termed "subclinical epileptiform activity" (SEA), on neurophysiologic studies in AD patients. SEA has been demonstrated to be common in AD, with prevalence estimates ranging between 22-54%. Converging lines of basic and clinical evidence imply that modifying a hyperexcitable state results in an improvement in cognition. In particular, though these results require further confirmation, post-hoc findings from a recent phase II clinical trial suggest a therapeutic effect with levetiracetam administration in patients with AD and IEDs. Here, we review key unanswered questions as well as potential clinical trial avenues. Specifically, we discuss postulated mechanisms and treatment of hyperexcitability in patients with AD, which are of interest in designing future disease-modifying therapies. Criteria to prompt screening and optimal screening methodology for hyperexcitability have yet to be defined, as does timing and personalization of therapeutic intervention.

%B J Alzheimers Dis %V 92 %P 13-27 %8 2023 %G eng %N 1 %R 10.3233/JAD-220983 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Lithium Provides Broad Therapeutic Benefits in an Alzheimer's Disease Mouse Model. %A Wiseman, Alyssa L %A Briggs, Clark A %A Peritt, Ariel %A Kapecki, Nicolas %A Peterson, Daniel A %A Shim, Seong S %A Stutzmann, Grace E %K Alzheimer Disease %K Animals %K Calcium %K Disease Models, Animal %K Hippocampus %K Lithium %K Mice %K Mice, Transgenic %K Nitric Oxide Synthase Type I %K tau Proteins %X

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder with a progressive loss of cognitive function. Currently, no effective treatment regimen is available. Lithium, a mood stabilizer for bipolar disorder, exerts broad neuroprotective and neurotrophic actions and improves cognitive function.

OBJECTIVE: The study investigated if lithium stabilizes Ca2+ signaling abnormalities in hippocampal neurons and subsequently normalize downstream effects on AD neuropathology and synaptic plasticity in young AD mice.

METHODS: Four-month-old 3xTg-AD mice were treated with a LiCl diet chow for 30 days. At the end of the lithium treatment, a combination of two-photon Ca2+ imaging, electrophysiology, and immunohistochemistry assays were used to assess the effects of the LiCl treatment on inositol trisphosphate receptor (IP3R)-dependent endoplasmic reticulum (ER) Ca2+ and voltage-gated Ca2+ channel (VGCC)-mediated Ca2+ signaling in CA1 neurons, neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels and synaptic plasticity in the hippocampus and overlying cortex from 3xTg-ADmice.

RESULTS: Thirty-day LiCl treatment reduced aberrant IP3R-dependent ER Ca2+ and VGCC-mediated Ca2+ signaling in CA1 pyramidal neurons from 3xTg-AD mice and restored neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels to control levels in the hippocampal subfields and overlying cortex. The LiCl treatment enhanced post-tetanic potentiation (PTP), a form of short-term plasticity in the hippocampus.

CONCLUSION: The study found that lithium exerts therapeutic effects across several AD-associated early neuronal signaling abnormalities including aberrant Ca2+ signaling, nNOS, and p-tau formation and enhances short-term synaptic plasticity. Lithium could serve as an effective treatment or co-therapeutic for AD.

%B J Alzheimers Dis %V 91 %P 273-290 %8 2023 %G eng %N 1 %R 10.3233/JAD-220758 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Mindfulness Prevents Depression and Psychopathology in Elderly People with Mild to Moderate Alzheimer's Disease: A Randomized Clinical Trial. %A Quintana-Hernández, Domingo J %A Rojas-Hernández, Jaime %A Santana-Del Pino, Angelo %A Céspedes Suárez, Carmen %A Pellejero Silva, Mónica %A Miró-Barrachina, María Teresa %A Ibáñez Fernández, Ignacio %A Estupiñán López, José Antonio %A Borkel, Lucas F %K Aged %K Alzheimer Disease %K Depression %K Donepezil %K Humans %K Longitudinal Studies %K Mindfulness %X

BACKGROUND: This longitudinal study addressed whether mindfulness practice prevents psychological and behavioral symptoms, especially mood disorders, in Alzheimer's disease (AD).

OBJECTIVE: To assess the incidence of depression in the course of AD and to determine which non-pharmacological treatment (NPT) is most effective in preventing psychopathological symptoms.

METHODS: We conducted a longitudinal, non-inferiority and equivalence randomized clinical trial, repeated-measures design, with a control group and three experimental treatments: mindfulness, cognitive stimulation, and relaxation. Each experimental group performed three weekly sessions for two years. The pharmacological treatment of all participants was donepezil (10 mg). Participants were patients with probable AD without diagnosed depression from the public neurology services of the Canary Health Service, Spain. Psychological evaluation was performed using the Geriatric Depression Scale (GDS), Hamilton Depression Rating Scale (HDRS), and Neuropsychiatric Inventory (NPI-Q). The statistical analysis included only patients who attended at least 75% of the sessions. A nonparametric, repeated-measures analysis was performed with Kruskal-Wallis H test and between-group differences with Mann-Whitney U test with Bonferroni correction (p < 0.008). Effect size was calculated with partial eta-squared.

RESULTS: The results showed significant differences with large effect sizes (η2p>0.14) between mindfulness and the rest of the experimental groups as well as the control in the GDS, HDRS, and NPI-Q scales.

CONCLUSION: Compared to the other experimental groups, only mindfulness prevented the onset of depression and other psychopathologies in early-stage AD. Based on its effectiveness in maintaining cognitive functions and preventing psychopathology, we recommend mindfulness as the first-choice NPT for mild to moderate AD.

%B J Alzheimers Dis %V 91 %P 471-481 %8 2023 %G eng %N 1 %R 10.3233/JAD-220889 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Mortality Risks and Causes of Death by Dementia Types in a Japanese Cohort with Dementia: NCGG-STORIES. %A Ono, Rei %A Sakurai, Takashi %A Sugimoto, Taiki %A Uchida, Kazuaki %A Nakagawa, Takeshi %A Noguchi, Taiji %A Komatsu, Ayane %A Arai, Hidenori %A Saito, Tami %K Aged %K Alzheimer Disease %K Cause of Death %K Cognitive Dysfunction %K Dementia %K East Asian People %K Female %K Humans %K Lewy Body Disease %K Male %X

BACKGROUND: Prognosis-related information regarding dementia needs to be updated, as changes in medical and long-term care environments for patients with dementia in recent decades may be improving the prognosis of the disease.

OBJECTIVE: We aimed to investigate the mortality, cause of death, and prognostic factors by types of dementia in a Japanese clinic-based cohort.

METHODS: The National Center for Geriatrics and Gerontology-Life Stories of People with Dementia consists of clinical records and prognostic data of patients who visited the Memory Clinic in Japan. Patients who attended the clinic between July 2010 and September 2018, or their close relatives, were asked about death information via a postal survey. A cohort of 3,229 patients (mean age, 76.9; female, 1,953) was classified into six groups: normal cognition (NC), mild cognitive impairment (MCI), Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration. A Cox proportional hazards model was employed to compare the mortality of each type of dementia, MCI, and NC.

RESULTS: Patients with all types of dementia and MCI had higher mortality rates than those with NC (hazard risks: 2.61-5.20). The most common cause of death was pneumonia, followed by cancer. In the MCI, AD, and DLB groups, older age, male sex, and low cognitive function were common prognostic factors but not presence of apolipoprotein E ɛ4 allele.

CONCLUSION: Our findings suggest important differences in the mortality risk and cause of death among patients with dementia, which will be useful in advanced care planning and policymaking.

%B J Alzheimers Dis %V 92 %P 487-498 %8 2023 %G eng %N 2 %R 10.3233/JAD-221290 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity. %A Castillo, Carolina %A Bravo-Arrepol, Gastón %A Wendt, Aline %A Saez-Orellana, Francisco %A Millar, Camila %A Burgos, Carlos F %A Gavilán, Javiera %A Pacheco, Carla %A Ahumada-Rudolph, Ramón %A Napiórkowska, Mariola %A Pérez, Claudia %A Becerra, José %A Fuentealba, Jorge %A Cabrera-Pardo, Jaime R %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Lignans %K Mice %K Neuroprotective Agents %K PC12 Cells %K Rats %X

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects.

OBJECTIVE: In this study, the neuroprotective abilities of Eu on synaptic failure induced by AβOs were analyzed.

METHODS: Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AβOs.

RESULTS: In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AβOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AβOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aβ aggregation process inducing a decrease in AβOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu.

CONCLUSION: We believe that Eu represents a novel lead that reduces the Aβ toxicity, opening new research venues for lignans as neuroprotective agents.

%B J Alzheimers Dis %V 94 %P S97-S108 %8 2023 %G eng %N s1 %R 10.3233/JAD-220935 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Phonological and Semantic Fluency in Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Olmos-Villaseñor, Rocio %A Sepulveda-Silva, Consuelo %A Julio-Ramos, Teresa %A Fuentes-Lopez, Eduardo %A Toloza-Ramirez, David %A Santibañez, Rodrigo A %A Copland, David A %A Mendez-Orellana, Carolina %K Alzheimer Disease %K Humans %K Linguistics %K Neuropsychological Tests %K Semantics %K Verbal Behavior %X

BACKGROUND: Semantic and Phonological fluency (SF and PF) are routinely evaluated in patients with Alzheimer's disease (AD). There are disagreements in the literature regarding which fluency task is more affected while developing AD. Most studies focus on SF assessment, given its connection with the temporoparietal amnesic system. PF is less reported, it is related to working memory, which is also impaired in probable and diagnosed AD. Differentiating between performance on these tasks might be informative in early AD diagnosis, providing an accurate linguistic profile.

OBJECTIVE: Compare SF and PF performance in healthy volunteers, volunteers with probable AD, and patients with AD diagnosis, considering the heterogeneity of age, gender, and educational level variables.

METHODS: A total of 8 studies were included for meta-analysis, reaching a sample size of 1,270 individuals (568 patients diagnosed with AD, 340 with probable AD diagnosis, and 362 healthy volunteers).

RESULTS: The three groups consistently performed better on SF than PF. When progressing to a diagnosis of AD, we observed a significant difference in SF and PF performance across our 3 groups of interest (p = 0.04). The age variable explained a proportion of this difference in task performance across the groups, and as age increases, both tasks equally worsen.

CONCLUSION: The performance of SF and PF might play a differential role in early AD diagnosis. These tasks rely on partially different neural bases of language processing. They are thus worth exploring independently in diagnosing normal aging and its transition to pathological stages, including probable and diagnosed AD.

%B J Alzheimers Dis %V 95 %P 1-12 %8 2023 %G eng %N 1 %R 10.3233/JAD-221272 %0 Journal Article %J J Alzheimers Dis %D 2023 %T PM2.5 and Dementia in a Low Exposure Setting: The Influence of Odor Identification Ability and APOE. %A Andersson, John %A Sundström, Anna %A Nordin, Maria %A Segersson, David %A Forsberg, Bertil %A Adolfsson, Rolf %A Oudin, Anna %K Air Pollutants %K Air Pollution %K Apolipoproteins E %K Cohort Studies %K Dementia %K Environmental Exposure %K Humans %K Longitudinal Studies %K Odorants %K Particulate Matter %X

BACKGROUND: Growing evidence show that long term exposure to air pollution increases the risk of dementia.

OBJECTIVE: The aim of this study was to investigate associations between PM2.5 exposure and dementia in a low exposure area, and to investigate the role of olfaction and the APOE ɛ4 allele in these associations.

METHODS: Data were drawn from the Betula project, a longitudinal study on aging, memory, and dementia in Sweden. Odor identification ability was assessed using the Scandinavian Odor Identification Test (SOIT). Annual mean PM2.5 concentrations were obtained from a dispersion-model and matched at the participants' residential address. Proportional hazard regression was used to calculate hazard ratios.

RESULTS: Of 1,846 participants, 348 developed dementia during the 21-year follow-up period. The average annual mean PM2.5 exposure at baseline was 6.77μg/m3, which is 1.77μg/m3 above the WHO definition of clean air. In a fully adjusted model (adjusted for age, sex, APOE, SOIT, cardiovascular diseases and risk factors, and education) each 1μg/m3 difference in annual mean PM2.5-concentration was associated with a hazard ratio of 1.23 for dementia (95% CI: 1.01-1.50). Analyses stratified by APOE status (ɛ4 carriers versus non-carriers), and odor identification ability (high versus low), showed associations only for ɛ4 carriers, and for low performance on odor identification ability.

CONCLUSION: PM2.5 was associated with an increased risk of dementia in this low pollution setting. The associations between PM2.5 and dementia seemed stronger in APOE carriers and those with below average odor identification ability.

%B J Alzheimers Dis %V 92 %P 679-689 %8 2023 %G eng %N 2 %R 10.3233/JAD-220469 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Soluble TREM2, Alzheimer's Disease Pathology, and Risk for Progression of Cerebral Small Vessel Disease: A Longitudinal Study. %A Wu, Chao %A Ma, Ya-Hui %A Hu, Hao %A Zhao, Bing %A Tan, Lan %K Alzheimer Disease %K Biomarkers %K Cerebral Small Vessel Diseases %K Humans %K Longitudinal Studies %K Membrane Glycoproteins %K Myeloid Cells %K Neuroinflammatory Diseases %K Receptors, Immunologic %X

BackgroundUntil recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimer's disease (AD), but they have not been fully explored in CSVD.ObjectiveTo determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression.MethodsA total of 426 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements of CSF sTREM2 and AD pathology (Aβ1-42, P-tau181P). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology.Results Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR = 1.28 [95% CI, 1.01-1.62]) and CMBs counts (OR = 1.32 [95% CI, 1.03-1.68]). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR = 1.44 [95% CI, 1.05-1.98]). Participants with AD pathology (Aβ1-42 and P-tau181P) showed a stronger association between CSF sTREM2 and CSVD progression.ConclusionThis longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation.

%B J Alzheimers Dis %V 92 %P 311-322 %8 2023 %G eng %N 1 %R 10.3233/JAD-220731 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association Between Serum Vitamins and the Risk of Alzheimer's Disease in Chinese Population. %A Liu, Xi-Xi %A Wu, Peng-Fei %A Liu, Ying-Zi %A Jiang, Ya-Ling %A Wan, Mei-Dan %A Xiao, Xue-Wen %A Yang, Qi-Jie %A Jiao, Bin %A Liao, Xin-Xin %A Wang, Jun-Ling %A Liu, Shao-Hui %A Zhang, Xuewei %A Shen, Lu %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Case-Control Studies %K China %K Female %K Folic Acid %K Humans %K Logistic Models %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Riboflavin %K Risk %K Vitamin B 12 %K Vitamin D %K Vitamin E %X

BACKGROUND: Alzheimer's disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely.

OBJECTIVE: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population.

METHODS: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants.

RESULTS: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score.

CONCLUSION: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.

%B J Alzheimers Dis %V 85 %P 829-836 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864672?dopt=Abstract %R 10.3233/JAD-215104 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Barriers to Effective Memory Assessments for Alzheimer's Disease. %A Parra, Mario A %K Alzheimer Disease %K Cognition %K Cognition Disorders %K Humans %K Longitudinal Studies %X

Recently, Alzheimer's Disease International (ADI) stressed that around 75% of people living with dementia globally are still not receiving a diagnosis. In this commentary, I reflect on how efforts towards better cognitive assessments, particularly of memory, can be aligned and harmonized to contribute to such needs. I highlight some barriers that ongoing collaborations and trials are facing and their potential drivers. I suggest some strategies that can help overcome them and in so doing, integrate research agendas. We need to ignite the debate towards strategies that can help level the playfield to tackle Alzheimer's disease with true global solutions.

%B J Alzheimers Dis %V 90 %P 981-988 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35147540?dopt=Abstract %R 10.3233/JAD-215445 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Clinical and Imaging Determinants of Neurocognitive Disorders in Post-Acute COVID-19 Patients with Cognitive Complaints. %A Andriuta, Daniela %A Si-Ahmed, Cherifa %A Roussel, Martine %A Constans, Jean-Marc %A Makki, Malek %A Aarabi, Ardalan %A Basille, Damien %A Andrejak, Claire %A Godefroy, Olivier %K Cognition %K COVID-19 %K Humans %K Leukoaraiosis %K Magnetic Resonance Imaging %K Neurocognitive Disorders %K Neuropsychological Tests %K Oxygen %K White Matter %X

BACKGROUND: Neurocognitive disorders (NCDs) are a part of the post-acute coronavirus disease (COVID-19) syndrome. No study has specifically evaluated NCDs in post-acute COVID-19 patients with cognitive complaints or their MRI determinants.

OBJECTIVE: To characterize NCDs in post-acute COVID-19 patients with cognitive complaints. The secondary objectives were to assess their clinical and MRI determinants.

METHODS: We included 46 patients with a post-acute COVID-19 cognitive complaint referred to the Amiens University Hospital Memory Center. They underwent a neuropsychological assessment and 36 had cerebral MRI. The G3 overall summary score was the sum of the mean z scores for the executive function, language, and action speed domains. Neuropsychological profiles were compared in a general linear model. Clinical determinants were analyzed by stepwise linear regression. White matter hyperintensities (WMH) masks were analyzed using parcel-based WMH symptom mapping to identify the locations of WMHs associated with cognitive performance.

RESULTS: Repeated ANOVA showed a group effect (p = 0.0001) due to overall lower performance for patients and a domain effect (p = 0.0001) due to a lower (p = 0.007) action speed score. The G3 overall summary score was significantly associated with solely the requirement for oxygen (R2 = 0.319, p = 0.031). WHMs were associated with the G3 overall summary score in the following structures, all right-sided (p < 0.01): superior frontal region, postcentral region, cingulum, cortico-spinal tract, inferior longitudinal fasciculus, internal capsule, and posterior segment of the arcuate fasciculus.

CONCLUSION: Post-acute COVID-19 patients with cognitive complaints had NCD, with prominent action slowing, significantly associated with the acute phase oxygen requirement and a right-sided WMH structure pattern.

%B J Alzheimers Dis %V 87 %P 1239-1250 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35431242?dopt=Abstract %R 10.3233/JAD-215506 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Digital Technologies to Prevent Social Isolation and Loneliness in Dementia: A Systematic Review. %A Rai, Harleen Kaur %A Kernaghan, David %A Schoonmade, Linda %A Egan, Kieren J %A Pot, Anne Margriet %K Dementia %K Digital Technology %K Humans %K Loneliness %K Quality of Life %K Social Isolation %X

BACKGROUND: Dementia poses significant and sustained challenges to global society. Diagnosis can lead to increased feelings of loneliness and social isolation. People with dementia living alone are particularly at risk. Considering the growing number of technologies proposed to aid people with dementia address social isolation and loneliness, we reviewed the existing literature.

OBJECTIVE: To collate and summarize current evidence for digital technologies to prevent social isolation and loneliness for people with dementia.

METHODS: Following the PRISMA guidelines, we systematically searched five databases to identify studies of digital technologies designed to support or prevent social isolation or loneliness for people with dementia. Pre-specified outcomes included social isolation, loneliness, and quality of life. We used deductive thematic analysis to synthesize the major themes emerging from the studies.

RESULTS: Ten studies met our inclusion criteria where all studies reported improvements in quality of life and seven reported benefits regarding social inclusion or a reduction in loneliness. Technologies were varied across purpose, delivery format, theoretical models, and levels of personalization. Two studies clearly described the involvement of people with dementia in the study design and five technologies were available outside the research context.

CONCLUSION: There is limited- but increasing- evidence that technologies hold potential to improve quality of life and reduce isolation/loneliness for people with dementia. Results presented are largely based in small-scale research studies. Involvement of people with dementia was limited and few research concepts are reaching implementation. Closer collaboration with people with dementia to provide affordable, inclusive, and person-centered solutions is urgently required.

%B J Alzheimers Dis %V 90 %P 513-528 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/36120780?dopt=Abstract %R 10.3233/JAD-220438 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Medial Temporal Atrophy in Posterior Cortical Atrophy and Its Relationship to the Cingulate Island Sign. %A Josephs, Kennedy A %A Pham, Nha Trang Thu %A Graff-Radford, Jonathan %A Machulda, Mary M %A Lowe, Val J %A Whitwell, Jennifer L %K Alzheimer Disease %K Atrophy %K Fluorodeoxyglucose F18 %K Humans %K Lewy Body Disease %K Magnetic Resonance Imaging %K Positron-Emission Tomography %X

BACKGROUND: It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA).

OBJECTIVE: To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing.

METHODS: Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured.

RESULTS: Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS.

CONCLUSION: Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA.

%B J Alzheimers Dis %V 86 %P 491-498 %8 2022 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35068459?dopt=Abstract %R 10.3233/JAD-215263 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Automatic Subtyping of Individuals with Primary Progressive Aphasia. %A Themistocleous, Charalambos %A Ficek, Bronte %A Webster, Kimberly %A den Ouden, Dirk-Bart %A Hillis, Argye E %A Tsapkini, Kyrana %K Acoustics %K Aged %K Aphasia, Primary Progressive %K Decision Trees %K Female %K Humans %K Linguistics %K Machine Learning %K Male %K Models, Theoretical %K Neural Networks, Computer %K Primary Progressive Nonfluent Aphasia %K Reproducibility of Results %K Support Vector Machine %X

BACKGROUND: The classification of patients with primary progressive aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists.

OBJECTIVE: The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA.

METHODS: In this paper, we present a machine learning model based on deep neural networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as to expert clinicians' classifications.

RESULTS: The DNN model outperformed the other machine learning models as well as expert clinicians' classifications with 80% classification accuracy. Importantly, 90% of patients with nfvPPA and 95% of patients with lvPPA was identified correctly, providing reliable subtyping of these patients into their corresponding PPA variants.

CONCLUSION: We show that the combined speech and language markers from connected speech productions can inform variant subtyping in patients with PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick, and inexpensive classification of patients with PPA.

%B J Alzheimers Dis %V 79 %P 1185-1194 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427742?dopt=Abstract %R 10.3233/JAD-201101 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches. %A Clark, I A %A Vissel, B %K Alzheimer Disease %K Anti-Inflammatory Agents, Non-Steroidal %K Brain %K Brain Injuries %K COVID-19 %K Disease Progression %K Etanercept %K Heart Arrest %K Humans %K Locus Coeruleus %K Neurodegenerative Diseases %K Norepinephrine %K Parkinson Disease %K Risk Factors %K SARS-CoV-2 %K Stroke %K Survivors %K Tumor Necrosis Factor-alpha %X

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

%B J Alzheimers Dis %V 79 %P 931-948 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33459706?dopt=Abstract %R 10.3233/JAD-201186 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer's Disease Pathology. %A Ryman, Sephira G %A Yutsis, Maya %A Tian, Lu %A Henderson, Victor W %A Montine, Thomas J %A Salmon, David P %A Galasko, Douglas %A Poston, Kathleen L %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Cognitive Dysfunction %K Female %K Humans %K Lewy Body Disease %K Male %X

BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology.

OBJECTIVE: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD.

METHODS: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer's Coordinating Center's Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical).

RESULTS: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage.

CONCLUSION: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.

%B J Alzheimers Dis %V 80 %P 1243-1256 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33646154?dopt=Abstract %R 10.3233/JAD-201187 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Dementia-Friendly "Design": Impact on COVID-19 Death Rates in Long-Term Care Facilities Around the World. %A Olson, Nancy L %A Albensi, Benedict C %K COVID-19 %K Dementia %K Environment Design %K Health Services Needs and Demand %K Humans %K Long-Term Care %K Pandemics %K Quality of Life %X

Persons with dementia (PWD) make up a large portion of the long-term care (LTC) population the world over. Before a global pandemic swept the world, governments and healthcare providers struggled with how to best care for this unique population. One of the greatest challenges is a PWD's tendency to "walk with purpose" and exhibit unsafe wayfinding and elopement, which places them at risk of falls and injury. Past solutions included increased use of restraints and pharmacological interventions, but these have fallen out of favor over the years and are not optimal. These challenges put enormous strain on staff and caregivers, who are often poorly trained in dementia care, underpaid, overworked, and overstressed. PWD are impacted by these stresses, and unmet needs in LTC places an even greater stress on them and increases their risks of morbidity and mortality. The physical design of their environments contributes to the problem. Old, institutionalized buildings have poor lighting, poor ventilation, long dead-end hallways, poor visual cues, lack of home-like décor, shared bedrooms and bathrooms, and are often dense and overcrowded. These design elements contribute to the four 'A's' of dementia: apathy, anxiety, agitation, and aggression, and they also contributed to the rapid spread of COVID-19 in these facilities the world over. In this review, we present current "dementia friendly" design models in the home, community, and LTC, and argue how they could have saved lives during the pandemic and reduced the stresses on both the dementia resident and the caregiver/staff.

%B J Alzheimers Dis %V 81 %P 427-450 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33814449?dopt=Abstract %R 10.3233/JAD-210017 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Economic Burden of Alzheimer's Disease Dementia in Japan. %A Ikeda, Shunya %A Mimura, Masaru %A Ikeda, Manabu %A Wada-Isoe, Kenji %A Azuma, Mie %A Inoue, Sachie %A Tomita, Kiyoyuki %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Caregivers %K Female %K Health Care Costs %K Humans %K Japan %K Long-Term Care %K Male %X

BACKGROUND: Alzheimer's disease dementia (ADD) is the leading cause of long-term care in Japan.

OBJECTIVE: This study estimates the annual healthcare and long-term care costs in fiscal year 2018 for adults over 65 years of age with ADD in Japan and the informal care costs and productivity loss for their families.

METHODS: Healthcare and long-term care costs for ADD were estimated according to the disease severity classified by the clinical dementia rating (CDR) score, using reports from a literature review. For the costs of time spent on caregiving activities, productivity loss for ADD family caregivers aged 20-69 and informal care costs for all ADD family caregivers were estimated.

RESULTS: The total healthcare cost of ADD was JPY 1,073 billion, of which 86% (JPY 923 billion) was attributed to healthcare costs other than ADD drug costs (JPY 151 billion). The healthcare costs other than ADD drug costs by severity were less than JPY 200 billion for CDR 0.5, CDR 1, and CDR 2, respectively, but increased to JPY 447 billion (48%) for CDR 3. The public long-term care costs were estimated to be JPY 4,783 billion, which increased according to the severity. Total productivity loss for ADD family caregivers aged 20-69 was JPY 1,547 billion and the informal care cost for all ADD family caregivers was JPY 6,772 billion.

CONCLUSION: ADD costs have a significant impact on public-funded healthcare, long-term care systems, and families in Japan. To minimize the economic burden of ADD, prolonging healthy life expectancy is the key factor to address.

%B J Alzheimers Dis %V 81 %P 309-319 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33780371?dopt=Abstract %R 10.3233/JAD-210075 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Elevated Norepinephrine Metabolism Gauges Alzheimer's Disease-Related Pathology and Memory Decline. %A Riphagen, Joost M %A van Egroo, Maxime %A Jacobs, Heidi I L %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Cohort Studies %K Disease Progression %K Female %K Humans %K Learning %K Locus Coeruleus %K Male %K Memory Disorders %K Methoxyhydroxyphenylglycol %K Middle Aged %K Neuropsychological Tests %K Norepinephrine %K Predictive Value of Tests %K tau Proteins %X

The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-β is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer's disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer's disease-related processes.

%B J Alzheimers Dis %V 80 %P 521-526 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554915?dopt=Abstract %R 10.3233/JAD-201411 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Is Engagement in Intellectual and Social Leisure Activities Protective Against Dementia Risk? Evidence from the English Longitudinal Study of Ageing. %A Almeida-Meza, Pamela %A Steptoe, Andrew %A Cadar, Dorina %K Aged %K Aged, 80 and over %K Aging %K Dementia %K Female %K Humans %K Incidence %K Leisure Activities %K Life Style %K Longitudinal Studies %K Male %K Marital Status %K Middle Aged %K Proportional Hazards Models %K Sex Factors %K Social Behavior %K Surveys and Questionnaires %K Survival Analysis %K United Kingdom %X

BACKGROUND: Studies have suggested that mentally stimulating activities and socially engaged lifestyles may reduce dementia risk; however, it is unclear which activities are more beneficial.

OBJECTIVE: We investigated intellectual and social leisure activities in relation to dementia incidence and explored the modifying role of sex and marital status in these associations.

METHODS: The sample was comprised of 8,030 participants aged 50+ from the English Longitudinal Study of Ageing, who joined at wave 1 (2002-2003), or waves 3 (2006-2007), or 4 (2008-2009). The end of the study period was wave 8 (2016-2017). Subdistribution hazard models investigated the role of leisure activities grouped into intellectual and social domains in relation to dementia while accounting for the risk of death. Subsequent analyses were conducted with individual leisure activities.

RESULTS: During the study period of up to 15 years, 412 participants developed dementia, and 2,192 died. We found that increased engagement in the intellectual activities' domain was associated with a decreased dementia incidence (SHR 0.85, 95% CI 0.76-0.96, p = 0.007), independent of the risk of death in married individuals, but not in those who were single, divorced, or widowed. Individual analyses for each leisure activity showed independent associations for reading newspapers in females (SHR 0.65, 95% CI 0.49-0.84, p = 0.001), mobile phone usage in males (SHR 0.61, 95% CI 0.45-0.84, p = 0.002), and having hobbies for married individuals (SHR 0.70, 95% CI 0.51-0.95, p = 0.02).

CONCLUSION: We found that intellectual leisure activities contribute to lower dementia risk in a representative population of English adults, suggesting intervention opportunities.

%B J Alzheimers Dis %V 80 %P 555-565 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554903?dopt=Abstract %R 10.3233/JAD-200952 %0 Journal Article %J J Alzheimers Dis %D 2021 %T How Do Persons with Young and Late Onset Dementia Die? %A Roβmeier, Carola %A Hartmann, Julia %A Riedl, Lina %A Dorn, Bianca %A Fischer, Julia %A Hartmann, Florentine %A Egert-Schwender, Silvia %A Kehl, Victoria %A Schneider-Schelte, Helga %A Jox, Ralf J %A Dinkel, Andreas %A Diehl-Schmid, Janine %K Advance Care Planning %K Age of Onset %K Aged %K Aged, 80 and over %K Caregivers %K Dementia %K Female %K Humans %K Long-Term Care %K Male %K Palliative Care %K Quality of Life %X

BACKGROUND: End of life symptoms and symptom management as well as the quality of dying (QoD) of persons with advanced dementia (PWAD) have not yet been systematically studied in Germany.

OBJECTIVE: 1) To investigate symptoms, treatment and care at the end of life, advance care planning, and circumstances of death of recently deceased PWAD; 2) To determine whether there are differences between young and late onset dementia (YOD and LOD).

METHODS: The study was performed in the context of the project EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of Young-onset and Late-Onset dementia in Germany). Closest relatives of recently deceased patients with advanced YOD (N = 46) and LOD (N = 54) living at home or in long term care were interviewed.

RESULTS: Circumstances of death, symptoms, and treatment appeared to be similar between YOD and LOD, except that persons with LOD had significantly more somatic comorbidities and were admitted to hospital in the last three months of life more often than persons with LOD. At end of life, 60% of PWAD appeared to be "at peace". Difficulty swallowing, gurgling, shortness of breath, and discomfort were observed most frequently. Large interindividual differences in suffering and QoD were present. Determinants of QoD were not identified.

CONCLUSION: Our findings suggest that low QoD was caused by inadequate recognition and/or insufficient treatment of burdensome physical and emotional symptoms. PWADs' needs should be assessed regularly, and strategies focusing on treatment and implementing support for both the patient and caregiver must be established.

%B J Alzheimers Dis %V 81 %P 843-852 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33843681?dopt=Abstract %R 10.3233/JAD-210046 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Impact of a Global Pandemic on People Living with Dementia and Their Care Partners: Analysis of 417 Lived Experience Reports. %A Tam, Mallorie T %A Dosso, Jill A %A Robillard, Julie M %K Adaptation, Psychological %K Aged %K Alzheimer Disease %K British Columbia %K Caregivers %K COVID-19 %K Disabled Persons %K Female %K Humans %K Loneliness %K Male %K Needs Assessment %K Psychosocial Support Systems %K Social Isolation %K Social Support %K Stress, Psychological %K Surveys and Questionnaires %X

BACKGROUND: The COVID-19 pandemic is impacting the physical and emotional health of older adults living with dementia and their care partners.

OBJECTIVE: Using a patient-centered approach, we explored the experiences and needs of people living with dementia and their care partners during the COVID-19 pandemic as part of an ongoing evaluation of dementia support services in British Columbia, Canada.

METHODS: A survey instrument was developed around the priorities identified in the context of the COVID-19 and Dementia Task Force convened by the Alzheimer Society of Canada.

RESULTS: A total of 417 surveys were analyzed. Overall, respondents were able to access information that was helpful for maintaining their own health and managing a period of social distancing. Care partners reported a number of serious concerns, including the inability to visit the person that they care for in long-term or palliative care. Participants also reported that the pandemic increased their levels of stress overall and that they felt lonelier and more isolated than they did before the pandemic. The use of technology was reported as a way to connect socially with their loved ones, with the majority of participants connecting with others at least twice per week.

CONCLUSION: Looking at the complex effects of a global pandemic through the experiences of people living with dementia and their care partners is vital to inform healthcare priorities to restore their quality of life and health and better prepare for the future.

%B J Alzheimers Dis %V 80 %P 865-875 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554905?dopt=Abstract %R 10.3233/JAD-201114 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Life Course Air Pollution Exposure and Cognitive Decline: Modelled Historical Air Pollution Data and the Lothian Birth Cohort 1936. %A Russ, Tom C %A Cherrie, Mark P C %A Dibben, Chris %A Tomlinson, Sam %A Reis, Stefan %A Dragosits, Ulrike %A Vieno, Massimo %A Beck, Rachel %A Carnell, Ed %A Shortt, Niamh K %A Muniz-Terrera, Graciela %A Redmond, Paul %A Taylor, Adele M %A Clemens, Tom %A van Tongeren, Martie %A Agius, Raymond M %A Starr, John M %A Deary, Ian J %A Pearce, Jamie R %K Adolescent %K Adult %K Aged %K Air Pollution %K Child %K Cognitive Dysfunction %K Environmental Exposure %K Female %K History, 20th Century %K Humans %K Linear Models %K Male %K Middle Aged %K Particulate Matter %K Scotland %K Young Adult %X

BACKGROUND: Air pollution has been consistently linked with dementia and cognitive decline. However, it is unclear whether risk is accumulated through long-term exposure or whether there are sensitive/critical periods. A key barrier to clarifying this relationship is the dearth of historical air pollution data.

OBJECTIVE: To demonstrate the feasibility of modelling historical air pollution data and using them in epidemiologicalmodels.

METHODS: Using the EMEP4UK atmospheric chemistry transport model, we modelled historical fine particulate matter (PM2.5) concentrations for the years 1935, 1950, 1970, 1980, and 1990 and combined these with contemporary modelled data from 2001 to estimate life course exposure in 572 participants in the Lothian Birth Cohort 1936 with lifetime residential history recorded. Linear regression and latent growth models were constructed using cognitive ability (IQ) measured by the Moray House Test at the ages of 11, 70, 76, and 79 years to explore the effects of historical air pollution exposure. Covariates included sex, IQ at age 11 years, social class, and smoking.

RESULTS: Higher air pollution modelled for 1935 (when participants would have been in utero) was associated with worse change in IQ from age 11-70 years (β = -0.006, SE = 0.002, p = 0.03) but not cognitive trajectories from age 70-79 years (p > 0.05). There was no support for other critical/sensitive periods of exposure or an accumulation of risk (all p > 0.05).

CONCLUSION: The life course paradigm is essential in understanding cognitive decline and this is the first study to examine life course air pollution exposure in relation to cognitive health.

%B J Alzheimers Dis %V 79 %P 1063-1074 %8 2021 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33427734?dopt=Abstract %R 10.3233/JAD-200910 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Locus Coeruleus in Aging and Alzheimer's Disease: A Postmortem and Brain Imaging Review. %A Beardmore, Rebecca %A Hou, Ruihua %A Darekar, Angela %A Holmes, Clive %A Boche, Delphine %K Aging %K Alzheimer Disease %K Animals %K Autopsy %K Brain Stem %K Humans %K Locus Coeruleus %K Magnetic Resonance Imaging %K Melanins %K Mice %K Norepinephrine %K Rats %K tau Proteins %X

The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer's disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway.

%B J Alzheimers Dis %V 83 %P 5-22 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34219717?dopt=Abstract %R 10.3233/JAD-210191 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Memory-Related Frontal Brainwaves Predict Transition to Mild Cognitive Impairment in Healthy Older Individuals Five Years Before Diagnosis. %A Jiang, Yang %A Li, Juan %A Schmitt, Frederick A %A Jicha, Gregory A %A Munro, Nancy B %A Zhao, Xiaopeng %A Smith, Charles D %A Kryscio, Richard J %A Abner, Erin L %K Aged %K Brain Waves %K Cognition %K Cognitive Dysfunction %K Electroencephalography %K Female %K Humans %K Longitudinal Studies %K Male %K Memory, Short-Term %K Neuropsychological Tests %K Prodromal Symptoms %X

BACKGROUND: Early prognosis of high-risk older adults for amnestic mild cognitive impairment (aMCI), using noninvasive and sensitive neuromarkers, is key for early prevention of Alzheimer's disease. We have developed individualized measures in electrophysiological brain signals during working memory that distinguish patients with aMCI from age-matched cognitively intact older individuals.

OBJECTIVE: Here we test longitudinally the prognosis of the baseline neuromarkers for aMCI risk. We hypothesized that the older individuals diagnosed with incident aMCI already have aMCI-like brain signatures years before diagnosis.

METHODS: Electroencephalogram (EEG) and memory performance were recorded during a working memory task at baseline. The individualized baseline neuromarkers, annual cognitive status, and longitudinal changes in memory recall scores up to 10 years were analyzed.

RESULTS: Seven of the 19 cognitively normal older adults were diagnosed with incident aMCI for a median 5.2 years later. The seven converters' frontal brainwaves were statistically identical to those patients with diagnosed aMCI (n = 14) at baseline. Importantly, the converters' baseline memory-related brainwaves (reduced mean frontal responses to memory targets) were significantly different from those who remained normal. Furthermore, differentiation pattern of left frontal memory-related responses (targets versus nontargets) was associated with an increased risk hazard of aMCI (HR = 1.47, 95% CI 1.03, 2.08).

CONCLUSION: The memory-related neuromarkers detect MCI-like brain signatures about five years before diagnosis. The individualized frontal neuromarkers index increased MCI risk at baseline. These noninvasive neuromarkers during our Bluegrass memory task have great potential to be used repeatedly for individualized prognosis of MCI risk and progression before clinical diagnosis.

%B J Alzheimers Dis %V 79 %P 531-541 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337367?dopt=Abstract %R 10.3233/JAD-200931 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Mild Behavioral Impairment and Subjective Cognitive Decline Predict Cognitive and Functional Decline. %A Ismail, Zahinoor %A McGirr, Alexander %A Gill, Sascha %A Hu, Sophie %A Forkert, Nils D %A Smith, Eric E %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Disease Progression %K Executive Function %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Odds Ratio %K Risk Assessment %X

BACKGROUND: Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) are dementia risk states, and potentially represent neurobehavioral and neurocognitive manifestations, respectively, of early stage neurodegeneration. Both MBI and SCD predict incident cognitive decline and dementia, are associated with known dementia biomarkers, and are both represented in the NIA-AA research framework for AD in Stage 2 (preclinical disease).

OBJECTIVE: To assess the associations of MBI and SCD, alone and in combination, with incident cognitive and functional decline in a population of older adults. We tested the hypothesis that MBI and SCD confer additive risk for decline.

METHODS: Cognitively normal participants were followed up annually at Alzheimer's Disease Centers. Logistic regression assessed the relationship between baseline classification (MBI-SCD-, MBI-SCD+, MBI+SCD-, or MBI+SCD+) and 3-year outcome.

RESULTS: Of 2,769 participants (mean age=76), 1,536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3 years, 349 (12.6%) declined to CDR >0, including 23.1% of the MBI+group, 23.5% of the SCD+group, and 30.9% of the intersection group of both MBI+and SCD+participants. Compared to SCD-MBI-, we observed an ordinal progression in risk (ORs [95% CI]): 3.61 [2.42-5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57-6.34] for MBI+SCD- (20.7%), and 8.15 [5.71-11.64] for MBI+SCD+(30.9%).

CONCLUSION: MBI and SCD together were associated with the greatest risk of decline. These complementary dementia risk syndromes can be used as simple and scalable methods to identify high-risk patients for workup or for clinical trial enrichment.

%B J Alzheimers Dis %V 80 %P 459-469 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554909?dopt=Abstract %R 10.3233/JAD-201184 %0 Journal Article %J J Alzheimers Dis %D 2021 %T MIND Diet, Common Brain Pathologies, and Cognition in Community-Dwelling Older Adults. %A Dhana, Klodian %A James, Bryan D %A Agarwal, Puja %A Aggarwal, Neelum T %A Cherian, Laurel J %A Leurgans, Sue E %A Barnes, Lisa L %A Bennett, David A %A Schneider, Julie A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid %K Autopsy %K Brain %K Chicago %K Cognition %K Diet, Mediterranean %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Surveys and Questionnaires %X

BACKGROUND: MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer's disease (AD) dementia in older adults.

OBJECTIVE: We aim to examine whether the association of the MIND diet with cognition is independent of common brain pathologies.

METHODS: Utilizing data from the Rush Memory and Aging Project (MAP), a longitudinal clinical-pathologic study, we studied 569 decedents with valid dietary data, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A series of regression analyses were used to examine associations of the MIND diet, dementia-related brain pathologies, and global cognition proximate to death adjusting for age, sex, education, APOEɛ4, late-life cognitive activities, and total energy intake.

RESULTS: A higher MIND diet score was associated with better global cognitive functioning proximate to death (β= 0.119, SE = 0.040, p = 0.003), and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model. The β-estimate after controlling for global AD pathology was 0.111 (SE = 0.037, p = 0.003). The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline (β= 0.121, SE = 0.042, p = 0.005) or in people diagnosed with postmortem diagnosis of AD based on NIA-Reagan consensus recommendations (β= 0.114, SE = 0.050, p = 0.023).

CONCLUSION: MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly.

%B J Alzheimers Dis %V 83 %P 683-692 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34334393?dopt=Abstract %R 10.3233/JAD-210107 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer's Disease. %A Nara, Peter L %A Sindelar, Daniel %A Penn, Marc S %A Potempa, Jan %A Griffin, W Sue T %K Alzheimer Disease %K Anti-Infective Agents %K Bacterial Outer Membrane Proteins %K Bacteroidaceae Infections %K Brain %K Cholinergic Agents %K Extremophiles %K Humans %K Iron %K Lactoferrin %K Porphyromonas gingivalis %K Saliva %X

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced "chronic" multi-systems inflammatory disease(s) including Alzheimer's disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria's direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the "infection hypothesis" of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of "Pg bacteria" residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the "Gingipains Hypothesis", AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

%B J Alzheimers Dis %V 82 %P 1417-1450 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/34275903?dopt=Abstract %R 10.3233/JAD-210448 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Primary Prevention of Dementia: An Ethical Review. %A Horstkötter, Dorothee %A Deckers, Kay %A Köhler, Sebastian %K Dementia %K Ethical Review %K Humans %K Life Style %K Primary Prevention %X

Dementia poses important medical and societal challenges, and of all health risks people face in life, dementia is one of the most feared. Recent research indicates that up to about 40% of all cases of dementia might be preventable. A series of environmental, social, and medical risk-factors have been identified that should be targeted from midlife onwards when people are still cognitively healthy. At first glance, this seems not merely advisable, but even imperative. However, these new developments trigger a series of new ethical questions and concerns which have hardly been addressed to date. Pro-active ethical reflection, however, is crucial to ensure that the interests and well-being of those affected, ultimately all of us, are adequately respected. This is the goal of the current contribution. Against the background of a concrete case in primary dementia prevention, it provides a systematic overview of the current ethical literature and sketches an ethical research agenda. First, possible benefits of increased well-being must be balanced with the burdens of being engaged in particularly long-term interventions for which it is unclear whether they will ever pay out on a personal level. Second, while knowledge about one's options to maintain brain health might empower people, it might also undermine autonomy, put high social pressure on people, medicalize healthy adults, and stigmatize those who still develop dementia. Third, while synergistic effects might occur, the ideals of dementia prevention might also conflict with other health and non-health related values people hold in life.

%B J Alzheimers Dis %V 79 %P 467-476 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33337375?dopt=Abstract %R 10.3233/JAD-201104 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Spiritual Fitness: A New Dimension in Alzheimer's Disease Prevention. %A Khalsa, Dharma Singh %A Newberg, Andrew B %K Alzheimer Disease %K Humans %K Life Style %K Love %K Meditation %K Spirituality %X

BACKGROUND: Religious and spiritual interventions may have an effect on Alzheimer's disease prevention. Kirtan Kriya meditation has been shown to mitigate the deleterious effects of chronic stress on cognition, reverse memory loss, and create psychological and spiritual wellbeing, which may reduce multiple drivers of Alzheimer's disease risk.

OBJECTIVE: To detail a new concept in medicine called Spiritual Fitness, a merging of stress reduction, basic wellbeing, and psycho/spiritual wellbeing to prevent Alzheimer's disease.

METHODS: The literature on the topics mentioned above is described, including an in-depth discussion on why and how each are critical to advancing the future of Alzheimer's disease prevention. The many negative effects of chronic stress, and the benefits of Kirtan Kriya, are reviewed. The four pillars of basic wellbeing, six practical aspects of psychological wellbeing, and the four new non-sectarian features of spiritual fitness are then disclosed. Moreover, instructions on practicing Kirtan Kriya are offered in the Supplementary Material.

CONCLUSION: Religious and spiritual practices, including Kirtan Kriya, are crucial components in the development of enhanced cognition and well-being, which may help prevent and, in some cases, reverse cognitive decline. The key point of this review is that making a commitment to live a brain longevity lifestyle including spiritual fitness is a critically important way for aging Alzheimer's disease free. We hope that this article will inspire scientists, clinicians, and patients to embrace this new concept of spiritual fitness and make it a part of every multidomain program for the prevention of cognitive disability.

%B J Alzheimers Dis %V 80 %P 505-519 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33554917?dopt=Abstract %R 10.3233/JAD-201433 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Comparative Cognitive Effects of Choreographed Exercise and Multimodal Physical Therapy in Older Adults with Amnestic Mild Cognitive Impairment: Randomized Clinical Trial. %A Bisbe, Marta %A Fuente-Vidal, Andrea %A López, Elisabet %A Moreno, Marta %A Naya, Marian %A de Benetti, Claudio %A Milà, Raimon %A Bruna, Olga %A Boada, Merce %A Alegret, Montserrat %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Combined Modality Therapy %K Dance Therapy %K Exercise Therapy %K Female %K Humans %K Linear Models %K Male %K Neuropsychological Tests %K Physical Therapy Modalities %K Single-Blind Method %X

BACKGROUND: Recent research on mild cognitive impairment (MCI) has primarily focused on searching for measures to prevent or delay the progression of MCI to dementia. Physical exercise has shown to be effective in the prevention of age-related cognitive decline in elderly adults with MCI. However, the most effective type and dose of exercise for the improvement of cognition are yet to be determined.

OBJECTIVE: To compare the cognitive effects of choreographed exercise (Choreography group) with a multimodal physical therapy program (Physical Therapy group) in elderly adults with amnestic MCI, a population with an increased risk of developing dementia.

METHODS: We conducted a randomized clinical trial with two parallel groups under allocation concealment and assessor blinding. Participants were allocated into Choreography or Physical Therapy group and performed exercises twice per week in 60-minute sessions during 12 weeks.

RESULTS: Thirty-six participants with amnestic MCI, ages 65 to 85, were assessed at baseline and after 12 weeks of intervention, by comprehensive validated neuropsychological and physical assessments. A Repeated measures General Lineal Model showed statistically significant differences in cognitive and physical outcomes. Both groups significantly improved in visual delayed recall. The Choreography group exhibited significantly more benefits on verbal recognition memory than the Physical Therapy group.

CONCLUSION: Greater cognitive benefits were achieved in the choreographic intervention than in the multimodal physical therapy, mainly in those functions more related to the risk of conversion to dementia. Additional studies are needed to confirm whether the observed effects are related to delayed onset of Alzheimer's disease in elderly adults with amnestic MCI.

%B J Alzheimers Dis %V 73 %P 769-783 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31868666?dopt=Abstract %R 10.3233/JAD-190552 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Resilience of Alzheimer's Disease to COVID-19. %A Li, Jingwen %A Long, Xi %A Huang, Heqing %A Tang, Jine %A Zhu, Chunli %A Hu, Shaoping %A Wu, Jing %A Li, Jinghong %A Lin, Zhicheng %A Xiong, Nian %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cluster Analysis %K Cohort Studies %K Coronavirus Infections %K COVID-19 %K Disease Progression %K Fatigue %K Female %K Humans %K Length of Stay %K Male %K Middle Aged %K Pandemics %K Patient Discharge %K Pleural Effusion %K Pneumonia %K Pneumonia, Viral %K Prognosis %K Resilience, Psychological %X

BACKGROUND: Facing the novel coronavirus disease 2019 (COVID-19), most vulnerable individuals are seniors, especially those with comorbidities. More attention needs to been paid to the COVID-19 patients with Alzheimer's disease (AD), which is the top age-related neurodegenerative disease.

OBJECTIVE: Since it is unclear whether AD patients are prone to COVID-19 infection and progression to severe stages, we report for the first time a retrospective analysis of the clinical characteristics of AD patients with COVID-19 pneumonia.

METHODS: We conducted a retrospective cohort study of the clinical data of 19 AD patients with COVID-19 pneumonia, compared with 23 non-AD COVID-19 patients admitted at the same time to our hospital. Demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed.

RESULTS: Between AD patients and non-AD patients with COVID-19 pneumonia, the pneumonia severity was not significantly different. AD patients had a higher clustering onset than non-AD patients. The median duration from symptom onset to hospitalization were shorter in AD patients than non-AD patients, indicating the former were sent to the hospital by their family or from nursing home earlier than the later. The median duration from hospitalization to discharge seemed shorter in AD patients than non-AD patients. Dementia patients seemed less likely to report fatigue. It is noticed that more AD patients might have pericardial effusion than the non-AD patients.

CONCLUSION: AD patients with COVID-19 were in milder conditions with a better prognosis than non-AD patients. AD patients who had adequate access to healthcare showed resilience to COVID-19 with shorter hospital stays.

%B J Alzheimers Dis %V 77 %P 67-73 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32804094?dopt=Abstract %R 10.3233/JAD-200649 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Telemedicine for Delivery of Care in Frontotemporal Lobar Degeneration During COVID-19 Pandemic: Results from Southern Italy. %A Capozzo, Rosa %A Zoccolella, Stefano %A Frisullo, Maria Elisa %A Barone, Roberta %A Dell'Abate, Maria Teresa %A Barulli, Maria Rosaria %A Musio, Marco %A Accogli, Miriam %A Logroscino, Giancarlo %K Aged %K Aged, 80 and over %K Behavior %K Coronavirus Infections %K COVID-19 %K Delivery of Health Care %K Disease Progression %K Female %K Frontotemporal Lobar Degeneration %K Humans %K Italy %K Language %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Pandemics %K Pneumonia, Viral %K Quality of Life %K Quarantine %K Surveys and Questionnaires %K Telemedicine %K Triage %X

BACKGROUND: The COVID-19 pandemic is changing clinical practice in neurology, after the governments decided the introduction of social distancing and interruption of medical non-emergency services in many countries. Teleneurology is an effective tool for the remote evaluation of patients but its adoption for frontotemporal lobar dementia (FTD) is in a preliminary stage.

OBJECTIVE: We evaluated multidisciplinary assessment of patients with FTD using telehealth during the COVID-19 pandemic.

METHODS: All patients received a diagnosis of FTD during 2018-2019 according to international criteria. A structured questionnaire and Clinical Dementia Rating Scale (CDR)-FTD were used by the neurologist with patients and/or caregivers. Index symptoms of COVID-19 infection were searched.

RESULTS: Twenty-eight clinical interviews were completed with caregivers and four with both patients/caregivers. Most patients and caregivers were satisfied with the neurological interview and expressed their willingness to continue to be included in remote evaluation programs (90%). Fifty percent of patients experienced significant worsening of clinical picture and quality of life since the start of social distancing. The CDR-FTD scale revealed a significant worsening of behavior (p = 0.01) and language functions (p = 0.009), compared to the last in-person evaluation at the center. One patient presented index symptoms of COVID-19 infection and was confirmed to be positive for COVID-19 with pharyngeal swab.

CONCLUSION: The study was conducted in Italy, one of the countries hit particularly hard by the COVID-19 pandemic, with interruption of all non-emergency medical services. Our study indicates that telemedicine is a valid tool to triage patients with FTD to increase practice outreach and efficiency.

%B J Alzheimers Dis %V 76 %P 481-489 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32651328?dopt=Abstract %R 10.3233/JAD-200589 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Albuminuria and Microalbuminuria as Predictors of Cognitive Performance in a General Population: An 11-Year Follow-Up Study. %A Ekblad, Laura L %A Toppala, Sini %A Johansson, Jouni K %A Koskinen, Seppo %A Sundvall, Jouko %A Rinne, Juha O %A Puukka, Pauli %A Viitanen, Matti %A Jula, Antti %K Adult %K Aged %K Albuminuria %K Cognition %K Cognitive Dysfunction %K Creatinine %K Cross-Sectional Studies %K Female %K Finland %K Follow-Up Studies %K Humans %K Kidney %K Linear Models %K Male %K Middle Aged %K Multivariate Analysis %K Neuropsychological Tests %K Risk Factors %X

Microalbuminuria, defined as urine albumin-to-creatinine ratio (UACR)>3.0 mg/mmol and ≤ 30 mg/mmol, is an early marker of endothelial damage of the renal glomeruli. Recent research suggests an association among microalbuminuria, albuminuria (UACR > 3.0 mg/mmol), and cognitive impairment. Previous studies on microalbuminuria, albuminuria, and cognition in the middle-aged have not provided repeated cognitive testing at different time-points. We hypothesized that albuminuria (micro- plus macroalbuminuria) and microalbuminuria would predict cognitive decline independently of previously reported risk factors for cognitive decline, including cardiovascular risk factors. In addition, we hypothesized that UACR levels even below the cut-off for microalbuminuria might be associated with cognitive functioning. These hypotheses were tested in the Finnish nationwide, population-based Health 2000 Survey (n = 5,921, mean age 52.6, 55.0% women), and its follow-up, Health 2011 (n = 3,687, mean age at baseline 49.3, 55.6% women). Linear regression analysis was used to determine the associations between measures of albuminuria and cognitive performance. Cognitive functions were assessed with verbal fluency, word-list learning, word-list delayed recall (at baseline and at follow-up), and with simple and visual choice reaction time tests (at baseline only). Here, we show that micro- plus macroalbuminuria associated with poorer word-list learning and a slower reaction time at baseline, with poorer word-list learning at follow-up, and with a steeper decline in word-list learning during 11 years after multivariate adjustments. Also, higher continuous UACR consistently associated with poorer verbal fluency at levels below microalbuminuria. These results suggest that UACR might have value in evaluating the risk for cognitive decline.

%B J Alzheimers Dis %V 62 %P 635-648 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480195?dopt=Abstract %R 10.3233/JAD-170972 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome. %A Lao, Patrick J %A Handen, Ben L %A Betthauser, Tobey J %A Mihaila, Iulia %A Hartley, Sigan L %A Cohen, Annie D %A Tudorascu, Dana L %A Bulova, Peter D %A Lopresti, Brian J %A Tumuluru, Rameshwari V %A Murali, Dhanabalan %A Mathis, Chester A %A Barnhart, Todd E %A Stone, Charles K %A Price, Julie C %A Devenny, Darlynne A %A Johnson, Sterling C %A Klunk, William E %A Christian, Bradley T %K Adult %K Alzheimer Disease %K Amyloid beta-Peptides %K Down Syndrome %K Female %K Fluorodeoxyglucose F18 %K Gray Matter %K Humans %K Linear Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Positron-Emission Tomography %K Radiopharmaceuticals %K United States %X

BACKGROUND: The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer's disease (AD).

OBJECTIVE: The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD.

METHODS: Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest.

RESULTS: Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume.

CONCLUSIONS: In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

%B J Alzheimers Dis %V 61 %P 631-644 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254096?dopt=Abstract %R 10.3233/JAD-170720 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Alzheimer's Disease rs11767557 Variant Regulates EPHA1 Gene Expression Specifically in Human Whole Blood. %A Liu, Guiyou %A Zhang, Yan %A Wang, Longcai %A Xu, Jianyong %A Chen, Xiaoyun %A Bao, Yunjuan %A Hu, Yang %A Jin, Shuilin %A Tian, Rui %A Bai, Weiyang %A Zhou, Wenyang %A Wang, Tao %A Han, Zhifa %A Zong, Jian %A Jiang, Qinghua %K Alzheimer Disease %K Case-Control Studies %K China %K Gene Expression %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %K Receptor, EphA1 %K Risk Assessment %X

Large-scale genome-wide association studies have reported EPHA1 rs11767557 variant to be associated with Alzheimer's disease (AD) risk in the European population. However, it is still unclear how this variant functionally contributes to the underlying disease pathogenesis. The rs11767557 variant is located approximately 3 kb upstream of EPHA1 gene. We think that rs11767557 may modify the expression of nearby genes such as EPHA1 and further cause AD risk. Until now, the potential association between rs11767557 and the expression of nearby genes has not been reported in previous studies. Here, we evaluate the potential expression association between rs11767557 and EPHA1 using multiple large-scale eQTLs datasets in human brain tissues and the whole blood. The results show that rs11767557 variant could significantly regulate EPHA1 gene expression specifically in human whole blood. These findings may further provide important supplementary information about the regulating mechanisms of rs11767557 variant in AD risk.

%B J Alzheimers Dis %V 61 %P 1077-1088 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332039?dopt=Abstract %R 10.3233/JAD-170468 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Antemortem-Postmortem Correlation of Florbetapir (18F) PET Amyloid Imaging with Quantitative Biochemical Measures of Aβ42 but not Aβ40. %A Beach, Thomas G %A Maarouf, Chera L %A Intorcia, Anthony %A Sue, Lucia I %A Serrano, Geidy E %A Lu, Ming %A Joshi, Abhinay %A Pontecorvo, Michael J %A Roher, Alex E %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidosis %K Aniline Compounds %K Autopsy %K Brain %K Ethylene Glycols %K Humans %K Linear Models %K Peptide Fragments %K Plaque, Amyloid %K Positron-Emission Tomography %X

Amyloid imaging demonstrates the in vivo presence of amyloid-β (Aβ) deposits in the aging human brain but it is still unknown which structural forms and modifications of Aβ are detected. In Alzheimer's disease, most amyloid deposits are predominantly composed of Aβ ending at amino acid residues Val40 or Ala42. It has been reported that Aβ40 is largely restricted to neuritic plaques while Aβ42 may be deposited in amyloid plaques of all types, and is often the sole component of diffuse plaques. The distinction is important as it is mainly the neuritic plaques that correlate with cognitive impairment while diffuse plaques may be the initial type of Aβ deposited. Whether PET amyloid ligands such as florbetapir-18F (Amyvid) are partially or wholly selective for brain deposits of Aβ40 or Aβ42 is currently unknown. We compared antemortem florbetapir PET cortical/cerebellar signal intensity (SUVr) of 55 subjects with postmortem biochemical (ELISA) measurements employing specific antibodies against Aβ40 and Aβ42. Spearman's univariable correlations were significant for both Aβ40 and Aβ42, but were much stronger for Aβ42. Multiple linear regression showed significance only for Aβ42. These results suggest that florbetapir binds only weakly, if at all, to Aβ40. This may be in part due to the higher likelihood for Aβ42 to be present in a β-pleated sheet tertiary structure, or to differences between Aβ40 and Aβ42 in β-pleated sheet tertiary or quaternary structure.

%B J Alzheimers Dis %V 61 %P 1509-1516 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376867?dopt=Abstract %R 10.3233/JAD-170762 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Aphasia in Progressive Supranuclear Palsy: As Severe as Progressive Non-Fluent Aphasia. %A Burrell, James R %A Ballard, Kirrie J %A Halliday, Glenda M %A Hodges, John R %K Aged %K Aged, 80 and over %K Case-Control Studies %K Cognition %K Female %K Humans %K Language Tests %K Male %K Middle Aged %K Primary Progressive Nonfluent Aphasia %K Semantics %K Speech %K Supranuclear Palsy, Progressive %X

BACKGROUND: Adynamic speech is characteristic of progressive supranuclear palsy (PSP), but higher language deficits have been reported inconsistently, in the context of clinical and pathological overlaps with progressive non-fluent aphasia (PNFA).

OBJECTIVE: The present study tested two hypotheses: 1) PSP and PNFA display impaired single word repetition, object naming, semantic knowledge, and syntactic comprehension; and 2) PSP have reduced speed on timed cognitive tasks.

METHODS: Structured clinical and neuropsychological assessments of language were performed on patients with clinically defined PSP and PNFA. Language was tested using the Sydney Language Battery (SYDBAT) and the Test of Reception of Grammar (TROG).

RESULTS: In total, 144 participants were studied (PSP 22, PNFA 29, and Control 93). PSP patients had prominent eye movement abnormalities, parkinsonism, and falls. All 4 PSP patients who underwent postmortem examination had 4-Repeat tauopathy, with PSP pathology in 3. The frequency and severity of impairment on the SYDBAT (naming, word comprehension, semantic association), and TROG (syntactic comprehension) did not differ between PSP and PNFA, but PSP were significantly slower on timed non-language cognitive tests.

CONCLUSION: Tested formally, aphasia may be seen in PSP, with a severity similar to that seen in PNFA.

%B J Alzheimers Dis %V 61 %P 705-715 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254097?dopt=Abstract %R 10.3233/JAD-170743 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline. %A Del-Aguila, Jorge L %A Fernández, Maria Victoria %A Schindler, Suzanne %A Ibanez, Laura %A Deming, Yuetiva %A Ma, Shengmei %A Saef, Ben %A Black, Kathleen %A Budde, John %A Norton, Joanne %A Chasse, Rachel %A Harari, Oscar %A Goate, Alison %A Xiong, Chengjie %A Morris, John C %A Cruchaga, Carlos %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Dementia %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Membrane Glycoproteins %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Immunologic %K Risk Assessment %X

Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

%B J Alzheimers Dis %V 62 %P 745-756 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480181?dopt=Abstract %R 10.3233/JAD-170834 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Association between α-Klotho and Deep White Matter Lesions in the Brain: A Pilot Case Control Study Using Brain MRI. %A Kuriyama, Nagato %A Ozaki, Etsuko %A Mizuno, Toshiki %A Ihara, Masafumi %A Mizuno, Shigeto %A Koyama, Teruhide %A Matsui, Daisuke %A Watanabe, Isao %A Akazawa, Kentaro %A Takeda, Kazuo %A Takada, Akihiro %A Inaba, Masaaki %A Yamada, Shinsuke %A Motoyama, Koka %A Takeshita, Wakiko %A Iwai, Komei %A Hashiguchi, Kanae %A Kobayashi, Daiki %A Kondo, Masaki %A Tamura, Aiko %A Yamada, Kei %A Nakagawa, Masanori %A Watanabe, Yoshiyuki %K Aged %K Aged, 80 and over %K Apolipoprotein E4 %K Brain %K C-Reactive Protein %K Case-Control Studies %K Cognition Disorders %K Female %K Glucuronidase %K Humans %K Image Processing, Computer-Assisted %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Pilot Projects %K Severity of Illness Index %X

BACKGROUND: The anti-aging protein, α-Klotho, may be involved in cognitive decline and has potential as a surrogate marker that reflects dementia. However, the role of α-Klotho in the brain has not been sufficiently investigated.

OBJECTIVE: Here, we investigated the association between α-Klotho and cognitive decline that is associated with cerebral deep white matter lesions (DWMLs).

METHODS: Two hundred-eighty participants (187 males and 93 females, mean age: 70.8 years old) were evaluated for DWMLs, and the Fazekas scale (Grade) was assessed following brain magnetic resonance imaging. A questionnaire concerning lifestyle and neuropsychological tests was administered, and their associations with the blood α-Klotho level were retrospectively investigated.

RESULTS: The α-Klotho level was 685.1 pg/mL in Grade 0 (68 subjects), 634.1 in G1 (134), 596.0 in G2 (62), and 571.6 in G3 (16), showing that the level significantly decreased with advanced grades. Significant correlations were noted between the α-Klotho level and higher brain function tests including the Mini-Mental State Examination and word fluency tests (p < 0.05). When a 90th percentile value of the level in the G0 group (400 pg/mL) or lower was defined as a low α-Klotho level, the odds ratio of the high-grade G3 group was 2.9 (95% confidence interval: 1.4-7.8) (after correction for age, sex, hypertension, and chronic kidney disease), which was significant.

CONCLUSION: A reduced blood α-Klotho level was correlated with grading of cerebral DWMLs and was accompanied by cognitive decline as an independent risk factor. The α-Klotho level may serve as a useful clinical index of vascular cognitive impairment.

%B J Alzheimers Dis %V 61 %P 145-155 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154273?dopt=Abstract %R 10.3233/JAD-170466 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations between Use of Specific Analgesics and Concentrations of Amyloid-β 42 or Phospho-Tau in Regions of Human Cerebral Cortex. %A Flanagan, Margaret E %A Larson, Eric B %A Walker, Rod L %A Keene, C Dirk %A Postupna, Nadia %A Cholerton, Brenna %A Sonnen, Joshua A %A Dublin, Sascha %A Crane, Paul K %A Montine, Thomas J %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Analgesics %K Analgesics, Opioid %K Anti-Inflammatory Agents, Non-Steroidal %K Autopsy %K Cerebral Cortex %K Female %K Humans %K Logistic Models %K Male %K Peptide Fragments %K Prospective Studies %K tau Proteins %X

Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimer's disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex.

%B J Alzheimers Dis %V 61 %P 653-662 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226863?dopt=Abstract %R 10.3233/JAD-170414 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Associations of Dietary Protein and Fiber Intake with Brain and Blood Amyloid-β. %A Fernando, W M A D Binosha %A Rainey-Smith, Stephanie R %A Gardener, Samantha L %A Villemagne, Victor L %A Burnham, Samantha C %A Macaulay, S Lance %A Brown, Belinda M %A Gupta, Veer Bala %A Sohrabi, Hamid R %A Weinborn, Michael %A Taddei, Kevin %A Laws, Simon M %A Goozee, Kathryn %A Ames, David %A Fowler, Christopher %A Maruff, Paul %A Masters, Colin L %A Salvado, Olivier %A Rowe, Christopher C %A Martins, Ralph N %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Australia %K Biomarkers %K Brain %K Cognition %K Cohort Studies %K Cross-Sectional Studies %K Dietary Fiber %K Dietary Proteins %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %X

Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer's disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-β (Aβ). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aβ burden (n = 541, and n = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of 'high' brain Aβ burden (PiB PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p = 0.008; p = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of 'high' Aβ burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aβ burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset.

%B J Alzheimers Dis %V 61 %P 1589-1598 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376865?dopt=Abstract %R 10.3233/JAD-170742 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer's Disease Patient. %A Le Guennec, Kilan %A Tubeuf, Hélène %A Hannequin, Didier %A Wallon, David %A Quenez, Olivier %A Rousseau, Stéphane %A Richard, Anne-Claire %A Deleuze, Jean-François %A Boland, Anne %A Frebourg, Thierry %A Gaildrat, Pascaline %A Campion, Dominique %A Martins, Alexandra %A Nicolas, Gaël %K Alzheimer Disease %K Case-Control Studies %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K LDL-Receptor Related Proteins %K Male %K Membrane Transport Proteins %K Middle Aged %K Risk Factors %X

Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer's disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5' splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient.

%B J Alzheimers Dis %V 62 %P 821-831 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480197?dopt=Abstract %R 10.3233/JAD-170981 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cardiorespiratory Fitness and White Matter Neuronal Fiber Integrity in Mild Cognitive Impairment. %A Ding, Kan %A Tarumi, Takashi %A Zhu, David C %A Tseng, Benjamin Y %A Thomas, Binu P %A Turner, Marcel %A Repshas, Justin %A Kerwin, Diana R %A Womack, Kyle B %A Lu, Hanzhang %A Cullum, C Munro %A Zhang, Rong %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anisotropy %K Cardiorespiratory Fitness %K Case-Control Studies %K Cognition %K Cognitive Dysfunction %K Diffusion Tensor Imaging %K Executive Function %K Female %K Humans %K Linear Models %K Male %K Memory %K Middle Aged %K Nerve Fibers, Myelinated %K Neuropsychological Tests %K Texas %K White Matter %X

BACKGROUND: Mounting evidence showed the self-reported levels of physical activity are positively associated with white matter (WM) integrity and cognitive performance in normal adults and patients with mild cognitive impairment (MCI). However, the objective measure of cardiorespiratory fitness (CRF) was not used in these studies.

OBJECTIVE: To determine the associations of CRF measured by maximal oxygen uptake (VO2max) with WM fiber integrity and neurocognitive performance in older adults with MCI.

METHODS: Eighty-one participants (age = 65±7 years, 43 women), including 26 cognitively normal older adults and 55 amnestic MCI patients, underwent VO2max test to measure CRF, diffusion tensor imaging (DTI) to assess WM fiber integrity, and neurocognitive assessment focused on memory and executive function. DTI data were analyzed by the tract-based spatial statistics and region-of-interest approach.

RESULTS: Cognitively normal older adults and MCI patients were not different in global WM fiber integrity and VO2max. VO2max was associated positively with DTI metrics of fractional anisotropy in ∼54% WM fiber tracts, and negatively with mean and radial diffusivities in ∼46% and ∼56% of the WM fiber tracts. The associations of VO2max with DTI metrics remained statistically significant after adjustment of age, sex, body mass index, WM lesion burden, and MCI status. The DTI metrics obtained from the area that correlated to VO2max were associated with executive function performance in MCI patients.

CONCLUSIONS: Higher levels of CRF are associated with better WM fiber integrity, which in turn is correlated with better executive function performance in MCI patients.

%B J Alzheimers Dis %V 61 %P 729-739 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226864?dopt=Abstract %R 10.3233/JAD-170415 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid C-C Motif Chemokine Ligand 2 Correlates with Brain Atrophy and Cognitive Impairment in Alzheimer's Disease. %A Kimura, Akio %A Yoshikura, Nobuaki %A Hayashi, Yuichi %A Inuzuka, Takashi %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Atrophy %K Biomarkers %K Chemokine CCL2 %K Cognitive Dysfunction %K Disease Progression %K Female %K Gray Matter %K Humans %K Linear Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K tau Proteins %K Temporal Lobe %X

BACKGROUND: Chronic neuroinflammation has been implicated in Alzheimer's disease (AD) pathology.

OBJECTIVE: To investigate the association between cytokine and anti-amyloid-β (Aβ) autoantibody levels and the degree of brain atrophy and cognitive impairment in AD patients.

METHODS: Cerebrospinal fluid (CSF) levels of C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8, C-X-C motif chemokine ligand 10, interleukin 6, and anti-Aβ autoantibody were evaluated in 69 AD patients. Serum levels of CCL2 and anti-Aβ autoantibody were also examined. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volumes of interest (VOI) in medial temporal structures. Cognitive function was evaluated by neuropsychological testing, including the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB).

RESULTS: CSF CCL2 levels correlated significantly with the severity (p = 0.023) and the extent (p = 0.022) of VOI atrophy, and with the extent of gray matter atrophy (p = 0.039) in AD patients. CSF anti-Aβ autoantibody levels were inversely correlated with the severity of VOI atrophy (p = 0.020), the extent of VOI atrophy (p = 0.015), and the ratio of VOI/GM atrophy (r = -0.358, p = 0.004). CSF CCL2 levels were also inversely correlated with MMSE (p = 0.0497) and FAB scores (p = 0.016).

CONCLUSIONS: CSF CCL2 levels are associated with the degree of medial temporal lobe and gray matter atrophy, and cognitive decline in AD.

%B J Alzheimers Dis %V 61 %P 581-588 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171996?dopt=Abstract %R 10.3233/JAD-170519 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Clinically-Translatable Machine Learning Algorithm for the Prediction of Alzheimer's Disease Conversion in Individuals with Mild and Premild Cognitive Impairment. %A Grassi, Massimiliano %A Perna, Giampaolo %A Caldirola, Daniela %A Schruers, Koen %A Duara, Ranjan %A Loewenstein, David A %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Area Under Curve %K Atrophy %K Brain %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Machine Learning %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Predictive Value of Tests %K Prognosis %K Regression Analysis %K Sensitivity and Specificity %K Support Vector Machine %X

BACKGROUND: Available therapies for Alzheimer's disease (AD) can only alleviate and delay the advance of symptoms, with the greatest impact eventually achieved when provided at an early stage. Thus, early identification of which subjects at high risk, e.g., with MCI, will later develop AD is of key importance. Currently available machine learning algorithms achieve only limited predictive accuracy or they are based on expensive and hard-to-collect information.

OBJECTIVE: The current study aims to develop an algorithm for a 3-year prediction of conversion to AD in MCI and PreMCI subjects based only on non-invasively and effectively collectable predictors.

METHODS: A dataset of 123 MCI/PreMCI subjects was used to train different machine learning techniques. Baseline information regarding sociodemographic characteristics, clinical and neuropsychological test scores, cardiovascular risk indexes, and a visual rating scale for brain atrophy was used to extract 36 predictors. Leave-pair-out-cross-validation was employed as validation strategy and a recursive feature elimination procedure was applied to identify a relevant subset of predictors.

RESULTS: 16 predictors were selected from all domains excluding sociodemographic information. The best model resulted a support vector machine with radial-basis function kernel (whole sample: AUC = 0.962, best balanced accuracy = 0.913; MCI sub-group alone: AUC = 0.914, best balanced accuracy = 0.874).

CONCLUSIONS: Our algorithm shows very high cross-validated performances that outperform the vast majority of the currently available algorithms, and all those which use only non-invasive and effectively assessable predictors. Further testing and optimization in independent samples will warrant its application in both clinical practice and clinical trials.

%B J Alzheimers Dis %V 61 %P 1555-1573 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29355115?dopt=Abstract %R 10.3233/JAD-170547 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cognitive Variability Predicts Incident Alzheimer's Disease and Mild Cognitive Impairment Comparable to a Cerebrospinal Fluid Biomarker. %A Gleason, Carey E %A Norton, Derek %A Anderson, Eric D %A Wahoske, Michelle %A Washington, Danielle T %A Umucu, Emre %A Koscik, Rebecca L %A Dowling, N Maritza %A Johnson, Sterling C %A Carlsson, Cynthia M %A Asthana, Sanjay %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Incidence %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Statistics, Nonparametric %K tau Proteins %X

BACKGROUND: Alzheimer's disease (AD) biomarkers are emerging as critically important for disease detection and monitoring. Most biomarkers are obtained through invasive, resource-intense procedures. A cognitive marker, intra-individual cognitive variability (IICV) may provide an alternative or adjunct marker of disease risk for individuals unable or disinclined to undergo lumbar puncture.

OBJECTIVE: To contrast risk of incident AD and mild cognitive impairment (MCI) associated with IICV to risk associated with well-established biomarkers: cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau181) and amyloid-β 42 (Aβ42) peptide.

METHODS: Dispersion in cognitive performance, IICV, was estimated with a published algorithm, and included Trail Making Test A and B, Rey Auditory Verbal Learning Test (RAVLT), and the American National Adult Reading Test (ANART). CSF biomarkers were expressed as a ratio: p-tau181/Aβ42, wherein high values signified pathognomonic profiles. Logistic regression models included longitudinal data from 349 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who completed lumbar puncture. All subjects were cognitively healthy (n = 105) or diagnosed with MCI (n = 244) at baseline. We examined odds of conversion associated with baseline elevations in IICV and/or ratio of CSF p-tau181/Aβ42.

RESULTS: When included in models alone or in combination with CSF p-tau181/Aβ42, one standard IICV unit higher was associated with an estimated odds ratio for incident AD or MCI of 2.81 (95% CI: 1.83-4.33) in the most inclusive sample, and an odds ratio of 3.41 (95% CI: 2.03-5.73) when restricted to participants with MCI. Iterative analyses suggested that IICV independently improved model fit even when individual index components were included in comparative models.

CONCLUSIONS: These analyses provide preliminary support for IICV as a marker of incident AD and MCI. This easily-disseminated, non-invasive marker compared favorably to well-established CSF biomarkers.

%B J Alzheimers Dis %V 61 %P 79-89 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125485?dopt=Abstract %R 10.3233/JAD-170498 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Combined Socio-Behavioral Evaluation Improves the Differential Diagnosis Between the Behavioral Variant of Frontotemporal Dementia and Alzheimer's Disease: In Search of Neuropsychological Markers. %A Dodich, Alessandra %A Cerami, Chiara %A Cappa, Stefano F %A Marcone, Alessandra %A Golzi, Valeria %A Zamboni, Michele %A Giusti, Maria Cristina %A Iannaccone, Sandro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Cognition %K Diagnosis, Differential %K Female %K Frontotemporal Dementia %K Humans %K Logistic Models %K Male %K Memory, Episodic %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Retrospective Studies %K Social Skills %X

BACKGROUND: Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer's disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult.

OBJECTIVES: In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups.

METHODS: We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n = 48) or typical AD (n = 47) pathology. A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo-spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD.

RESULTS: Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD.

CONCLUSION: Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD.

%B J Alzheimers Dis %V 61 %P 761-772 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254091?dopt=Abstract %R 10.3233/JAD-170650 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults: The HATICE Trial. %A Barbera, Mariagnese %A Mangialasche, Francesca %A Jongstra, Susan %A Guillemont, Juliette %A Ngandu, Tiia %A Beishuizen, Cathrien %A Coley, Nicola %A Brayne, Carol %A Andrieu, Sandrine %A Richard, Edo %A Soininen, Hilkka %A Kivipelto, Miia %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cognitive Dysfunction %K Counseling %K Europe %K Exercise %K Female %K Healthy Aging %K Humans %K Internet %K Life Style %K Male %K Practice Guidelines as Topic %K Risk Factors %K Telemedicine %X

BACKGROUND: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults.

OBJECTIVE: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries.

METHODS: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention.

RESULTS: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country.

CONCLUSION: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.

%B J Alzheimers Dis %V 62 %P 649-663 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480185?dopt=Abstract %R 10.3233/JAD-170858 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Detection of Dementia Cases in Two Swedish Health Registers: A Validation Study. %A Rizzuto, Debora %A Feldman, Adina L %A Karlsson, Ida K %A Dahl Aslan, Anna K %A Gatz, Margaret %A Pedersen, Nancy L %K Aged %K Aged, 80 and over %K Cause of Death %K Dementia %K Female %K Humans %K Incidence %K Longitudinal Studies %K Male %K Middle Aged %K Registries %K Sensitivity and Specificity %K Sweden %K Twin Studies as Topic %X

BACKGROUND: Population-based health registers are potential assets in epidemiological research; however, the quality of case ascertainment is crucial.

OBJECTIVE: To compare the case ascertainment of dementia, from the National Patient Register (NPR) and the Cause of Death Register (CDR) with dementia diagnoses from six Swedish population based studies.

METHODS: Sensitivity, specificity, and positive predictive value (PPV) of dementia identification in NPR and CDR were estimated by individual record linkage with six Swedish population based studies (n = 19,035). Time to detection in NPR was estimated using data on dementia incidence from longitudinal studies with more than two decades of follow-up.

RESULTS: Barely half of the dementia cases were ever detected by NPR or CDR. Using data from longitudinal studies we estimated that a record with a dementia diagnosis appears in the NPR on average 5.5 years after first diagnosis. Although the ability of the registers to detect dementia cases was moderate, the ability to detect non-dementia cases was almost perfect (99%). When registers indicate that there is a dementia diagnosis, there are very few instances in which the clinicians determined the person was not demented. Indeed, PPVs were close to 90%. However, misclassification between dementia subtype diagnoses is quite common, especially in NPR.

CONCLUSIONS: Although the overall sensitivity is low, the specificity and the positive predictive value are very high. This suggests that hospital and death registers can be used to identify dementia cases in the community, but at the cost of missing a large proportion of the cases.

%B J Alzheimers Dis %V 61 %P 1301-1310 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376854?dopt=Abstract %R 10.3233/JAD-170572 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Diagnostic and Prognostic Value of a Dual-Tasking Paradigm in a Memory Clinic. %A Nielsen, Malene Schjnning %A Simonsen, Anja Hviid %A Siersma, Volkert %A Hasselbalch, Steen Gregers %A Hoegh, Peter %K Aged %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Prognosis %K Prospective Studies %K ROC Curve %X

BACKGROUND: Daily living requires the ability to perform dual-tasking. As cognitive skills decrease in dementia, performing a cognitive and motor task simultaneously become increasingly challenging and subtle gait abnormalities may even be present in pre-dementia stages. Therefore, a dual-tasking paradigm, such as the Timed Up and Go-Dual Task (TUG-DT), may be useful in the diagnostic assessment of mild cognitive impairment (MCI).

OBJECTIVE: To investigate the diagnostic and prognostic ability of a dual-tasking paradigm in patients with MCI or mild Alzheimer's disease (AD) and to evaluate the association between the dual-tasking paradigm and cerebrospinal fluid (CSF) AD biomarkers.

METHODS: The study is a prospective cohort study conducted in a clinical setting in two memory clinics. Eighty-six patients were included (28 MCI, 17 AD, 41 healthy controls (HC)). The ability to perform dual-tasking was evaluated by the TUG-DT. Patients underwent a standardized diagnostic assessment and were evaluated to determine progression yearly.

RESULTS: ROC curve analysis illustrated a high discriminative ability of the dual-tasking paradigm in separating MCI patients from HC (AUC: 0.78, AUC: 0.82) and a moderate discriminative ability in separating MCI from AD (AUC: 0.73, AUC: 0.55). Performance discriminated clearly between all groups (p < 0.01). Logistic regression analyses revealed a low prognostic value of the dual-tasking paradigm for progression and rate of cognitive decline. A moderately strong correlation between the dual-tasking paradigm and CSF AD biomarkers was observed.

CONCLUSION: In our study, we found that patients with MCI and mild AD have increasing difficulties in dual-tasking compared to healthy elderly. Hence, the dual-tasking paradigm may be a potential complement in the diagnostic assessment in a typical clinical setting.

%B J Alzheimers Dis %V 61 %P 1189-1199 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29278887?dopt=Abstract %R 10.3233/JAD-161310 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Differential Pattern of Phospholipid Profile in the Temporal Cortex from E280A-Familiar and Sporadic Alzheimer's Disease Brains. %A Villamil-Ortiz, Javier Gustavo %A Barrera-Ocampo, Alvaro %A Arias-Londoño, Julián David %A Villegas, Andrés %A Lopera, Francisco %A Cardona-Gómez, Gloria Patricia %K Adult %K Aged %K Aged, 80 and over %K Alanine %K Alzheimer Disease %K Analysis of Variance %K Fatty Acids %K Female %K Gene Expression Regulation %K Glutamic Acid %K Humans %K Lysophosphatidylcholines %K Male %K Mass Spectrometry %K Middle Aged %K Mutation %K Phosphatidylethanolamines %K Phospholipids %K Presenilin-1 %K Temporal Lobe %X

Lipids are considered important factors in the pathogenesis of Alzheimer's disease (AD). In this study, we realized a comparative analysis of the phospholipid profile and phospholipid composition of the temporal cortex from E280A-familiar AD (FAD), sporadic AD (SAD), and healthy human brains. Findings showed a significant decrease of lysophosphatidylcholine and phosphatidylethanolamine formed by low levels of polyunsaturated fatty acids (20 : 4, 22 : 6) in AD brains. However, phosphatidylethanolamine-ceramide and phosphoglycerol were significantly increased in SAD, conformed by high levels of (18 : 0/18 : 1) and (30/32/36 : 0/1/2), respectively. Together, the findings suggest a deficiency in lysophosphacholine and phosphatidylethanolamine, and alteration in the balance between poly- and unsaturated fatty acids in both types of AD, and a differential pattern of phospholipid profile and fatty acid composition between E280A FAD and SAD human brains.

%B J Alzheimers Dis %V 61 %P 209-219 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125487?dopt=Abstract %R 10.3233/JAD-170554 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dilated Perivascular Spaces in the Centrum Semiovale Begin to Develop in Middle Age. %A Ishikawa, Masatsune %A Yamada, Shigeki %A Yamamoto, Kazuo %K Adult %K Aged %K Aged, 80 and over %K Aging %K Cerebral Amyloid Angiopathy %K Corpus Callosum %K Cross-Sectional Studies %K Female %K Humans %K Japan %K Logistic Models %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Prospective Studies %K Young Adult %X

BACKGROUND: Dilated perivascular spaces in the centrum semiovale (CSO-PVS) are closely related to small vessel disease. However, recent studies have revealed that cerebral amyloid angiopathy can cause dilation of the CSO-PVS and obstruction of interstitial fluid flow along the intramural periarterial drainage.

OBJECTIVE: To examine the severity and age-related prevalence of CSO-PVS through magnetic resonance imaging (MRI) and investigate their clinically relevant factors.

METHODS: This study included 1,060 subjects who participated in our brain program. The subjects ranged from 23 to 83 years in age and were active in society. The frequencies of the MRI abnormalities of small vessel diseases, including CSO-PVS, were examined. The CSO-PVS severity was classified into three grades: G0, G1, G2, according to the visual rating. The subjects were divided into five age groups and their age-related frequencies were also studied. Using the clinico-laboratory data of 712 subjects, the clinically relevant factors of CSO-PVS were investigated using logistic regression analysis.

RESULTS: The frequencies of all G0 ("normal") MRI abnormalities significantly decreased with age. A high prevalence of G2 CSO-PVS was observed (24%) in the youngest group aged≤39 years, whereas other MRI abnormalities in this group were not or rarely observed. In multivariable logistic regression analyses, G2 CSO-PVS was found to be closely associated with age, hypertension, and the estimated glomerular filtration ratio.

CONCLUSIONS: This study reveals that CSO-PVS begin to develop in subjects aged less than 39 years. Age-related changes are involved. Further studies are necessary to elucidate the pathophysiological role of the CSO-PVS.

%B J Alzheimers Dis %V 61 %P 1619-1626 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376866?dopt=Abstract %R 10.3233/JAD-170755 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Drugs for Dementia and Excess of Hospitalization: A Longitudinal French Study. %A François, Mathilde %A Sicsic, Jonathan %A Pelletier Fleury, Nathalie %K Aged %K Aged, 80 and over %K Cholinesterase Inhibitors %K Dementia %K Female %K France %K Health Expenditures %K Hospitalization %K Humans %K Longitudinal Studies %K Male %K Rivastigmine %X

BACKGROUND: The impact of adverse effects of drugs for dementia on the risk of hospitalization has not been much studied despite the impact of hospitalizations on cognitive decline.

OBJECTIVE: To determine if the main adverse effects of cholinesterase inhibitors and memantine may be associated with excess of hospitalization and to quantify the subsequent impact on healthcare expenditures.

METHODS: A representative sample of the French national health insurance beneficiaries aged 65 and older and suffering from dementia were included and followed from 2007 to 2014. Binary logit models for longitudinal data (GEE estimation technique) were used to estimate the excess of hospitalization events related to the adverse effects of anti-dementia drugs and then to derive the additional costs of hospitalizations for the public health insurance fund.

RESULTS: In total, 7,668 patients were followed, generating 111,133 individual observations over the 8-year period. Treated patients were hospitalized significantly more than non-treated patients (adjusted Odd Ratio (OR) = 1.08, 95% confidence interval (95% CI) = [1.02 to 1.13], p = 0.004), mainly with cholinesterase inhibitors for cardiac (OR = 1.21, 95% CI = [1.01 to 1.46], p = 0.034) and gastrointestinal events (OR = 1.43, 95% CI = [1.01-2.05], p = 0.045), especially with rivastigmine. When extrapolated to the entire population, this corresponded to an annual additional cost of € 55,000.

CONCLUSION: Prescription of antidementia drugs, more specifically rivastigmine, increases the risk of hospitalizations via their cardiac and gastrointestinal adverse effects and lead to additional health care expenditures. Even though these results must be confirmed, they may encourage cautious consideration of the balance between benefits and harms before a prescription is given.

%B J Alzheimers Dis %V 61 %P 1627-1637 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376848?dopt=Abstract %R 10.3233/JAD-170371 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early and Persistent O-GlcNAc Protein Modification in the Streptozotocin Model of Alzheimer's Disease. %A Dos Santos, João Paulo Almeida %A Vizuete, Adriana %A Hansen, Fernanda %A Biasibetti, Regina %A Gonçalves, Carlos-Alberto %K Alzheimer Disease %K Analysis of Variance %K Animals %K Antibiotics, Antineoplastic %K Brain %K Disease Models, Animal %K Glial Fibrillary Acidic Protein %K Glucose %K Glutathione %K Insulin Receptor Substrate Proteins %K Lactoylglutathione Lyase %K Male %K Maze Learning %K N-Acetylglucosaminyltransferases %K Rats %K Rats, Wistar %K S100 Calcium Binding Protein beta Subunit %K Streptozocin %K Time Factors %X

 O-GlcNAc transferase (OGT), an enzyme highly expressed in brain tissue, catalyzes the addition of N-acetyl-glucosamine (GlcNAc) to hydroxyl residues of serine and threonine of proteins. Brain protein O-GlcNAcylation is diminished in Alzheimer's disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1). We hypothesized that ICV streptozotocin (STZ) also affects O-GlcNAc protein modification. We investigated hippocampal metabolic changes in Wistar rats, particularly OGT levels and insulin resistance, as well as related astroglial activities, immediately after ICV STZ administration (first week) and later on (fourth week). We found an early (at one week) and persistent (at fourth week) decrease in OGT in the ICV STZ model of AD, characterized by a spatial cognitive deficit. Consistent with this observation, we observed a decrease in protein O-GlnNAc modification at both times. Increased phosphorylation at serine-307 of IRS-1, which is related to insulin resistance, was observed on the fourth week. The decrease in OGT and consequent protein O-GlnNAc modifications appear to precede the decrease in glucose uptake and increment of the glyoxalase system observed in the hippocampus. Changes in glial fibrillary acidic protein and S100B in the hippocampus, as well as the alterations in cerebrospinal fluid S100B, confirm the astrogliosis. Moreover, decreases in glutamine synthetase and glutathione content suggest astroglial dysfunction, which are likely implicated in the neurodegenerative cascade triggered in this model. Together, these data contribute to the understanding of neurochemical changes in the ICV STZ model of sporadic AD, and may explain the decreases in protein O-GlcNAc levels and insulin resistance observed in AD.

%B J Alzheimers Dis %V 61 %P 237-249 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154269?dopt=Abstract %R 10.3233/JAD-170211 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age-Adjusted Alzheimer's Disease Mortality in Texas. %A Fajardo, Val Andrew %A Fajardo, Val Andrei %A LeBlanc, Paul J %A MacPherson, Rebecca E K %K Adult %K Age Factors %K Alzheimer Disease %K Drinking Water %K Female %K Humans %K Lithium %K Longitudinal Studies %K Male %K Obesity %K Prevalence %K Risk Factors %K Statistics as Topic %K Texas %K Young Adult %X

BACKGROUND: Alzheimer's disease (AD) mortality rates have steadily increased over time. Lithium, the current gold standard treatment for bipolar disorder, can exert neuroprotective effects against AD.

OBJECTIVE: We examined the relationship between trace levels of lithium in drinking water and changes in AD mortality across several Texas counties.

METHODS: 6,180 water samples from public wells since 2007 were obtained and averaged for 234 of 254 Texas counties. Changes in AD mortality rates were calculated by subtracting aggregated age-adjusted mortality rates obtained between 2000-2006 from those obtained between 2009-2015. Using aggregated rates maximized the number of counties with reliable mortality data. Correlational analyses between average lithium concentrations and changes in AD mortality were performed while also adjusting for gender, race, education, rural living, air pollution, physical inactivity, obesity, and type 2 diabetes.

RESULTS: Age-adjusted AD mortality rate was significantly increased over time (+27%, p < 0.001). Changes in AD mortality were negatively correlated with trace lithium levels (p = 0.01, r = -0.20), and statistical significance was maintained after controlling for most risk factors except for physical inactivity, obesity, and type 2 diabetes. Furthermore, the prevalence of obesity and type 2 diabetes positively correlated with changes in AD mortality (p = 0.01 and 0.03, respectively), but also negatively correlated with trace lithium in drinking water (p = 0.05 and <0.0001, respectively).

CONCLUSION: Trace lithium in water is negatively linked with changes in AD mortality, as well as obesity and type 2 diabetes, which are important risk factors for AD.

%B J Alzheimers Dis %V 61 %P 425-434 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29103043?dopt=Abstract %R 10.3233/JAD-170744 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Executive and Language Subjective Cognitive Decline Complaints Discriminate Preclinical Alzheimer's Disease from Normal Aging. %A Valech, Natalia %A Tort-Merino, Adrià %A Coll-Padrós, Nina %A Olives, Jaume %A León, María %A Rami, Lorena %A Molinuevo, José Luis %K Aged %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Executive Function %K Factor Analysis, Statistical %K Female %K Humans %K Language %K Male %K Middle Aged %K Neuropsychological Tests %K Self Report %X

BACKGROUND: There is a need to specify the profile of subjective cognitive decline in preclinical Alzheimer's disease (preAD).

OBJECTIVES: To explore specific items of the Subjective Cognitive Decline Questionnaire (SCD-Q) that discriminate preAD from normal aging.

METHODS: 68 cognitively normal older adults were classified as controls (n = 52) or preAD (n = 16) according to amyloid-β (Aβ) levels. An exploratory factor analysis and item analysis of the SCD-Q were performed. Informant reports of the SCD-Q were used to corroborate the findings of self-reports. One-year neuropsychological follow-up was available.

RESULTS: Four SCD-Q factors were extracted: EM-factor (episodic memory), A-factor (attention), O-factor (organization), and L-factor (language). PreAD reported a significantly higher decline in L-factor (F(1) = 6.49; p = 0.014) and A-factor (F(1) = 4.04; p = 0.049) compared to controls, and showed a higher frequency of perceived decline in SCD-Q items related with language and executive tasks (Sig-items.) Significant discriminative powers for Aβ-positivity were found for L-factor (AUC = 0.75; p = 0.003) and A-factor (AUC = 0.74; p = 0.004). Informants in the preAD group confirmed significantly higher scores in L-factor and Sig-items. A significant time×group interaction was found in the Semantic Fluency and Stroop tests, with the preAD group showing a decrease in performance at one-year.

CONCLUSIONS: Our results suggest that SCD-Q items related with language and executive decline may help in prediction algorithms to detect preAD. Validation in an independent population is needed.

%B J Alzheimers Dis %V 61 %P 689-703 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254090?dopt=Abstract %R 10.3233/JAD-170627 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Executive Dysfunction Detected with the Frontal Assessment Battery in Alzheimer's Disease Versus Vascular Dementia. %A D'Onofrio, Grazia %A Panza, Francesco %A Sancarlo, Daniele %A Addante, Filomena %A Solfrizzi, Vincenzo %A Cantarini, Chiara %A Mangiacotti, Antonio %A Lauriola, Michele %A Cascavilla, Leandro %A Paris, Francesco %A Lozupone, Madia %A Daniele, Antonio %A Greco, Antonio %A Seripa, Davide %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Comorbidity %K Dementia, Vascular %K Executive Function %K Female %K Frontal Lobe %K Geriatric Assessment %K Humans %K Logistic Models %K Male %K Polypharmacy %K Severity of Illness Index %X

Alzheimer's disease (AD) and vascular dementia (VaD) lead to progressive decline in executive function. We estimated the prevalence of executive dysfunction in AD and VaD patients, investigating cognitive, functional, and clinical correlates and also using a multidimensional approach based on a standardized comprehensive geriatric assessment (CGA). We included 215 patients (115 AD patients and 100 VaD patients) consecutively evaluated with a complete cognitive and affective assessment, a CGA, and the Frontal Assessment Battery (FAB) with six subtests investigating conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. The prevalence of dysexecutive syndrome screened with a FAB score <12 points was high in both AD (97 patients) and VaD (77 patients) (84.3% versus 77.0%, p = 0.171). AD patients were significantly younger, with higher grade of cognitive impairment and less severe comorbidity and polypharmacy than VaD patients. AD patients showed a significantly higher impairment in FAB total score and five FAB subtests (conceptualization, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy) than VaD patients. These findings were largely confirmed in a sub-analysis conducted subdividing the sample in mild and moderate-to-severe demented patients and suggesting that in moderate-to-severe AD there was higher impairment in FAB total score and four FAB subtests (conceptualization, sensitivity to interference, inhibitory control, and environmental autonomy). Executive dysfunction could be greater in AD patients with moderate-to-severe dementia compared to VaD patients, although our groups were also not matched for age, comorbidity or polypharmacy, which could also exert an effect.

%B J Alzheimers Dis %V 62 %P 699-711 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480171?dopt=Abstract %R 10.3233/JAD-170365 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Gradual Cerebral Hypoperfusion Impairs Fear Conditioning and Object Recognition Learning and Memory in Mice: Potential Roles of Neurodegeneration and Cholinergic Dysfunction. %A Mehla, Jogender %A Lacoursiere, Sean %A Stuart, Emily %A McDonald, Robert J %A Mohajerani, Majid H %K Animals %K Brain %K Carotid Stenosis %K Cerebrovascular Circulation %K Choline O-Acetyltransferase %K Conditioning (Psychology) %K Disease Models, Animal %K Fear %K Fluoresceins %K Learning Disorders %K Male %K Mice %K Mice, Inbred C57BL %K Phosphopyruvate Hydratase %K Postural Balance %K Recognition (Psychology) %X

In the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer's disease pathology.

%B J Alzheimers Dis %V 61 %P 283-293 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154281?dopt=Abstract %R 10.3233/JAD-170635 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Hedonic Assessment of Odors: A Comparison of Two Sensory Scales for Use with Alzheimer's Disease Patients and Elderly Individuals. %A Atanasova, Boriana %A Mondon, Karl %A Dreyfuss, Lise %A Beaufils, Emilie %A Desmidt, Thomas %A Hommet, Caroline %A El-Hage, Wissam %A Belzung, Catherine %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Humans %K Linear Models %K Male %K Olfaction Disorders %K Olfactory Perception %K Severity of Illness Index %K Smell %X

BACKGROUND: Several clinical studies concerning the olfactory function of patients with cognitive impairment have used sensory scales to investigate hedonic perception. However, no study has focused on the choice of the most appropriate sensory hedonic scale for the individuals with neurodegenerative disorders or other psychiatric diseases involving cognitive deficits.

OBJECTIVE: The aim of this study was to investigate the ability of patients with Alzheimer's disease (AD) to use two hedonic scales (category scale and linear scale) and compare their discriminatory capacity, repeatability, and ease of use. This should allow us to identify the most appropriate hedonic scale for patients with AD.

METHODS: We recruited 18 patients with mild to moderate AD, and 20 healthy volunteers matched for gender, age, smoking status, and educational level. The participants underwent a clinical assessment and hedonic evaluation of three odorants (pleasant, unpleasant, and neutral), using a five-point category scale and a 10-cm linear scale with a marked mid-point.

RESULTS: AD patients were able to use hedonic scales as well as paired healthy elderly subjects. The linear scale performed slightly better in terms of ease of use for both patients and healthy controls and discriminatory capacity for AD patients. The results for AD patients and controls with both scales were repeatable.

CONCLUSION: The linear scale may be more appropriate for AD patients pending further studies involving a larger population of patients, using several odorants.

%B J Alzheimers Dis %V 61 %P 929-938 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254084?dopt=Abstract %R 10.3233/JAD-170433 %0 Journal Article %J J Alzheimers Dis %D 2018 %T High Caregiver Burden in Young Onset Dementia: What Factors Need Attention? %A Lim, Linda %A Zhang, Angeline %A Lim, Levinia %A Choong, Tanya-Marie %A Silva, Eveline %A Ng, Adeline %A Kandiah, Nagaendran %K Adaptation, Psychological %K Age of Onset %K Aged %K Aged, 80 and over %K Behavioral Symptoms %K Caregivers %K Cost of Illness %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Stress, Psychological %K Surveys and Questionnaires %X

BACKGROUND: There is an increase in prevalence of young onset dementia (YOD). The specific problems among YOD patients and levels of caregiver burden (CB) in this group warrants further evaluation.

OBJECTIVE: To evaluate and compare level of CB in YOD and late onset dementia (LOD). Also, we sought to understand the specific factors, such as neuropsychiatric symptoms, that may affect the levels of caregiver burden in the YOD group.

METHODS: Patient-caregiver dyads with YOD and LOD were recruited from a tertiary neurology center. Levels of CB between YOD and LOD were compared among 183 patient-caregiver dyads. CB was quantified using the Zarit Burden Inventory (ZBI). Neuropsychological evaluations as well as the Neuropsychiatric Inventory were performed. Factors that influenced level of CB in YOD group was investigated with regression analyses.

RESULTS: There were 57 YOD and 126 LOD dyads. Caregivers of YOD subjects reported significantly higher levels of burden compared to caregivers of LOD subjects (ZBI: 17.3 versus 13.94; p = 0.015). 52.6% of YOD caregivers reported a high caregiver burden. When compared to caregivers of LOD, the odds of a caregiver of YOD reporting high caregiver burden was 2.34 (95% CI: 1.22-4.49: p = 0.010). YOD dyads with a high caregiver burden had significantly higher neuropsychiatric inventory scores. Risk factors for high caregiver burden in YOD included family history of dementia and behavioral symptoms including disinhibited behavior, delusions, and apathy.

CONCLUSION: Targeted support for caregivers of patients with YOD is needed to address the higher CB in this group.

%B J Alzheimers Dis %V 61 %P 537-543 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171995?dopt=Abstract %R 10.3233/JAD-170409 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impaired IL-17 Production in Gut-Residing Immune Cells of 5xFAD Mice with Alzheimer's Disease Pathology. %A Saksida, Tamara %A Koprivica, Ivan %A Vujičić, Milica %A Stošić-Grujičić, Stanislava %A Perović, Milka %A Kanazir, Selma %A Stojanović, Ivana %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K B-Lymphocytes %K Disease Models, Animal %K Female %K Interleukin-17 %K Lymph Nodes %K Male %K Mice %K Mice, Transgenic %K MicroRNAs %K Peyer's Patches %K Th17 Cells %X

Alzheimer's disease (AD) is characterized by accumulation of amyloid-β plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut-associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This study aimed to determine cell composition of GALT in 5xFAD mice, an established model for AD. Immune cells isolated from Peyer's patches (PP) and mesenteric lymph nodes (MLN) were stained with surface and intracellular markers for T helper (Th) subpopulations, B lymphocytes and macrophages and analyzed cytofluorimetrically, while cytokine expression and production were determined by qPCR and ELISA, respectively. Inflammation was detected in GALT of 5xFAD mice with established AD pathology. Although the production of IFN-γ, IL-4, and IL-10 was comparable between the strains, lower IL-17 production was observed in PP and MLN cells. This phenomenon could not be attributed to a lower abundance of Th17 cells, or cytokines that initiate their formation or propagation (TGF-β, IL-6, and IL-23). Also, reduced IL-17 production was not a consequence of altered Il-17 mRNA transcription or deficiency of Rorγt, a key transcription factor for IL-17. However, the expression of miR-155 (a non-coding micro RNA that promotes the development of Th17 cells), was significantly lower in MLN cells of 5xFAD mice. In contrast, mice without AD neuropathology did not have inflammation in GALT or altered Th17 numbers, nor decreased IL-17 production. In conclusion, the observed changes in GALT of 5xFAD mice mirror the disease progression and might reflect inadequate immune surveillance in the gut and lead to enhanced AD pathology.

%B J Alzheimers Dis %V 61 %P 619-630 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254086?dopt=Abstract %R 10.3233/JAD-170538 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer's Disease Development. %A Lövheim, Hugo %A Olsson, Jan %A Weidung, Bodil %A Johansson, Anders %A Eriksson, Sture %A Hallmans, Göran %A Elgh, Fredrik %K Aged %K Alzheimer Disease %K Antibodies, Viral %K Case-Control Studies %K Cytomegalovirus %K Cytomegalovirus Infections %K Enzyme-Linked Immunosorbent Assay %K Female %K Herpes Simplex %K Herpesvirus 1, Human %K Humans %K Immunoglobulin G %K Immunoglobulin M %K Logistic Models %K Male %K Middle Aged %X

BACKGROUND: Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies.

OBJECTIVE: To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD.

METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses.

RESULTS: The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007).

CONCLUSION: The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system.

%B J Alzheimers Dis %V 61 %P 939-945 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254081?dopt=Abstract %R 10.3233/JAD-161305 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Interactions between Atrial Fibrillation, Cardiovascular Risk Factors, and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer's Disease: A Prospective Cohort Study. %A Falsetti, Lorenzo %A Viticchi, Giovanna %A Buratti, Laura %A Grigioni, Francesco %A Capucci, Alessandro %A Silvestrini, Mauro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Atherosclerosis %K Atrial Fibrillation %K Carotid Intima-Media Thickness %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Prospective Studies %K Risk Factors %K Tomography, X-Ray Computed %X

BACKGROUND: An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized.

OBJECTIVE: We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer's disease (AD) in the presence of vascular or genetic risk factors.

METHODS: 310 consecutive patients affected by mild-moderate AD were included and followed for a 24-month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, Framingham cardiovascular risk profile (FCRP), CHA2DS2-VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome.

RESULTS: Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE ɛ4 allele and affected by pNVAF, the lowest MMSE (14.90±7.62) and the highest mIMT (1.16±0.17 mm) and FCRP (26.24±3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2DS2-VASc, or mIMT.

CONCLUSIONS: pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE ɛ4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration.

%B J Alzheimers Dis %V 62 %P 713-725 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480173?dopt=Abstract %R 10.3233/JAD-170544 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lentivirus-Mediated HDAC3 Inhibition Attenuates Oxidative Stress in APPswe/PS1dE9 Mice. %A Yu, Linjie %A Liu, Yi %A Jin, Yuexinzi %A Cao, Xiang %A Chen, Jian %A Jin, Jiali %A Gu, Yue %A Bao, Xinyu %A Ren, Zhuoying %A Xu, Yun %A Zhu, Xiaolei %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Disease Models, Animal %K Hippocampus %K Histone Deacetylases %K Lentivirus %K Male %K Maze Learning %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Neurons %K Oxidative Stress %K Plaque, Amyloid %K Primary Cell Culture %K Reactive Oxygen Species %K Spatial Memory %K tau Proteins %X

Amyloid-β (Aβ) induces a burst of oxidative stress and plays a critical role in the pathogenesis of Alzheimer's disease (AD). Our previous results have shown that histone deacetylase 3 (HDAC3) inhibition ameliorates spatial memory deficits and decreases the Aβ burden in the brains of 9-month-old APPswe/PS1dE9 (APP/PS1) mice. In this study, we investigated the role of HDAC3 inhibition in oxidative stress in vivo and in vitro models of AD. HDAC3 was detected mainly in the neurons, and HDAC3 inhibition significantly decreased reactive oxygen species generation and improved primary cortical neuron viability. In addition, HDAC3 inhibition attenuated spatial memory dysfunction in 6-month-old APP/PS1 mice, and decreased the apoptotic rate in the hippocampi as demonstrated by TUNEL staining. HDAC3 inhibition also reduced markers of lipid peroxidation, protein oxidation, and DNA/RNA oxidation in the hippocampi of APP/PS1 mice. Moreover, HDAC3 inhibition inactivated the c-Abl/MST1/YAP signaling pathway in the hippocampi of APP/PS1 mice. In conclusion, our data show that HDAC3 inhibition can attenuate spatial memory deficits and inhibit oxidative stress in APP/PS1 mice; these results indicate a potential strategy for AD treatment.

%B J Alzheimers Dis %V 61 %P 1411-1424 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376873?dopt=Abstract %R 10.3233/JAD-170844 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Link between Subjective Perceptions of Memory and Physical Function: Implications for Subjective Cognitive Decline. %A Cosentino, Stephanie %A Devanand, Davangere %A Gurland, Barry %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Executive Function %K Female %K Humans %K Linear Models %K Male %K Memory %K Neuropsychological Tests %K New York City %K Perception %X

Subjective impairment in memory is a frequently defining feature of subjective cognitive decline (SCD), a state hypothesized to precede objectively apparent cognitive symptoms of Alzheimer's disease (AD) and to hold promise as a non-invasive, inexpensive, preclinical indicator of AD. However, a full model of the factors that contribute to subjective memory (SM), and therefore to SCD, has yet to be articulated. While SM impairment is widely known to be associated with negative affect, the extent to which SM functioning may also reflect other factors, particularly subjective beliefs or perceptions about one's health, is not known. To examine the extent to which SM is associated with subjective perceptions of health more broadly, the current study investigated the link between SM and subjective physical functioning (independent of depressive affect, and objective cognitive and physical function) in an ethnically diverse sample of 471 older adults enrolled in the population-based Northern Manhattan Aging Project. 199 (42%) participants endorsed no difficulty on a 5-point SM index while 272 (58%) endorsed some degree of difficulty. As hypothesized, SM correlated with both depression and subjective physical function, but not with age, education, global cognition, or objective physical function. When objective and subjective physical function were entered in two separate, adjusted linear regressions predicting SM, only subjective physical function and depressive affect independently predicted SM. Subjective perceptions of memory appear to reflect individuals' broader health perceptions in part. Articulating the various correlates of SM will improve identification of SCD specific to preclinical AD.

%B J Alzheimers Dis %V 61 %P 1387-1398 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376850?dopt=Abstract %R 10.3233/JAD-170495 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Lipid Metabolism and Survival Across the Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Spectrum: Relationships to Eating Behavior and Cognition. %A Ahmed, Rebekah M %A Highton-Williamson, Elizabeth %A Caga, Jashelle %A Thornton, Nicolette %A Ramsey, Eleanor %A Zoing, Margaret %A Kim, Woojin Scott %A Halliday, Glenda M %A Piguet, Olivier %A Hodges, John R %A Farooqi, I Sadaf %A Kiernan, Matthew C %K Adult %K Aged %K Amyotrophic Lateral Sclerosis %K Australia %K Body Mass Index %K Case-Control Studies %K Cholesterol %K Cholesterol, HDL %K Cognition %K Energy Intake %K Feeding Behavior %K Female %K Frontotemporal Dementia %K Humans %K Lipid Metabolism %K Male %K Middle Aged %K Neuropsychological Tests %K Survival Analysis %X

BACKGROUND: Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels.

OBJECTIVE: This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival.

METHODS: One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behavior (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses.

RESULTS: There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p < 0.001), total cholesterol/HDL ratio (p < 0.001), and lower HDL levels (p = 0.001) in all patient groups compared to controls. While there was no increase in total cholesterol levels, a higher cholesterol level was found to correlate with 3.25 times improved survival (p = 0.008). Triglyceride and HDL cholesterol levels correlated to fat intake, BMI, and measures of cognition and disease duration.

CONCLUSION: A spectrum of changes in lipid metabolism has been identified in ALS-FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival.

%B J Alzheimers Dis %V 61 %P 773-783 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254092?dopt=Abstract %R 10.3233/JAD-170660 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Longitudinal Changes in Serum Glucose Levels are Associated with Metabolic Changes in Alzheimer's Disease Related Brain Regions. %A Burns, Christine M %A Kaszniak, Alfred W %A Chen, Kewei %A Lee, Wendy %A Bandy, Daniel J %A Caselli, Richard J %A Reiman, Eric M %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Blood Glucose %K Brain %K Brain Mapping %K Female %K Fluorodeoxyglucose F18 %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Positron-Emission Tomography %K Prospective Studies %K Radiopharmaceuticals %X

BACKGROUND: The association between longitudinal changes in serum glucose level and longitudinal changes in [18F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer's disease (AD) risk are unknown.

OBJECTIVE: To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer's disease (AD).

METHODS: Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) ɛ4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4±1.0-years. An automated brain-mapping algorithm was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl.

RESULTS: This study included 80 adults aged 61.5±5 years, including 38 carriers and 42 non-carriers of the APOE ɛ4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p < 0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE ɛ4 status and baseline and advancing age.

CONCLUSIONS: Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD.

%B J Alzheimers Dis %V 62 %P 833-840 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480176?dopt=Abstract %R 10.3233/JAD-170767 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin. %A Cuberas-Borrós, Gemma %A Roca, Isabel %A Boada, Merce %A Tárraga, Lluís %A Hernandez, Isabel %A Buendia, Mar %A Rubio, Lourdes %A Torres, Gustavo %A Bittini, Ángel %A Guzmán-de-Villoria, Juan A %A Pujadas, Francesc %A Torres, Mireia %A Núñez, Laura %A Castell, Joan %A Páez, Antonio %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuroimaging %K Plasma Exchange %K Serum Albumin, Human %K Time Factors %K Tomography, Emission-Computed, Single-Photon %K Treatment Outcome %X

BACKGROUND: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement.

OBJECTIVE: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial.

METHODS: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline.

RESULTS: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls.

CONCLUSIONS: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.

%B J Alzheimers Dis %V 61 %P 321-332 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154283?dopt=Abstract %R 10.3233/JAD-170693 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment. %A Wang, Hua %A Stewart, Tessandra %A Toledo, Jon B %A Ginghina, Carmen %A Tang, Lu %A Atik, Anzari %A Aro, Patrick %A Shaw, Leslie M %A Trojanowski, John Q %A Galasko, Douglas R %A Edland, Steven %A Jensen, Poul H %A Shi, Min %A Zhang, Jing %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Alzheimer Disease %K Biomarkers %K Cognitive Dysfunction %K Cross-Sectional Studies %K Disease Progression %K Executive Function %K Female %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Memory Disorders %K Multivariate Analysis %K Neuropsychological Tests %K Phosphorylation %K tau Proteins %X

Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42), tau, and phosphorylated tau (p-tau181)] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer's Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ42, tau, and p-tau181. pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β= 0.0026, p = 0.041, 95% CI [(0.0001)-(0.005)]). CSF α-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (β= -0.59, p = 0.0015, 95% CI [(-0.96)-(-0.23)]), memory (β= 0.4, p = 0.00025, 95% CI [(0.16)-(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)-(0.93)]) function composite scores, and progression from MCI to AD (β= 0.019, p = 0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (β= -2.55, p = 0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β= 0.64, p = 0.0012, 95% CI [(0.48)-(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.

%B J Alzheimers Dis %V 61 %P 1541-1553 %8 2018 Jan 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376878?dopt=Abstract %R 10.3233/JAD-171013 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOEɛ4 Carriers. %A Sapkota, Shraddha %A Dixon, Roger A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Brain-Derived Neurotrophic Factor %K Canada %K Catechol O-Methyltransferase %K Clusterin %K Cognitive Aging %K Cognitive Dysfunction %K Executive Function %K Female %K Genetic Predisposition to Disease %K Heterozygote %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Monomeric Clathrin Assembly Proteins %K Neuropsychological Tests %K Receptors, Complement 3b %X

BACKGROUND: Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk.

OBJECTIVE: We organize three possible combinations into a "network" of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer's disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein).

METHOD: We use an accelerated longitudinal design (n = 634; age range = 55-95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (ɛ4+ versus ɛ4-).

RESULTS: APOEɛ4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOEɛ4 carriers with low AD-GRS.

CONCLUSIONS: APOEɛ4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differentially predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.

%B J Alzheimers Dis %V 62 %P 887-900 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480189?dopt=Abstract %R 10.3233/JAD-170909 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuropsychiatric and Cognitive Subtypes among Community-Dwelling Older Persons and the Association with DSM-5 Mild Neurocognitive Disorder: Latent Class Analysis. %A Liew, Tau Ming %A Yu, Junhong %A Mahendran, Rathi %A Ng, Tze-Pin %A Kua, Ee-Heok %A Feng, Lei %K Aged %K Cognition %K Cognitive Dysfunction %K Diagnostic and Statistical Manual of Mental Disorders %K Female %K Humans %K Latent Class Analysis %K Logistic Models %K Longitudinal Studies %K Male %K Middle Aged %K Neuropsychological Tests %K Sensitivity and Specificity %X

BACKGROUND: Neuropsychiatric symptoms (NPS) have been shown to increase the risk of neurocognitive disorders (NCD), leading to the recently-published criteria of mild behavioral impairment (MBI) to identify pre-dementia using NPS alone. However, MBI drew concerns about over-diagnosing subclinical psychiatric disorders.

OBJECTIVE: We hypothesized that the specificity of NPS in predicting NCD may be improved by considering NPS together with various domains of cognitive deficits. We tested this hypothesis by identifying subtypes based on the combination of NPS and cognitive deficits among community-dwelling older persons, and evaluating how the identified subtypes were associated with mild NCD.

METHODS: Our participants were from a community-based cohort study. They completed assessments such as Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), and Montreal Cognitive Assessment (MoCA). Those with possible cognitive impairment underwent further evaluations for mild NCD. Latent class analysis was conducted using GDS, GAI, and MoCA domains. Logistic regression was performed to investigate the association between the latent-classes and mild NCD.

RESULTS: We included 825 participants, and identified four distinct subtypes: Subtype 1 (no NPS or cognitive deficits), Subtype 2 (NPS alone), Subtype 3 (cognitive deficits alone), and Subtype 4 (both NPS and cognitive deficits). Subtype 1 and 2 had low risk of prevalent mild NCD (OR 0.92- 1.00), while Subtype 3 conferred a moderate risk (OR 4.47- 4.85) and Subtype 4 had the highest risk (OR 7.95- 8.63).

CONCLUSION: We demonstrated the benefits of combining NPS and cognitive deficits to predict those at highest risk of prevalent mild NCD. Our findings highlighted the relevance of subclinical psychiatric symptoms in predicting NCD, and indirectly supported the need for longer durations of NPS to improve its specificity.

%B J Alzheimers Dis %V 62 %P 675-686 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480192?dopt=Abstract %R 10.3233/JAD-170947 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer's Disease. %A Tao, Qiushan %A Zhu, Haihao %A Chen, Xi %A Stern, Robert A %A Kowall, Neil %A Au, Rhoda %A Blusztajn, Jan Krzysztof %A Qiu, Wei Qiao %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Female %K Humans %K Islet Amyloid Polypeptide %K Logistic Models %K Male %K Middle Aged %K Phosphatidylcholines %K ROC Curve %K tau Proteins %X

Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer's disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-β peptide (Aβ), and total tau (t-tau) in plasma at different time points were measured and treated as individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (p < 0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Aβ levels, other PCs were associated with both Aβ and t-tau levels. A receiver operating characteristic analysis of the PCs was combined with the Aβ and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls, and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI.

%B J Alzheimers Dis %V 62 %P 597-609 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480193?dopt=Abstract %R 10.3233/JAD-170948 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Prediction of Alzheimer's Dementia in Patients with Amnestic Mild Cognitive Impairment in Clinical Routine: Incremental Value of Biomarkers of Neurodegeneration and Brain Amyloidosis Added Stepwise to Cognitive Status. %A Lange, Catharina %A Suppa, Per %A Pietrzyk, Uwe %A Makowski, Marcus R %A Spies, Lothar %A Peters, Oliver %A Buchert, Ralph %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloidosis %K Brain %K Cognitive Dysfunction %K Female %K Fluorodeoxyglucose F18 %K Humans %K Imaging, Three-Dimensional %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Survival Analysis %K tau Proteins %X

The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer's disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Aβ1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as 'negative' or 'positive' for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Aβ provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient's status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients.

%B J Alzheimers Dis %V 61 %P 373-388 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154285?dopt=Abstract %R 10.3233/JAD-170705 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Progression of Alzheimer's Disease: A Longitudinal Study in Norwegian Memory Clinics. %A Eldholm, Rannveig Sakshaug %A Barca, Maria Lage %A Persson, Karin %A Knapskog, Anne-Brita %A Kersten, Hege %A Engedal, Knut %A Selbæk, Geir %A Brækhus, Anne %A Skovlund, Eva %A Saltvedt, Ingvild %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Disease Progression %K Female %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Memory %K Neuropsychological Tests %K Norway %X

BACKGROUND: The course of Alzheimer's disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression.

OBJECTIVE: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0-18), the cognitive test Mini-Mental State Examination (MMSE, 0-30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1).

METHODS: The Progression of AD and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics.

RESULTS: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores.

CONCLUSION: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate.

%B J Alzheimers Dis %V 61 %P 1221-1232 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254085?dopt=Abstract %R 10.3233/JAD-170436 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Progression of Neuropsychiatric Symptoms in Alzheimer's Disease During a Five-Year Follow-Up: Kuopio ALSOVA Study. %A Hallikainen, Ilona %A Hongisto, Kristiina %A Välimäki, Tarja %A Hänninen, Tuomo %A Martikainen, Janne %A Koivisto, Anne M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Anxiety %K Caregivers %K Delusions %K Disease Progression %K Female %K Finland %K Hallucinations %K Humans %K Linear Models %K Male %K Motor Activity %K Multivariate Analysis %K Neuropsychological Tests %K Severity of Illness Index %X

BACKGROUND: An improved understanding of the role of neuropsychiatric symptoms (NPS) in the course of Alzheimer's disease (AD) has recently emerged. NPS lead to hospitalization and caregiver stress, but are more variable during the course of the disease than other symptoms. Knowledge about the role of specific NPS in disease progression and prognosis is especially limited.

OBJECTIVES: To examine the relationship between specific NPS and AD severity during a 5-year follow-up period, and to determine which baseline NPS predict AD progression.

METHODS: 236 persons with very mild (CDR 0.5) or mild (CDR 1) AD at baseline and their caregivers were followed up for five years as part of the ALSOVA study. The Neuropsychiatric Inventory was used to assess NPS, and AD severity progression was measured with the Clinical Dementia Rating Sum of Boxes. Data was analyzed with Generalized Estimated Equations and Linear Mixed Models.

RESULTS: The baseline NPS that best predicted AD progression were delusions, agitation, and aberrant motor behavior, while AD severity during follow-up was associated with hallucinations, delusions, agitation, apathy, aberrant motor behavior, and sleep and appetite disturbances.

CONCLUSIONS: Persons with mild AD presenting delusions, agitation, and aberrant motor behavior at the time of diagnosis could have a more rapidly progressing disease, and some NPS are associated with AD severity. These results highlight the importance of evaluating NPS at the time of AD diagnosis, and the need to offer additional support to persons presenting delusions, agitation and aberrant motor behavior, and their caregivers.

%B J Alzheimers Dis %V 61 %P 1367-1376 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376861?dopt=Abstract %R 10.3233/JAD-170697 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial. %A Wharton, Whitney %A Goldstein, Felicia C %A Tansey, Malú G %A Brown, Alexandra L %A Tharwani, Sonum D %A Verble, Danielle D %A Cintron, Amarallys %A Kehoe, Patrick G %K African Americans %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Antihypertensive Agents %K Biomarkers %K Blood Pressure %K Brain %K Clinical Trials, Phase I as Topic %K Female %K Georgia %K Humans %K Linear Models %K Male %K Middle Aged %K Randomized Controlled Trials as Topic %K Renin-Angiotensin System %K Telmisartan %X

Research indicates that certain antihypertensive medications alter Alzheimer's disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-β (Aβ) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify the brain RAS, cerebrospinal fluid (CSF) Aβ, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45-70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Aβ, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design.

%B J Alzheimers Dis %V 61 %P 815-824 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254080?dopt=Abstract %R 10.3233/JAD-161198 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Rationale and Design of the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) Trial. %A Kehoe, Patrick G %A Blair, Peter S %A Howden, Beth %A Thomas, David L %A Malone, Ian B %A Horwood, Jeremy %A Clement, Clare %A Selman, Lucy E %A Baber, Hannah %A Lane, Athene %A Coulthard, Elizabeth %A Passmore, Anthony Peter %A Fox, Nick C %A Wilkinson, Ian B %A Ben-Shlomo, Yoav %K Activities of Daily Living %K Alzheimer Disease %K Antihypertensive Agents %K Atrophy %K Blood Pressure Monitors %K Brain %K Clinical Trials, Phase II as Topic %K Disease Progression %K Double-Blind Method %K Female %K Humans %K Losartan %K Magnetic Resonance Imaging %K Male %K Multivariate Analysis %K Quality of Life %K Randomized Controlled Trials as Topic %K Regression Analysis %K Renin-Angiotensin System %X

BACKGROUND: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer's disease (AD) pathology and reduce the rate of disease progression.

OBJECTIVE: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR).

METHODS: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables.

RESULTS: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits.

CONCLUSION: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted.

%B J Alzheimers Dis %V 61 %P 803-814 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226862?dopt=Abstract %R 10.3233/JAD-170101 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Real World Recruiting of Older Subjects with Mild Cognitive Impairment for Exercise Trials: Community Readiness is Pivotal. %A Sanders, Marit L %A Stuckenschneider, Tim %A Devenney, Kate E %A Lawlor, Brian %A Schneider, Stefan %A Olde Rikkert, Marcel G M %K Aged %K Cognitive Dysfunction %K Europe %K Exercise %K Female %K Humans %K Life Style %K Male %K Middle Aged %K Patient Selection %X

Prevention trials in subjects with mild cognitive impairment (MCI), especially lifestyle interventions, can be difficult to carry out, particularly the recruitment and retention of subjects. We experienced these challenges in our multi-site one-year exercise trial in MCI, NeuroExercise. Trial recruitment rates differed significantly across sites; the non-medical sport university site, providing free access to a range of group exercise in a sports environment, proved far more successful than memory clinics linked to hospitals. This suggests that non-medical settings and a non-medical research community facilitating physical activities may be important factors in recruitment of subjects with MCI for large prevention trials.

%B J Alzheimers Dis %V 62 %P 579-581 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480202?dopt=Abstract %R 10.3233/JAD-171083 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reduced Gray Matter Volume of the Thalamus and Hippocampal Region in Elderly Healthy Adults with no Impact of APOE ɛ4: A Longitudinal Voxel-Based Morphometry Study. %A Squarzoni, Paula %A Duran, Fabio Luis Souza %A Busatto, Geraldo F %A Alves, Tania Correa Toledo de Ferraz %K Aged %K Aging %K Apolipoprotein E4 %K Atrophy %K Cross-Sectional Studies %K Female %K Gray Matter %K Healthy Volunteers %K Hippocampus %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Organ Size %K Thalamus %X

BACKGROUND: Many cross-sectional voxel-based morphometry (VBM) investigations have shown significant inverse correlations between chronological age and gray matter (GM) volume in several brain regions in healthy humans. However, few VBM studies have documented GM decrements in the healthy elderly with repeated MRI measurements obtained in the same subjects. Also, the extent to which the APOE ɛ4 allele influences longitudinal findings of GM reduction in the healthy elderly is unclear.

OBJECTIVE: Verify whether regional GM changes are associated with significant decrements in cognitive performance taking in account the presence of the APOE ɛ4 allele.

METHODS: Using structural MRI datasets acquired in 55 cognitively intact elderly subjects at two time-points separated by approximately three years, we searched for voxels showing significant GM reductions taking into account differences in APOE genotype.

RESULTS: We found global GM reductions as well as regional GM decrements in the right thalamus and left parahippocampal gyrus (p < 0.05, family-wise error corrected for multiple comparisons over the whole brain). These findings were not affected by APOE ɛ4.

CONCLUSIONS: Irrespective of APOE ɛ4, longitudinal VBM analyses show that the hippocampal region and thalamus are critical sites where GM shrinkage is greater than the degree of global volume reduction in healthy elderly subjects.

%B J Alzheimers Dis %V 62 %P 757-771 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480170?dopt=Abstract %R 10.3233/JAD-161036 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Relationships Between Lower Olfaction and Brain White Matter Lesions in Elderly Subjects with Mild Cognitive Impairment. %A Heinrich, Juliette %A Vidal, Jean-Sébastien %A Simon, Axelle %A Rigaud, Anne-Sophie %A Hanon, Olivier %A Epelbaum, Jacques %A Viollet, Cécile %A Duron, Emmanuelle %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Atrophy %K Cognitive Dysfunction %K Cross-Sectional Studies %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Multivariate Analysis %K Neuropsychological Tests %K Olfaction Disorders %K Severity of Illness Index %K White Matter %X

BACKGROUND: Olfactory impairment is reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and is associated with hippocampal atrophy. In elderly people, dementia with AD neuropathology and white matter lesions (WML) is common. In this context, olfactory impairment could also depend on the presence of WML.

OBJECTIVE: To assess the cross-sectional relationship between olfaction and WML in elderly subjects with MCI.

METHODS: Consecutive subjects, >65 years old, diagnosed as MCI after a comprehensive neuropsychological assessment in an expert memory center, with a brain MRI performed within a year and without major depressive state, were included. Olfaction was assessed by the Brief Smell Identification Test (BSIT). Two trained neuroradiologists, blind to cognitive and olfaction status, visually assessed hippocampal atrophy according to Scheltens' scale and WML according to Fazekas criteria.

RESULTS: Seventy-five MCI subjects (mean age (SD) = 77.1 (6.2) years, 74.7% of women) were included. After adjustment for age and sex, factors associated with low BSIT scores were older age (p = 0.007), lower BMI (p = 0.08), lower MMSE score (p = 0.05), lower FCRST (p = 0.008), hippocampal atrophy (p = 0.04), periventricular WML (p = 0.007), and deep WML burden (p = 0.005). In multivariate analysis, severe deep WML (OR (95% CI) = 6.29 (1.4-35.13), p = 0.02) remained associated with low BSIT score independently from hippocampal atrophy.

CONCLUSION: In elderly MCI subjects, low olfactory performances are associated with WML, whose progression may be slowed by vascular treatments. A longitudinal study to evaluate whether the progression of WML, hippocampal atrophy and low olfactory function, can predict accurately conversion from MCI to dementia is ongoing.

%B J Alzheimers Dis %V 61 %P 1133-1141 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332036?dopt=Abstract %R 10.3233/JAD-170378 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease. %A Alegret, Montserrat %A Peretó, Mar %A Pérez, Alba %A Valero, Sergi %A Espinosa, Ana %A Ortega, Gemma %A Hernandez, Isabel %A Mauleón, Ana %A Rosende-Roca, Maitee %A Vargas, Liliana %A Rodríguez-Gómez, Octavio %A Abdelnour, Carla %A Berthier, Marcelo L %A Bak, Thomas H %A Ruiz, Agustin %A Tárraga, Lluís %A Boada, Merce %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Case-Control Studies %K Cognitive Dysfunction %K Cross-Sectional Studies %K Early Diagnosis %K Executive Function %K Female %K Humans %K Language Tests %K Logistic Models %K Longitudinal Studies %K Male %K Middle Aged %K Proportional Hazards Models %K Sensitivity and Specificity %K Spain %X

BACKGROUND: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool.

OBJECTIVE: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population.

METHODS: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion.

RESULTS: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels).

CONCLUSION: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia.

%B J Alzheimers Dis %V 62 %P 611-619 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480180?dopt=Abstract %R 10.3233/JAD-170826 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sally-Anne Test in Patients with Alzheimer's Disease Dementia. %A Takenoshita, Shintaro %A Terada, Seishi %A Yokota, Osamu %A Kutoku, Yumiko %A Wakutani, Yosuke %A Nakashima, Makoto %A Maki, Yohko %A Hattori, Hideyuki %A Yamada, Norihito %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Logistic Models %K Male %K Neuropsychological Tests %K Social Behavior Disorders %K Theory of Mind %X

Social cognition has recently been recognized as one of the essential cognitive domains. Some reports suggested that patients with Alzheimer's disease dementia (ADD) presented significant theory of mind deficits even in the mild condition. However, most previous studies included only small numbers of patients with ADD. The present study administered the first-order false belief (Sally-Anne) test to 116 consecutive patients with ADD from the outpatient units of the Memory Clinic and compared the characteristics of the two groups with correct and incorrect answers on the test. Then various clinical characteristics were evaluated. Only 37.1% of patients with ADD correctly answered the Sally-Anne test with the right explanation. Comparison between the two groups of correct and incorrect answers revealed a significant association between the frontal assessment battery score and the result of the Sally-Anne test in the multiple logistic regression analyses. Thus, patients with ADD presented a significant deficit in social cognition even in the mild condition. Frontal dysfunction was thought to be related to the deficits in mild ADD.

%B J Alzheimers Dis %V 61 %P 1029-1036 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332047?dopt=Abstract %R 10.3233/JAD-170621 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Sex Influences the Accuracy of Subjective Memory Complaint Reporting in Older Adults. %A Sundermann, Erin E %A Edmonds, Emily C %A Delano-Wood, Lisa %A Galasko, Douglas R %A Salmon, David P %A Rubin, Leah H %A Bondi, Mark W %K Aged %K Cognitive Dysfunction %K Female %K Humans %K Logistic Models %K Male %K Memory Disorders %K Mental Recall %K Neuropsychological Tests %K Self Report %K Sex Factors %X

Subjective memory complaints (SMC) are required when diagnosing amnestic mild cognitive impairment (aMCI), although their relationship with objective memory performance and Alzheimer's disease (AD) pathology remains unclear. We investigated whether the sex of the patient/participant moderates these associations. Participants were 940 normal control (NC) and aMCI participants from the Alzheimer's Disease Neuroimaging Initiative. SMC were assessed via the memory scale of the Everyday Cognition questionnaire. Discrepancy scores were calculated between self- and informant-reports and categorized into "overestimates," "comparable estimates", and "underestimates" of SMC. We conducted linear and logistic regressions to examine the interaction of sex with self- and informant-reported SMC and discrepancy group on the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall and on PET measures of amyloid-β (Aβ) positivity. Diagnosis-stratified analyses were also conducted. Overall, there were sex by self- and informant-reported SMC interactions for Immediate and Delayed Recall. Despite a higher proportion of "overestimates" in women, greater self- and informant-reported SMC showed a stronger relationship to poorer RAVLT scores in women versus men. Diagnosis-stratified analyses revealed that results were driven by aMCI participants. Conversely, overall, greater self- and informant-reported SMC related to greater odds of Aβ positivity regardless of sex. In diagnosis-stratified analyses, only informant-reported SMC related to Aβ positivity in aMCI. Relative to "comparable estimates," "underestimates" of SMC were associated with poorer RAVLT scores across sexes in the overall sample and in aMCI. The predictive utility of self-report SMC may be limited to women in aMCI. Sex differences should be considered when evaluating SMC.

%B J Alzheimers Dis %V 61 %P 1163-1178 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332038?dopt=Abstract %R 10.3233/JAD-170425 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments. %A McEwen, Sarah C %A Siddarth, Prabha %A Abedelsater, Berna %A Kim, Yena %A Mui, Wenli %A Wu, Pauline %A Emerson, Natacha D %A Lee, Jacob %A Greenberg, Shayna %A Shelton, Tiffany %A Kaiser, Scott %A Small, Gary W %A Merrill, David A %K Aged %K Attention %K California %K Cognition %K Executive Function %K Exercise %K Female %K Humans %K Learning %K Male %K Memory %K Memory Disorders %K Middle Aged %K Treatment Outcome %X

BACKGROUND: Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance.

OBJECTIVE: The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults.

METHODS: 55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention.

RESULTS: The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p = 0.0001, ES = 0.96).

CONCLUSION: These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults.

%B J Alzheimers Dis %V 62 %P 795-806 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480182?dopt=Abstract %R 10.3233/JAD-170846 %0 Journal Article %J J Alzheimers Dis %D 2018 %T SORL1 Variants in Familial Alzheimer's Disease. %A Gómez-Tortosa, Estrella %A Ruggiero, María %A Sainz, Ma José %A Villarejo-Galende, Alberto %A Prieto-Jurczynska, Cristina %A Venegas Pérez, Begoña %A Ordás, Carlos %A Agüero, Pablo %A Guerrero-López, Rosa %A Pérez-Pérez, Julián %K Aged %K Alzheimer Disease %K Case-Control Studies %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Humans %K LDL-Receptor Related Proteins %K Male %K Membrane Transport Proteins %K Middle Aged %K Mutation %K Polymorphism, Single Nucleotide %K Siblings %K Spain %X

The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer's disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease.

%B J Alzheimers Dis %V 61 %P 1275-1281 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376855?dopt=Abstract %R 10.3233/JAD-170590 %0 Journal Article %J J Alzheimers Dis %D 2018 %T SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging. %A Seddighi, Sahba %A Varma, Vijay R %A An, Yang %A Varma, Sudhir %A Beason-Held, Lori L %A Tanaka, Toshiko %A Kitner-Triolo, Melissa H %A Kraut, Michael A %A Davatzikos, Christos %A Thambisetty, Madhav %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Brain %K Calcium-Binding Proteins %K Cerebrovascular Circulation %K Cognition Disorders %K Extracellular Matrix Proteins %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Polymorphism, Single Nucleotide %K Positron-Emission Tomography %X

We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.

%B J Alzheimers Dis %V 61 %P 401-414 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154276?dopt=Abstract %R 10.3233/JAD-170557 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. %A Power, Rebecca %A Coen, Robert F %A Beatty, Stephen %A Mulcahy, Riona %A Moran, Rachel %A Stack, Jim %A Howard, Alan N %A Nolan, John M %K Adult %K Cognition %K Dietary Supplements %K Double-Blind Method %K Executive Function %K Female %K Healthy Volunteers %K Humans %K Lutein %K Macular Pigment %K Male %K Memory, Episodic %K Middle Aged %K Retina %K Vision Tests %K Zeaxanthins %X

BACKGROUND: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties.

OBJECTIVE: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels.

METHODS: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z (n = 45) or placebo (n = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured.

RESULTS: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p = 0.009]; PAL errors [rANOVA, p = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p = 0.005) and observed increases in serum concentrations of L (p = 0.009).

CONCLUSION: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study.

%B J Alzheimers Dis %V 61 %P 947-961 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332050?dopt=Abstract %R 10.3233/JAD-170713 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer's Disease. %A Roe, Catherine M %A Babulal, Ganesh M %A Mishra, Shruti %A Gordon, Brian A %A Stout, Sarah H %A Ott, Brian R %A Carr, David B %A Ances, Beau M %A Morris, John C %A Benzinger, Tammie L S %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid %K Automobile Driving %K Biomarkers %K Carbolines %K Female %K Humans %K Logistic Models %K Male %K Neuroimaging %K Positron-Emission Tomography %K tau Proteins %X

Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.

%B J Alzheimers Dis %V 61 %P 509-513 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29171997?dopt=Abstract %R 10.3233/JAD-170521 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Treatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry. %A Subic, Ana %A Cermakova, Pavla %A Religa, Dorota %A Han, Shuang %A von Euler, Mia %A Kåreholt, Ingemar %A Johnell, Kristina %A Fastbom, Johan %A Bognandi, Liselia %A Winblad, Bengt %A Kramberger, Milica G %A Eriksdotter, Maria %A Garcia-Ptacek, Sara %K Aged %K Aged, 80 and over %K Anticoagulants %K Atrial Fibrillation %K Dementia %K Female %K Hemorrhage %K Humans %K Longitudinal Studies %K Male %K Registries %K Risk Factors %K Stroke %K Survival Analysis %K Sweden %K Warfarin %X

BACKGROUND: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF).

OBJECTIVE: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF.

METHODS: Of 49,792 patients registered in the Swedish Dementia Registry 2007-2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death.

RESULTS: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59-0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01-1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03-1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment.

CONCLUSIONS: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible.

%B J Alzheimers Dis %V 61 %P 1119-1128 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29286925?dopt=Abstract %R 10.3233/JAD-170575 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Validation of the Delayed Matching-to-Sample Task 48 (DMS48) in Elderly Chinese. %A Feng, Xueyan %A Zhou, Aihong %A Liu, Zhixin %A Li, Fangyu %A Wei, Cuibai %A Zhang, Guili %A Jia, Jianping %K Aged %K Aged, 80 and over %K Alzheimer Disease %K China %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Linear Models %K Male %K Memory Disorders %K Middle Aged %K Neuropsychological Tests %K ROC Curve %K Sensitivity and Specificity %K Severity of Illness Index %X

BACKGROUND: Delayed Matching-to-Sample Task 48 (DMS48), a brief tool measuring visual recognition memory, is valid to identify the early stage of Alzheimer's disease (AD) in Caucasians. However, little data is available in Chinese.

OBJECTIVE: To develop norms and optimal cutoff points for the DMS48 in Chinese elders.

METHODS: A cross-sectional study was conducted in seven memory clinics from five cities across China. DMS48 was applied to 369 Chinese aged 50 or older (138 cognitively normal [CN], 112 mild cognitive impairment due to AD (MCI-A), and 119 mild AD dementia). The demographic factors which influence DMS48 scores were investigated and the norms were established considering those factors. Receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff points.

RESULTS: Age was shown to influence DMS48 scores (r = -0.36, p < 0.05), and we presented the age-stratified normative data for the DMS48. The optimal cutoff point is 42/43 for identifying cognitive impairment (MCI-A and AD dementia) against CN (sensitivity 97.80% and specificity 89.13%) and MCI-A against CN (sensitivity 86.60% and specificity 94.20%). A cutoff of 39/40 obtained good sensitivity (100.00%) and specificity (94.90%) in discriminating AD dementia from CN. The age-stratified optimal cutoff points for identifying MCI-A were 43/44 for individuals aged 50 to 59 years old, 42/43 for 60 to 69 years old, 41/42 for 70 to 79 years old, and 40/41 for 80 or older, respectively (sensitivity 84.80% and specificity 95.70%).

CONCLUSION: This study proved that DMS48 is of good validation in screening MCI-A in elderly Chinese.

%B J Alzheimers Dis %V 61 %P 1611-1618 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376851?dopt=Abstract %R 10.3233/JAD-170530 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Vestibular Loss Predicts Poorer Spatial Cognition in Patients with Alzheimer's Disease. %A Wei, Eric X %A Oh, Esther S %A Harun, Aisha %A Ehrenburg, Matthew %A Agrawal, Yuri %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Bilateral Vestibulopathy %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Linear Models %K Male %K Multivariate Analysis %K Neuropsychological Tests %K Prospective Studies %K Spatial Navigation %K Vestibular Function Tests %X

The vestibular system is an important contributor to balance control, spatial orientation, and falls risk. Recent evidence has shown that Alzheimer's disease (AD) patients have a higher prevalence of vestibular impairment relative to healthy controls. We sought to evaluate whether vestibular loss is specifically associated with poor spatial cognitive skills among patients with mild cognitive impairment (MCI) and AD. We enrolled 50 patients (22 MCI and 28 AD) from an interdisciplinary Memory Clinic and measured vestibular physiologic function in all patients. Spatial cognitive function was assessed using the Money Road Map Test (MRMT) and the Trail Making Test Part B (TMT-B). General cognitive function was assessed with the Mini-Mental Status Examination (MMSE). In multivariable linear regression analyses adjusted for age, gender, education level, and MMSE, MCI and AD patients with vestibular loss made significantly more errors on the MRMT relative to patients with normal vestibular function (β= 7.3, 95% CI 2.4, 12.1 for unilateral vestibular loss and β= 6.4, 95% CI 1.9, 10.9 for bilateral vestibular loss). We further stratified AD patients into "spatially normal" and "spatially impaired" groups based on MRMT performance, and found that the prevalence of vestibular loss was significantly higher in the spatially impaired AD group relative to the spatially normal AD group. These findings support the hypothesis that vestibular loss contributes specifically to a decline in spatial cognitive ability in MCI and AD patients, independently of general cognitive decline, and may predict a "spatially impaired" subtype of AD.

%B J Alzheimers Dis %V 61 %P 995-1003 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254098?dopt=Abstract %R 10.3233/JAD-170751 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Exercise Training and Functional Connectivity Changes in Mild Cognitive Impairment and Healthy Elders. %A Chirles, Theresa J %A Reiter, Katherine %A Weiss, Lauren R %A Alfini, Alfonso J %A Nielson, Kristy A %A Smith, J Carson %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Exercise %K Exercise Test %K Female %K Gyrus Cinguli %K Humans %K Image Processing, Computer-Assisted %K Linear Models %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Oxygen %K Psychiatric Status Rating Scales %X

BACKGROUND: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer's disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD.

OBJECTIVE: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders.

METHODS: Sixteen MCI and 16 healthy elders (age range = 60-88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was used as a seed for correlated brain activity maps.

RESULTS: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes.

CONCLUSION: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated.

%B J Alzheimers Dis %V 57 %P 845-856 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304298?dopt=Abstract %R 10.3233/JAD-161151 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort. %A Kramberger, Milica G %A Auestad, Bjørn %A Garcia-Ptacek, Sara %A Abdelnour, Carla %A Olmo, Josep Garre %A Walker, Zuzana %A Lemstra, Afina W %A Londos, Elisabet %A Blanc, Frédéric %A Bonanni, Laura %A McKeith, Ian %A Winblad, Bengt %A de Jong, Frank Jan %A Nobili, Flavio %A Stefanova, Elka %A Petrova, Maria %A Falup-Pecurariu, Cristian %A Rektorova, Irena %A Bostantjopoulou, Sevasti %A Biundo, Roberta %A Weintraub, Daniel %A Aarsland, Dag %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognition Disorders %K Cohort Studies %K Female %K Humans %K International Cooperation %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %X

BACKGROUND/OBJECTIVE: The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) patients.

METHODS: Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features.

RESULTS: The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p = 0.07 compared to DLB) and 1.8 in PDD (p = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features.

CONCLUSIONS: The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

%B J Alzheimers Dis %V 57 %P 787-795 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304294?dopt=Abstract %R 10.3233/JAD-161109 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modulating the Balance of Synaptic and Extrasynaptic NMDA Receptors Shows Positive Effects against Amyloid-β-Induced Neurotoxicity. %A Huang, Yan %A Shen, Wei %A Su, Jie %A Cheng, Bin %A Li, Dong %A Liu, Gang %A Zhou, Wen-Xia %A Zhang, Yong-Xiang %K Amyloid beta-Peptides %K Animals %K Antimetabolites %K Cycloserine %K Disease Models, Animal %K Excitatory Amino Acid Antagonists %K Excitatory Postsynaptic Potentials %K Hippocampus %K Locomotion %K Male %K Maze Learning %K N-Methylaspartate %K Nesting Behavior %K Neurotoxicity Syndromes %K Peptide Fragments %K Piperidines %K Rats %K Rats, Wistar %K Receptors, N-Methyl-D-Aspartate %K Recognition (Psychology) %K Signal Transduction %K Synapses %X

Alzheimer's disease (AD) patients suffer a disturbance in the balance between synaptic (GluN2A, mediating the protective pathway) and extrasynaptic NMDA receptors (NMDARs) (GluN2B, mediating the excitotoxic pathway), and, therefore, restoring the balance of GluN2A and GluN2B should be beneficial for AD. In this study, the GluN2B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effect on amyloid-β (Aβ)-induced long-term potentiation deficits. Enhancing the activity of GluN2A had a protective effect against Aβ, and specific activation of GluN2A and inhibition of GluN2B showed a better protective effect. In Aβ ICV-injected animals, the combination of ifenprodil and D-cycloserine (a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests (nest building, novel object recognition, and Morris water maze) than ifenprodil (Morris water maze) or D-cycloserine (nest building) alone. Signal pathway analysis showed that Aβ disturbed the GluN2A/GluN2B-related pathway. The ratio of GluN2A to GluN2B decreased in Aβ-treated animals, and TORC dephosphorylation and ERK1/2 activation, which could be initiated by GluN2A, also decreased in the hippocampal tissues of Aβ-treated animals. As a result, the activation of CREB and the content of brain-derived BDNF decreased. The combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone, indicating that Aβ-induced toxicology was mediated both by functionally inhibiting GluN2A and enhancing GluN2B. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Aβ-induced neurotoxicity, suggesting that modulation of the balance between GluN2A and GluN2B could be a potential strategy for AD drug development and therapy.

%B J Alzheimers Dis %V 57 %P 885-897 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28269783?dopt=Abstract %R 10.3233/JAD-161186 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PCSK9 Promotes oxLDL-Induced PC12 Cell Apoptosis Through the Bcl-2/Bax-Caspase 9/3 Signaling Pathway. %A Liu, Lu-Shan %A Bai, Xue-Qin %A Gao, Ya %A Wu, Qi %A Ren, Zhong %A Li, Qing %A Pan, Li-Hong %A He, Ni-Ya %A Peng, Juan %A Tang, Zhi-Han %K Amyloid beta-Peptides %K Analysis of Variance %K Animals %K Apoptosis %K bcl-2-Associated X Protein %K Caspases %K Culture Media, Serum-Free %K Dose-Response Relationship, Drug %K Flow Cytometry %K Lipid Metabolism %K Lipoproteins, LDL %K PC12 Cells %K Peptide Fragments %K Proprotein Convertase 9 %K Proto-Oncogene Proteins c-bcl-2 %K Rats %K RNA, Messenger %K RNA, Small Interfering %K Signal Transduction %K Transfection %X

BACKGROUND: Hyperlipidemia is a risk factor for neurodegenerative diseases. Proprotein convertase subtilisin / Kexin type 9 (PCSK9) degrades hepatic low-density lipoprotein receptor (LDLR) to regulate lipid metabolism. It is unclear if PCSK9 plays a role in neurodegenerative diseases.

OBJECTIVE: This study was designed to determine whether PCSK9 is crucial between hyperlipidemia and Alzheimer's disease. The interrelationship between PCSK9 and neuronal apoptosis was explored in PC12 cells in response to treatment with oxidized low-density lipoprotein (oxLDL).

METHODS: Cultured PC12 cells were serum-starved and incubated with different concentrations of oxLDL for 24 h. Intracytoplasmic lipid droplets were observed by oil red O staining. Morphological assessment of apoptotic cells was performed using Hoechst 33258 staining and flow cytometry analysis. The expression of mRNA and protein was detected by reverse-transcription polymerase chain reaction (RT-PCR) and western blot analyses, respectively. Transfection of small interfering RNA (siRNA) into PC12 cells was conducted using HiperFect Transfection Reagent. Concentrations of Aβ40 and Aβ42 were detected by enzyme-linked immunosorbent assay (ELISA) kit.

RESULTS: Intracellular lipid content, the number of apoptotic cells, and PCSK9 expression were increased in PC12 cells after oxLDL treatment. Transfection with PCSK9 siRNA reduced the oxLDL-induced apoptosis of PC12 cells. We further confirmed the involvement of Bcl-2/Bax-Caspase (9, 3) signaling pathway in the regulation of PC12 cells apoptosis.β-Secretase 1, another target gene of PCSK9, was downregulated in PC12 cells in response to oxLDL treatment. Aβ40 and Aβ42 contents were also decreased.

CONCLUSION: PCSK9 promotes oxLDL-induced PC12 cell apoptosis through the Bcl-2/Bax-Caspase 9/3 signaling pathway.

%B J Alzheimers Dis %V 57 %P 723-734 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304296?dopt=Abstract %R 10.3233/JAD-161136 %0 Journal Article %J J Alzheimers Dis %D 2017 %T The Progression of Alzheimer's Disease: Are Fast Decliners Really Fast? A Four-Year Follow-Up. %A Barocco, Federica %A Spallazzi, Marco %A Concari, Letizia %A Gardini, Simona %A Pelosi, Annalisa %A Caffarra, Paolo %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Male %K Psychiatric Status Rating Scales %K ROC Curve %K Time Factors %X

BACKGROUND: The rate of cognitive and functional decline in Alzheimer's disease (AD) changes across individuals.

OBJECTIVES: Our purpose was to assess whether the concept of "fast decline" really fits its definition and whether cognitive and functional variables at onset can predict the progression of AD.

METHODS: 324 AD patients were included. We retrospectively examined their Mini-Mental State Examination (MMSE) total score and sub-items, Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) at baseline and every six months for a 4-year follow-up. Patients were divided into "fast decliners" (n = 62), defined by a loss ≥5 points on the MMSE score within the first year from the baseline; "intermediate decliners" (n = 37), by a loss ≥5 points after the first year and before the 18th month; or "slow decliners" (n = 225), composed of the remaining patients.

RESULTS: At baseline, the groups did not differ on demographic, clinical, and cognitive variables. The decline at the end of the 4-year follow-up period seems to be similar among the different decline clusters. Predictors of disease progression have not been identified; only the MMSE total score at 12 months <14/30 was indicative of a poor prognosis.

CONCLUSIONS: Even with the limitation due to the small sample size, the lack of differences in the disease progression in time in the different clusters suggest the inconsistency of the so-called "fast decliners". This study was unable to show any significant difference among clusters of AD progression within a 4-year time interval. Further studies should better clarify whether a more consistent distinction exists between slow and fast decliners.

%B J Alzheimers Dis %V 57 %P 775-786 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304306?dopt=Abstract %R 10.3233/JAD-161264 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice. %A Iwahara, Naotoshi %A Hisahara, Shin %A Kawamata, Jun %A Matsumura, Akihiro %A Yokokawa, Kazuki %A Saito, Taro %A Fujikura, Mai %A Manabe, Tatsuo %A Suzuki, Hiromi %A Matsushita, Takashi %A Suzuki, Syuuichirou %A Shimohama, Shun %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Brain %K Cells, Cultured %K Disease Models, Animal %K Female %K Humans %K Interleukin-6 %K Lipopolysaccharides %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Microglia %K Neurons %K Presenilin-1 %K Suppressor of Cytokine Signaling 3 Protein %K Tumor Necrosis Factor-alpha %X

In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer's disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clearance of amyloid-β (Aβ) through phagocytosis. We previously demonstrated that microglial activation and increase in oxidative stress started from the middle age in APPswe/PS1dE9 mice, and hypothesized that M1 activation occurs in middle-aged AD mice by Aβ stimulation. In the present study, we analyzed in vivo expressions of pro-inflammatory cytokines (M1 microglial markers), M2 microglial markers, and suppressor of cytokine signaling (SOCS) family, and examined the microglial phenotypic profile in APPswe/PS1dE9 mice. Then we compared the in vitro gene expression patterns of Aβ- and lipopolysaccharide (LPS)-stimulated primary-cultured microglia. Microglia in APPswe/PS1dE9 mice exhibited an M1-like phenotype, expressing tumor necrosis factor α (TNFα) but not interleukin 6 (IL6). Aβ-stimulated primary-cultured microglia also expressed TNFα but not IL6, whereas LPS-stimulated primary-cultured microglia expressed both pro-inflammatory cytokines. Furthermore, both microglia in APPswe/PS1dE9 mice and Aβ-stimulated primary-cultured microglia expressed SOCS3. Reduction of SOCS3 expression in Aβ-challenged primary-cultured microglia resulted in upregulation of IL6 expression. Our findings indicate that SOCS3 suppresses complete polarization to M1 phenotype through blocking IL6 production, and Aβ-challenged primary-cultured microglia replicate the in vivo gene expression pattern of microglia in APPswe/PS1dE9 mice. Aβ may induce the M1-like phenotype through blocking of IL6 by SOCS3.

%B J Alzheimers Dis %V 55 %P 1235-1247 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27814300?dopt=Abstract %R 10.3233/JAD-160887 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Sleep Deprivation Induced Plasma Amyloid-β Transport Disturbance in Healthy Young Adults. %A Wei, Meng %A Zhao, Beiyu %A Huo, Kang %A Deng, Yongning %A Shang, Suhang %A Liu, Jie %A Li, Yanbo %A Ma, Louyan %A Jiang, Yu %A Dang, Liangjun %A Chen, Chen %A Wei, Shan %A Zhang, Juanli %A Yang, Hailei %A Gao, Fan %A Qu, Qiumin %K Adult %K Amyloid beta-Peptides %K Female %K Humans %K Low Density Lipoprotein Receptor-Related Protein-1 %K Male %K Malondialdehyde %K Peptide Fragments %K Receptor for Advanced Glycation End Products %K Sleep Deprivation %K Superoxide Dismutase %K Time Factors %K Young Adult %X

BACKGROUND: Sleep is an important physiological process and beneficial in the removal of brain metabolites and functional recovery. Prior studies have shown that sleep disorders are significant risk factors for Alzheimer's disease (AD).

OBJECTIVE: The present study was designed to characterize the effect of short-term total sleep deprivation (TSD) on plasma amyloid-β (Aβ) concentrations.

METHODS: A clinical trial was conducted between March 1, 2016, and April 1, 2016. Twenty volunteers (age 27.3±3.4 years) with normal cognitive function and sleeping habits were recruited from the local population. Participants underwent 24 h of TSD. Periprocedural blood samples were collected to compare the changes of plasma Aβ42, Aβ40, low-density lipoprotein receptor-related protein (sLRP-1), soluble receptors for advanced glycation end products (sRAGE), and serum superoxide dismutase (SOD) and malonaldehyde (MDA).

RESULTS: TSD increased morning plasma Aβ40 levels by 32.6% (p < 0.001) and decreased the Aβ42/Aβ40 ratio by 19.3% (p < 0.001). A positive relationship was found between TSD duration and plasma Aβ40 level (r = 0.51, p < 0.001) and Aβ40/Aβ42 ratio (r = 0.25, p = 0.003). Plasma concentrations of sLRP1 (p = 0.018) and sRAGE (p = 0.001) decreased significantly after TSD. Aβ40 and Aβ42 plasma concentrations correlated with plasma levels of sLRP1 and sRAGE. Serum SOD decreased after TSD (p = 0.005), whereas serum MDA was increased (p = 0.001).

CONCLUSION: Sleep deprivation can lead to an elevation of plasma Aβ40 and decrease of the Aβ42/Aβ40 ratio. The underlying mechanisms may be related to increased oxidative stress and impaired peripheral Aβ clearance as pathomechanisms of AD.

%B J Alzheimers Dis %V 57 %P 899-906 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304302?dopt=Abstract %R 10.3233/JAD-161213 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Trends, Predictors, and Outcomes of Healthcare Resources Used in Patients Hospitalized with Alzheimer's Disease with at Least One Procedure: The Nationwide Inpatient Sample. %A Beydoun, May A %A Gamaldo, Alyssa A %A Beydoun, Hind A %A Shaked, Danielle %A Zonderman, Alan B %A Eid, Shaker M %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Female %K Health Resources %K Hospitalization %K Humans %K Inpatients %K Length of Stay %K Male %K Middle Aged %K Morbidity %K Outcome Assessment (Health Care) %K Predictive Value of Tests %K United States %X

We assessed trends, predictors and outcomes of resource utilization in hospital inpatient discharges with a principal diagnosis of Alzheimer's disease (AD) with at least one procedure. Using Nationwide Inpatient Sample data (NIS, 2002-2012), discharges primarily diagnosed with AD, aged ≥60 y and with ≥1 procedure, were selected (Weighted N = 92,300). Hospital resource utilization were assessed using ICD-9-CM codes, while hospitalization outcomes included total charges (TC, 2012$), length of stay (LOS, days), and mortality risk (MR, %). Brain and respiratory/gastrointestinal procedure utilization both dropped annually by 3-7%, while cardiovascular procedures/evaluations, blood evaluations, blood transfusion, and resuscitation ("CVD/Blood") as well as neurophysiological and psychological evaluation and treatment ("Neuro") procedures increased by 5-8%. Total charges, length of stay, and mortality risk were all markedly higher with use of respiratory/gastrointestinal procedures as opposed to being reduced with use of "Brain" procedures. Procedure count was positively associated with all three hospitalization outcomes. In sum, patterns of hospital resources that were used among AD inpatients changed over-time, and were associated with hospitalization outcomes such as total charges, length of stay, and mortality risk.

%B J Alzheimers Dis %V 57 %P 813-824 %8 2017 %G eng %N 3 %R 10.3233/JAD-161225 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Triceps and Subscapular Skinfold in Men Aged 40-65 and Dementia Prevalence 36 Years Later. %A Ravona-Springer, Ramit %A Schnaider-Beeri, Michal %A Goldbourt, Uri %K Adipose Tissue %K Aged %K Anthropometry %K Arm %K Body Mass Index %K Dementia %K Exercise %K Humans %K Israel %K Leisure Activities %K Longitudinal Studies %K Male %K Middle Aged %K Muscle, Skeletal %K Obesity %K Odds Ratio %K Prevalence %K Shoulder %K Skinfold Thickness %K Social Class %X

BACKGROUND: The relationship of obesity with risk for dementia is complex and may change with age.

OBJECTIVE: To analyze the relationship between measures of obesity at age 40-65 and dementia prevalence in survivors 36 years later.

METHODS: Obesity-related measures of triceps and subscapular skinfold thickness were assessed in 1963 in n = 9,760 men aged 40-65 participating in the Israel Ischemic Heart Disease study. Cognitive evaluation and assessment of dementia prevalence were performed in n = 1,643 participants of the original cohort who survived until 1999/2000 (age ≥76 years) and had anthropometric measures in 1963.

RESULTS: Age-adjusted prevalence of dementia in survivors in 1999/2000 by baseline triceps skinfold quintile was 20.5%, 21.2%, 17.6%, 15.6%, and 14.5%, respectively, from lowest to highest (p = 0.006 in trend test). Using logistic regression, a 6-mm increment of triceps skinfold was associated with an age and BMI-adjusted odds ratio of 0.81 (95% CI, 0.70-0.94) for dementia prevalence among survivors. Age-adjusted risk for dementia by subscapular skinfold quintile demonstrated 20.5%, 17.1%, 15.7%, 19.4%, and 18.1%, respectively, in groups of subjects by subscapular skinfold quintile from lowest to highest (p = 0.6 in trend test).

CONCLUSIONS: Lower triceps skinfold at age 40-65, reflecting diminished peripheral fat, was associated with higher dementia prevalence in late life, potentially suggesting a protective role of peripheral fat to brain health.

%B J Alzheimers Dis %V 57 %P 873-883 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304287?dopt=Abstract %R 10.3233/JAD-160786 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age and its association with low insulin and high amyloid-β peptides in blood. %A Li, Huajie %A Zhu, Haihao %A Wallack, Max %A Mwamburi, Mkaya %A Abdul-Hay, Samer O %A Leissring, Malcolm A %A Qiu, Wei Qiao %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Biomarkers %K Cognition Disorders %K Cross-Sectional Studies %K Female %K Humans %K Insulin %K Islet Amyloid Polypeptide %K Linear Models %K Male %K Middle Aged %K Multivariate Analysis %K Peptide Fragments %X

Age is the major risk factor for developing Alzheimer's disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-β peptide (Aβ) in plasma were measured. We further measured the activity of serum Aβ degradation by using fluorescein- and biotin-labeled Aβ40. Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60-70, 70-80, and ≥80 years old. We found that the older the subjects, the lower the concentration of insulin (p = 0.001) and the higher the concentration of Aβ1-40 (p = 0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aβ1-42. These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aβ degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aβ40 are aging factors related to the risk of AD.

%B J Alzheimers Dis %V 49 %P 129-37 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444783?dopt=Abstract %R 10.3233/JAD-150428 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Age-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer's Disease (3xTg-AD). %A Do, Tuan Minh %A Dodacki, Agnès %A Alata, Wael %A Calon, Frederic %A Nicolic, Sophie %A Scherrmann, Jean-Michel %A Farinotti, Robert %A Bourasset, Fanchon %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K ATP Binding Cassette Transporter, Sub-Family G, Member 1 %K ATP Binding Cassette Transporter, Sub-Family G, Member 2 %K ATP-Binding Cassette Transporters %K Biological Transport %K Blood-Brain Barrier %K Brain %K Carbon Isotopes %K Cholesterol %K Disease Models, Animal %K Humans %K Lipoproteins %K Mice %K Mice, Transgenic %K P-Glycoproteins %K Peptide Fragments %K Receptors, LDL %K Sucrose %K Tritium %K Tumor Suppressor Proteins %X

The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer's disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3-18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H]cholesterol and [3H]Aβ1 - 40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Aβ through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up-regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ.

%B J Alzheimers Dis %V 49 %P 287-300 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484906?dopt=Abstract %R 10.3233/JAD-150350 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Analysis of the MIRIAD Data Shows Sex Differences in Hippocampal Atrophy Progression. %A Ardekani, Babak A %A Convit, Antonio %A Bachman, Alvin H %K Alzheimer Disease %K Atrophy %K Disease Progression %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %X

BACKGROUND: Hippocampus (HC) atrophy is a hallmark of early Alzheimer's disease (AD). Atrophy rates can be measured by high-resolution structural MRI. Longitudinal studies have previously shown sex differences in the progression of functional and cognitive deficits and rates of brain atrophy in early AD dementia. It is important to corroborate these findings on independent datasets.

OBJECTIVE: To study temporal rates of HC atrophy over a one-year period in probable AD patients and cognitively normal (CN) subjects by longitudinal MRI scans obtained from the Minimal Interval Resonance Imaging in AD (MIRIAD) database.

METHODS: We used a novel algorithm to compute an index of hippocampal (volumetric) integrity (HI) at baseline and one-year follow-up in 43 mild-moderate probable AD patients and 22 CN subjects in MIRIAD. The diagnostic power of longitudinal HI measurement was assessed using a support vector machines (SVM) classifier.

RESULTS: The HI was significantly reduced in the AD group (p <  10(-20)). In addition, the annualized percentage rate of reduction in HI was significantly greater in the AD group (p <  10(-13)). Within the AD group, the annual reduction of HI in women was significantly greater than in men (p = 0.008). The accuracy of SVM classification between AD and CN subjects was estimated to be 97% by 10-fold cross-validation.

CONCLUSION: In the MIRIAD patients with probable AD, the HC atrophies at a significantly faster rate in women as compared to men. Female sex is a risk factor for faster descent into AD. The HI measure has potential for AD diagnosis, as a biomarker of AD progression and a therapeutic target in clinical trials.

%B J Alzheimers Dis %V 50 %P 847-57 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836168?dopt=Abstract %R 10.3233/JAD-150780 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease. %A Gomar, Jesus J %A Conejero-Goldberg, Concepcion %A Davies, Peter %A Goldberg, Terry E %K Adult %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Atrophy %K Brain %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Prodromal Symptoms %K Regression Analysis %K Statistics, Nonparametric %K tau Proteins %X

BACKGROUND: The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood.

OBJECTIVE: To examine dynamic interrelationships between Aβ42 and tau in preclinical AD.

METHODS: We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18).

RESULTS: In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau.

CONCLUSIONS: The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

%B J Alzheimers Dis %V 51 %P 1085-97 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967213?dopt=Abstract %R 10.3233/JAD-150937 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Apathy and Attentional Biases in Alzheimer's Disease. %A Chau, Sarah A %A Chung, Jonathan %A Herrmann, Nathan %A Eizenman, Moshe %A Lanctôt, Krista L %K Aged %K Alzheimer Disease %K Apathy %K Attentional Bias %K Cognition %K Cross-Sectional Studies %K Emotions %K Eye Movement Measurements %K Eye Movements %K Female %K Humans %K Linear Models %K Male %K Neuropsychological Tests %K Photic Stimulation %K Severity of Illness Index %K Social Perception %X

BACKGROUND: Apathy, one of the most prevalent neuropsychiatric symptoms in Alzheimer's disease (AD), can be difficult to assess as cognition deteriorates. There is a need for more objective assessments that do not rely on patient insight, communicative capacities, or caregiver observation.

OBJECTIVE: We measured visual scanning behavior, using an eye-tracker, to explore attentional bias in the presence of competing stimuli to assess apathy in AD patients.

METHODS: Mild-to-moderate AD patients (Standardized Mini-Mental Status Examination, sMMSE >10) were assessed for apathy (Neuropsychiatric Inventory [NPI] apathy, Apathy Evaluation Scale [AES]). Participants were presented with 16 slides, each containing 4 images of different emotional themes (2 neutral, 1 social, 1 dysphoric). The duration of time spent, and fixation frequency on images were measured.

RESULTS: Of the 36 AD patients (14 females, age = 78.2±7.8, sMMSE = 22.4±3.5) included, 17 had significant apathy (based on NPI apathy ≥4) and 19 did not. These groups had comparable age and sMMSE. Repeated-measures analysis of covariance models, controlling for total NPI, showed group (apathetic versus non-apathetic) by image (social versus dysphoric) interactions for duration (F(1,32) = 4.31, p = 0.046) and fixation frequency (F(1,32) = 11.34, p = 0.002). Apathetic patients demonstrated reduced duration and fixation frequency on social images compared with non-apathetic patients. Additionally, linear regression models suggest that more severe apathy predicted decreasing fixation frequency on social images (R2 = 0.26, Adjusted R2 = 0.19, F(3,32) = 3.65, p = 0.023).

CONCLUSION: These results suggest that diminished attentional bias toward social-themed stimuli is a marker of apathy in AD. Measurements of visual scanning behavior may have the potential to predict and monitor treatment response in apathy.

%B J Alzheimers Dis %V 51 %P 837-46 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890774?dopt=Abstract %R 10.3233/JAD-151026 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Application of the IWG-2 Diagnostic Criteria for Alzheimer's Disease to the ADNI. %A Wang, Hui-Fu %A Tan, Lan %A Cao, Lei %A Zhu, Xi-Chen %A Jiang, Teng %A Tan, Meng-Shan %A Liu, Ying %A Wang, Chong %A Tsai, Richard M %A Jia, Jian-Ping %A Yu, Jin-Tai %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid Precursor Protein Secretases %K Aspartic Acid Endopeptidases %K Cognitive Dysfunction %K Databases, Factual %K Disease Progression %K Female %K Humans %K Longitudinal Studies %K Male %K Multicenter Studies as Topic %K Neuroimaging %K Psychiatric Status Rating Scales %K tau Proteins %X

BACKGROUND: The International Working Group (IWG) recently proposed the revised diagnostic criteria for Alzheimer's disease (AD) to define and refine several types of AD, and to reclassify AD-related biomarkers into diagnostic and progression markers, but its performance is not known.

OBJECTIVE: This study was designed to describe the application of the revised IWG criteria in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and to ascertain whether diagnostic and progression markers show significant differences in their relationships to AD severity and progression.

METHODS: Based on the requirements of the refined criteria, 857 ADNI subjects with memory evaluation and at least one pathophysiological marker (CSF or amyloid imaging biomarkers) were eligible and reclassified in this study, and we calculated the associations of diagnostic (CSF and amyloid PET) and progression markers (MRI and fluorodeoxyglucose-PET) with AD severity and progression respectively.

RESULTS: The majority (84.2% ) of ADNI AD group (n = 117) and 173 MCI (37.4% ) subjects in ADNI met the definition of typical AD; and 105 cognitively normal (41.0% ) individuals were diagnosed as asymptomatic AD. Furthermore, diagnostic and progression markers showed significant differences when correlated to AD severity and progression.

CONCLUSION: A large proportion of AD dementia subjects were categorized as typical AD, and the revised criteria could identify typical AD from MCI status as well as asymptomatic AD at the asymptomatic stage. Moreover, the significant differences between diagnostic and progression markers further supported the new biomarkers categorization in the refined criteria.

%B J Alzheimers Dis %V 51 %P 227-36 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836176?dopt=Abstract %R 10.3233/JAD-150824 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association Between Serum Ceruloplasmin Specific Activity and Risk of Alzheimer's Disease. %A Siotto, Mariacristina %A Simonelli, Ilaria %A Pasqualetti, Patrizio %A Mariani, Stefania %A Caprara, Deborah %A Bucossi, Serena %A Ventriglia, Mariacarla %A Molinario, Rossana %A Antenucci, Mirca %A Rongioletti, Mauro %A Rossini, Paolo Maria %A Squitti, Rosanna %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Area Under Curve %K Biomarkers %K Blood Chemical Analysis %K Ceruloplasmin %K Copper %K Female %K Genotype %K Genotyping Techniques %K Humans %K Logistic Models %K Male %K Multivariate Analysis %K Prognosis %K Risk %K ROC Curve %K Sensitivity and Specificity %K Transferrin %X

Meta-analyses demonstrate copper involvement in Alzheimer's disease (AD), and the systemic ceruloplasmin status in relation to copper is an emerging issue. To deepen this matter, we evaluated levels of ceruloplasmin concentration, ceruloplasmin activity, ceruloplasmin specific activity (eCp/iCp), copper, non-ceruloplasmin copper iron, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype in a sample of 84 AD patients and 58 healthy volunteers. From the univariate logistic analyses we found that ceruloplasmin concentration, eCp/iCp, copper, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype were significantly associated with the probability of AD. In the multivariable logistic regression analysis, we selected the best subset of biological predictors by the forward stepwise procedure. The analysis showed a decrease of the risk of having AD for eCp/iCp (p = 0.001) and an increase of this risk for non-ceruloplasmin copper (p = 0.008), age (p = 0.001), and APOE-ɛ4 allele (p <  0.001). The estimated model showed a good power in discriminating AD patients from healthy controls (area under curve: 88% ; sensitivity: 66% ; specificity 93%). These data strength the breakdown of copper homeostasis and propose eCp/iCp as a reliable marker of ceruloplasmin status.

%B J Alzheimers Dis %V 50 %P 1181-9 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836154?dopt=Abstract %R 10.3233/JAD-150611 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Butyrylcholinesterase-K Allele and Apolipoprotein E ɛ4 Allele with Cognitive Decline in Dementia with Lewy Bodies and Alzheimer's Disease. %A Vijayaraghavan, Swetha %A Darreh-Shori, Taher %A Rongve, Arvid %A Berge, Guro %A Sando, Sigrid B %A White, Linda R %A Auestad, Bjørn H %A Witoelar, Aree %A Andreassen, Ole A %A Ulstein, Ingun D %A Aarsland, Dag %K Aged %K Aged, 80 and over %K Alleles %K Alzheimer Disease %K Apolipoprotein E4 %K Butyrylcholinesterase %K Cognition %K Disease Progression %K Female %K Gene Frequency %K Genotype %K Humans %K Lewy Body Disease %K Male %K Neuropsychological Tests %X

BACKGROUND: A common polymorphism of the butyrylcholinesterase gene, the K-variant (BCHE-K) is associated with reduced butyrylcholinesterase (BuChE) activity. Insufficient studies exist regarding the frequency and role of BCHE-K in dementias.

OBJECTIVE: To determine the association of BCHE-K and APOEɛ4 with diagnosis and rate of cognitive decline in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients.

METHODS: Genomic DNA from 368 subjects (108 AD, 174 DLB, and 86 controls) from two routine clinical cohort studies in Norway; DemVest and TrønderBrain, were genotyped for BCHE-K and APOEɛ4. The mild dementia DemVest subjects received annual Mini-Mental State Examination assessments for five years.

RESULTS: BCHE-K frequency was lower in DLB (33.9% ; p <  0.01) than in control subjects (51.2%), and was numerically lower in AD as well (38.9% ; p = 0.11). More rapid cognitive decline was associated with the APOEɛ4 genotype, but not with the BCHE-K genotype. In an exploratory analysis of patients who completed all five follow-up visits, there was greater cognitive decline in BCHE-K carriers in the presence of the APOEɛ4 allele than in the absence of these polymorphisms.

CONCLUSION: BCHE-K is associated with a reduced risk for AD and DLB whereas APOEɛ4 is associated with more rapid cognitive decline. The greater cognitive decline in individuals with both APOEɛ4 and BCHE-K alleles require prospective confirmation in well-controlled trials.

%B J Alzheimers Dis %V 50 %P 567-76 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757188?dopt=Abstract %R 10.3233/JAD-150750 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Frontotemporal Dementia GWAS Loci with Late-Onset Alzheimer's Disease in a Northern Han Chinese Population. %A Tan, Chen-Chen %A Wan, Yu %A Tan, Meng-Shan %A Zhang, Wei %A Wang, Zi-Xuan %A Sun, Fu-Rong %A Miao, Dan %A Tan, Lan %A Yu, Jin-Tai %K Age of Onset %K Aged %K Alzheimer Disease %K Apolipoprotein E4 %K Asian Continental Ancestry Group %K Case-Control Studies %K China %K Female %K Frontotemporal Dementia %K Gene Frequency %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Genotyping Techniques %K Humans %K Linkage Disequilibrium %K Male %K Mental Status Schedule %K Polymorphism, Single Nucleotide %X

BACKGROUND: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are a class of neurodegenerative diseases. Strong similarities in cerebrospinal fluid biomarker, imaging markers, and disease progression profiles suggest that some or most of the pathophysiology is shared between AD and FTD. A recent large genome-wide association study reported several single nucleotide polymorphisms (SNPs) at the RAB38, RAB38/CTSC, HLA-DRA/HLA-DRB5, and BTNL2 in association with FTD.

OBJECTIVE: To explore whether these SNPs are associated with AD risk.

METHODS: We conducted a case-control study to investigate the association of FTD-associated loci in 2338 Han Chinese subjects.

RESULTS: We observed significant differences in genotype distributions of rs302668 (pc = 0.025), rs9268877 (pc = 0.025), rs9268856 (p <  0.001), and rs1980493 (pc = 0.045) between cases and controls. The SNPs rs16913634 for RAB38/CTSC was unrelated to LOAD risk (p = 0.088).

CONCLUSION: The SNPs rs302668 in RAB38, rs9268877 and rs9268856 polymorphism in HLA-DRA/HLA-DRB5, and rs1980493 polymorphism in BTNL2 might play a role in the susceptibility to late-onset AD in the Han Chinese population.

%B J Alzheimers Dis %V 52 %P 43-50 %8 2016 02 26 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967218?dopt=Abstract %R 10.3233/JAD-151073 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Associations between Serum Omega-3 Fatty Acid Levels and Cognitive Functions among Community-Dwelling Octogenarians in Okinawa, Japan: The KOCOA Study. %A Nishihira, Junko %A Tokashiki, Takashi %A Higashiuesato, Yasushi %A Willcox, Donald Craig %A Mattek, Nora %A Shinto, Lynne %A Ohya, Yusuke %A Dodge, Hiroko H %K Age Factors %K Aged, 80 and over %K Arachidonic Acid %K Blood Chemical Analysis %K Cognition %K Cross-Sectional Studies %K Educational Status %K Fatty Acids, Omega-3 %K Female %K Humans %K Japan %K Logistic Models %K Male %K Mental Status Schedule %K Obesity %K Prospective Studies %K Sex Factors %X

BACKGROUND: Epidemiological studies have found frequent consumption of fatty fish is protective against cognitive decline. However, the association between circulating omega-3 polyunsaturated fatty acid (PUFA) levels and cognitive functions among the oldest old is not well known.

OBJECTIVE: To examine the association between serum PUFA levels and cognitive function among community-dwelling, non-demented elderly aged over 80 years old.

METHODS: The data came from the Keys to Optimal Cognitive Aging (KOCOA) study; an ongoing cohort of relatively healthy volunteers aged over 80 years old, living in Okinawa, Japan. One hundred eighty five participants (mean age 84.1±3.4 years) assessed in 2011 who were free from frank dementia (defined as Clinical Dementia Rating <1.0) were used for the current cross-sectional study. We examined whether serum omega-3 PUFAs (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), arachidonic acid (AA), EPA/AA ratio, DHA/AA ratio, and DHA+EPA are associated with (1) age and (2) global cognitive function (Japanese MMSE) and executive function (Verbal Fluency Letter). Data was analyzed univariately by t-test and multivariately by cumulative logistic regression models controlling for age, gender, years of education, obesity, hypertension, diabetes, and dyslipidemia.

RESULTS: Serum DHA levels decreased with increasing age (p = 0.04). Higher global cognitive function was associated with higher levels of serum EPA (p = 0.03) and DHA + EPA (p = 0.03) after controlling for confounders.

CONCLUSIONS: Higher serum EPA and DHA + EPA levels were independently associated with better scores on global cognitive function among the oldest old, free from dementia. Longitudinal follow-up studies are warranted.

%B J Alzheimers Dis %V 51 %P 857-66 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890763?dopt=Abstract %R 10.3233/JAD-150910 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Biomarkers Differentiating Dementia with Lewy Bodies from Other Dementias: A Meta-Analysis. %A Mishima, Aki %A Nihashi, Takashi %A Ando, Yoshio %A Kawai, Hisashi %A Kato, Takashi %A Ito, Kengo %A Terasawa, Teruhiko %K Biomarkers %K Dementia %K Diagnosis, Differential %K Humans %K Lewy Bodies %K PubMed %K Radionuclide Imaging %K Retrospective Studies %X

BACKGROUND: Several nuclear imaging and cerebrospinal fluid (CSF) biomarkers are under investigation, aimed at facilitating the differential diagnosis of dementias.

OBJECTIVE: To quantitatively synthesize data on test performance in differentiating dementia with Lewy bodies (DLB) from other dementias.

METHODS: We searched PubMed (January 2000- March 2015) for English-language publications that assessed a selected set of five imaging and three CSF biomarkers for this purpose. We meta-analyzed measures of agreement between biomarker results and clinical diagnosis.

RESULTS: Forty-five publications were eligible. The majority of evidence was based on studies that enrolled representative disease populations. For differentiating between DLB and Alzheimer's disease (AD) or other dementias, metaiodobenzylguanidine scintigraphy and dopamine transporter (DAT) single photon emission computed tomography (SPECT) showed, respectively, excellent (summary kappa = 0.85; 95% confidence interval [95% CI], 0.74-0.96) and good (summary kappa = 0.71; 95% CI, 0.43-0.99) agreement. Metaiodobenzylguanidine scintigraphy appeared superior to fluorodeoxyglucose- positron emission tomography (summary kappa = 0.53; 95% CI, 0.36-0.69) and cerebral blood flow SPECT (summary kappa = 0.40; 95% CI, 0.33-0.47). For differentiating DLB from AD, CSF t-tau levels (summary kappa = 0.68; 95% CI, 0.55-0.82) performed comparably to metaiodobenzylguanidine scintigraphy and DAT SPECT. Sparse direct comparative evidence failed to corroborate these indirect comparisons.

CONCLUSION: Metaiodobenzylguanidine scintigraphy and DAT SPECT are highly concordant with clinical diagnosis in differentiating DLB from other dementias. However, given the limitations in the study design, the applicability of these results to real-world differential diagnosis remains unclear. Prospective studies targeting patients with atypical presentations that adopt gold standard tests would reliably estimate the true test performance of these promising biomarkers.

%B J Alzheimers Dis %V 50 %P 161-74 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639967?dopt=Abstract %R 10.3233/JAD-150675 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Bridging Integrator 1 (BIN1) Genotypes Mediate Alzheimer's Disease Risk by Altering Neuronal Degeneration. %A Wang, Hui-Fu %A Wan, Yu %A Hao, Xiao-Ke %A Cao, Lei %A Zhu, Xi-Chen %A Jiang, Teng %A Tan, Meng-Shan %A Tan, Lin %A Zhang, Dao-Qiang %A Tan, Lan %A Yu, Jin-Tai %K Adaptor Proteins, Signal Transducing %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Brain %K Databases, Factual %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Glucose %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Nerve Degeneration %K Nuclear Proteins %K Polymorphism, Single Nucleotide %K Positron-Emission Tomography %K Risk %K tau Proteins %K Tumor Suppressor Proteins %X

BACKGROUND: Bridging integrator 1 (BIN1) has been identified as one of the most associated loci for Alzheimer's disease (AD), and recently was reported to modulate tau pathology to mediate AD in vitro. However, the effects of BIN1 on the AD related biomarkers in AD continuum were not specifically assessed.

OBJECTIVE: We explored the effects of BIN1 loci on AD specific biomarkers (CSF proteins, brain structures, glucose and amyloid-β (Aβ) metabolisms) to investigate the role BIN1 in AD pathogenesis.

METHODS: We calculated the associations of BIN1 loci with these markers at baseline and follow-up in multiple linear models in 812 ADNI subjects.

RESULTS: BIN1 loci were significantly associated with the levels of T-tau (rs744373: pc = 0.047, rs13031703: pc = 0.042) and P-tau (rs744373: pc = 0.044, rs13031703: pc = 0.019), but not with Aβ in CSF test. BIN1 genotypes were strongly related to atrophy of hippocampus (rs7561528: pc = 0.011), CA1 (rs1469980: pc = 0.029) and parahippocampus (rs72838284, pc = 0.017) on MRI, and to glucose metabolism on FDG-PET, but not to Aβ deposition on AV45-PET imaging. Furthermore, haplotype and subgroup analysis confirmed these significant findings. In addition, the loci associated with these markers were also identified to influence the risk for AD in the meta-analysis of 74 046 European individuals.

CONCLUSION: This study supported that BIN1 contributes to the risk of AD by altering neural degeneration (abnormal tau, brain atrophy and glucose metabolism) but not Aβ pathology.

%B J Alzheimers Dis %V 52 %P 179-90 %8 2016 03 15 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003210?dopt=Abstract %R 10.3233/JAD-150972 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Capillary amyloid-β protein deposition in a population-based study (Vantaa 85+). %A Mäkelä, Mira %A Paetau, Anders %A Polvikoski, Tuomo %A Myllykangas, Liisa %A Tanskanen, Maarit %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoprotein E4 %K Autopsy %K Capillaries %K Cerebral Amyloid Angiopathy %K Female %K Finland %K Genotype %K Humans %K Immunohistochemistry %K Logistic Models %K Male %K Multivariate Analysis %K Occipital Lobe %K Prospective Studies %K Severity of Illness Index %X

BACKGROUND: Capillary amyloid-β (capAβ) deposition in the cerebral cortex is the neuropathological feature providing the basis for categorizing cerebral amyloid angiopathy (CAA) into two distinct types, CAA-Type1 with capAβ and CAA-Type2 without capAβ.

OBJECTIVE: We investigated the neuropathological and clinical characteristics of capAβ deposition in a prospective population-based study.

METHODS: Vantaa 85+ includes 601 individuals aged ≥85 years, of which 300 were studied clinically and neuropathologically. 278 subjects were analyzed for the apolipoprotein E (APOE) genotype. The diagnosis of capAβ was determined using immunohistochemistry against Aβ, and of CAA using Congo red confirmed by Aβ immunohistochemistry, both analyzed in six brain areas. The severity of capAβ was graded semi-quantitatively, and the severity of CAA was based on the percentage of affected vessels. Alzheimer's disease (AD)-type neuropathology (CERAD score and Braak stage) was analyzed using standard methods.

RESULTS: CAA-Type1 was present in 86/300, CAA-Type2 in 135/300, and 79/300 had no CAA. CapAβ was most frequent in the occipital lobe (79/86). CAA-Type1 was associated with the severity of CAA (p <  0.001), dementia (p <  0.001), severe AD-type neuropathology (p-value 0.09 for CERAD C and 0.017 for Braak stages V-VI), and APOE ɛ4 allele carrier status (p <  0.001).

CONCLUSIONS: This population-based study confirmed the presence of distinct CAA-Type1 and its association with the severity of CAA, severe AD-type neuropathology, and the APOE ɛ4 carrier status. Both the severity and localization of the deposition seemed to determine the clinical significance of capAβ.

%B J Alzheimers Dis %V 49 %P 149-57 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444758?dopt=Abstract %R 10.3233/JAD-150241 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Fatty Acid-Binding Protein 3 is Related to Dementia Development in a Population-Based Sample of Older Adult Women Followed for 8 Years. %A Bjerke, Maria %A Kern, Silke %A Blennow, Kaj %A Zetterberg, Henrik %A Waern, Margda %A Börjesson-Hanson, Anne %A Östling, Svante %A Kern, Jürgen %A Skoog, Ingmar %K Aged %K Aged, 80 and over %K Albumins %K Amyloid beta-Peptides %K Community Health Planning %K Dementia %K Fatty Acid-Binding Proteins %K Female %K Humans %K Longitudinal Studies %K Peptide Fragments %K Sweden %K tau Proteins %X

BACKGROUND: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer's disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking.

OBJECTIVE: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Aβ42, T-tau, P-tau181, and CSF: serum albumin ratio.

METHODS: 86 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-93. CSF-FABP-3, Aβ42, T-tau, P-tau181, and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria.

RESULTS: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05-1.76] p = 0.022) and the subtype AD (OR 1.38 CI [1.06-1.82), p = 0.019) during follow-up. FABP-3 correlated with CSF T-tau (r = 0.88, p <  0.001), P-tau181 (r = 0.619, p <  0.001), and CSF:serum albumin ratio (r = 0.233, p = 0.031), but not with Aβ42 (r = -0.08, p = 0.444)CONCLUSION:CSF FABP-3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Aβ metabolism.

%B J Alzheimers Dis %V 49 %P 733-41 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484922?dopt=Abstract %R 10.3233/JAD-150525 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebrospinal Fluid Markers of Alzheimer's Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer's Disease. %A Melah, Kelsey E %A Lu, Sharon Yuan-Fu %A Hoscheidt, Siobhan M %A Alexander, Andrew L %A Adluru, Nagesh %A Destiche, Daniel J %A Carlsson, Cynthia M %A Zetterberg, Henrik %A Blennow, Kaj %A Okonkwo, Ozioma C %A Gleason, Carey E %A Dowling, N Maritza %A Bratzke, Lisa C %A Rowley, Howard A %A Sager, Mark A %A Asthana, Sanjay %A Johnson, Sterling C %A Bendlin, Barbara B %K Adipokines %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Chemokine CCL2 %K Chitinase-3-Like Protein 1 %K Diffusion Tensor Imaging %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Lectins %K Male %K Microglia %K Middle Aged %K Peptide Fragments %K tau Proteins %K White Matter %X

BACKGROUND: The immune response in Alzheimer's disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown.

OBJECTIVE: To determine whether neuroinflammation exacerbates neural damage in preclinical AD.

METHODS: We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age = 60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI.

RESULTS: Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus.

CONCLUSION: Inflammation may play a role in neural damage in preclinical AD.

%B J Alzheimers Dis %V 50 %P 873-86 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836182?dopt=Abstract %R 10.3233/JAD-150897 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer's Disease. %A Novak, Gerald %A Fox, Nick %A Clegg, Shona %A Nielsen, Casper %A Einstein, Steven %A Lu, Yuan %A Tudor, Iulia Cristina %A Gregg, Keith %A Di, Jianing %A Collins, Peter %A Wyman, Bradley T %A Yuen, Eric %A Grundman, Michael %A Brashear, H Robert %A Liu, Enchi %K Aged %K Alzheimer Disease %K Antibodies, Monoclonal, Humanized %K Apolipoprotein E4 %K Brain %K Double-Blind Method %K Female %K Heterozygote %K Humans %K Least-Squares Analysis %K Magnetic Resonance Imaging %K Male %K Nootropic Agents %K Organ Size %K Severity of Illness Index %K Treatment Outcome %X

BACKGROUND: Bapineuzumab, an anti-amyloid-β monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*ɛ4 carriers and noncarriers, respectively, with Alzheimer's disease.

OBJECTIVES: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change.

METHODS: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures.

RESULTS: For BBSI and HBSI, there were no significant treatment-related differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers.

CONCLUSIONS: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-β clearance or its consequences.

%B J Alzheimers Dis %V 49 %P 1123-34 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639957?dopt=Abstract %R 10.3233/JAD-150448 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Chronic Sleep Deprivation Exacerbates Learning-Memory Disability and Alzheimer's Disease-Like Pathologies in AβPP(swe)/PS1(ΔE9) Mice. %A Qiu, Hongyan %A Zhong, Rujia %A Liu, Hui %A Zhang, Feng %A Li, Song %A Le, Weidong %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Apoptosis %K Brain %K Cognition Disorders %K Disease Models, Animal %K Humans %K In Situ Nick-End Labeling %K Learning Disorders %K Mice %K Mice, Transgenic %K Mitochondrial Diseases %K Mutation %K Phosphorylation %K Plaque, Amyloid %K Presenilin-1 %K Reversal Learning %K Sleep Deprivation %K tau Proteins %X

Recently, there is an increasing concern over the association between sleep disorders and Alzheimer's disease (AD). Clinical observations have reported that chronic sleep deprivation (SD) may serve as a risk factor for AD. However, the pathological evidence for this assumption is still lacking. In the present study, we examined the potential impacts of chronic SD on learning-memory and AD-related pathologies in AβPP(swe)/PS1(ΔE9) transgenic (TG) mice and their wild-type (WT) littermates. Results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-β protein precursor processing, an elevated level of phosphorylated tau protein, and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-β(1-42) production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic SD is a risk factor for AD.

%B J Alzheimers Dis %V 50 %P 669-85 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757041?dopt=Abstract %R 10.3233/JAD-150774 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cigarette Smoke-Induced Alterations in Frontal White Matter Lipid Profiles Demonstrated by MALDI-Imaging Mass Spectrometry: Relevance to Alzheimer's Disease. %A Nunez, Kavin %A Kay, Jared %A Krotow, Alexander %A Tong, Ming %A Agarwal, Amit R %A Cadenas, Enrique %A de la Monte, Suzanne M %K Aldehydes %K Analysis of Variance %K Animals %K Dinoprost %K Disease Models, Animal %K Enzyme-Linked Immunosorbent Assay %K Frontal Lobe %K Lipid Metabolism %K Male %K Mice %K Phospholipids %K Principal Component Analysis %K Protein Carbonylation %K Smoking %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %K Substance Withdrawal Syndrome %K White Matter %X

BACKGROUND: Meta-analysis has shown that smokers have significantly increased risks for Alzheimer's disease (AD), and neuroimaging studies showed that smoking alters white matter (WM) structural integrity.

OBJECTIVE: Herein, we characterize the effects of cigarette smoke (CS) exposures and withdrawal on WM myelin lipid composition using matrix assisted laser desorption and ionization-imaging mass spectrometry (MALDI-IMS).

METHODS: Young adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). Frontal lobe WM was examined for indices of lipid and protein oxidation and lipid profile alterations by MALDI-IMS. Lipid ions were identified by MS/MS with the LIPID MAPS prediction tools database. Inter-group comparisons were made using principal component analysis and R-generated heatmap.

RESULTS: CS increased lipid and protein adducts such that higher levels were present in CS8 compared with CS4 samples. CS8 + R reversed CS8 effects and normalized the levels of oxidative stress. MALDI-IMS demonstrated striking CS-associated alterations in WM lipid profiles characterized by either reductions or increases in phospholipids (phosphatidylinositol, phosphatidylserine, phosphatidylcholine, or phosphatidylethanolamine) and sphingolipids (sulfatides), and partial reversal of CS's inhibitory effects with recovery. The heatmap hierarchical dendrogram and PCA distinguished CS exposure, duration, and withdrawal effects on WM lipid profiles.

CONCLUSION: CS-mediated WM degeneration is associated with lipid peroxidation, protein oxidative injury, and alterations in myelin lipid composition, including shifts in phospholipids and sphingolipids needed for membrane integrity, plasticity, and intracellular signaling. Future goals are to delineate WM abnormalities in AD using MALDI-IMS, and couple the findings with MRI-mass spectroscopy to improve in vivo diagnostics and early detection of brain biochemical responses to treatment.

%B J Alzheimers Dis %V 51 %P 151-63 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836183?dopt=Abstract %R 10.3233/JAD-150916 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Clinical utility of the informant AD8 as a dementia case finding instrument in primary healthcare. %A Chan, Qun Lin %A Xu, Xin %A Shaik, Muhammad Amin %A Chong, Steven Shih Tsze %A Hui, Richard Jor Yeong %A Chen, Christopher Li-Hsian %A Dong, YanHong %K Aged %K Aged, 80 and over %K Dementia %K Female %K Humans %K Language %K Logistic Models %K Male %K Mass Screening %K Middle Aged %K Neuropsychological Tests %K Primary Health Care %K Reproducibility of Results %K ROC Curve %K Sensitivity and Specificity %K Singapore %K Surveys and Questionnaires %X

The informant AD8 has excellent discriminant ability for dementia case finding in tertiary healthcare settings. However, its clinical utility for dementia case finding at the forefront of dementia management, primary healthcare, is unknown. Therefore, we recruited participants from two primary healthcare centers in Singapore and measured their performance on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and a local formal neuropsychological battery, in addition to the AD8. Logistic regression was conducted to examine the associations between demographic factors and dementia. Area under the receiver operating characteristics (ROC) curve analysis was used to establish the optimal cut-off points for dementia case finding. Of the 309 participants recruited, 243 (78.7%) had CDR = 0, 22 (7.1%) CDR = 0.5, and 44 (14.2%) CDR ≥1. Age was strongly associated with dementia, and the optimal age for dementia case finding in primary healthcare settings was ≥75 years. In this age group, the AD8 has excellent dementia case finding capability and was superior to the MMSE and equivalent to the MoCA [AD8 AUC (95% CI): 0.95 (0.91-0.99), cut-off: ≥3, sensitivity: 0.90, specificity: 0.88, PPV: 0.79 and NPV: 0.94; MMSE AUC (95% CI): 0.87 (0.79-0.94), p = 0.04; MoCA AUC (95% CI): 0.88 (0.82-0.95), p = 0.06]. In conclusion, the AD8 is well suited for dementia case finding in primary healthcare settings.

%B J Alzheimers Dis %V 49 %P 121-7 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444776?dopt=Abstract %R 10.3233/JAD-150390 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Impairment after Mild Stroke: Development and Validation of the SIGNAL2 Risk Score. %A Kandiah, Nagaendran %A Chander, Russell Jude %A Lin, Xuling %A Ng, Aloysius %A Poh, Yen Yeong %A Cheong, Chin Yee %A Cenina, Alvin Rae %A Assam, Pryseley Nkouibert %K Aged %K Aging %K Area Under Curve %K Brain %K Brain Ischemia %K Cognition Disorders %K Constriction, Pathologic %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Logistic Models %K Male %K Middle Aged %K Prospective Studies %K Retrospective Studies %K Risk %K Severity of Illness Index %K Stroke %K White Matter %X

BACKGROUND: Post stroke cognitive impairment (PSCI), an important complication of strokes, has numerous risk factors. A scale adequately classifying risk of cognitive impairment 3-6 months after mild stroke will be useful for clinicians.

OBJECTIVE: To develop a risk score based on clinical and neuroimaging variables that will be useful in identifying mild ischemic stroke patients at high risk for PSCI.

METHODS: The risk score development cohort comprised of a retrospective dataset of 209 mild stroke patients with MRI confirmed infarcts, without pre-stroke cognitive impairment, and evaluated within 6 months post-stroke for PSCI. Logistic regression identified factors predictive of PSCI and a risk score was developed based on regression coefficients. The risk score was checked for stability using 10-fold cross-validation and validated in an independent prospective cohort of 185 ischemic mild stroke patients.

RESULTS: Within 6 months post-stroke, 37.32% developed PSCI in the retrospective dataset. A 15-point risk score based on age, education, acute cortical infarcts, white matter hyperintensity, chronic lacunes, global cortical atrophy, and intracranial large vessel stenosis was highly predictive of PSCI with an AUC of 0.829. 10.11% with low scores, 52.69% with moderate scores, and 74.07% with high scores developed PSCI. In the prospective validation cohort, the model had an AUC of 0.776, and exhibited similar accuracy and stability statistics at both 6 and 12 months.

CONCLUSION: The seven item risk score adequately identified mild stroke patients who are at an increased risk of developing PSCI.

%B J Alzheimers Dis %V 49 %P 1169-77 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599056?dopt=Abstract %R 10.3233/JAD-150736 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Profile and its Association with Neuroimaging Markers of Non-Demented Cerebral Amyloid Angiopathy Patients in a Stroke Unit. %A Xiong, Li %A Davidsdottir, Sigurros %A Reijmer, Yael D %A Shoamanesh, Ashkan %A Roongpiboonsopit, Duangnapa %A Thanprasertsuk, Sekh %A Martinez-Ramirez, Sergi %A Charidimou, Andreas %A Ayres, Alison M %A Fotiadis, Panagiotis %A Gurol, Edip %A Blacker, Deborah L %A Greenberg, Steven M %A Viswanathan, Anand %K Aged %K Atrophy %K Brain %K Cerebral Amyloid Angiopathy %K Cognition %K Cognition Disorders %K Female %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Stroke %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a cause of cognitive impairment in the elderly, but the cognitive profile in patients with the disease has not been well characterized.

OBJECTIVE: To characterize the neuropsychological profile of CAA patients without dementia and to determine the association between cognitive performance in different domains and neuroimaging lesions characteristic of CAA.

METHODS: Fifty-eight non-demented CAA patients were compared to 138 cognitively normal subjects using a standard neuropsychological test battery. Total brain volume (TBV), white matter hyperintensities, number of lobar cerebral microbleeds, hippocampal volume, and cortical superficial siderosis in all CAA patients were assessed. The association between these neuroimaging markers and neuropsychological performance in different cognitive domains in the CAA group were analyzed.

RESULTS: Patients with CAA had significantly worse performance on all individual neuropsychological domains tested, when compared to the cognitive normal group. The cognitive decline of CAA patients was most noticeable in tests for processing speed with a Z score of -1.92±1.56 (mean±SD), then followed by executive function (-0.93±1.01), episodic memory (-0.87±1.29), semantic fluency (-0.73±1.06), and attention (-0.42±0.98). TBV of the CAA patients was correlated with processing speed (β= 0.335, p = 0.03) and executive function (β= 0.394, p = 0.01).

CONCLUSIONS: Non-demented patients with CAA had cognitive deficits in multiple areas. Lower TBV was related to slower processing speed and worse executive function.

%B J Alzheimers Dis %V 52 %P 171-8 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060947?dopt=Abstract %R 10.3233/JAD-150890 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Concanavalin agglutinin levels are decreased in peripheral blood of Alzheimer's disease patients. %A Sun, Xuying %A Ma, Ronghong %A Yao, Xiuqing %A Shang, Xiaoling %A Wang, Qun %A Wang, Jian-Zhi %A Liu, Gongping %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Case-Control Studies %K Concanavalin A %K Female %K Humans %K Lectins %K Male %K Plant Lectins %X

Alzheimer's disease (AD) seriously threatens patients' lives and causes severe burden to the families. Early prevention and treatment can alleviate the development of the disease; therefore it is important to find new effective and non-traumatic biomarkers for early diagnosis. In this study, peripheral blood samples were collected from 24 AD patients and the same number of age- and gender-matched control subjects. Lectin reactive glycosylation levels including beta-D-galactosyl ricinus communis agglutinin 120 (RCA), peanut agglutinin (PNA), concanavalin agglutinin (Con A), alpha-L-fucosyl ulex europeus agglutinin (UEA), dolichos biflorus agglutinin (DBA), and galanthus nivalis (GNL), in the red blood cells of peripheral blood were examined by western blotting. We found that lectin levels were altered with aging and gender; some lectin levels were different between AD patients and the control subjects. Only Con A levels were significantly decreased in AD patients compared to age-matched control subjects. These results suggest that Con A levels in peripheral blood may be a potent diagnostic marker for AD.

%B J Alzheimers Dis %V 49 %P 63-72 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444791?dopt=Abstract %R 10.3233/JAD-150539 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Course and Determinants of Anosognosia in Alzheimer's Disease: A 12-Month Follow-up. %A Turró-Garriga, Oriol %A Garre-Olmo, Josep %A Calvó-Perxas, Laia %A Reñé-Ramírez, Ramón %A Gascón-Bayarri, Jordi %A Conde-Sala, Josep Lluís %K Age Factors %K Aged %K Agnosia %K Alzheimer Disease %K Disability Evaluation %K Disease Progression %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Incidence %K Logistic Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Prevalence %K Prospective Studies %K Risk Factors %K Severity of Illness Index %X

Anosognosia in Alzheimer's disease (AD) has been associated with greater cognitive impairment and more behavioural and psychological symptoms of dementia (BPSD). This study examines the incidence, persistence, and remission rates of anosognosia over a 12-month period, as well as the related risk factors. This was an observational 12-month prospective study. The longitudinal sample comprised 177 patients with mild or moderate AD, and their respective caregivers. Anosognosia was assessed using the Anosognosia Questionnaire in Dementia, and we also evaluated cognitive status (Mini-Mental State Examination), functional disability (Disability Assessment in Dementia), and the presence of BPSD (Neuropsychiatric Inventory). Multinomial logistic regression was used to determine the variables associated with the incidence, persistence and remission of anosognosia. The prevalence of anosognosia was 39.5% (95% CI = 32.1-47.1) at baseline. At 12 months, incidence was 38.3% (95% CI = 28.6-48.0), persistence was 80.0% (95% CI = 69.9-90.1) and remission was 20.0% (95% CI = 9.9-30.1). The regression model identified lower age, more education, and the presence of delusions as variables associated with incidence, and more education, lower instrumental DAD score, and disinhibition as variables associated with persistence. No variables were associated with remission (n = 14). The presence of anosognosia in AD patients is high. Education and certain neuropsychiatric symptoms may explain a greater and earlier incidence of anosognosia. However, anosognosia also increases with greater cognitive impairment and disease severity.

%B J Alzheimers Dis %V 51 %P 357-66 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890611?dopt=Abstract %R 10.3233/JAD-150706 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Depressive Symptoms and Small Hippocampal Volume Accelerate the Progression to Dementia from Mild Cognitive Impairment. %A Chung, Jun Ku %A Plitman, Eric %A Nakajima, Shinichiro %A Chakravarty, M Mallar %A Caravaggio, Fernando %A Takeuchi, Hiroyoshi %A Gerretsen, Philip %A Iwata, Yusuke %A Patel, Raihaan %A Mulsant, Benoit H %A Graff-Guerrero, Ariel %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Dementia %K Depression %K Disease Progression %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Psychiatric Status Rating Scales %X

Previous studies have highlighted that decreased hippocampal volume, an early neural correlate of dementia, is commonly observed in patients with mild cognitive impairment (MCI). However, it is unclear whether neurodegenerative and resultant clinical trajectories are accelerated in MCI patients with concomitant depressive symptoms, leading to a faster conversion to dementia stages than those who are not depressed. No longitudinal study has investigated whether depressed amnestic MCI (DEP+aMCI) patients show an earlier onset of progression to dementia than non-depressed amnestic MCI (DEP-aMCI) patients and whether progressive hippocampal volume reductions are related in the conversion process. Using data from Alzheimer's Disease Neuroimaging Initiative, we examined 2-year follow-up data from 38 DEP+aMCI patients and 38 matched DEP-aMCI patients and compared their ages of conversion from aMCI to AD and trajectories of progressive hippocampal volume changes. DEP+ and DEP- patients were defined as having baseline Geriatric Depression Scale scores of 5 or above and 0, respectively. DEP+ converters showed earlier ages of conversion to dementia (p = 0.009) and greater left hippocampal volume loss than both DEP- converters and DEP+ non-converters over the 2-year period (p = 0.003, p = 0.001, respectively). These findings could not be explained by changes in total brain volume, differences in their clinical symptoms of dementia, daily functioning, or apolipoprotein E4 genotypes. No difference in conversion rate to dementia or progressive hippocampal volume change was found between DEP+ patients and DEP-patients, which suggested depressive symptoms themselves may not lead to progression of dementia from MCI. In conclusion, there is a synergistic effect of depressive symptoms and smaller left hippocampal volume in MCI patients that accelerates conversion to dementia.

%B J Alzheimers Dis %V 49 %P 743-54 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519442?dopt=Abstract %R 10.3233/JAD-150679 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Diagnostic Value of Cerebrospinal Fluid Biomarkers (Phospho-Tau181, total-Tau, Aβ42, and Aβ40) in Prodromal Stage of Alzheimer's Disease and Dementia with Lewy Bodies. %A Bousiges, Olivier %A Cretin, Benjamin %A Lavaux, Thomas %A Philippi, Nathalie %A Jung, Barbara %A Hezard, Sylvie %A Heitz, Camille %A Demuynck, Catherine %A Gabel, Aurelia %A Martin-Hunyadi, Catherine %A Blanc, Frédéric %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Lewy Body Disease %K Male %K Middle Aged %K Peptide Fragments %K Prodromal Symptoms %K Psychiatric Status Rating Scales %K Retrospective Studies %K Statistics, Nonparametric %K tau Proteins %X

BACKGROUND: Dementia with Lewy bodies (DLB) symptoms are close to those of Alzheimer's disease (AD), and the differential diagnosis is difficult especially early in the disease. Unfortunately, AD biomarkers in cerebrospinal fluid (CSF), and more particularly Aβ1 - 42, appear to be altered in dementia with Lewy bodies (DLB). However, the level of these biomarkers has never been studied in the prodromal stage of the disease.

OBJECTIVE: To compare these biomarkers between DLB and AD, with a particular focus on the prodromal stage.

METHODS: A total of 166 CSF samples were collected at the memory clinic of Strasbourg. They were obtained from prodromal DLB (pro-DLB), DLB dementia, prodromal AD (pro-AD), and AD dementia patients, and elderly controls. Phospho-Tau181, total-Tau, Aβ42, and Aβ40 were measured in the CSF.

RESULTS: At the prodromal stage, contrary to AD patients, DLB patients' biomarker levels in the CSF were not altered. At the demented stage of DLB, Aβ42 levels were reduced as well as Aβ40 levels. Thus, the Aβ42/Aβ40 ratio remained unchanged between the prodromal and demented stages, contrary to what was observed in AD. Tau and Phospho-Tau181 levels were unaltered in DLB patients.

CONCLUSIONS: We have shown that at the prodromal stage the DLB patients had no pathological profile. Consequently, CSF AD biomarkers are extremely useful for differentiating AD from DLB patients particularly at this stage when the clinical diagnosis is difficult. Thus, these results open up new perspectives on the interpretation of AD biomarkers in DLB.

%B J Alzheimers Dis %V 51 %P 1069-83 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923009?dopt=Abstract %R 10.3233/JAD-150731 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Different Expression Patterns of Amyloid-β Protein Precursor Secretases in Human and Mouse Hippocampal Neurons: A Potential Contribution to Species Differences in Neuronal Susceptibility to Amyloid-β Pathogenesis. %A Xu, Zhi-Qiang %A Huang, Huang %A Chen, Ya-Li %A Gao, Yun-Ying %A Xu, Jun %A Marshall, Charles %A Cai, Zhi-You %A Xiao, Ming %K ADAM10 Protein %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Animals %K Antibodies %K Aspartic Acid Endopeptidases %K Cell Count %K Dose-Response Relationship, Drug %K Female %K Gene Expression Regulation %K Hippocampus %K Humans %K Low Density Lipoprotein Receptor-Related Protein-1 %K Male %K Mice %K Mice, Transgenic %K Middle Aged %K Mutation %K Neurons %K Peptide Fragments %K Presenilin-1 %K Species Specificity %K Time Factors %X

Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer's disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-β protein precursor (AβPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aβ pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aβ deposits in the 10-month-old transgenic mutant human AβPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α-secretase, and its neuroprotective products soluble AβPPα, but low levels of amyloidogenic β-secretase and γ-secretase, and a neurotoxic product, Aβ42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed β-secretase and γ-secretase, but not α-secretase, which could increase Aβ generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48 h following local microinjection of α-secretase antibody ADAM10 into the hippocampus of AβPP/PS1 mice further suggests that high α-secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α-secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AβPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD.

%B J Alzheimers Dis %V 51 %P 179-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836155?dopt=Abstract %R 10.3233/JAD-150634 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Diagnosis of Dementia with High Levels of Cerebrospinal Fluid Tau Protein. %A Grangeon, Lou %A Paquet, Claire %A Bombois, Stephanie %A Quillard-Muraine, Muriel %A Martinaud, Olivier %A Bourre, Bertrand %A Lefaucheur, Romain %A Nicolas, Gaël %A Dumurgier, Julien %A Gerardin, Emmanuel %A Jan, Mary %A Laplanche, Jean-Louis %A Peoc'h, Katell %A Hugon, Jacques %A Pasquier, Florence %A Maltête, David %A Hannequin, Didier %A Wallon, David %K Adult %K Age of Onset %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Creutzfeldt-Jakob Syndrome %K Dementia, Vascular %K Diagnosis, Differential %K Female %K France %K Frontotemporal Dementia %K Humans %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %K Phosphorylation %K Retrospective Studies %K Sex Factors %K tau Proteins %X

BACKGROUND: Total Tau concentration in cerebrospinal fluid (CSF) is widely used as a biomarker in the diagnosis of neurodegenerative process primarily in Alzheimer's disease (AD). A particularly high Tau level may indicate AD but may also be associated with Creutzfeldt-Jakob disease (CJD). In such situations little is known about the distribution of differential diagnoses.

OBJECTIVE: Our study aimed to describe the different diagnoses encountered in clinical practice for patients with dementia and CSF Tau levels over 1000 pg/ml. We studied the p-Tau/Tau ratio to specify its ability to distinguish AD from CJD.

METHODS: Patients (n = 202) with CSF Tau levels over 1000 pg/ml were recruited in three memory clinics in France. All diagnoses were made using the same diagnostic procedure and criteria.

RESULTS: Patients were diagnosed with AD (n = 148, 73.2%), mixed dementia (n = 38, 18.8%), CJD, vascular dementia (n = 4, 2.0% for each), Lewy body dementia, and frontotemporal dementia (n = 3, 1.5% for each). Dispersion of CSF Tau levels clearly showed an overlap between all diagnoses. Using the p-Tau/Tau ratio suggestive of CJD (<0.075), all CJD patients were correctly categorized and only two AD patients were miscategorized. This ratio was highly associated with CJD compared to AD (p < 0.0001).

CONCLUSION: Our study showed that in clinical practice, extremely high CSF Tau levels are mainly related to diagnosis of AD. CJD patients represent a minority. Our results support a sequential interpretation algorithm for CSF biomarkers in dementia. High CSF Tau levels should alert clinicians to check the p-Tau/Tau ratio to consider a probable diagnosis of CJD.

%B J Alzheimers Dis %V 51 %P 905-13 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890785?dopt=Abstract %R 10.3233/JAD-151111 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Mass Spectrometry Profiles of Tau Protein in the Cerebrospinal Fluid of Patients with Alzheimer's Disease, Progressive Supranuclear Palsy, and Dementia with Lewy Bodies. %A Barthélemy, Nicolas R %A Gabelle, Audrey %A Hirtz, Christophe %A Fenaille, François %A Sergeant, Nicolas %A Schraen-Maschke, Susanna %A Vialaret, Jérôme %A Buée, Luc %A Junot, Christophe %A Becher, François %A Lehmann, Sylvain %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Analysis of Variance %K Chromatography, Liquid %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Lewy Body Disease %K Male %K Mental Status Schedule %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Peptide Fragments %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %K Statistics as Topic %K Supranuclear Palsy, Progressive %K tau Proteins %X

Microtubule-associated Tau proteins are major actors in neurological disorders, the so-called tauopathies. In some of them, and specifically in Alzheimer's disease (AD), hyperphosphorylated forms of Tau aggregate into neurofibrillary tangles. Following and understanding the complexity of Tau's molecular profile with its multiple isoforms and post-translational modifications represent an important issue, and a major analytical challenge. Immunodetection methods are, in fact, limited by the number, specificity, sensitivity, and capturing property of the available antibodies. Mass spectrometry (MS) has recently allowed protein quantification in complex biological fluids using isotope-labeled recombinant standard for absolute quantification (PSAQ). To study Tau proteins, which are found at very low concentrations within the cerebrospinal fluid (CSF), we relied on an innovative two-step pre-fractionation strategy, which was not dependent on immuno-enrichment. We then developed a sensitive multiplex peptide detection capability using targeted high-resolution MS to quantify Tau-specific peptides covering its entire sequence. This approach was used on a clinical cohort of patients with AD, progressive supranuclear palsy (PSP), and dementia with Lewy body (DLB) and with control non-neurodegenerative disorders. We uncovered a common CSF Tau molecular profile characterized by a predominance of central core expression and 1N/3R isoform detection. While PSP and DLB tau profiles showed minimal changes, AD was characterized by a unique pattern with specific modifications of peptide distribution. Taken together these results provide important information on Tau biology for future therapeutic interventions, and improved molecular diagnosis of tauopathies.

%B J Alzheimers Dis %V 51 %P 1033-43 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923020?dopt=Abstract %R 10.3233/JAD-150962 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Divergent Longitudinal Propagation of White Matter Degradation in Logopenic and Semantic Variants of Primary Progressive Aphasia. %A Tu, Sicong %A Leyton, Cristian E %A Hodges, John R %A Piguet, Olivier %A Hornberger, Michael %K Aged %K Analysis of Variance %K Aphasia, Primary Progressive %K Brain %K Cohort Studies %K Cross-Sectional Studies %K Disease Progression %K Female %K Humans %K Image Processing, Computer-Assisted %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Names %K Neuropsychological Tests %K Semantics %X

BACKGROUND: Clinico-pathological distinction of primary progressive aphasia (PPA) can be challenging at clinic presentation. In particular, cross-sectional neuroimaging signatures across the logopenic (lvPPA) and semantic (svPPA) variants are difficult to establish, with longitudinal profiles showing greater divergence.

OBJECTIVE: Assess longitudinal propagation of white matter degradation in lvPPA and svPPA to determine disease progression over time, and whether this reflects distinct underlying pathology.

METHOD: A cohort of 27 patients with dementia (12 lvPPA; 15 svPPA) and 12 healthy controls were assessed at baseline and 1-year follow-up on the Addenbrooke's Cognitive Examination-Revised and Sydney Language Battery. Diffusion weighted images were collected at both time-points and analyzed for longitudinal white matter change using DTI-TK and TBSS.

RESULTS: LvPPA patients showed a significant decline in naming and repetition, over 1 year, while svPPA patients declined in naming and comprehension. Longitudinal imaging revealed widespread bilateral degradation of white matter tracts in lvPPA over a 1-year period with early involvement of the left posterior inferior longitudinal fasciculus (ILF). SvPPA demonstrated focal left lateralized white matter degradation involving the uncinate fasciculus (UF) and anterior ILF, propagating to the right UF with disease progression.

CONCLUSIONS: LvPPA and svPPA cohorts showed distinct longitudinal cognitive and white matter profiles. We propose differences in multi-centric and focal white matter dysfunction in lvPPA and svPPA, respectively, reflect underlying pathological differences. The clinical relevance of white matter degradation and mechanisms underlying disease propagation are discussed.

%B J Alzheimers Dis %V 49 %P 853-61 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484929?dopt=Abstract %R 10.3233/JAD-150626 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dogs with Cognitive Dysfunction as a Spontaneous Model for Early Alzheimer's Disease: A Translational Study of Neuropathological and Inflammatory Markers. %A Schütt, Trine %A Helboe, Lone %A Pedersen, Lars Østergaard %A Waldemar, Gunhild %A Berendt, Mette %A Pedersen, Jan Torleif %K Aging %K Alzheimer Disease %K Animals %K Brain %K Cognitive Dysfunction %K Cytokines %K Denmark %K Disease Models, Animal %K Disease Progression %K Dog Diseases %K Dogs %K Female %K Humans %K Immunohistochemistry %K Longitudinal Studies %K Male %K Plaque, Amyloid %K Severity of Illness Index %K Species Specificity %K tau Proteins %K Translational Medical Research %X

Aged companion dogs with canine cognitive dysfunction (CCD) spontaneously develop varying degrees of progressive cognitive decline and particular neuropathological features correspondent to the changes associated with Alzheimer's disease (AD) in humans. The aim of the present study was to characterize certain aspects of neuropathology and inflammatory markers related to aging and CCD in dogs in comparison with human AD. Fifteen brains from aged dogs with normal cognitive function, mild cognitive impairment, or CCD were investigated and compared with two control brains from young dogs and brain sections from human AD subjects. The neuropathological investigations included evaluation of amyloid-β (Aβ) plaque deposition (N-terminally truncated and pyroglutamyl-modified Aβ included), tau pathology, and inflammatory markers in prefrontal cortex. Cortical Aβ deposition was found to be only of the diffuse subtype as no dense-core or neuritic plaques were found. The Aβ deposition followed a progressive pattern in four maturation stages. Accumulation of the Aβ peptide was also observed in the vessel walls. Both immunohistochemically and biochemically measured levels of Aβ pathology in prefrontal cortex showed a consistent positive correlation to age but not to cognitive deficit severity. No evidence of neurofibrillary tau pathology was found. The level of pro-inflammatory cytokines was generally low and showed no significant association to cognitive status. The findings of the present study support the senescent dog with spontaneous cognitive dysfunction as a valuable non-transgenic model for further investigations of the molecular events involved in the neurodegenerative processes associated with aging and early stage AD, especially the Aβ-related pathology.

%B J Alzheimers Dis %V 52 %P 433-49 %8 2016 03 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27003213?dopt=Abstract %R 10.3233/JAD-151085 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early-Life Exposure to Lead (Pb) Alters the Expression of microRNA that Target Proteins Associated with Alzheimer's Disease. %A Masoud, Anwar M %A Bihaqi, Syed W %A Machan, Jason T %A Zawia, Nasser H %A Renehan, William E %K Age Factors %K Amyloid beta-Protein Precursor %K Animals %K Animals, Newborn %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Female %K Gene Expression Regulation, Developmental %K Lead %K Male %K Mice %K Mice, Inbred C57BL %K MicroRNAs %K Pregnancy %K RNA, Messenger %K Sp1 Transcription Factor %X

There is a growing recognition of the impact of environmental toxins on the epigenetic regulation of gene expression, including the genes that play a critical role in neural development, neural function, and neurodegeneration. We have shown previously that exposure to the heavy metal lead (Pb) in early life results in a latent over-expression of AD-related proteins in rodents and primates. The present study provides evidence that early postnatal exposure to Pb also alters the expression of select miRNA. Mice were exposed to 0.2% Pb acetate from Postnatal Day 1 (PND 1, first 24 h after birth) to PND 20 via their mother's milk. Brain tissue was harvested at PND 20, 180, or 700, and miRNA were isolated and quantified by qPCR. This exposure produced a transient increase (relative to control) in the expression of miR-106b (binds to AβPP mRNA), miR-29b (targets the mRNA for the transcription factor SP1) and two miRNAs (miR-29b and miR-132) that have the ability to inhibit translation of proteins involved in promoter methylation. The expression of miR-106b decreased over time in the Pb-exposed animals and was significantly less than the levels exhibited by the control animals at PND700. The level of miR-124, which binds to SP1 mRNA, was also reduced (relative to controls) at PND700. In summary, we show that exposure to the heavy metal Pb in early life has a significant impact on the short- and long-term expression of miRNA that target epigenetic mediators and neurotoxic proteins.

%B J Alzheimers Dis %V 51 %P 1257-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923026?dopt=Abstract %R 10.3233/JAD-151018 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Tween-20 on Core Biomarkers Measured in Cerebrospinal Fluid from Patients with Alzheimer's Disease, Mild Cognitive Impairment, or Healthy Control Individuals. %A Berge, Guro %A Lauridsen, Camilla %A Sando, Sigrid Botne %A Holder, Daniel Joseph %A Møller, Ina %A Aasly, Jan Olav %A Bråthen, Geir %A Savage, Mary Josephine %A White, Linda Rosemary %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Cognitive Dysfunction %K Enzyme-Linked Immunosorbent Assay %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Polysorbates %K ROC Curve %K Surface-Active Agents %K tau Proteins %X

BACKGROUND: There is substantial variation caused by preanalytical procedures in the measurement of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) reported in the literature.

OBJECTIVE: Determine whether the detergent Tween-20 improves diagnostic accuracy.

METHODS: CSF proteins (Aβ42, Aβ40, total tau, and phosphorylated tau) were measured by standard ELISA, in uncentrifuged CSF with or without 0.05% Tween-20 from patients with AD or amnestic mild cognitive impairment, and healthy elderly controls. In the main study, collection tubes containing Tween-20 (Sarstedt 15 mL) were filled with 5 mL CSF to ensure consistent detergent concentration across subsequent aliquots into Corning 2 mL tubes. These latter were also the primary collection vessel for samples without Tween-20. The effect of centrifugation, and extra tube transfer of samples with Tween-20 were also examined.

RESULTS: 0.05% Tween-20 significantly increased mean measured CSF concentration of Aβ42 (30% ), Aβ40 (23% ), and total tau (4% ), but not phosphorylated tau. Generally, these increases were similar in all groups, although for Aβ42, the mean percentage increase with Tween-20 was slightly larger for AD. Areas under receiver-operator characteristic curves were similar whether Tween-20 was present or not. Centrifuged CSF without Tween-20 significantly reduced the measured concentration of Aβ42 versus non-centrifuged samples, a difference not seen when detergent was added. Similar CSF Aβ42 levels were found whether Tween-20 was added at collection in an extra tube or directly to the main collection tube.

CONCLUSION: Addition of Tween-20 to CSF did not improve differentiation of patients from controls.

%B J Alzheimers Dis %V 49 %P 493-502 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484901?dopt=Abstract %R 10.3233/JAD-150234 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Effects of Latrepirdine on Amyloid-β Aggregation and Toxicity. %A Porter, Tenielle %A Bharadwaj, Prashant %A Groth, David %A Paxman, Adrian %A Laws, Simon M %A Martins, Ralph N %A Verdile, Giuseppe %K Amyloid beta-Peptides %K Analysis of Variance %K Antipsychotic Agents %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Drug Interactions %K Humans %K Indoles %K L-Lactate Dehydrogenase %K Microscopy, Atomic Force %K Neuroblastoma %K Peptide Fragments %K Protein Aggregates %X

Latrepirdine (Dimebon) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties.

%B J Alzheimers Dis %V 50 %P 895-905 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836170?dopt=Abstract %R 10.3233/JAD-150790 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease. %A Ongali, Brice %A Nicolakakis, Nektaria %A Tong, Xing-Kang %A Aboulkassim, Tahar %A Imboden, Hans %A Hamel, Edith %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloidosis %K Analysis of Variance %K Animals %K Antihypertensive Agents %K Cerebrovascular Disorders %K Cholinesterases %K Disease Models, Animal %K Drug Combinations %K Enalapril %K Female %K Glial Fibrillary Acidic Protein %K Humans %K Losartan %K Male %K Maze Learning %K Memory Disorders %K Mice %K Mice, Transgenic %K Mutation %X

The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.

%B J Alzheimers Dis %V 51 %P 1183-95 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923013?dopt=Abstract %R 10.3233/JAD-150868 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease. %A White, Matthew T %A Shaw, Leslie M %A Xie, Sharon X %K Alzheimer Disease %K Amyloid beta-Peptides %K Area Under Curve %K Biomarkers %K Databases, Factual %K Female %K Humans %K Likelihood Functions %K Male %K Peptide Fragments %K Phosphorylation %K ROC Curve %K tau Proteins %X

Studies of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have indicated that much of the variability observed in the biomarkers may be due to measurement error. Biomarkers are often obtained with measurement error, which may make the diagnostic biomarker appear less effective than it truly is. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, technical replicates of CSF biomarkers are available; the National Alzheimer's Coordinating Center database contains longitudinal replicates of CSF biomarkers. We focus on the area under the receiver operating characteristic curve (AUC) as the measure of diagnostic effectiveness for differentiating AD from normal cognition using CSF biomarkers and compare AUC estimates obtained by a more standard, naïve method (which uses a single observation per subject and ignores measurement error) to a maximum likelihood (ML) based method (which uses all replicates per subject and adjusts for measurement error). The choice of analysis method depends upon the noise to signal ratio (i.e., the magnitude of the measurement error variability relative to the true biomarker variability); moderate to high ratios may significantly bias the naïve AUC estimate, and the ML-based method would be preferred. The noise to signal ratios were low for the ADNI biomarkers but high for the tTau and pTau biomarkers in NACC. Correspondingly, the naïve and ML-based AUC estimates were nearly identical in the ADNI data but dissimilar for the tTau and pTau biomarkers in the NACC data. Therefore, using the naïve method is adequate for analysis of CSF biomarkers in the ADNI study, but the ML method is recommended for the NACC data.

%B J Alzheimers Dis %V 51 %P 463-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890778?dopt=Abstract %R 10.3233/JAD-151045 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Evolution of Caregiver Burden in Frontotemporal Dementia with and without Amyotrophic Lateral Sclerosis. %A Hsieh, Sharpley %A Leyton, Cristian E %A Caga, Jashelle %A Flanagan, Emma %A Kaizik, Cassandra %A O'Connor, Claire M %A Kiernan, Matthew C %A Hodges, John R %A Piguet, Olivier %A Mioshi, Eneida %K Adaptation, Psychological %K Aged %K Amyotrophic Lateral Sclerosis %K Analysis of Variance %K Caregivers %K Case-Control Studies %K Cost of Illness %K Disease Progression %K Female %K Frontotemporal Dementia %K Humans %K Interviews as Topic %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Surveys and Questionnaires %X

BACKGROUND AND AIMS: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent a disease spectrum. Caregiver burden in subtypes of FTD has not yet been directly compared with those patients who have co-existent FTD and ALS (ALSFTD).

METHOD: Perceived caregiver burden was evaluated using the short Zarit Burden Interview (ZBI) in patients with behavioral-variant FTD (bvFTD, n = 21), semantic dementia (SD, n = 18), and ALSFTD (n = 15) at the initial clinical presentation and follow-up assessments. The Mini-Addenbrooke's Cognitive Examination (M-ACE) and the Motor Neuron Disease Behaviour Scale (MiND-B) were also used. Linear mixed effects models examined longitudinal changes on the ZBI, M-ACE, and MiND-B across groups.

RESULTS: Burden at baseline was highest for the bvFTD group. Longitudinally, perceived burden increased for the SD and ALSFTD groups whereas in bvFTD, the level of burden which was high at baseline and remained high with disease progression. The severity of abnormal behaviors at baseline, as assessed by the MiND-B, correlated with baseline levels of caregiver burden and further accounted for 23% of the variance in caregiver burden at clinical follow-up.

CONCLUSIONS: The trajectory of perceived burden differs across the FTD-ALS spectrum, with SD and ALSFTD caregivers demonstrating an increased burden that develops over time, compared to a persistently high level for bvFTD caregivers, evident throughout the disease course. The evolution of burden in these three syndromes likely reflects the initial presentation and clinical characterization that develops with time. Psycho-education programs for caregivers, which provide better coping strategies for challenging behaviors, may reduce levels of burden experienced with disease progression.

%B J Alzheimers Dis %V 49 %P 875-85 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519438?dopt=Abstract %R 10.3233/JAD-150475 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Fluoxetine Treatment Induces Seizure Behavior and Premature Death in APPswe/PS1dE9 Mice. %A Sierksma, Annerieke S R %A de Nijs, Laurence %A Hoogland, Govert %A Vanmierlo, Tim %A van Leeuwen, Fred W %A Rutten, Bart P F %A Steinbusch, Harry W M %A Prickaerts, Jos %A van den Hove, Daniel L A %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Anticonvulsants %K Body Weight %K Disease Models, Animal %K Fluoxetine %K Humans %K Logistic Models %K Male %K Mice, Inbred C57BL %K Mice, Transgenic %K Neuroprotective Agents %K Presenilin-1 %K Seizures %X

Treatment of Alzheimer's disease (AD) patients with the antidepressant fluoxetine is known to improve memory and cognitive function. However, the mechanisms underlying these effects are largely unknown. To unravel these mechanisms, we aimed to treat APPswe/PS1dE9 mice with fluoxetine. Unexpectedly, with time, an increased number of animals displayed seizure behavior and died. Although spontaneous behavioral seizures have been reported previously in this mouse model, the observation of seizures and death consequential to fluoxetine treatment is new. Our results warrant further research on the underlying mechanisms as this may refine the treatment of AD patients.

%B J Alzheimers Dis %V 51 %P 677-82 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890781?dopt=Abstract %R 10.3233/JAD-151066 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Future Dementia Severity is Almost Entirely Explained by the Latent Variable δ's Intercept and Slope. %A Palmer, Raymond F %A Royall, Donald R %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Cognitive Dysfunction %K Factor Analysis, Statistical %K Female %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Psychiatric Status Rating Scales %X

BACKGROUND: Structural equation models (SEM) can explicitly distinguish dementia-relevant variance in cognitive task performance. The resulting latent construct "δ" (for dementia) provides a relatively "error free" continuously varying dementia-specific phenotype.

OBJECTIVE: To estimate δ's change over time (Δδ) and determine Δδ's predictive validity using future dementia status as an outcome.

METHODS: Data from n = 2,191 participants of the Texas Alzheimer's Research and Care Consortium (TARCC) were used to construct a latent growth curve model of longitudinal change over four years using five cognitive measures and one measure of Instrumental Activities of Daily Living. Four final latent factors, including baseline δ and Δδ, were simultaneously entered as predictors of wave 4 dementia severity, as estimated by the Clinical Dementia Rating Scale "sum of boxes" (CDR).

RESULTS: All observed measures exhibited significant change [χ2 = 1,152 (df = 229); CFI = 0.968; RMSEA = 0.043]. The final model demonstrated excellent fit to the data [χ2 = 543 (df = 245); CFI = 0.991; RMSEA = 0.023]. All latent indicator loadings were significant, yielding four distinct factors. After adjustment for demographic covariates and baseline CDR scores, d and Δd were significantly independently associated with CDR4, explaining 25% and 49% of its variance, respectively. The latent variable g' significantly explained 3% of CDR4 variance independently of d and Δd. Δg' was not significantly associated with CDR4. Baseline CDR explained 16% of CDR4 variance.

CONCLUSIONS: Future dementia severity is almost entirely explained by the latent construct δ's intercept and slope.

%B J Alzheimers Dis %V 49 %P 521-9 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444763?dopt=Abstract %R 10.3233/JAD-150254 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians. %A Kim, Sungeun %A Nho, Kwangsik %A Ramanan, Vijay K %A Lai, Dongbing %A Foroud, Tatiana M %A Lane, Katie %A Murrell, Jill R %A Gao, Sujuan %A Hall, Kathleen S %A Unverzagt, Frederick W %A Baiyewu, Olusegun %A Ogunniyi, Adesola %A Gureje, Oye %A Kling, Mitchel A %A Doraiswamy, P Murali %A Kaddurah-Daouk, Rima %A Hendrie, Hugh C %A Saykin, Andrew J %K Adaptor Proteins, Signal Transducing %K African Americans %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cohort Studies %K Cystathionine beta-Synthase %K Cytoskeletal Proteins %K Female %K Genetic Variation %K Genome-Wide Association Study %K Heterozygote %K Homocysteine %K Humans %K Indiana %K Longitudinal Studies %K Male %K Nigeria %K Prospective Studies %X

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.

%B J Alzheimers Dis %V 49 %P 991-1003 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519441?dopt=Abstract %R 10.3233/JAD-150651 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease. %A Spiegel, Jonathan %A Pirraglia, Elizabeth %A Osorio, Ricardo S %A Glodzik, Lidia %A Li, Yi %A Tsui, Wai %A Saint Louis, Leslie A %A Randall, Catherine %A Butler, Tracy %A Xu, Jinfeng %A Zinkowski, Raymond P %A Zetterberg, Henrik %A Fortea, Juan %A Fossati, Silvia %A Wisniewski, Thomas %A Davies, Peter %A Blennow, Kaj %A de Leon, Mony J %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Case-Control Studies %K Cross-Sectional Studies %K Female %K Humans %K Logistic Models %K Male %K Middle Aged %K Phosphorylation %K ROC Curve %K Sensitivity and Specificity %K tau Proteins %X

Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.

%B J Alzheimers Dis %V 49 %P 93-100 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444757?dopt=Abstract %R 10.3233/JAD-150167 %0 Journal Article %J J Alzheimers Dis %D 2016 %T GSK-3β is Dephosphorylated by PP2A in a Leu309 Methylation-Independent Manner. %A Chu, Dandan %A Tan, Jianxin %A Xie, Shutao %A Jin, Nana %A Yin, Xiaomin %A Gong, Cheng-Xin %A Iqbal, Khalid %A Liu, Fei %K Animals %K Brain %K Carboxylic Ester Hydrolases %K Cell Line, Transformed %K Dose-Response Relationship, Drug %K Enzyme Inhibitors %K Excitatory Amino Acid Agonists %K Glycogen Synthase Kinase 3 %K Glycogen Synthase Kinase 3 beta %K Humans %K Kainic Acid %K Leucine %K Luminescent Proteins %K Male %K Methylation %K Mice %K Phosphorylation %K Protein O-Methyltransferase %K Protein Phosphatase 2 %K RNA, Small Interfering %K Serine %K tau Proteins %X

Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase-3β (GSK-3β) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3β activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3β and PP2A signaling and showed that PP2A could dephosphorylate GSK-3β at Ser9. Here, we investigated the dephosphorylation of GSK-3β in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3β at Ser9. PP2A interacted with GSK-3β and suppressed its Ser9 phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK-3β in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3β phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3β at Ser9.

%B J Alzheimers Dis %V 49 %P 365-75 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484916?dopt=Abstract %R 10.3233/JAD-150497 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease. %A Louwersheimer, Eva %A Keulen, M Antoinette %A Steenwijk, Martijn D %A Wattjes, Mike P %A Jiskoot, Lize C %A Vrenken, Hugo %A Teunissen, Charlotte E %A van Berckel, Bart N M %A van der Flier, Wiesje M %A Scheltens, Philip %A van Swieten, John C %A Pijnenburg, Yolande A L %K Aged %K Alzheimer Disease %K Aphasia, Primary Progressive %K Atrophy %K Biomarkers %K Brain %K Female %K Humans %K Language %K Language Tests %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Organ Size %K Positron-Emission Tomography %K Retrospective Studies %X

BACKGROUND: The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer's disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences.

OBJECTIVE: We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI.

METHODS: Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer.

RESULTS: We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern.

CONCLUSION: Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.

%B J Alzheimers Dis %V 51 %P 581-90 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890751?dopt=Abstract %R 10.3233/JAD-150812 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Higher Fasting Plasma Glucose Levels, within the Normal Range, are Associated with Decreased Processing Speed in High Functioning Young Elderly. %A Raizes, Meytal %A Elkana, Odelia %A Franko, Motty %A Ravona Springer, Ramit %A Segev, Shlomo %A Beeri, Michal Schnaider %K Aged %K Blood Glucose %K Cognition %K Diabetes Mellitus, Type 2 %K Fasting %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Neuropsychological Tests %K Psychomotor Performance %K Reaction Time %K Reference Values %X

We explored the association of plasma glucose levels within the normal range with processing speed in high functioning young elderly, free of type 2 diabetes mellitus (T2DM). A sample of 41 participants (mean age = 64.7, SD = 10; glucose 94.5 mg/dL, SD = 9.3), were examined with a computerized cognitive battery. Hierarchical linear regression analysis showed that higher plasma glucose levels, albeit within the normal range (<110 mg/dL), were associated with longer reaction times (p <  0.01). These findings suggest that even in the subclinical range and in the absence of T2DM, monitoring plasma glucose levels may have an impact on cognitive function.

%B J Alzheimers Dis %V 49 %P 589-92 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484908?dopt=Abstract %R 10.3233/JAD-150433 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Hippocampal Lipid Homeostasis in APP/PS1 Mice is Modulated by a Complex Interplay Between Dietary DHA and Estrogens: Relevance for Alzheimer's Disease. %A Díaz, Mario %A Fabelo, Noemí %A Casañas-Sánchez, Verónica %A Marin, Raquel %A Gómez, Tomás %A Quinto-Alemany, David %A Pérez, José A %K Acyl Coenzyme A %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Disease Models, Animal %K Docosahexaenoic Acids %K Dose-Response Relationship, Drug %K Estrogens %K Gene Expression Regulation %K Hippocampus %K Homeostasis %K Humans %K Lipid Metabolism %K Mice %K Mice, Transgenic %K Mutation %K Presenilin-1 %K RNA, Messenger %X

Current evidence suggests that lipid homeostasis in the hippocampus is affected by different genetic, dietary, and hormonal factors, and that its deregulation may be associated with the onset and progression of Alzheimer's disease (AD). However, the precise levels of influence of each of these factors and their potential interactions remain largely unknown, particularly during neurodegenerative processes. In the present study, we have performed multifactorial analyses of the combined effects of diets containing different doses of docosahexaenoic acid (DHA), estrogen status (ovariectomized animals receiving vehicle or 17β-estradiol), and genotype (wild-type or transgenic APP/PS1 mice) in hippocampal lipid profiles. We have observed that the three factors affect lipid classes and fatty acid composition to different extents, and that strong interactions between these factors exist. The most aberrant lipid profiles were observed in APP/PS1 animals receiving DHA-poor diets and deprived of estrogens. Conversely, wild-type animals under a high-DHA diet and receiving estradiol exhibited a lipid profile that closely resembled that of the hippocampus of control animals. Interestingly, though the lipid signatures of APP/PS1 hippocampi markedly differed from wild-type, administration of a high-DHA diet in the presence of estrogens gave rise to a lipid profile that approached that of control animals. Paralleling changes in lipid composition, patterns of gene expression of enzymes involved in lipid biosynthesis were also altered and affected by combination of experimental factors. Overall, these results indicate that hippocampal lipid homeostasis is strongly affected by hormonal and dietary conditions, and that manipulation of these factors might be incorporated in AD therapeutics.

%B J Alzheimers Dis %V 49 %P 459-81 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519437?dopt=Abstract %R 10.3233/JAD-150470 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Homotaurine Effects on Hippocampal Volume Loss and Episodic Memory in Amnestic Mild Cognitive Impairment. %A Spalletta, Gianfranco %A Cravello, Luca %A Gianni, Walter %A Piras, Federica %A Iorio, Mariangela %A Cacciari, Claudia %A Casini, Anna Rosa %A Chiapponi, Chiara %A Sancesario, Giuseppe %A Fratangeli, Claudia %A Orfei, Maria Donata %A Caltagirone, Carlo %A Piras, Fabrizio %K Aged %K Aged, 80 and over %K Analysis of Variance %K Chi-Square Distribution %K Cognitive Dysfunction %K Female %K Hippocampus %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Memory, Episodic %K Mental Status Schedule %K Middle Aged %K Neuroprotective Agents %K Neuropsychological Tests %K Taurine %X

Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances in amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 year. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which was associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI has a positive effect on hippocampus atrophy and episodic memory loss. Future studies should further clarify the mechanisms of its effects on brain morphometry.

%B J Alzheimers Dis %V 50 %P 807-16 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757035?dopt=Abstract %R 10.3233/JAD-150484 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impact of Depressive Symptoms on Conversion from Mild Cognitive Impairment Subtypes to Alzheimer's Disease: A Community-Based Longitudinal Study. %A Kida, Jiro %A Nemoto, Kiyotaka %A Ikejima, Chiaki %A Bun, Shogyoku %A Kakuma, Tatsuyuki %A Mizukami, Katsuyoshi %A Asada, Takashi %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Depression %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Prodromal Symptoms %K Prognosis %K Risk %X

BACKGROUND: While longitudinal studies have investigated the relationships between mild cognitive impairment (MCI) subtypes and dementia subtypes, the results have been contradictory. In addition, some research shows that depression accompanied by MCI might increase the risk of Alzheimer's disease (AD).

OBJECTIVE: The aim of this study is to longitudinally investigate the relationships between MCI subtypes and dementia subtypes, with special attention to the effect of comorbid depressive symptoms in a Japanese rural community.

METHODS: Non-demented participants (n = 802) completed a baseline and follow-up study. Outcomes were conversion to dementia especially AD, MCI, or no conversion. A complementary log-log analysis was conducted to investigate the risk of dementia and AD in amnestic MCI (aMCI) compared to nonamnestic MCI (naMCI) groups. The impact of depressive symptoms on the transition from MCI to AD and from cognitively normal to MCI or AD was also analyzed.

RESULTS: The risk of developing dementia, in particular AD, for the aMCI group was significantly higher than that for the naMCI group. In the aMCI group, the presence of depressive symptoms increased the risk of developing AD, but depressive symptoms in the naMCI group did not. In the cognitively normal group, the presence of depressive symptoms increased the risk of aMCI but not naMCI or AD.

CONCLUSION: MCI subtyping could be useful in finding a prodrome for dementia and in particular for AD. The differing impacts of depressive symptoms on the development of AD suggest that the relationship between depressive symptoms and cognitive impairment could differ in aMCI and naMCI patients.

%B J Alzheimers Dis %V 51 %P 405-15 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890740?dopt=Abstract %R 10.3233/JAD-150603 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impact of Omega-3 Fatty Acid Supplementation on Memory Functions in Healthy Older Adults. %A Külzow, Nadine %A Witte, A Veronica %A Kerti, Lucia %A Grittner, Ulrike %A Schuchardt, Jan Philipp %A Hahn, Andreas %A Flöel, Agnes %K Aged %K Apolipoproteins E %K Auditory Perception %K Blood Chemical Analysis %K Cognitive Aging %K Dietary Supplements %K Double-Blind Method %K Fatty Acids, Omega-3 %K Feeding Behavior %K Female %K Humans %K Learning %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Nootropic Agents %K Treatment Outcome %X

As the process of Alzheimer's disease (AD) begins years before disease onset, searching for prevention strategies is of major medical and economic importance. Nutritional supplementation with long-chain polyunsaturated omega-3 fatty acids (LC-n3-FA) may exert beneficial effects on brain structure and function. However, experimental evidence in older adults without clinical dementia is inconsistent, possibly due to low sensitivity of previously employed test batteries for detecting subtle improvements in cognition in healthy individuals. Here we used LOCATO, recently described as a robust and sensitive tool for assessing object-location memory (OLM) in older adults, to evaluate the impact of LC-n3-FA supplementation on learning and memory formation. In a double-blind placebo-controlled proof-of-concept study, 44 (20 female) cognitively healthy individuals aged 50-75 years received either LC-n3-FA (2,200 mg/day, n = 22) or placebo (n = 22) for 26 weeks. Before and after intervention, memory performance in the OLM-task (primary) was tested. As secondary outcome parameters, performance in Rey Auditory Verbal Learning Test (AVLT), dietary habits, omega-3-index, and other blood-derived parameters were assessed. Omega-3 index increased significantly in the LC-n3-FA group compared with the placebo group. Moreover, recall of object locations was significantly better after LC-n3-FA supplementation compared with placebo. Performance in the AVLT was not significantly affected by LC-n3-FA. This double-blind placebo-controlled proof-of-concept study provides further experimental evidence that LC-n3-FA exert positive effects on memory functions in healthy older adults. Our findings suggest novel strategies to maintain cognitive functions into old age.

%B J Alzheimers Dis %V 51 %P 713-25 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890759?dopt=Abstract %R 10.3233/JAD-150886 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Impaired Parahippocampus Connectivity in Mild Cognitive Impairment and Alzheimer's Disease. %A Liu, Jieqiong %A Zhang, Xinqing %A Yu, Chunshui %A Duan, Yunyun %A Zhuo, Junjie %A Cui, Yue %A Liu, Bing %A Li, Kuncheng %A Jiang, Tianzi %A Liu, Yong %K Aged %K Alzheimer Disease %K Apolipoproteins E %K Brain Mapping %K Cognitive Dysfunction %K Female %K Hippocampus %K Humans %K Limbic System %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Neural Pathways %K Rest %K Severity of Illness Index %X

BACKGROUND: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases.

OBJECTIVE: To investigate if disease severity associated altered PHG connectivity in Alzheimer's disease (AD) exists.

METHODS: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson's correlation coefficients between the bilateral PHG and whole brain. Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability.

RESULTS: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini-Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe.

CONCLUSIONS: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD.

%B J Alzheimers Dis %V 49 %P 1051-64 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599055?dopt=Abstract %R 10.3233/JAD-150727 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors. %A Miwa, Kaori %A Tanaka, Makiko %A Okazaki, Shuhei %A Yagita, Yoshiki %A Sakaguchi, Manabu %A Mochizuki, Hideki %A Kitagawa, Kazuo %K Aged %K Carotid Intima-Media Thickness %K Cerebral Small Vessel Diseases %K Dementia %K Female %K Homocysteine %K Humans %K Incidence %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Predictive Value of Tests %K Proportional Hazards Models %K Risk Factors %K Statistics, Nonparametric %X

BACKGROUND: Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia.

OBJECTIVE: The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors.

METHODS: Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 μmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia.

RESULTS: In the 643 subjects (age: 67.2 ± 8.4 years, male: 59% ; education: 12.9 ± 2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2-13), 47 patients were diagnosed with dementia (Alzheimer's disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE ɛ4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p = 0.043) and the highest tertile of tHcy (HR: 2.50, p = 0.047) for all-cause dementia remained significant.

CONCLUSIONS: Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk.

%B J Alzheimers Dis %V 49 %P 503-13 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484913?dopt=Abstract %R 10.3233/JAD-150458 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Influence of Incipient Dementia on Hospitalization for Primary Care Sensitive Conditions: A Population-Based Cohort Study. %A Pimouguet, Clément %A Rizzuto, Debora %A Fastbom, Johan %A Lagergren, Mårten %A Fratiglioni, Laura %A Xu, Weili %K Acute Disease %K Age Factors %K Aged %K Aged, 80 and over %K Chronic Disease %K Dementia %K Female %K Follow-Up Studies %K Hospitalization %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Primary Health Care %K Registries %K Risk %K Sensitivity and Specificity %K Socioeconomic Factors %K Sweden %X

BACKGROUND: Studies have reported that moderate/severe stages of dementia are linked to increased hospitalization rates, but little is known about the influence of incipient dementia on hospitalizations for primary care sensitive conditions (PCSCs).

OBJECTIVE: To examine the associations between incipient dementia and hospitalization outcomes, including all-cause and PCSC hospitalization.

METHODS: A total of 2,268 dementia-free participants in the Swedish National study on Aging and Care-Kungsholmen were interviewed and clinically examined at baseline. Participants aged ≥78 years were followed for 3 years, and those aged 60-72 years, for 6 years. Number of hospitalizations was retrieved from the National Patient Register. Dementia was diagnosed in accordance with Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Hospitalization outcomes were compared in participants who did and did not develop dementia. Zero-inflated Poisson regressions and logistic regressions were used in data analysis.

RESULTS: During the follow-up, 175 participants developed dementia. The unadjusted PCSC admission rate was 88.2 per 1000 person-years in those who developed dementia and 25.6 per 1000 person-years in those who did not. In the fully adjusted logistic regression model, incipient dementia was associated with an increased risk of hospitalization for PCSCs (OR = 2.3, 95% CI 1.3-3.9) but not with the number of hospitalizations or with all-cause hospitalization. Risks for hospitalization for diabetes, congestive heart failure, and pyelonephritis were higher in those who developed dementia than in those who did not. About 10% participants had a PCSC hospitalization attributable to incipient dementia.

CONCLUSION: People with incipient dementia are more prone to hospitalization for PCSCs but not to all-cause hospitalization.

%B J Alzheimers Dis %V 52 %P 213-22 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060943?dopt=Abstract %R 10.3233/JAD-150853 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Inhibition of Cholesterol Biosynthesis Reduces γ-Secretase Activity and Amyloid-β Generation. %A Kim, Yoonhee %A Kim, Chaeyoung %A Jang, Hye Young %A Mook-Jung, Inhee %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Analysis of Variance %K Animals %K Anticholesteremic Agents %K Cell Line %K Cholesterol %K Cricetinae %K Down-Regulation %K Humans %K In Situ Nick-End Labeling %K Luminescent Proteins %K Membrane Glycoproteins %K Membrane Microdomains %K Mutation %K Presenilin-1 %K Protein Transport %K trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride %K Transfection %X

Amyloid-β (Aβ) is one of major molecules contributing to the pathogenesis of Alzheimer's disease (AD). Aβ is derived from amyloid-β protein precursor (AβPP) through sequential cleavages by β- and γ-secretases. Regulation of these components is thought to be an important factor in Aβ generation during the pathogenesis of AD. AβPP, β-secretase, and γ-secretase reside in lipid rafts, where cholesterol regulates the integrity and flexibility of membrane proteins and Aβ is generated. However, the relationship between cholesterol and Aβ generation is controversial. In this study, we aimed to elucidate the direct effects of cholesterol depletion on AβPP processing using AY9944, which blocks the last step of cholesterol biosynthesis and thus minimizes the unknown side effects of upstream inhibitors, such as HMG-CoA reductase inhibitors. Treatment with AY9944 decreased γ-secretase activity and Aβ generation. These results suggested that changes in membrane composition by lowering cholesterol with AY9944 affected γ-secretase activity and Aβ generation, which is associated with AD pathogenesis.

%B J Alzheimers Dis %V 51 %P 1057-68 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923021?dopt=Abstract %R 10.3233/JAD-150982 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal Neurons. %A Krishna, Kumar %A Behnisch, Thomas %A Sajikumar, Sreedharan %K Acrylamides %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Excitatory Postsynaptic Potentials %K Hippocampus %K Histone Deacetylase Inhibitors %K Histone Deacetylases %K Long-Term Potentiation %K Male %K Patch-Clamp Techniques %K Peptide Fragments %K Phenylenediamines %K Pyramidal Cells %K Rats, Wistar %K Tissue Culture Techniques %X

Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with alterations in epigenetic factors leading to cognitive decline. Histone deacetylase 3 (HDAC3) is a known critical epigenetic negative regulator of learning and memory. In this study, attenuation of long-term potentiation by amyloid-β oligomer, and its reversal by specific HDAC3 inhibitor RGFP966, was performed in rat CA1 pyramidal neurons using whole cell voltage-clamp and field recording techniques. Our findings provide the first evidence that amyloid-β oligomer-induced synaptic plasticity impairment can be prevented by inhibition of HDAC3 enzyme both at the single neuron as well as in a population of neurons, thus identifying HDAC3 as a potential target for ameliorating AD related plasticity impairments.

%B J Alzheimers Dis %V 51 %P 783-91 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890755?dopt=Abstract %R 10.3233/JAD-150838 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Integrated Analysis of Alzheimer's Disease and Schizophrenia Dataset Revealed Different Expression Pattern in Learning and Memory. %A Li, Wen-Xing %A Dai, Shao-Xing %A Liu, Jia-Qian %A Wang, Qian %A Li, Gong-Hua %A Huang, Jing-Fei %K Adult %K Aged %K Aged, 80 and over %K Algorithms %K Alzheimer Disease %K Bayes Theorem %K Brain %K Datasets as Topic %K Gene Expression Profiling %K Humans %K Learning %K Memory %K Microarray Analysis %K Middle Aged %K Schizophrenia %K Schizophrenic Psychology %K Young Adult %X

Alzheimer's disease (AD) and schizophrenia (SZ) are both accompanied by impaired learning and memory functions. This study aims to explore the expression profiles of learning or memory genes between AD and SZ. We downloaded 10 AD and 10 SZ datasets from GEO-NCBI for integrated analysis. These datasets were processed using RMA algorithm and a global renormalization for all studies. Then Empirical Bayes algorithm was used to find the differentially expressed genes between patients and controls. The results showed that most of the differentially expressed genes were related to AD whereas the gene expression profile was little affected in the SZ. Furthermore, in the aspects of the number of differentially expressed genes, the fold change and the brain region, there was a great difference in the expression of learning or memory related genes between AD and SZ. In AD, the CALB1, GABRA5, and TAC1 were significantly downregulated in whole brain, frontal lobe, temporal lobe, and hippocampus. However, in SZ, only two genes CRHBP and CX3CR1 were downregulated in hippocampus, and other brain regions were not affected. The effect of these genes on learning or memory impairment has been widely studied. It was suggested that these genes may play a crucial role in AD or SZ pathogenesis. The different gene expression patterns between AD and SZ on learning and memory functions in different brain regions revealed in our study may help to understand the different mechanism between two diseases.

%B J Alzheimers Dis %V 51 %P 417-25 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890750?dopt=Abstract %R 10.3233/JAD-150807 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Language Profile of Behavioral Variant Frontotemporal Dementia. %A Hardy, Chris J D %A Buckley, Aisling H %A Downey, Laura E %A Lehmann, Manja %A Zimmerer, Vitor C %A Varley, Rosemary A %A Crutch, Sebastian J %A Rohrer, Jonathan D %A Warrington, Elizabeth K %A Warren, Jason D %K Aged %K Aphasia, Primary Progressive %K Atrophy %K Brain %K Cognition %K Comprehension %K Female %K Frontotemporal Dementia %K Humans %K Language %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Primary Progressive Nonfluent Aphasia %X

BACKGROUND: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined.

OBJECTIVE: We aimed to quantify the extent of language deficits in this patient group.

METHODS: We assessed a cohort of patients with bvFTD (n = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n = 14), nonfluent variant primary progressive aphasia (nfvPPA; n = 18), and healthy age-matched individuals (n = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients' brain magnetic resonance images.

RESULTS: Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network.

CONCLUSIONS: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker.

%B J Alzheimers Dis %V 50 %P 359-71 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682693?dopt=Abstract %R 10.3233/JAD-150806 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Late Life Risk Index for Severe Cognitive Impairment in Mexico. %A Downer, Brian %A Veeranki, Sreenivas P %A Wong, Rebeca %K Age Factors %K Aged %K Cognitive Dysfunction %K Female %K Humans %K Life Style %K Logistic Models %K Longitudinal Studies %K Male %K Mexico %K Middle Aged %K Multivariate Analysis %K Risk Factors %K Social Behavior %K Socioeconomic Factors %X

BACKGROUND: Several dementia risk indices have been developed for older adults in high-income countries. However, no index has been developed for populations in low- or middle-income countries.

OBJECTIVE: To create a risk index for predicting severe cognitive impairment among adults aged ≥60 in Mexico and to compare the accuracy of this index to the Dementia Screening Indicator (DSI).

METHODS: This study included 3,002 participants from the Mexican Health and Aging Study (MHAS) interviewed in 2001 and 2012. The MHAS risk index included sociodemographic, health, and functional characteristics collected in 2001. A point value based on the beta coefficients from a multivariable logistic regression model was assigned to each risk factor and the total score was calculated.

RESULTS: The MHAS risk index (AUC = 0.74 95% CI = 0.70-0.77) and DSI (AUC = 0.72 95% CI = 0.69-0.77) had similar accuracy for discriminating between participants who developed severe cognitive impairment from those who did not. A score of ≥16 on the MHAS risk index had a sensitivity of 0.69 (95% CI = 0.64-0.70) and specificity of 0.67 (95% CI = 0.66-0.69). A score of ≥23 on the DSI had a sensitivity of 0.56 (95% CI = 0.50-0.63) and specificity of 0.78 (95% CI = 0.76-0.79).

DISCUSSION: The MHAS risk index and DSI have moderate accuracy for predicting severe cognitive impairment among older adults in Mexico. This provides evidence that existing dementia risk indices may be applicable in low- and middle-income countries such as Mexico. Future research should seek to identify additional risk factors that can improve the accuracy of the MHAS risk index.

%B J Alzheimers Dis %V 52 %P 191-203 %8 2016 03 08 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27060940?dopt=Abstract %R 10.3233/JAD-150702 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment. %A Koppara, Alexander %A Wolfsgruber, Steffen %A Kleineidam, Luca %A Schmidtke, Klaus %A Frölich, Lutz %A Kurz, Alexander %A Schulz, Stefanie %A Hampel, Harald %A Heuser, Isabella %A Peters, Oliver %A Reischies, Friedel M %A Jahn, Holger %A Luckhaus, Christian %A Hüll, Michael %A Gertz, Hermann-Josef %A Schröder, Johannes %A Pantel, Johannes %A Rienhoff, Otto %A Rüther, Eckart %A Henn, Fritz %A Wiltfang, Jens %A Maier, Wolfgang %A Jessen, Frank %A Kornhuber, Johannes %A Wagner, Michael %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptide Fragments %K Phenotype %K Predictive Value of Tests %K Retrospective Studies %K tau Proteins %X

BACKGROUND: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials.

OBJECTIVE: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI).

METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences.

RESULTS: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects.

CONCLUSION: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.

%B J Alzheimers Dis %V 49 %P 547-60 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484902?dopt=Abstract %R 10.3233/JAD-150257 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Late-Onset Metachromatic Leukodystrophy with Early Onset Dementia Associated with a Novel Missense Mutation in the Arylsulfatase A Gene. %A Stoeck, Katharina %A Psychogios, Marios Nikos %A Ohlenbusch, Andreas %A Steinfeld, Robert %A Schmidt, Jens %K Age of Onset %K Brain %K Cerebroside-Sulfatase %K Dementia %K Diagnosis, Differential %K DNA Mutational Analysis %K Exons %K Humans %K Leukodystrophy, Metachromatic %K Male %K Middle Aged %K Mutation, Missense %K Neuropsychological Tests %X

A 48-year-old male patient presented with personality changes and progressive memory loss over 2 years with initially suspected Hashimoto's encephalopathy. Strategy of diagnostic workup of early onset dementia included dementia from neurodegenerative, neuroinflammatory, metabolic/toxic, and psychiatric origin. The patient's neurological exam was normal. MRI revealed a leukencephalopathy, predominantly in the frontal periventricular white matter, without notable changes over 2 years. On neurophysiological examination, prolonged central conduction times and a sensorimotor polyneuropathy were noted. Neuropsychological impairment included disorientation in place and a reduced short time memory. Behavioral alterations were predominated by sudden mood changes and disinhibition. Cerebrospinal fluid was normal. Despite presence of thyroid autoantibodies, glucocorticosteroid treatment did not improve the dementia. A metachromatic leukodystrophy was diagnosed by decreased arylsulfatase-A activity in leucocytes/fibroblasts and identification of a compound heterozygous mutation in the ARSA gene: c.542T>G (exon 3) and the novel mutation c.1013T>C (exon 6). Pathogenic function was suggested by bioinformatic mutation search. In a patient with early onset dementia, strategic diagnostic workup including genetic assessment revealed an adult-onset metachromatic leukodystrophy with a novel mutation in the arylsulfatase A gene.

%B J Alzheimers Dis %V 51 %P 683-7 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890752?dopt=Abstract %R 10.3233/JAD-150819 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer's Disease. %A Fischer, Corinne E %A Qian, Winnie %A Schweizer, Tom A %A Millikin, Colleen P %A Ismail, Zahinoor %A Smith, Eric E %A Lix, Lisa M %A Shelton, Paul %A Munoz, David G %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition Disorders %K Databases, Factual %K Dementia, Vascular %K Female %K Hemorrhage %K Humans %K Lewy Bodies %K Male %K Middle Aged %K Psychiatric Status Rating Scales %K Psychotic Disorders %K Retrospective Studies %K Risk Factors %K Severity of Illness Index %K Surveys and Questionnaires %X

BACKGROUND: The neuropathological correlates of psychosis in Alzheimer's disease (AD) is unclear, with some studies reporting a correlation between psychosis and increased AD pathology while others have found no association.

OBJECTIVE: To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD.

METHOD: We separately reviewed two overlapping groups of clinically diagnosed (cAD) AD patients with neuropathology data and neuropathologically definite (npAD) cases (regardless of clinical diagnosis) from the NACC database, and explored the relationships between psychosis and clinical variables, neuropathologic correlates, and vascular risk factors. Delusions and hallucinations, defined according to the NPI-Q, were analyzed separately.

RESULTS: 1,073 subjects in the database fulfilled our criteria (890 cAD and 728 npAD patients). 34% of cAD and 37% of npAD had psychotic symptoms during their illness. Hallucinations were associated with greater cognitive and functional impairments on the MMSE and CDR, while delusional patients showed less impairment on CDR, consistent across cAD and npAD groups. Burden of AD pathology appears to relate to presence of psychotic symptoms in the clinical AD group, but this result is not confirmed in the neuropathologically confirmed group suggesting the findings in the clinical group were due to misdiagnosis of AD. Lewy body pathology, subcortical arteriosclerotic leukoencephalopathy, and vascular risk factors, including a history of hypertension and diabetes, were associated with the development of psychosis.

METHOD: Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD.

%B J Alzheimers Dis %V 50 %P 283-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682680?dopt=Abstract %R 10.3233/JAD-150606 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lifelong Reading Disorder and Mild Cognitive Impairment: Implications for Diagnosis. %A Lebowitz, Brian K %A Weinstein, Cheryl %A Beiser, Alexa %A Seshadri, Sudha %A Wolf, Philip A %A Auerbach, Sandford %A Au, Rhoda %K Aged %K Aged, 80 and over %K Cognitive Dysfunction %K Dyslexia %K Female %K Humans %K Independent Living %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Psychometrics %K Retrospective Studies %X

Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification.

%B J Alzheimers Dis %V 50 %P 41-5 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639959?dopt=Abstract %R 10.3233/JAD-150543 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Linguistic Features Identify Alzheimer's Disease in Narrative Speech. %A Fraser, Kathleen C %A Meltzer, Jed A %A Rudzicz, Frank %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Diagnosis, Computer-Assisted %K Factor Analysis, Statistical %K Female %K Humans %K Language Disorders %K Linguistics %K Logistic Models %K Machine Learning %K Male %K Mental Status Schedule %K Middle Aged %K Narration %K Photic Stimulation %K Speech %K Verbal Behavior %X

BACKGROUND: Although memory impairment is the main symptom of Alzheimer's disease (AD), language impairment can be an important marker. Relatively few studies of language in AD quantify the impairments in connected speech using computational techniques.

OBJECTIVE: We aim to demonstrate state-of-the-art accuracy in automatically identifying Alzheimer's disease from short narrative samples elicited with a picture description task, and to uncover the salient linguistic factors with a statistical factor analysis.

METHODS: Data are derived from the DementiaBank corpus, from which 167 patients diagnosed with "possible" or "probable" AD provide 240 narrative samples, and 97 controls provide an additional 233. We compute a number of linguistic variables from the transcripts, and acoustic variables from the associated audio files, and use these variables to train a machine learning classifier to distinguish between participants with AD and healthy controls. To examine the degree of heterogeneity of linguistic impairments in AD, we follow an exploratory factor analysis on these measures of speech and language with an oblique promax rotation, and provide interpretation for the resulting factors.

RESULTS: We obtain state-of-the-art classification accuracies of over 81% in distinguishing individuals with AD from those without based on short samples of their language on a picture description task. Four clear factors emerge: semantic impairment, acoustic abnormality, syntactic impairment, and information impairment.

CONCLUSION: Modern machine learning and linguistic analysis will be increasingly useful in assessment and clustering of suspected AD.

%B J Alzheimers Dis %V 49 %P 407-22 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484921?dopt=Abstract %R 10.3233/JAD-150520 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer's Disease. %A Serra, Laura %A Cercignani, Mara %A Mastropasqua, Chiara %A Torso, Mario %A Spanò, Barbara %A Makovac, Elena %A Viola, Vanda %A Giulietti, Giovanni %A Marra, Camillo %A Caltagirone, Carlo %A Bozzali, Marco %K Aged %K Alzheimer Disease %K Atrophy %K Brain %K Brain Mapping %K Cognitive Dysfunction %K Cross-Sectional Studies %K Discriminant Analysis %K Disease Progression %K Female %K Follow-Up Studies %K Gray Matter %K Humans %K Image Processing, Computer-Assisted %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Neural Pathways %K Neuropsychological Tests %K Prognosis %K Rest %X

This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer's disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.

%B J Alzheimers Dis %V 51 %P 377-89 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890769?dopt=Abstract %R 10.3233/JAD-150961 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Memory Profiles in Behavioral-Variant Frontotemporal Dementia and Alzheimer's Disease. %A Schubert, Samantha %A Leyton, Cristian E %A Hodges, John R %A Piguet, Olivier %K Alzheimer Disease %K Aniline Compounds %K Brain %K Diagnosis, Differential %K Disease Progression %K Executive Function %K Female %K Follow-Up Studies %K Frontotemporal Dementia %K Humans %K Longitudinal Studies %K Male %K Memory %K Middle Aged %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Thiazoles %X

BACKGROUND: Alzheimer's disease (AD) and behavioral-variant of frontotemporal dementia (bvFTD) can present with an overlapping neuropsychological profile, which often hinders their clinical differentiation.

OBJECTIVE: To compare changes over time in memory, general cognition tasks, and functional scales between bvFTD and AD.

METHODS: Consecutive cases diagnosed with probable bvFTD (n = 22) and typical AD (n = 31) with at least two clinical visits were selected. Of these, 13 (9 AD, 4 bvFTD) underwent Pittsburgh compound B PET scan, which supported the clinical diagnosis in all cases. Mixed-model regressions were used to estimate the differential rate of decline on selected tasks between cohorts.

RESULTS: Analyses demonstrated that, despite equivalent baseline performance, bvFTD patients experienced a more rapid functional deterioration and a steeper decline in global cognition than AD patients. At baseline, both groups were impaired on executive function and memory tasks compared to controls, but these deficits were more marked in the bvFTD group. In addition, performance on these domains continued to decline more rapidly in this group.

CONCLUSIONS: Neither the initial neuropsychological assessment nor projected performances can reliably distinguish the totality of bvFTD and AD individuals. Nevertheless, annual rates of progression on cognitive tasks provide valuable information and will potentially help establish the impact of future therapeutic treatments in these dementia syndromes.

%B J Alzheimers Dis %V 51 %P 775-82 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890749?dopt=Abstract %R 10.3233/JAD-150802 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer's Disease. %A Sattlecker, Martina %A Khondoker, Mizanur %A Proitsi, Petroula %A Williams, Stephen %A Soininen, Hilkka %A Kłoszewska, Iwona %A Mecocci, Patrizia %A Tsolaki, Magda %A Vellas, Bruno %A Lovestone, Simon %A Dobson, Richard Jb %K Aged %K Alzheimer Disease %K Biomarkers %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Mental Status Schedule %K Neuropsychological Tests %X

Biomarkers of Alzheimer's disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects.

%B J Alzheimers Dis %V 49 %P 1105-14 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599049?dopt=Abstract %R 10.3233/JAD-140669 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Lower Prevalence of Alzheimer's Disease among Tibetans: Association with Religious and Genetic Factors. %A Huang, Fukai %A Shang, Ying %A Luo, Yuandai %A Wu, Peng %A Huang, Xue %A Tan, Xiaohui %A Lu, Xingyi %A Zhen, Lifang %A Hu, Xianda %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Clusterin %K Cognition Disorders %K Cross-Sectional Studies %K Female %K Genetic Association Studies %K Genetic Predisposition to Disease %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Polymorphism, Single Nucleotide %K Psychiatric Status Rating Scales %K Religion %K Risk Factors %K Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization %K Tibet %X

BACKGROUND: The prevalence of dementia differs among racial groups, the highest prevalence being in Latin America (8.5%) compared to sub-Saharan African regions (2-4%). The most common type of dementia is Alzheimer's disease (AD).

OBJECTIVE: To estimate the prevalence of AD in the Qinghai-Tibet plateau and to investigate the related factors.

METHODS: This was a cross-sectional, multistage cluster sampling design survey. Data was collected from May 2014 to September 2014 from 4,060 Tibetan aged >60 years. Participants underwent clinical examinations and neuropsychological evaluations. MALDI-TOF was used to test the genotypes of CLU, TFAM, TP53INP1, IGHV1-67, CR1, ApoE, and BIN1. Logistic regression models were used to ascertain the associations with AD.

RESULTS: The prevalence of AD among Tibetan individuals aged >60 years was 1.33% (95% CI: 0.98-1.69). The CLU haplotypes AA+GA (odds ratio (OR) = 4.483; 95% CI: 1.069-18.792) of rs2279590 was correlated with AD. The CLU haplotypes GG+GC (OR = 0.184; 95% CI: 0.038-0.888) of rs9331888 and kowtow (OR = 0.203; 95% CI 0.046-0.896) were negatively correlated with AD.

CONCLUSION: A low prevalence of AD was found in Tibetans from the Qinghai-Tibet plateau. Multivariate analysis might suggest that regular "mind-body" religious meditative activities may be negatively associated with AD in this population, as well as the CLU genotype at rs9331888.

%B J Alzheimers Dis %V 50 %P 659-67 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757186?dopt=Abstract %R 10.3233/JAD-150697 %0 Journal Article %J J Alzheimers Dis %D 2016 %T MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium. %A Pastor, Pau %A Moreno, Fermín %A Clarimón, Jordi %A Ruiz, Agustin %A Combarros, Onofre %A Calero, Miguel %A López de Munain, Adolfo %A Bullido, Maria J %A de Pancorbo, Marian M %A Carro, Eva %A Antonell, Anna %A Coto, Eliecer %A Ortega-Cubero, Sara %A Hernandez, Isabel %A Tárraga, Lluís %A Boada, Merce %A Lleo, Alberto %A Dols-Icardo, Oriol %A Kulisevsky, Jaime %A Vázquez-Higuera, José Luis %A Infante, Jon %A Rábano, Alberto %A Fernández-Blázquez, Miguel Ángel %A Valentí, Meritxell %A Indakoetxea, Begoña %A Barandiarán, Myriam %A Gorostidi, Ana %A Frank-García, Ana %A Sastre, Isabel %A Lorenzo, Elena %A Pastor, María A %A Elcoroaristizabal, Xabier %A Lennarz, Martina %A Maier, Wolfang %A Rámirez, Alfredo %A Serrano-Ríos, Manuel %A Lee, Suzee E %A Sánchez-Juan, Pascual %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Apolipoprotein E4 %K Female %K Frontotemporal Dementia %K Genetic Predisposition to Disease %K Haplotypes %K Humans %K Logistic Models %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Spain %K tau Proteins %X

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.

%B J Alzheimers Dis %V 49 %P 343-52 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444794?dopt=Abstract %R 10.3233/JAD-150555 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Memory for Public Events in Mild Cognitive Impairment and Alzheimer's Disease: The Importance of Rehearsal. %A Langlois, Roxane %A Joubert, Sven %A Benoit, Sophie %A Dostie, Valérie %A Rouleau, Isabelle %K Aged %K Alzheimer Disease %K Cognitive Dysfunction %K Female %K Humans %K Learning %K Male %K Memory %K Psychological Tests %K Semantics %X

Ribot's law refers to the better preservation of remote memories compared with recent ones that presumably characterizes retrograde amnesia. Even if Ribot-type temporal gradient has been extensively studied in retrograde amnesia, particularly in Alzheimer's disease (AD), this pattern has not been consistently found. One explanation for these results may be that rehearsal frequency rather than remoteness accounts for the better preservation of these memories. Thus, the aim of present study was to address this question by studying retrograde semantic memory in subjects with amnestic mild cognitive impairment (aMCI) (n = 20), mild AD (n = 20) and in healthy older controls (HC; n = 19). In order to evaluate the impact of repetition as well as the impact of remoteness, we used a test assessing memory for enduring and transient public events that occurred in the recent and remote past. Results show no clear temporal gradient across time periods (1960-1975; 1976-1990; 1991-2005; 2006-2011), but a better performance was observed in all three groups for enduring compared with transient events. Moreover, although deficits were globally found in both patients groups compared with HC, more specific analyses revealed that aMCI patients were only impaired on transient events while AD patients were impaired on both transient and enduring events. Exploratory analyses also revealed a tendency suggesting preservation of remote transient events in aMCI. These findings are discussed with regards to memory consolidation models.

%B J Alzheimers Dis %V 50 %P 1023-33 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836162?dopt=Abstract %R 10.3233/JAD-150722 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation. %A Son, Sung Min %A Shin, Hong-Joon %A Byun, Jayoung %A Kook, Sun Young %A Moon, Minho %A Chang, Yu Jin %A Mook-Jung, Inhee %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Autophagy %K Cell Line, Tumor %K Disease Models, Animal %K Female %K Humans %K Hypoglycemic Agents %K Lysosomes %K Metformin %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microscopy, Electron %K Mutation %K Neuroblastoma %K Signal Transduction %X

The evidence of strong pathological associations between type 2 diabetes and Alzheimer's disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage®) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ-secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ-secretase activity and Aβ generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes.

%B J Alzheimers Dis %V 51 %P 1197-208 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967226?dopt=Abstract %R 10.3233/JAD-151200 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Mindfulness in the Maintenance of Cognitive Capacities in Alzheimer's Disease: A Randomized Clinical Trial. %A Quintana-Hernández, Domingo J %A Miró-Barrachina, María T %A Ibáñez-Fernández, Ignacio J %A Pino, Angelo Santana-Del %A Quintana-Montesdeoca, María P %A Rodríguez-de Vera, Bienvenida %A Morales-Casanova, David %A Pérez-Vieitez, María Del Carmen %A Rodríguez-García, Javier %A Bravo-Caraduje, Noelia %K Age Factors %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Cognition Disorders %K Double-Blind Method %K Female %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Mindfulness %K Neuropsychological Tests %K Treatment Outcome %X

BACKGROUND: The Canary Islands longitudinal study on non-pharmacological treatments showed the overall effectiveness of mindfulness in Alzheimer's disease (AD). However, no specific data on the maintenance of cognitive capacities were presented.

OBJECTIVE: To determine whether the practice of mindfulness modifies the course of cognitive impairment in AD.

METHODS:

DESIGN: Longitudinal, non-inferiority and equivalence, randomized clinical trial, repeated-measures design, with three experimental groups and one control group.

PARTICIPANTS: Patients with AD who voluntarily attended the Lidia García Foundation (n = 502). Only those who were treated with donepezil and MMSE ≥18 were included (n = 120).

INTERVENTION: Over a two-year period, each group carried out three weekly sessions of stimulation based on mindfulness, cognitive stimulation therapy, and progressive muscle relaxation.

MEASURES: Cognitive assessment CAMDEX-R (MMSE and CAMCOG).

STATISTICAL ANALYSIS: Repeated-measures ANOVA (p <  0.05) and the effect size Cohen's d were performed.

RESULTS: The mindfulness group showed significant scores compared with the control and muscle relaxation groups (p <  0.05), while mindfulness and cognitive stimulation therapy were equivalent (p≥0.05). Group cognitive stimulation evolved better than the control (p <  0.05) group but not better than the muscle relaxation group (p≥0.05). The effect size compared over two years was large for the mindfulness group (p≥0.80), moderate for the relaxation group (p≥0.50), and low for the cognitive stimulation group (p≥0.20).

CONCLUSION: The practice of mindfulness maintained cognitive function over a period of two years. This longitudinal study suggests that mindfulness can be used as a non-pharmacological treatment to slow cognitive impairment in AD.

%B J Alzheimers Dis %V 50 %P 217-32 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639952?dopt=Abstract %R 10.3233/JAD-143009 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Naphthoquinone-Tryptophan Hybrid Inhibits Aggregation of the Tau-Derived Peptide PHF6 and Reduces Neurotoxicity. %A Frenkel-Pinter, Moran %A Tal, Sharon %A Scherzer-Attali, Roni %A Abu-Hussien, Malak %A Alyagor, Idan %A Eisenbaum, Tal %A Gazit, Ehud %A Segal, Daniel %K Animals %K Carrier Proteins %K Disease Models, Animal %K Drosophila %K Drosophila Proteins %K Eye %K Female %K Humans %K Immunoprecipitation %K In Vitro Techniques %K Larva %K Locomotion %K Mice, Transgenic %K Microscopy, Electron, Scanning %K Naphthoquinones %K Neurotoxicity Syndromes %K Protein Aggregates %K Retinal Pigments %K tau Proteins %K Tryptophan %X

Tauopathies, such as Alzheimer's disease (AD), are a group of disorders characterized neuropathologically by intracellular toxic accumulations of abnormal protein aggregates formed by misfolding of the microtubule-associated protein tau. Since protein self-assembly appears to be an initial key step in the pathology of this group of diseases, intervening in this process can be both a prophylactic measure and a means for modifying the course of the disease for therapeutic purposes. We and others have shown that aromatic small molecules can be effective inhibitors of aggregation of various protein assemblies, by binding to the aromatic core in aggregation-prone motifs and preventing their self-assembly. Specifically, we have designed a series of small aromatic naphthoquinone-tryptophan hybrid molecules as candidate aggregation inhibitors of β -sheet based assembly and demonstrated their efficacy toward inhibiting aggregation of the amyloid-β peptide, another culprit of AD, as well as of various other aggregative proteins involved in other protein misfolding diseases. Here we tested whether a leading naphthoquinone-tryptophan hybrid molecule, namely NQTrp, can be repurposed as an inhibitor of the aggregation of the tau protein in vitro and in vivo. We show that the molecule inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau protein, reduces hyperphosphorylated tau deposits and ameliorates tauopathy-related behavioral defect in an established transgenic Drosophila model expressing human tau. We suggest that NQTrp, or optimized versions of it, could act as novel disease modifying drugs for AD and other tauopathies.

%B J Alzheimers Dis %V 51 %P 165-78 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836184?dopt=Abstract %R 10.3233/JAD-150927 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Non-Verbal Episodic Memory Deficits in Primary Progressive Aphasias are Highly Predictive of Underlying Amyloid Pathology. %A Ramanan, Siddharth %A Flanagan, Emma %A Leyton, Cristian E %A Villemagne, Victor L %A Rowe, Christopher C %A Hodges, John R %A Hornberger, Michael %K Aged %K Alzheimer Disease %K Amyloid %K Aniline Compounds %K Aphasia, Primary Progressive %K Brain %K Diagnosis, Differential %K Female %K Humans %K Logistic Models %K Male %K Memory, Episodic %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Speech Perception %K Thiazoles %X

Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer's disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases.

%B J Alzheimers Dis %V 51 %P 367-76 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890745?dopt=Abstract %R 10.3233/JAD-150752 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease. %A Fà, Mauro %A Zhang, Hong %A Staniszewski, Agnieszka %A Saeed, Faisal %A Shen, Li W %A Schiefer, Isaac T %A Siklos, Marton I %A Tapadar, Subhasish %A Litosh, Vladislav A %A Libien, Jenny %A Petukhov, Pavel A %A Teich, Andrew F %A Thatcher, Gregory R J %A Arancio, Ottavio %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cysteine Proteinase Inhibitors %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Fear %K Glycoproteins %K Hippocampus %K Humans %K In Vitro Techniques %K Long-Term Potentiation %K Maze Learning %K Memory %K Mice %K Mice, Inbred ICR %K Mice, Transgenic %K Mutation %K Patch-Clamp Techniques %K Peptide Fragments %K Presenilin-1 %K Spectrin %X

Alzheimer's disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-β, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer's disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid-β elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease.

%B J Alzheimers Dis %V 49 %P 707-21 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484927?dopt=Abstract %R 10.3233/JAD-150618 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Nutritional Status is Associated with Faster Cognitive Decline and Worse Functional Impairment in the Progression of Dementia: The Cache County Dementia Progression Study1. %A Sanders, Chelsea %A Behrens, Stephanie %A Schwartz, Sarah %A Wengreen, Heidi %A Corcoran, Chris D %A Lyketsos, Constantine G %A Tschanz, JoAnn T %K Age of Onset %K Aged, 80 and over %K Alzheimer Disease %K Dementia, Vascular %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Nutritional Status %K Severity of Illness Index %K Sex Factors %K Utah %X

Nutritional status may be a modifiable factor in the progression of dementia. We examined the association of nutritional status and rate of cognitive and functional decline in a U.S. population-based sample. Study design was an observational longitudinal study with annual follow-ups up to 6 years of 292 persons with dementia (72% Alzheimer's disease, 56% female) in Cache County, UT using the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-sb), and modified Mini Nutritional Assessment (mMNA). mMNA scores declined by approximately 0.50 points/year, suggesting increasing risk for malnutrition. Lower mMNA score predicted faster rate of decline on the MMSE at earlier follow-up times, but slower decline at later follow-up times, whereas higher mMNA scores had the opposite pattern (mMNA by time β= 0.22, p = 0.017; mMNA by time2 β= -0.04, p = 0.04). Lower mMNA score was associated with greater impairment on the CDR-sb over the course of dementia (β= 0.35, p <  0.001). Assessment of malnutrition may be useful in predicting rates of progression in dementia and may provide a target for clinical intervention.

%B J Alzheimers Dis %V 52 %P 33-42 %8 2016 02 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967207?dopt=Abstract %R 10.3233/JAD-150528 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Older Adults Taking AT1-Receptor Blockers Exhibit Reduced Cerebral Amyloid Retention. %A Nation, Daniel A %A Ho, Jean %A Yew, Belinda %K Aged %K Aged, 80 and over %K Aging %K Amyloid beta-Peptides %K Angiotensin Receptor Antagonists %K Antihypertensive Agents %K Chi-Square Distribution %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Psychiatric Status Rating Scales %K Regression Analysis %K tau Proteins %K Time Factors %X

BACKGROUND: Evidence suggests that angiotensin II AT1-receptor blockers (ARBs) may be protective against dementia, and studies in transgenic animals indicate that this may be due to improved amyloid-β (Aβ) clearance.

OBJECTIVE: We investigated whether taking ARBs was associated with an attenuation of age-related increases in cerebral Aβ retention, and reduced progression to dementia.

METHODS: Eight hundred seventy-one stroke-free and dementia-free older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study underwent baseline lumbar puncture, and a subgroup (n = 124) underwent 12 and 24 month follow-up lumbar puncture. Participants were followed at variable intervals for clinical progression to dementia. Linear mixed models and ANCOVA compared ARBs users with those taking other antihypertensives (O-antiHTN) or no antihypertensives (No-antiHTN) on cerebrospinal fluid (CSF) Aβ and phosphorylated tau (P-tau) levels. Cox regression and chi-square analyses compared groups on progression to dementia.

RESULTS: ARBs users exhibited greater vascular risk and lower educational attainment than the No-antiHTN group. Longitudinal analyses indicated higher CSF Aβ and lower P-tau in ARBs users versus other groups. Cross-sectional analyses revealed age-related decreases in CSF Aβ in other groups but not ARBs users. ARBs users were less likely to progress to dementia and showed reduced rate of progression relative to the No-antiHTN group.

DISCUSSION: Patients taking ARBs showed an attenuation of age-related decreases in CSF Aβ, a finding that is consistent with studies done in transgenic animals. These findings may partly explain why ARBs users show reduced progression to dementia despite their lower educational attainment and greater vascular risk burden.

%B J Alzheimers Dis %V 50 %P 779-89 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757036?dopt=Abstract %R 10.3233/JAD-150487 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Pain Assessment in Elderly with Behavioral and Psychological Symptoms of Dementia. %A Malara, Alba %A De Biase, Giuseppe Andrea %A Bettarini, Francesco %A Ceravolo, Francesco %A Di Cello, Serena %A Garo, Michele %A Praino, Francesco %A Settembrini, Vincenzo %A Sgrò, Giovanni %A Spadea, Fausto %A Rispoli, Vincenzo %K Affect %K Aged, 80 and over %K Analgesics %K Anxiety %K Dementia %K Depression %K Female %K Humans %K Italy %K Logistic Models %K Long-Term Care %K Male %K Multivariate Analysis %K Nursing Homes %K Pain %K Pain Measurement %K Prevalence %K Prospective Studies %K Psychiatric Status Rating Scales %K Self Report %K Severity of Illness Index %X

BACKGROUND: Pain is under-detected and undertreated in people with dementia. The present study investigates the prevalence of pain in people with dementia hospitalized in nursing homes that are members of National Association of Third Age Residences (ANASTE) Calabria, and evaluates the association among pain, mood, and behavioral and psychological symptoms of dementia (BPSD).

OBJECTIVE: The aim of this study is to define the prevalence of pain in people with dementia in long term care facilities using scales of self-reporting and observational tools and, particularly, to study the relationship between pain and BPSD.

METHODS: A prospective observational study was carried out on 233 patients. Pain assessment was performed using self-reporting tools such as the Numeric Rating Scale (NRS) for patients with slight cognitive impairment or no cognitive impairment and observational tools such as Pain Assessment In Advanced Dementia Scale (PAINAD) for patients with moderate or severe cognitive impairment. Mood was evaluated through the Cornell Scale for Depression in Dementia (CSDD) while behavioral problems were assessed through the Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory (NPI).

RESULTS: Only 42.5% of patients evaluated by NRS provided a reliable answer; of these, 20.4% reported no pain. The percentage of pain evaluated by PAINAD was 51.8% . Analysis of data showed a statistically significant correlation between diagnosis of pain and depressive symptoms, assessed with CSDD (p = 0.0113), as well as by single items of NPI, such as anxiety (p = 0.0362) and irritability (p = 0.0034), and F1 profile (Aggression) of CMAI (p = 0.01).

CONCLUSION: This study confirms that self-report alone is not sufficient to assess pain in elderly people with dementia; the observational tool is a necessary and suitable way of assessing pain in patients with cognitive impairment. If not adequately treated, chronic pain can cause depression, agitation, and aggression in patients with dementia.

%B J Alzheimers Dis %V 50 %P 1217-25 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757042?dopt=Abstract %R 10.3233/JAD-150808 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Palmomental Reflex a Relevant Sign in Early Alzheimer's Disease Diagnosis? %A Gabelle, Audrey %A Gutierrez, Laure-Anne %A Dartigues, Jean-François %A Ritchie, Karen %A Touchon, Jacques %A Berr, Claudine %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Early Diagnosis %K Female %K Follow-Up Studies %K France %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Reflex %X

BACKGROUND: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer's disease (AD). The amyloid process seems to be early in AD, and brain amyloid load affects the frontal lobe.

OBJECTIVE: To determine if certain simple clinical signs, especially frontal-related signs, could help reach an earlier and better diagnosis.

METHODS: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of AD to controls matched for age, gender, and education. The standardized neurological exam included extrapyramidal signs (akinesia, rigidity, rest tremor), pyramidal symptoms (spastic rigidity, Babinski reflex), primitive reflexes (snout, palmomental reflex grasping), and tremor (essential, intentional, head) at the time of diagnosis and two years before.

RESULTS: We compared 106 incident AD subjects (mean age at diagnosis 82.2 (SD = 5.9); median MMSE at diagnosis = 23) to 208 matched controls. In patients younger than 80, palmomental reflexes were more frequent in AD than controls, two years before diagnosis (25.0 versus 7.0% , p = 0.03) and at time of diagnosis (30.3 versus 12.3% , p = 0.02). No difference was observed for other signs two years before diagnosis or for patients older than 80.

CONCLUSION: Before diagnosis, the clinical examination of AD patients is not strictly normal; the primitive reflexes appear to be pathological. It might be in connection with the frontal amyloid load at an early stage of the disease. Clinical examination can reveal simple and interesting signs that deserve consideration as well as the other more invasive and expensive biomarkers.

%B J Alzheimers Dis %V 49 %P 1135-41 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639955?dopt=Abstract %R 10.3233/JAD-150436 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patients with Mild Alzheimer's Disease Fail When Using Their Working Memory: Evidence from the Eye Tracking Technique. %A Fernández, Gerardo %A Manes, Facundo %A Politi, Luis E %A Orozco, David %A Schumacher, Marcela %A Castro, Liliana %A Agamennoni, Osvaldo %A Rotstein, Nora P %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Eye Movements %K Female %K Humans %K Linear Models %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Short-Term %K Mental Recall %K Mental Status Schedule %K Predictive Value of Tests %K Semantics %K Verbal Learning %X

Patients with Alzheimer's disease (AD) develop progressive language, visuoperceptual, attentional, and oculomotor changes that can have an impact on their reading comprehension. However, few studies have examined reading behavior in AD, and none have examined the contribution of predictive cueing in reading performance. For this purpose we analyzed the eye movement behavior of 35 healthy readers (Controls) and 35 patients with probable AD during reading of regular and high-predictable sentences. The cloze predictability of words N - 1, and N + 1 exerted an influence on the reader's gaze duration. The predictabilities of preceding words in high-predictable sentences served as task-appropriate cues that were used by Control readers. In contrast, these effects were not present in AD patients. In Controls, changes in predictability significantly affected fixation duration along the sentence; noteworthy, these changes did not affect fixation durations in AD patients. Hence, only in healthy readers did predictability of upcoming words influence fixation durations via memory retrieval. Our results suggest that Controls used stored information of familiar texts for enhancing their reading performance and imply that contextual-word predictability, whose processing is proposed to require memory retrieval, only affected reading behavior in healthy subjects. In AD patients, this loss reveals impairments in brain areas such as those corresponding to working memory and memory retrieval. These findings might be relevant for expanding the options for the early detection and monitoring in the early stages of AD. Furthermore, evaluation of eye movements during reading could provide a new tool for measuring drug impact on patients' behavior.

%B J Alzheimers Dis %V 50 %P 827-38 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836011?dopt=Abstract %R 10.3233/JAD-150265 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Performance on Specific Cognitive Domains and Cause of Death: A Prospective Population-Based Study in Non-Demented Older Adults (NEDICES). %A Benito-León, Julián %A Contador, Israel %A Mitchell, Alex J %A Domingo-Santos, Ángela %A Bermejo-Pareja, Félix %K Aged %K Cause of Death %K Cerebrovascular Disorders %K Cognitive Aging %K Dementia %K Educational Status %K Female %K Follow-Up Studies %K Humans %K Intelligence %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Prospective Studies %K Risk %K Spain %X

Evidence regarding the relationship between performance on specific cognitive domains and cause of death is scarce. We assessed whether specific cognitive domains predicted mortality and the presence of any association with specific causes of death in a population-dwelling sample of non-demented older adults. In this population-based, prospective study (NEDICES), 2,390 non-demented subjects ≥65 years completed a brief neuropsychological battery. Cox's proportional hazards models, adjusted by sociodemographic and comorbidity factors, global cognitive performance, educational level, and premorbid intelligence were used to assess the risk of death. Participants were followed for a median of 9.2 years (range 0.01-10.7), after which the death certificates of those who died were examined. 880 (36.8%) of 2,390 participants died over a median follow-up of 5.5 years (range 0.01-10.5). Using adjusted Cox regression models, we found that hazard ratios for mortality in participants within the lowest tertiles (worse performance) were 1.31 (speed of cognitive processing, p = 0.03); 1.22 (semantic fluency, p = 0.04), 1.32 (delayed free recall, p = 0.003), and 1.23 (delayed logical memory, p = 0.03). Poor performance on delayed recall and speed of cognitive processing tests were associated with dementia and cerebrovascular disease mortality, respectively. Further, poor performance on semantic fluency was associated with decreased cancer mortality. In this study of community dwelling non-demented older adults, worse neuropsychological performance was associated with increased risk of mortality. Performance on specific cognitive domains were related to different causes of death. Of particular note there appears to be an inverse association between poor semantic fluency and cancer mortality.

%B J Alzheimers Dis %V 51 %P 533-44 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890757?dopt=Abstract %R 10.3233/JAD-150875 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Plasma Phospholipid and Sphingolipid Alterations in Presenilin1 Mutation Carriers: A Pilot Study. %A Chatterjee, Pratishtha %A Lim, Wei L F %A Shui, Guanghou %A Gupta, Veer B %A James, Ian %A Fagan, Anne M %A Xiong, Chengjie %A Sohrabi, Hamid R %A Taddei, Kevin %A Brown, Belinda M %A Benzinger, Tammie %A Masters, Colin %A Snowden, Stuart G %A Wenk, Marcus R %A Bateman, Randall J %A Morris, John C %A Martins, Ralph N %K Adult %K Alzheimer Disease %K Apolipoproteins E %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Mutation %K Phospholipids %K Pilot Projects %K Presenilin-1 %K Sphingolipids %X

BACKGROUND AND OBJECTIVE: Aberrant lipid metabolism has been implicated in sporadic Alzheimer's disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD).

METHODS: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman's correlation coefficient.

RESULTS: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p <  0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p <  0.05).

CONCLUSION: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.

%B J Alzheimers Dis %V 50 %P 887-94 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836186?dopt=Abstract %R 10.3233/JAD-150948 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Platelet Membrane β-Secretase Activity in Mild Cognitive Impairment and Conversion to Dementia: a Longitudinal Study. %A McGuinness, Bernadette %A Fuchs, Marc %A Barrett, Suzanne L %A Passmore, A Peter %A Johnston, Janet A %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid Precursor Protein Secretases %K Biomarkers %K Blood Platelets %K Cholesterol %K Cognitive Dysfunction %K Cross-Sectional Studies %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Neuropsychological Tests %K Sensitivity and Specificity %X

A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer's disease (AD) would be invaluable. Previous pilot studies by our group identified elevated platelet membrane β-secretase activity in patients with AD and MCI, as compared to controls, and this activity was influenced by membrane cholesterol levels. The present study investigated baseline platelet membrane β-secretase activity and cholesterol levels in 97 MCI participants and 85 controls and explored whether these parameters differed in individuals with stable MCI, as compared to those who subsequently developed AD. To evaluate signal specificity, β-secretase activity assays were conducted in the presence and absence of beta-site amyloid-β protein precursor-cleaving enzyme (BACE) inhibitors. Baseline platelet membrane β-secretase activity did not differ significantly in MCI participants, as compared to controls, and platelet membrane cholesterol levels were significantly lower in the MCI group. The longitudinal study indicated that the activities inhibited by two different BACE inhibitors did not predict conversion to AD; however, the activity that was not affected by BACE inhibitors was significantly (40%) higher in individuals with stable MCI, as compared with those who subsequently developed AD. These findings indicated that further research into the source of this activity could contribute to a measure facilitating prediction of the risk of conversion from MCI to AD.

%B J Alzheimers Dis %V 49 %P 1095-103 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639974?dopt=Abstract %R 10.3233/JAD-150795 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictive factors for disease progression in patients with early-onset Alzheimer's disease. %A Yoon, Bora %A Shim, Yong S %A Park, Hee-Kyung %A Park, Sun Ah %A Choi, Seong Hye %A Yang, Dong Won %K Activities of Daily Living %K Adult %K Age Factors %K Aged %K Alleles %K Alzheimer Disease %K Apolipoproteins E %K Disease Progression %K Female %K Genotype %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Middle Aged %K Neuropsychological Tests %K Risk Factors %K Sex Factors %X

BACKGROUND: Only a few studies have investigated disease progression in patients with early-onset Alzheimer's disease (EOAD). Therefore, the aim of this study was to investigate disease progression in patients with EOAD and the influence of various factors, such as gender, education, and apolipoprotein E (APOE) genotype on disease progression.

METHODS: A total of 288 EOAD patients were enrolled in the study. Linear mixed models were used to investigate the rate of cognitive and functional decline in terms of age at onset, gender, education, follow-up period, and APOE genotype.

RESULTS: EOAD patients showed an annual decline of -1.54 points/years in the Korean version mini-mental examination score, an annual increase of 3.46 points/year in the Seoul instrumental activities of daily living (SIADL) score, and an annual increase of 1.15 points/year in the clinical dementia rating scale-sum of boxes score. After stratification, higher educated patients showed faster disease progression in all three parameters, and female patients demonstrated faster disease progression as assessed by the SIADL score. Age at onset and APOE genotype had no influence on disease progression.

CONCLUSION: We confirmed the rate of disease progression in Korean patients with EOAD in real-life hospital-based clinical practice. The results of this study suggest that education and female gender, not APOE genotype, may be important as independent strong predictive factors for disease progression in patients with EOAD.

%B J Alzheimers Dis %V 49 %P 85-91 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444786?dopt=Abstract %R 10.3233/JAD-150462 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Predictors of Response to Cholinesterase Inhibitors Treatment of Alzheimer's Disease: Date Mining from the TREDEM Registry. %A Gallucci, Maurizio %A Spagnolo, Pierpaolo %A Aricò, Maria %A Grossi, Enzo %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cerebrovascular Disorders %K Cholinesterase Inhibitors %K Female %K Humans %K Life Style %K Male %K Marital Status %K Mental Status Schedule %K Neural Networks (Computer) %K Neuropsychological Tests %K Occupations %K Outpatients %K Prognosis %K Registries %K Treatment Outcome %X

BACKGROUND: The pharmacological treatment of Alzheimer's disease (AD) is based largely on cholinesterase inhibitors (ChEI).

OBJECTIVE: To investigate whether or not some non-pharmacological and contextual factors measured prior to starting treatment such as past occupation, lifestyles, marital status, degree of autonomy and cognitive impairment, living alone or with others, and the degree of brain atrophy are associated with a better response to ChEI treatment.

METHODS: Eighty-four AD and six AD with cerebrovascular disease (AD + CVD) outpatients of Treviso Dementia (TREDEM) Registry, with an average cholinesterase inhibitors treatment length of four years, were considered. The outpatients had undergone a complete evaluation and some non-pharmacological and contextual factors were collected. We defined responder a patient with a delta score T0 - T1 equal or inferior to 2.0 points per year of MMSE and a non-responder a patient with a delta score T0 - T1 superior to 2.0 points per year. In order to identify hidden relationships between variables related to response and non-response, we use a special kind of artificial neural network called Auto-CM, able to create a semantic connectivity map of the variables considered in the study.

RESULTS: A higher cognitive profile, a previous intellectual occupation, healthier lifestyles, being married and not living alone, a higher degree of autonomy, and lower degree of brain atrophy at baseline resulted in affecting the response to long-term ChEI therapy.

CONCLUSION: Non-pharmacological and contextual factors appear to influence the effectiveness of treatment with ChEI in the long term.

%B J Alzheimers Dis %V 50 %P 969-79 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836164?dopt=Abstract %R 10.3233/JAD-150747 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer's Disease. %A Dugger, Brittany N %A Whiteside, Charisse M %A Maarouf, Chera L %A Walker, Douglas G %A Beach, Thomas G %A Sue, Lucia I %A Garcia, Angelica %A Dunckley, Travis %A Meechoovet, Bessie %A Reiman, Eric M %A Roher, Alex E %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Blotting, Western %K Colon %K Enzyme-Linked Immunosorbent Assay %K Female %K Frontal Lobe %K Gray Matter %K Humans %K Immunohistochemistry %K Liver %K Male %K Neurofibrillary Tangles %K Phosphorylation %K Severity of Illness Index %K Sex Characteristics %K Skin %K Submandibular Gland %K tau Proteins %X

Tau becomes excessively phosphorylated in Alzheimer's disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p = 0.009) and pT231 (p = 0.005) in AD cases but not total tau (p = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage.

%B J Alzheimers Dis %V 51 %P 345-56 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890756?dopt=Abstract %R 10.3233/JAD-150859 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prevalence and Risk Factor of Cognitive Impairment were Different between Urban and Rural Population: A Community-Based Study. %A Tang, Hui-Dong %A Zhou, Yi %A Gao, Xiang %A Liang, Liang %A Hou, Miao-Miao %A Qiao, Yuan %A Ma, Jian-Fang %A Chen, Sheng-Di %K Aged %K Aged, 80 and over %K China %K Cognition Disorders %K Female %K Humans %K Logistic Models %K Male %K Mental Status Schedule %K Middle Aged %K Multivariate Analysis %K Prevalence %K Risk Factors %K Rural Population %K Urban Population %X

BACKGROUND: China is facing a continuously rising numbers of people with cognitive impairment (CI).

OBJECTIVES: To investigate the prevalence and risk factors of CI among elderly people living in rural and urban communities.

METHODS: We conducted a face-to-face survey of CI on 7,900 individuals aged 50 years or older meeting inclusion criteria in the Malu (rural community, n = 4,429) and Wuliqiao (urban community, n = 3,471) communities of Shanghai. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive function. Information on demographic features and potential risk factors for CI was collected during the interview. Multivariate logistic regression was performed to identify risk factors associated with CI.

RESULTS: Based on the education modified MMSE score, we identified 329 CI cases in rural community and 227 in urban community. The prevalence of CI was 7.43% in rural population and 6.54% in urban population (p = 0.13). In the urban population, risk of having CI was associated with age (OR = 1.04; 95% CI: 1.01-1.08), lack of physical activities (OR = 2.25; 95% CI: 1.11-4.57), presence of diabetes mellitus (OR = 1.79; 95% CI: 1.04-3.07), and having three or more children (OR = 2.39; 95% CI: 1.27-4.50). In contrast, factors associated with rural populations included female gender (OR = 2.03; 95% CI: 1.08-3.82), age (OR = 1.06; 95% CI: 1.03-1.08), exposure to pesticides (OR = 4.68; 95% CI: 1.27-17.21), history of encephalitis or meningitis (OR = 6.02; 95% CI: 1.92-18.85) and head trauma (OR = 1.89; 95% CI: 1.10-3.24).

CONCLUSIONS: Urban rural and populations showed different risk factors for CI, suggesting that different preventive strategies in these areas should be performed.

%B J Alzheimers Dis %V 49 %P 917-25 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519443?dopt=Abstract %R 10.3233/JAD-150748 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease. %A Tripathi, Ajai K %A Singh, Neena %K Animals %K Brain %K Cell Line, Tumor %K Creutzfeldt-Jakob Syndrome %K Endocytosis %K Ferritins %K Green Fluorescent Proteins %K Hemin %K Hemoglobins %K Humans %K In Vitro Techniques %K Leukemia, Erythroblastic, Acute %K Mice %K Mice, Transgenic %K Neuroblastoma %K Neuroglia %K Neurons %K Organ Culture Techniques %K Prion Proteins %K Transfection %K Up-Regulation %X

Hemin is known to induce endocytosis of prion-protein (PrP(C)) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrP(Sc)) isoform. Hemin is therefore an attractive disease-modifying option for sporadic Creutzfeldt-Jakob disease (sCJD), a human prion disorder with no effective treatment. The hemin-PrP(C) interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrP(C). Interestingly, PrP(C) is upregulated in penumbric neurons surrounding CH and is known to confer neuroprotection in a dose-dependent manner. The underlying mechanism, however, is not clear. Here, we report that hemin binds PrP(C) on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrP(C) interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrP(C). A similar response is noted in brain organotypic cultures where exposure to hemin induces significantly more α-globin in wild-type (PrP(+/+)) relative to PrP-knock-out (PrP(-/-)) samples. Furthermore, red blood cells and brain tissue from PrP(-/-) mice show significantly less α-globin relative to PrP(+/+) controls, indicating a positive effect of PrP(C) on Hb synthesis under physiological conditions as well. Surprisingly, levels of α-globin are significantly higher in sCJD brain tissue relative to controls, suggesting compensatory upregulation of Hb synthesis by surviving neurons or misregulation in diseased brains. These observations reveal a unique function of PrP(C) that is likely to impact the therapeutic management of CH and sCJD.

%B J Alzheimers Dis %V 51 %P 107-21 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836195?dopt=Abstract %R 10.3233/JAD-151039 %0 Journal Article %J J Alzheimers Dis %D 2016 %T PRNP P39L Variant is a Rare Cause of Frontotemporal Dementia in Italian Population. %A Oldoni, Emanuela %A Fumagalli, Giorgio G %A Serpente, Maria %A Fenoglio, Chiara %A Scarioni, Marta %A Arighi, Andrea %A Bruno, Giuseppe %A Talarico, Giuseppina %A Confaloni, Annamaria %A Piscopo, Paola %A Nacmias, Benedetta %A Sorbi, Sandro %A Rainero, Innocenzo %A Rubino, Elisa %A Pinessi, Lorenzo %A Binetti, Giuliano %A Ghidoni, Roberta %A Benussi, Luisa %A Grande, Giulia %A Arosio, Beatrice %A Bursey, Devan %A Kauwe, John S %A Cioffi, Sara Mg %A Arcaro, Marina %A Mari, Daniela %A Mariani, Claudio %A Scarpini, Elio %A Galimberti, Daniela %K Aged %K Atrophy %K Frontal Lobe %K Frontotemporal Dementia %K Genetic Predisposition to Disease %K Humans %K Italy %K Language %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Short-Term %K Neuropsychological Tests %K Prion Proteins %K Prions %K Temporal Lobe %X

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%).

%B J Alzheimers Dis %V 50 %P 353-7 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757195?dopt=Abstract %R 10.3233/JAD-150863 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates. %A Tosto, Giuseppe %A Monsell, Sarah E %A Hawes, Stephen E %A Bruno, Giuseppe %A Mayeux, Richard %K Aged %K Algorithms %K Alzheimer Disease %K Cluster Analysis %K Databases, Factual %K Disease Progression %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Severity of Illness Index %X

BACKGROUND: Extrapyramidal signs (EPS) are frequent in Alzheimer's disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson's disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions.

OBJECTIVE: To identify clusters of EPS progression over time and their clinical and neuropathological correlates.

METHODS: 3,502 AD patients with longitudinal assessment from the National Alzheimer's Coordinating Center database were included; 394 provided neuropathological data. k-means algorithm was employed to identify clusters of EPS progression and those were compared in terms of cognitive profile, neuropsychiatric features and neuropathological findings.

RESULTS: Three clusters of EPS progression were identified: no/low (n = 1,583), medium (n = 1,259), and high (n = 660) EPS burden. Compared to those with no/low and medium EPS, those with high EPS had greater cognitive and neuropsychiatric impairment, specifically hallucinations. Despite similar AD-pathology across the three clusters, the high EPS cluster had a significantly number of subjects diagnosed with dementia with Lewy bodies.

CONCLUSIONS: Cluster analysis of EPS progression over time identified different subgroups of AD patients with distinct clinical and neuropathological features.

%B J Alzheimers Dis %V 49 %P 1085-93 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26599050?dopt=Abstract %R 10.3233/JAD-150244 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice. %A Elahi, Montasir %A Hasan, Zafrul %A Motoi, Yumiko %A Matsumoto, Shin-Ei %A Ishiguro, Koichi %A Hattori, Nobutaka %K Adaptor Proteins, Signal Transducing %K Animals %K Antibiotics, Antineoplastic %K Brain %K Calcium-Binding Proteins %K Calcium-Calmodulin-Dependent Protein Kinase Type 2 %K Cell Proliferation %K Diabetes Mellitus, Experimental %K Disease Models, Animal %K Encephalitis %K Female %K Humans %K Lipid Peroxidation %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microfilament Proteins %K Neuroglia %K Oxidative Stress %K Reactive Oxygen Species %K Streptozocin %K tau Proteins %X

Recent epidemiological evidence suggests that diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). One of the pathological hallmarks of AD is hyperphosphorylated tau protein, which forms neurofibrillary tangles. Oxidative stress and the activation of inflammatory pathways are features that are associated with both DM and AD. However, the brain region specificity of AD-related neurodegeneration, which mainly occurs in the hippocampus while the cerebellum is relatively unaffected, has not yet been clarified. Therefore, we used experimental DM mice (caused by an intraperitoneal injection of streptozotocin [STZ]) to determine whether these neurodegeneration-associated mechanisms were associated with region-specific selective vulnerability or tau phosphorylation. The hippocampus, midbrain, and cerebellum of aged (14 to 18 months old) non-transgenic (NTg) and transgenic mice overexpressing wild-type human tau (Tg601 mice) were evaluated after a treatment with STZ. The STZ injection increased reactive oxygen species, lipid peroxidation markers such as 4-hydroxynonenal and malondialdehyde in the hippocampus, but not in the midbrain or cerebellum. The STZ treatment also increased the number of Iba-1-positive and CD68-positive microglial cells, astrocytes, and IL-1β, IL-6, IL-10, and IL-18 levels in the hippocampus, but not in the midbrain or cerebellum. Tau hyperphosphorylation was also enhanced in the hippocampus, but not in the midbrain or cerebellum. When the effects of STZ were compared between Tg601 and NTg mice, microglial proliferation and elevations in IL-6 and phosphorylated tau were higher in Tg601 mice. These results suggest that neuroinflammation and oxidative stress in STZ-treated mice are associated with tau hyperphosphorylation, which may contribute to selective neurodegeneration in human AD.

%B J Alzheimers Dis %V 51 %P 1209-24 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923011?dopt=Abstract %R 10.3233/JAD-150820 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reproductive history and risk of cognitive impairment in elderly women: a cross-sectional study in eastern China. %A Li, Fu-Dong %A He, Fan %A Chen, Ting-Rui %A Xiao, Yuan-Yuan %A Lin, Shang-Tong %A Shen, Wei %A Wang, Xin-Yi %A Zhai, Yu-Jia %A Shang, Xiao-Peng %A Lin, Jun-Fen %K Aged %K Aged, 80 and over %K China %K Cognition %K Cognition Disorders %K Contraceptives, Oral %K Cross-Sectional Studies %K Estrogens %K Female %K Humans %K Intrauterine Devices %K Logistic Models %K Middle Aged %K Neuropsychological Tests %K Odds Ratio %K Postmenopause %K Psychiatric Status Rating Scales %K Reproductive History %X

BACKGROUND: Epidemiological studies suggest that proxies of higher lifetime estrogen exposure are associated with better cognitive function in postmenopausal women, but this has not been found consistently.

OBJECTIVE: To determine whether reproductive history, an important modifier of estrogen exposure across the lifetime, is associated with risk of cognitive impairment in postmenopausal women.

METHODS: We analyzed the baseline data from Zhejiang Major Public Health Surveillance Program (ZPHS) including 4,796 postmenopausal women. Cognitive impairment was assessed through the application of Mini-Mental State Examination questionnaire. Logistic regression models, controlled for an extensive range of potential confounders, were generated to examine the associations between women's reproductive history and risk of cognitive impairment in their later life.

RESULTS: The length of reproductive period was inversely associated with risk of cognitive impairment (p = 0.001). Odds ratio (OR) of cognitive impairment were 1.316 (95% CI 1.095∼1.582) for women with 5 or more times of full-term pregnancies, compared with those with 1∼4 times of full-term pregnancies. Women without incomplete pregnancy had a significant higher risk of cognitive impairment (OR = 1.194, 95% CI 1.000∼1.429), compared with the reference (1∼2 times of incomplete pregnancies). Oral contraceptive use (OR = 0.489, 95% CI 0.263∼0.910) and intrauterine device (IUD) use (OR = 0.684, 95% CI 0.575∼0.815) were associated with significantly reduced risk of cognitive impairment.

CONCLUSION: Our results indicated that shorter reproductive period, higher number of full-term pregnancies and no incomplete pregnancy history were associated with an increased risk of cognitive impairment. In contrast, oral contraceptive and IUD use corresponded to reduced risk of cognitive impairment.

%B J Alzheimers Dis %V 49 %P 139-47 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444784?dopt=Abstract %R 10.3233/JAD-150444 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Risk of dementia in patients with celiac disease: a population-based cohort study. %A Lebwohl, Benjamin %A Luchsinger, Jose A %A Freedberg, Daniel E %A Green, Peter H R %A Ludvigsson, Jonas F %K Aged %K Celiac Disease %K Cohort Studies %K Databases, Factual %K Dementia %K Female %K Humans %K Incidence %K Logistic Models %K Male %K Middle Aged %K Proportional Hazards Models %K Risk Factors %K Sweden %X

BACKGROUND: Patients with celiac disease (CD) frequently report cognitive symptoms when they are exposed to gluten, and cognitive deficits have been quantified in patients with newly diagnosed CD.

OBJECTIVE: To determine whether patients with CD have an increased risk of dementia.

METHODS: Using a population-based database of older adults (age ≥50 years) with histologically proven CD (duodenal/jejunal villous atrophy) from all 28 pathology departments in Sweden, we compared the incidence of a subsequent dementia diagnosis to those of age- and gender-matched controls.

RESULTS: Among patients with CD (n = 8,846) and controls (n = 43,474), the median age was 63 years and 56% were female. During a median follow-up time of 8.4 years, dementia was diagnosed in 4.3% of CD patients and 4.4% of controls (HR 1.07; 95% CI 0.95-1.20). Although there was an increased risk of dementia in the first year following a diagnosis of CD (HR 1.73; 95% CI 1.15-2.61), this risk was not present in the whole observation period. Among those subjects with a dementia subtype specified, the increased risk was restricted to vascular dementia (HR 1.28; 95% CI 1.00-1.64) and was not present for Alzheimer's dementia (HR 1.12; 95% CI 0.91-1.37).

CONCLUSIONS: Patients with CD are not at increased risk for dementia overall, though subgroup analysis suggests that they may be at increased risk for vascular dementia.

%B J Alzheimers Dis %V 49 %P 179-85 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444775?dopt=Abstract %R 10.3233/JAD-150388 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Ethnicity in Alzheimer's Disease: Findings From The C-PATH Online Data Repository. %A Chen, Huei-Yang %A Panegyres, Peter K %K African Americans %K Age Factors %K Aged %K Alaska Natives %K Alzheimer Disease %K Apolipoproteins E %K Asian Continental Ancestry Group %K Clinical Trials as Topic %K Comorbidity %K Databases, Factual %K European Continental Ancestry Group %K Female %K Hispanic Americans %K Humans %K Indians, North American %K Internet %K Logistic Models %K Male %K Oceanic Ancestry Group %K Risk %K Sex Factors %X

BACKGROUND: Ethnic minorities seem to be at an increased risk of Alzheimer's disease (AD). However, little is known about ethnic differences and the risks of early onset AD (EOAD).

OBJECTIVE: Cognitive function changes over time and odds of EOAD by ethnicity were analyzed by the mixed model and the logistic regression.

METHODS: Information on demographics, self-reported co-morbidities, cognitive functions (MMSE and ADAS-COG), and ApoE genotypes were collected for 6,500 subjects with AD obtained from the placebo arm of clinical trials; this data was examined by ethnicities: Caucasian, Asian, African American, Hispanic, and other minorities--including Native Alaskans, Americans, and Hawaiians.

RESULTS: Of the total subjects, Caucasians accounted for 89.0% , followed by 4.7% Asians, 2.7% African Americans, 2.4% Hispanics, and 1.2% Native Americans, Alaskans, and Hawaiians. Age, gender, EOAD status, co-morbidities, family history of AD, and ApoE genotypes were significantly different by ethnicity. ApoE ɛ2 allele is possibly overrepresented in the Native Americans, Africans, Hawaiians, and African Americans. A significant interaction with time, ethnicity, and cognitive performance was found, indicating more cognitive deterioration in other minorities than Caucasians for mini-mental state (p <  0.01). After adjusting for co-morbidities and gender, the odds of EOAD among African Americans (OR: 1.6, 95% CI: 1.1-2.4) and Native Alaskans, Americans, and Hispanics (OR: 2.1, 95% CI: 1.2-3.5) were significantly higher, compared with Caucasians.

CONCLUSIONS: Ethnicity may impact AD through age of onset, co-morbidities, family history, ApoE gene status, and cognitive change over time. The greater odds of EOAD among African Americans, Alaskans, and Hawaiians suggest that some ethnicities may be at risk of AD at a younger age.

%B J Alzheimers Dis %V 51 %P 515-23 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890783?dopt=Abstract %R 10.3233/JAD-151089 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Self-Reported Traumatic Brain Injury and Mild Cognitive Impairment: Increased Risk and Earlier Age of Diagnosis. %A LoBue, Christian %A Denney, David %A Hynan, Linda S %A Rossetti, Heidi C %A Lacritz, Laura H %A Hart, John %A Womack, Kyle B %A Woon, Fu L %A Cullum, C Munro %K Age of Onset %K Aged %K Apolipoproteins E %K Brain Injuries, Traumatic %K Cognitive Dysfunction %K Cohort Studies %K Databases, Factual %K Depression %K Educational Status %K Female %K Humans %K Logistic Models %K Male %K Risk Factors %K Self Report %K United States %X

This study examined whether history of traumatic brain injury (TBI) is associated with increased risk and earlier onset of mild cognitive impairment (MCI). Subjects with MCI (n = 3,187) and normal cognition (n = 3,244) were obtained from the National Alzheimer's Coordinating Center database. TBI was categorized based on lifetime reported TBI with loss of consciousness (LOC) without chronic deficit. Logistic regression was used to examine TBI history as a predictor of MCI, adjusted for demographics, apolipoprotein E-ɛ4 (ApoE4), a composite vascular risk score, and history of psychiatric factors. ANCOVA was used to examine whether age at MCI diagnosis and estimated age of onset differed between those with (TBI+) and without (TBI-) a history of TBI. TBI history was a significant predictor (p <  0.01) and associated with increased odds of MCI diagnosis in unadjusted (OR = 1.25; 95% CI = 1.05-1.49) and adjusted models, accounting for age, education, ApoE4, and a composite vascular score (OR = 1.32; 95% CI = 1.10-1.58). This association, however, was largely attenuated (OR = 1.14; 95% CI = 0.94-1.37; p = 0.18) after adjustment for reported history of depression. MCI was diagnosed a mean of 2.3 years earlier (p <  0.001) in the TBI+ group, and although TBI+ subjects had an estimated mean of decline 1.7 years earlier, clinician-estimated age of onset failed to differ (p = 0.13) when gender and psychiatric factors were controlled. This is the first report of a possible role for TBI as a risk factor in MCI, but its association may be related to other factors such as gender and depression and requires further investigation.

%B J Alzheimers Dis %V 51 %P 727-36 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890760?dopt=Abstract %R 10.3233/JAD-150895 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Shared Genetic Etiology between Type 2 Diabetes and Alzheimer's Disease Identified by Bioinformatics Analysis. %A Gao, Lei %A Cui, Zhen %A Shen, Liang %A Ji, Hong-Fang %K Alzheimer Disease %K Apolipoprotein C-I %K Computational Biology %K Databases, Factual %K Diabetes Mellitus, Type 2 %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Male %K Polymorphism, Single Nucleotide %X

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two major health issues, and increasing evidence in recent years supports the close connection between these two diseases. The present study aimed to explore the shared genetic etiology underlying T2D and AD based on the available genome wide association studies (GWAS) data collected through August 2014. We performed bioinformatics analyses based on GWAS data of T2D and AD on single nucleotide polymorphisms (SNPs), gene, and pathway levels, respectively. Six SNPs (rs111789331, rs12721046, rs12721051, rs4420638, rs56131196, and rs66626994) were identified for the first time to be shared genetic factors between T2D and AD. Further functional enrichment analysis found lipid metabolism related pathways to be common between these two disorders. The findings may have important implications for future mechanistic and interventional studies for T2D and AD.

%B J Alzheimers Dis %V 50 %P 13-7 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639962?dopt=Abstract %R 10.3233/JAD-150580 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Societal Cost of Dementia in Singapore: Results from the WiSE Study. %A Abdin, Edimansyah %A Subramaniam, Mythily %A Achilla, Evanthia %A Chong, Siow Ann %A Vaingankar, Janhavi Ajit %A Picco, Louisa %A Sambasivam, Rajeswari %A Pang, Shirlene %A Chua, Boon Yiang %A Ng, Li Ling %A Chua, Hong Choon %A Heng, Derrick %A Prince, Martin %A McCrone, Paul %K Adult %K Aged, 80 and over %K Cost of Illness %K Dementia %K Female %K Humans %K Linear Models %K Male %K Middle Aged %K Singapore %X

BACKGROUND: There is currently limited evidence on the economic burden that dementia exerts on multi-ethnic Asian populations.

OBJECTIVE: The present study aimed to estimate the economic cost of dementia in Singapore.

METHODS: We used data from the Well-being of the Singapore Elderly study, a nationally representative survey of the older Singapore Resident population aged 60 years and above. Generalized linear modeling was used to estimate factors associated with costs.

RESULTS: The total cost of dementia in 2013 was estimated at S$532 million (95% CI, S$361 million to S$701 million) while the annual cost per person was estimated at S$10,245 per year (95% CI, S$6,954 to S$12,495). Apart from dementia, higher total societal cost were also significantly associated with older age, Indian ethnicity, and those who were diagnosed with heart problems, stroke, diabetes or depression, whereas being divorced/separated, lower education, and those who were diagnosed with hypertension were significantly associated with lower total societal cost.

CONCLUSION: The study provides a rich body of information on healthcare utilization and cost of dementia, which is essential for future planning of services for the elderly population.

%B J Alzheimers Dis %V 51 %P 439-49 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890766?dopt=Abstract %R 10.3233/JAD-150930 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Spatial Navigation in Preclinical Alzheimer's Disease. %A Allison, Samantha L %A Fagan, Anne M %A Morris, John C %A Head, Denise %K Aged %K Alzheimer Disease %K Biomarkers %K Educational Status %K Female %K Humans %K Learning %K Male %K Neuropsychological Tests %K Prodromal Symptoms %K Psychomotor Performance %K ROC Curve %K Spatial Navigation %K tau Proteins %K User-Computer Interface %X

Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Aβ42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD.

%B J Alzheimers Dis %V 52 %P 77-90 %8 2016 02 09 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967209?dopt=Abstract %R 10.3233/JAD-150855 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Subjective Memory Complaints in APOEɛ4 Carriers are Associated with High Amyloid-β Burden. %A Zwan, Marissa D %A Villemagne, Victor L %A Doré, Vincent %A Buckley, Rachel %A Bourgeat, Pierrick %A Veljanoski, Robyn %A Salvado, Olivier %A Williams, Rob %A Margison, Laura %A Rembach, Alan %A Macaulay, S Lance %A Martins, Ralph %A Ames, David %A van der Flier, Wiesje M %A Ellis, Kathryn A %A Scheltens, Philip %A Masters, Colin L %A Rowe, Christopher C %K Aged %K Aging %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E4 %K Benzothiazoles %K Brain %K Cognition Disorders %K Female %K Genotyping Techniques %K Heterozygote %K Humans %K Logistic Models %K Male %K Neuropsychological Tests %K Positron-Emission Tomography %K Radiopharmaceuticals %K Thiazoles %X

BACKGROUND: APOEɛ4 genotype and aging have been identified as risk factors for Alzheimer's disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning.

OBJECTIVE: To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly.

METHODS: 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aβ pathology.

RESULTS: Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01).

CONCLUSION: Aging, APOEɛ4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.

%B J Alzheimers Dis %V 49 %P 1115-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639956?dopt=Abstract %R 10.3233/JAD-150446 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Thyroid-Stimulating Hormone and Mild Cognitive Impairment: Results of the Heinz Nixdorf Recall Study. %A Winkler, Angela %A Weimar, Christian %A Jöckel, Karl-Heinz %A Erbel, Raimund %A Dragano, Nico %A Broecker-Preuss, Martina %A Moebus, Susanne %A Führer-Sakel, Dagmar %A Dlugaj, Martha %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Case-Control Studies %K Cognitive Dysfunction %K Female %K Follow-Up Studies %K Humans %K Logistic Models %K Male %K Middle Aged %K Neuropsychological Tests %K Risk Factors %K Sex Characteristics %K Statistics, Nonparametric %K Thyrotropin %X

BACKGROUND: Although some studies reported on the association of serum thyroid-stimulating hormone (TSH) concentration and cognition, only one population-based study investigated the association of TSH concentration and mild cognitive impairment (MCI).

OBJECTIVE: To investigate the gender-specific association of low- and high-normal TSH concentrations with MCI in euthyroid participants.

METHODS: Analysis sample 1 included 2,563 euthyroid participants (aged 50-80 years) from the second examination of the population-based Heinz Nixdorf Recall study. Gender-specific TSH quintiles (Q1 low, Q2-Q4 middle, Q5 high TSH concentration) were determined and group comparisons of age- and education-adjusted mean scores were performed for all cognitive subtests. Analysis sample 2 included 378 participants with MCI and 931 cognitively normal participants. MCI was diagnosed according to previously published MCI criteria. Multivariate logistic regression models were performed using TSH quintiles (Q2-Q4 as reference) to assess the association of low- and high-normal TSH concentration with MCI. Models were performed unadjusted and adjusted for sociodemographic and cardiovascular risk factors.

RESULTS: Group comparisons showed significant differences only in the immediate recall of the verbal memory task in women. Only women showed a strong association of high-normal TSH concentration with MCI (unadjusted: odds ratio 2.09, 95% confidence interval 1.29-3.37, full adjusted: 1.86, 1.06-3.27). There was no association with low-normal TSH concentration in women and no association of either low- or high-normal TSH concentration with MCI in men.

CONCLUSIONS: These results suggest that women with high-normal TSH concentration might be at higher risk of cognitive decline. This needs to be confirmed in the longitudinal analysis.

%B J Alzheimers Dis %V 49 %P 797-807 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519440?dopt=Abstract %R 10.3233/JAD-150561 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Time trends in antipsychotic drug use in patients with dementia: a nationwide study. %A Nørgaard, Ane %A Jensen-Dahm, Christina %A Gasse, Christiane %A Hansen, Hanne Vibe %A Waldemar, Gunhild %K Aged %K Aged, 80 and over %K Anti-Anxiety Agents %K Antidepressive Agents %K Antipsychotic Agents %K Dementia %K Denmark %K Drug Prescriptions %K Female %K Homes for the Aged %K Humans %K Hypnotics and Sedatives %K Longitudinal Studies %K Male %K Multivariate Analysis %K Nursing Homes %K Registries %X

BACKGROUND: Antipsychotics are often used to treat neuropsychiatric symptoms in dementia, but the evidence for effect is limited. Antipsychotics have been associated with increased risk of adverse events and mortality in patients with dementia, leading to safety regulations worldwide.

OBJECTIVE: To investigate time trends in use of antipsychotics and other psychotropic drugs in dementia care.

METHODS: The study included longitudinal data on all Danish residents ≥65 years. The study population was defined on January 1 of each year from 2000-2012. Data included prescriptions, discharge diagnoses, and somatic and psychiatric comorbidities. Multivariate time trend analyses of psychotropic drug use in patients with dementia within 4-year age bands were performed.

RESULTS: Overall, among patients with dementia the prevalence of antipsychotic drug use decreased from 31.3% in 2000 to 20.4% in 2012. The decreasing use of antipsychotics was accompanied by decreasing use of anxiolytics and hypnotics/sedatives, but an increase in the use of antidepressants from 43.3% in 2000 to 53.8% in 2012. These changes were significant across almost all age groups. Treatment intensity among patients using antipsychotics increased as the annual median number of defined daily doses (DDD) increased from 33.3 to 42.0 DDD.

CONCLUSIONS: The changing patterns of psychotropic drug use may be caused by warnings against use of antipsychotics. Further research is needed to explore the implications for patient safety.

%B J Alzheimers Dis %V 49 %P 211-20 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444790?dopt=Abstract %R 10.3233/JAD-150481 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration. %A Yu, Rosa %A Deochand, Chetram %A Krotow, Alexander %A Leão, Raiane %A Tong, Ming %A Agarwal, Amit R %A Cadenas, Enrique %A de la Monte, Suzanne M %K 2',3'-Cyclic-Nucleotide Phosphodiesterases %K AC133 Antigen %K Animals %K Antigens, CD %K Brain %K Disease Models, Animal %K Galactosylceramides %K Gene Expression Regulation %K Glycoproteins %K Leukoencephalopathies %K Male %K Mice %K Nerve Degeneration %K Nerve Tissue Proteins %K Neuroglia %K Neurons %K Oligodendroglia %K Papain %K Peptides %K Smoking %K Tobacco %K Transcription Factors %X

BACKGROUND: Meta-analysis studies showed that smokers have increased risk for developing Alzheimer's disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity.

OBJECTIVE: The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions.

METHODS: Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis.

RESULTS: Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated.

CONCLUSION: CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD.

%B J Alzheimers Dis %V 50 %P 133-48 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639972?dopt=Abstract %R 10.3233/JAD-150751 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Transferring cut-off values between assays for cerebrospinal fluid Alzheimer's disease biomarkers. %A García Barrado, Leandro %A Coart, Els %A Vanderstichele, Hugo M J %A Burzykowski, Tomasz %K Alzheimer Disease %K Amyloid beta-Peptides %K Bayes Theorem %K Biomarkers %K Cognitive Dysfunction %K Datasets as Topic %K Humans %K Linear Models %K Multivariate Analysis %K Peptide Fragments %K tau Proteins %X

Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimer's disease pathology report different concentrations in function of technology and suffer from between-laboratory variability. Hence, lab- and technology-specific cut-off values are required. It is common practice to establish cut-off values on small datasets and, in the absence of well-characterized samples, to transfer the cut-offs to another assay format using 'side-by-side' testing of samples with both assays. We evaluated the uncertainty in cut-off estimation and the performance of two methods of cut-off transfer by using two clinical datasets and simulated data. The cut-off for the new assay was transferred by applying the commonly-used linear regression approach and a new Bayesian method, which consists of using prior information about the current assay for estimation of the biomarker's distributions for the new assay. Simulations show that cut-offs established with current sample sizes are insufficiently precise and also show the effect of increasing sample sizes on the cut-offs' precision. The Bayesian method results in unbiased and less variable cut-offs with substantially narrower 95% confidence intervals compared to the linear-regression transfer. For the BIODEM datasets, the transferred cut-offs for INNO-BIA Aβ1-42 are 167.5 pg/mL (95% credible interval [156.1, 178.0] and 172.8 pg/mL (95% CI [147.6, 179.6]) with Bayesian and linear regression methods, respectively. For the EUROIMMUN assay, the estimated cut-offs are 402.8 pg/mL (95% credible interval [348.0, 473.9]) and 364.4 pg/mL (95% CI [269.7, 426.8]). Sample sizes and statistical methods used to establish and transfer cut-off values have to be carefully considered to guarantee optimal diagnostic performance of biomarkers.

%B J Alzheimers Dis %V 49 %P 187-99 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484919?dopt=Abstract %R 10.3233/JAD-150511 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Unstable Body Mass Index and Progression to Probable Alzheimer's Disease Dementia in Patients with Amnestic Mild Cognitive Impairment. %A Ye, Byoung Seok %A Jang, Eun Young %A Kim, Seong Yoon %A Kim, Eun-Joo %A Park, Sun Ah %A Lee, Yunhwan %A Hong, Chang Hyung %A Choi, Seong Hye %A Yoon, Bora %A Yoon, Soo Jin %A Na, Hae Ri %A Lee, Jae-Hong %A Jeong, Jee H %A Kim, Hee Jin %A Na, Duk L %A Seo, Sang Won %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Body Mass Index %K Body Weight %K Cognitive Dysfunction %K Dementia %K Disease Progression %K Female %K Humans %K Kaplan-Meier Estimate %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Registries %X

BACKGROUND AND OBJECTIVE: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients.

METHODS: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimer's disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value.

RESULTS: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD.

CONCLUSIONS: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline.

%B J Alzheimers Dis %V 49 %P 483-91 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484923?dopt=Abstract %R 10.3233/JAD-150556 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Usefulness of an Integrated Analysis of Different Memory Tasks to Predict the Progression from Mild Cognitive Impairment to Alzheimer's Disease: The Episodic Memory Score (EMS). %A Marra, Camillo %A Gainotti, Guido %A Fadda, Lucia %A Perri, Roberta %A Lacidogna, Giordano %A Scaricamazza, Eugenia %A Piccininni, Chiara %A Quaranta, Davide %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognitive Dysfunction %K Disease Progression %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Memory, Episodic %K Mental Recall %K Neuropsychological Tests %K ROC Curve %X

Taking into the account both the severity and the consistency of performances obtained on memory tests by patients with amnestic mild cognitive impairment (aMCI) could improve the power to predict their progression to Alzheimer's disease. For this purpose, we constructed the Episodic Memory Score (EMS), which is obtained by subdividing in tertiles performances obtained at baseline in verbal (RAVLT) and visual episodic memory (Rey-Osterrieth Figure-delayed recall) and giving a score ranging from 1 (worst result) to 3 (best result) to results falling within each tertile. The EMS was computed for each patient by summing the tertile score obtained on each memory task, so that the total score ranged from 4 (worst performance) to 12 (best performance). The aMCI sample consisted of 198 subjects who completed the two-year follow-up, at the end of which 55 subjects had converted to dementia. The mean EMS score obtained by aMCI converters was significantly lower than that of aMCI-stable patients. In detecting conversion to dementia, the comparison between EMS and individual memory scores obtained at baseline was made by computing ROC curves, and estimating the respective area under the curve (AUC). The EMS had a larger AUC than the individual memory scores. At baseline aMCI converters performed worse than non-converters not only on memory tasks, but also on executive functions tasks. However, in a multiple variables logistic regression analysis in which all scores showing statistically significant differences between aMCI-converters and aMCI-stable were entered, the EMS was the only reliable predictor of progression from aMCI to dementia.

%B J Alzheimers Dis %V 50 %P 61-70 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639965?dopt=Abstract %R 10.3233/JAD-150613 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Utilization of Retinal Nerve Fiber Layer Thickness to Predict Cognitive Deterioration. %A Shi, Zhongyong %A Zhu, Yingbo %A Wang, Meijuan %A Wu, Yujie %A Cao, Jing %A Li, Chunbo %A Xie, Zhongcong %A Shen, Yuan %K Aged %K Cognition Disorders %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Male %K Nerve Fibers %K Neuropsychological Tests %K Predictive Value of Tests %K Retina %K ROC Curve %K Statistics, Nonparametric %K Tomography, Optical Coherence %X

Our previous studies have shown that longitudinal reduction in retinal nerve fiber layer (RNFL) thickness is associated with cognitive deterioration. However, whether the combination of longitudinal reduction in RNFL thickness with baseline episodic memory performance can better predict cognitive deterioration remains unknown. Therefore, we set out to re-analyze the data obtained from our previous studies with 78 elderly adults (mean age 74.4 ± 3.83 years, 48.7% male) in the community over a 25-month period. The participants were categorized as either stable participants whose cognitive status did not change (n = 60) or converted participants whose cognitive status deteriorated (n = 18). A logistic regression analysis was applied to determine a conversion score for predicting the cognitive deterioration in the participants. We found that the area under the receiver operating characteristic curve (AUC) for the multivariable model was 0.854 (95% CI 0.762-0.947) using baseline story recall as a predictor, but the AUC increased to 0.915 (95% CI 0.849-0.981) with the addition of the longitudinal reduction of RNFL thickness in the inferior quadrant. The conversion score was significantly higher for the converted participants than the stable participants (0.59 ± 0.30 versus 0.12 ± 0.19, p <  0.001). Finally, the optimal cutoff value of the conversion score (0.134) was determined by the analysis of receiver operating characteristic curve, and this conversion score generated a sensitivity of 0.944 and a specificity of 0.767 in predicting the cognitive deterioration. These findings have established a system to perform a larger scale study to further test whether the longitudinal reduction in RNFL thickness could serve as a biomarker of Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 399-405 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484909?dopt=Abstract %R 10.3233/JAD-150438 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Validation of the Spanish version of the Baylor Profound Mental Status Examination. %A Salmerón, Sergio %A Huedo, Isabel %A López-Utiel, Melisa %A Soler-Moratalla, Isabel %A Flores-Ruano, Teresa %A Fernández-Sánchez, Miguel %A Noguerón, Alicia %A Doody, Rachelle S %A Abizanda, Pedro %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cognition %K Cognition Disorders %K Female %K Humans %K Language %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Reproducibility of Results %K Severity of Illness Index %K Spain %X

BACKGROUND: There are no short valid instruments to evaluate cognitive status in severe Alzheimer's disease (AD) patients in the Spanish language.

OBJECTIVE: To validate the Spanish version of the Baylor Profound Mental Status Examination (BPMSE-Sp).

METHODS: The Baylor Profound Mental Status Examination (BPMSE) was translated to Spanish and back translated. Validation was conducted in 100 patients with severe probable AD with a Mini-Mental State Examination (MMSE) <12. We assessed internal consistency (Cronbach's alpha), concurrent validity (Pearson's correlations) with the MMSE, Severe Impairment Battery (SIB), Neuropsychiatric Inventory Short Form (NPI-Q) and the Functional Assessment Staging and reliability.

RESULTS: The mean age of patients was 84.9; 74% were female; 64% were institutionalized. The mean MMSE was 5.6; the mean BPMSE-Sp was 13.6; the mean BPMSE-Sp behavior was 1.2; the mean SIB was 42.2; and the mean NPI-Q was 4.7. BPMSE-Sp presented good internal consistency (Cronbach α= 0.84). There were significant correlations between the BPMSE-Sp and MMSE (r = 0.86, p <  0.001), and between the BPMSE-Sp and SIB (r = 0.92, p <  0.001). Inter-rater and test-retest reliability were in both cases excellent, ranging between 0.96 and 0.99 (p <  0.001). BPMSE-Sp had fewer floor and ceiling effects than the MMSE.

CONCLUSIONS: The BPMSE-Sp is a valid tool for use in daily practice and research in the evaluation of cognitive function of patients with severe AD.

%B J Alzheimers Dis %V 49 %P 73-8 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444781?dopt=Abstract %R 10.3233/JAD-150422 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview. %A Jefferson, Angela L %A Gifford, Katherine A %A Acosta, Lealani Mae Y %A Bell, Susan P %A Donahue, Manus J %A Davis, L Taylor %A Gottlieb, JoAnn %A Gupta, Deepak K %A Hohman, Timothy J %A Lane, Elizabeth M %A Libon, David J %A Mendes, Lisa A %A Niswender, Kevin %A Pechman, Kimberly R %A Rane, Swati %A Ruberg, Frederick L %A Su, Yan Ru %A Zetterberg, Henrik %A Liu, Dandan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Blood Pressure Monitoring, Ambulatory %K Brain %K Case-Control Studies %K Cerebral Angiography %K Cognitive Dysfunction %K Echocardiography %K Epidemiologic Research Design %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Neuropsychological Tests %K Research Design %X

BACKGROUND: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities.

OBJECTIVE: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics.

METHODS: From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection.

RESULTS: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants.

CONCLUSION: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.

%B J Alzheimers Dis %V 52 %P 539-59 %8 2016 03 08 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967211?dopt=Abstract %R 10.3233/JAD-150914 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vascular Health Indices and Cognitive Domain Function: Singapore Longitudinal Ageing Studies. %A Lim, Shir Lynn %A Gao, Qi %A Nyunt, Ma Shwe Zin %A Gong, Lingli %A Lunaria, Josephine B %A Lim, May Li %A Ling, Audrey %A Lam, Carolyn Su-Ping %A Richards, Arthur Mark %A Ling, Lieng Hsi %A Ng, Tze Pin %K Aged %K Blood Flow Velocity %K Blood Pressure %K Cardiovascular Diseases %K Carotid Intima-Media Thickness %K Cognitive Aging %K Female %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Singapore %K Vascular Stiffness %X

BACKGROUND: Few studies have comprehensively evaluated the relationship between vascular disease and cognition of older adults without cardiac disease.

OBJECTIVE: We explored the associations of structural atherosclerosis, vascular stiffness, and reactivity with global, memory, attention, language, visuospatial ability, and executive function in community-dwelling, non-demented older Asians without cardiac diseases.

METHODS: Cognition was assessed by Mini-Mental State Examination (MMSE) (n = 308) and detailed neuropsychological tests (n = 155). Vascular measures included carotid intima-media thickness; aortic stiffness [carotid-femoral pulse wave velocity (CFPWV), aortic augmentation index (AI), and aortic pulse pressure (PP)]; carotid stiffness [elasticity modulus (Ep), beta index (β), arterial compliance (AC), carotid AI]; and endothelial function [reactive hyperemia index (RHI)]. Multivariable analyses controlled for potential confounding by demographics, apolipoprotein E genotype and cardiovascular risk factors.

RESULTS: The participants' mean age was 63.0 ± 6.1 years. Inverse associations with MMSE were found for AC (β= 0.128, p = 0.019), Ep (β= -0.151, p = 0.008), β index (β= -0.122, p = 0.029), carotid stiffness z-score (β= -0.154, p = 0.007); with executive function for CFPWV (β= -0.209, p = 0.026), AC (β= 0.214, p = 0.005), Ep (β= -0.160, p = 0.050), β index (β= -0.165, p = 0.041), and both aortic (β= -0.229, p = 0.010) and carotid (β= -0.208, p = 0.010) stiffness z-scores; with verbal memory for AI (β= -0.229, p = 0.004) and aortic (β= -0.263, p = 0.004) stiffness z-score; with language for AI (β= -0.155, p = 0.025), aortic stiffness z-score (β= -0.196, p = 0.011). RHI positively correlated with visuospatial ability (β= 0.195, p = 0.013) and executive function (β= 0.151, p = 0.045).

CONCLUSION: The results support a link between systemic vascular health and neurocognitive function in older Asian adults. Subclinical noninvasive measures of arterial stiffness and reactivity may identify individuals vulnerable to cognitive impairment.

%B J Alzheimers Dis %V 50 %P 27-40 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639958?dopt=Abstract %R 10.3233/JAD-150516 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Ventilatory Response to Hypercapnia Predicts Dementia with Lewy Bodies in Late-Onset Major Depressive Disorder. %A Takahashi, Sho %A Mizukami, Katsuyoshi %A Arai, Tetsuaki %A Ogawa, Ryoko %A Kikuchi, Norihiro %A Hattori, Satoshi %A Darby, David %A Asada, Takashi %K 3-Iodobenzylguanidine %K Aged %K Aged, 80 and over %K Depressive Disorder, Major %K Follow-Up Studies %K Heart Rate %K Humans %K Hypercapnia %K Hypotension, Orthostatic %K Kaplan-Meier Estimate %K Lewy Body Disease %K Middle Aged %K Partial Pressure %K Psychiatric Status Rating Scales %K Retrospective Studies %K Ventilators, Mechanical %X

BACKGROUND: Studies have shown that developing major depressive disorder (MDD) at 50 years of age or older can predict dementia. Depression is particularly common in dementia with Lewy bodies (DLB), and occasionally occurs before the onset of extrapyramidal symptoms. Moreover, systemic autonomic dysfunction, including an abnormal ventilatory response to hypercapnia (VRH), is common in patients with DLB.

OBJECTIVE: Here, we aimed to determine whether the VRH is useful for distinguishing depression that is predictive of DLB from other types of MDD.

METHODS: Participants were 35 consecutive patients with first onset MDD at 50 years or older with bradykinesia. After diagnosing the clinical subtype of MDD according to DSM-IV criteria, each subject underwent a battery of psychological tests, autonomic examinations including VRH, brain magnetic resonance imaging, and 123I-meta-iodobenzylguanidine scintigraphy.

RESULTS: Longitudinal follow-up showed that all 18 patients with abnormal VRH results developed DLB, whereas none of the 17 patients with normal VRH results converted to DLB within the study period (sensitivity: 100% , specificity: 100%). Additionally, over half of the DLB converters showed abnormalities on other autonomic examinations. For converters, the most common MDD subtype had psychotic and melancholic features simultaneously. The frequency of hypersensitivity to psychotropics was higher in converters than it was in non-converters.

CONCLUSION: In the present study, patients with abnormal VRH results were very likely to develop DLB. Thus, for patients with late-onset MDD accompanied by bradykinesia, the VRH in combination with the clinical subtype of MDD or hypersensitivity to psychotropics may be useful for diagnosing prodromal DLB.

%B J Alzheimers Dis %V 50 %P 751-8 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757183?dopt=Abstract %R 10.3233/JAD-150507 %0 Journal Article %J J Alzheimers Dis %D 2016 %T δ Scores are Exportable Across Cultural and Linguistic Boundaries. %A Royall, Donald R %A Palmer, Raymond F %A Matsuoka, Teruyuki %A Kato, Yuka %A Taniguchi, Shogo %A Ogawa, Mayu %A Fujimoto, Hiroshi %A Okamura, Aiko %A Shibata, Keisuke %A Nakamura, Kaeko %A Nakaaki, Shutaro %A Koumi, Hiroyuki %A Mimura, Masaru %A Fukui, Kenji %A Narumoto, Jin %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Cognitive Dysfunction %K Cohort Studies %K Culture %K Executive Function %K Female %K Humans %K Linguistics %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Psychometrics %K Reproducibility of Results %K ROC Curve %K Texas %X

The latent variable "δ", can accurately diagnose dementia. Its generalizability across populations is unknown. We constructed a δ homolog ("dT2J") in data collected by the Texas Alzheimer's Research and Care Consortium (TARCC). From this, we calculated a composite d-score "d". We then tested d's generalizability across random subsets of TARCC participants and to a convenience sample of elderly Japanese persons with normal cognition (NC), mild cognitive impairment (MCI), and dementia (AD) (n = 176). dT2J was indicated by Instrumental Activities of Daily Living and psychometric measures. Embedded in this battery were the Mini-Mental Status Examination (MMSE) and an executive clock-drawing task (CLOX). Only MMSE and CLOX were available in both TARCC and the Japanese cohort. Therefore, a second composite variable, "T2J", was constructed solely from the factor loadings of CLOX and MMSE on d. The diagnostic accuracy of T2J was estimated in the validation sample, the remainder of the TARCC cohort, and in the Japanese sample. The areas under the receiver operating curve (AUC; ROC) for T2J were compared in each sample, and against d in TARCC. The AUCs for T2J were statistically indiscriminable within TARCC, and in Japanese persons. In Japanese persons, AUCs for T2J were 0.97 for the discrimination between AD versus NC, 0.86 for AD versus MCI, and 0.79 for NC versus MCI. The AUCs for T2J in Japanese persons were higher than any individual psychometric measure in that sample. Valid d-score composites can be abstracted from a subset of δ's indicators. Moreover, those composites are exportable across cultural and linguistic boundaries.

%B J Alzheimers Dis %V 49 %P 561-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26444764?dopt=Abstract %R 10.3233/JAD-150261 %0 Journal Article %J Nat Med %D 2014 %T Plasma phospholipids identify antecedent memory impairment in older adults. %A Mapstone, Mark %A Cheema, Amrita K %A Fiandaca, Massimo S %A Zhong, Xiaogang %A Mhyre, Timothy R %A MacArthur, Linda H %A Hall, William J %A Fisher, Susan G %A Peterson, Derick R %A Haley, James M %A Nazar, Michael D %A Rich, Steven A %A Berlau, Dan J %A Peltz, Carrie B %A Tan, Ming T %A Kawas, Claudia H %A Federoff, Howard J %K Aged %K Alzheimer Disease %K Asparagine %K Biomarkers %K Carnitine %K Cohort Studies %K Dipeptides %K Female %K Humans %K Longitudinal Studies %K Lysophosphatidylcholines %K Malates %K Male %K Memory Disorders %K Metabolome %K Mild Cognitive Impairment %K Neuropsychological Tests %K Phosphatidylcholines %K Phosphatidylinositols %K Phospholipids %K Proline %K Prospective Studies %K Sensitivity and Specificity %K Sphingomyelins %K Ursodeoxycholic Acid %X

Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies. Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels, structural and functional magnetic resonance imaging and the recent use of brain amyloid imaging or inflammaging, are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity. Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease.

%B Nat Med %V 20 %P 415-8 %8 2014 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24608097?dopt=Abstract %R 10.1038/nm.3466 %0 Journal Article %J Nature %D 2014 %T REST and stress resistance in ageing and Alzheimer's disease. %A Lu, Tao %A Aron, Liviu %A Zullo, Joseph %A Pan, Ying %A Kim, Haeyoung %A Chen, Yiwen %A Yang, Tun-Hsiang %A Kim, Hyun-Min %A Drake, Derek %A Liu, X Shirley %A Bennett, David A %A Colaiácovo, Monica P %A Yankner, Bruce A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Autophagy %K Brain %K Caenorhabditis elegans Proteins %K Cell Death %K Cell Nucleus %K Chromatin Immunoprecipitation %K Cognition %K DNA-Binding Proteins %K Down-Regulation %K Frontotemporal Dementia %K Gene Expression Regulation %K Humans %K Lewy Body Disease %K Longevity %K Mice %K Mild Cognitive Impairment %K Neurons %K Neuroprotective Agents %K Oxidative Stress %K Phagosomes %K Repressor Proteins %K Transcription Factors %K Up-Regulation %K Wnt Signaling Pathway %K Young Adult %X

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

%B Nature %V 507 %P 448-54 %8 2014 Mar 27 %G eng %N 7493 %1 http://www.ncbi.nlm.nih.gov/pubmed/24670762?dopt=Abstract %R 10.1038/nature13163 %0 Journal Article %J Ann Neurol %D 2012 %T An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease. %A Jack, Clifford R %A Knopman, David S %A Weigand, Stephen D %A Wiste, Heather J %A Vemuri, Prashanthi %A Lowe, Val %A Kantarci, Kejal %A Gunter, Jeffrey L %A Senjem, Matthew L %A Ivnik, Robert J %A Roberts, Rosebud O %A Rocca, Walter A %A Boeve, Bradley F %A Petersen, Ronald C %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Aniline Compounds %K Biomarkers %K Brain %K Cognition Disorders %K Disease Progression %K Female %K Fluorodeoxyglucose F18 %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K National Institute on Aging (U.S.) %K Neuropsychological Tests %K Positron-Emission Tomography %K Thiazoles %K United States %X

OBJECTIVE: A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines.

METHODS: We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria.

RESULTS: The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non-AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP.

INTERPRETATION: This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1-3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important.

%B Ann Neurol %V 71 %P 765-75 %8 2012 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/22488240?dopt=Abstract %R 10.1002/ana.22628 %0 Journal Article %J Cell %D 2011 %T Astrocyte-neuron lactate transport is required for long-term memory formation. %A Suzuki, Akinobu %A Stern, Sarah A %A Bozdagi, Ozlem %A Huntley, George W %A Walker, Ruth H %A Magistretti, Pierre J %A Alberini, Cristina M %K Animals %K Arabinose %K Astrocytes %K Glycogen %K Hippocampus %K Imino Furanoses %K Lactic Acid %K Memory, Long-Term %K Monocarboxylic Acid Transporters %K Muscle Proteins %K Neurons %K Rats %K Sugar Alcohols %K Symporters %X

We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation.

%B Cell %V 144 %P 810-23 %8 2011 Mar 4 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21376239?dopt=Abstract %R 10.1016/j.cell.2011.02.018 %0 Journal Article %J Nature %D 2011 %T Caspase signalling controls microglia activation and neurotoxicity. %A Burguillos, Miguel A %A Deierborg, Tomas %A Kavanagh, Edel %A Persson, Annette %A Hajji, Nabil %A Garcia-Quintanilla, Albert %A Cano, Josefina %A Brundin, Patrik %A Englund, Elisabet %A Venero, Jose L %A Joseph, Bertrand %K Alzheimer Disease %K Animals %K Caspase 3 %K Caspase 7 %K Caspase 8 %K Caspase Inhibitors %K Caspases %K Cell Death %K Cells, Cultured %K Dopamine %K Enzyme Activation %K Frontal Lobe %K Gene Knockdown Techniques %K Humans %K Lipopolysaccharides %K Mice %K Microglia %K Neostriatum %K Neurotoxicity Syndromes %K Parkinson Disease %K Protein Kinase C-delta %K Rats %K Signal Transduction %K Substantia Nigra %K Toll-Like Receptor 4 %X

Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.

%B Nature %V 472 %P 319-24 %8 2011 Apr 21 %G eng %N 7343 %1 http://www.ncbi.nlm.nih.gov/pubmed/21389984?dopt=Abstract %R 10.1038/nature09788 %0 Journal Article %J Arch Neurol %D 2011 %T Evidence for ordering of Alzheimer disease biomarkers. %A Jack, Clifford R %A Vemuri, Prashanthi %A Wiste, Heather J %A Weigand, Stephen D %A Aisen, Paul S %A Trojanowski, John Q %A Shaw, Leslie M %A Bernstein, Matthew A %A Petersen, Ronald C %A Weiner, Michael W %A Knopman, David S %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Biomarkers %K Female %K Hippocampus %K Humans %K Longitudinal Studies %K Male %K Mild Cognitive Impairment %K tau Proteins %X

OBJECTIVE: To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.

DESIGN: Validation sample.

SETTING: Multisite, referral centers.

PARTICIPANTS: A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.

MAIN OUTCOME MEASURES: Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume).

RESULTS: Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months.

CONCLUSIONS: A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.

%B Arch Neurol %V 68 %P 1526-35 %8 2011 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21825215?dopt=Abstract %R 10.1001/archneurol.2011.183 %0 Journal Article %J Nat Neurosci %D 2011 %T Neuronal activity regulates the regional vulnerability to amyloid-β deposition. %A Bero, Adam W %A Yan, Ping %A Roh, Jee Hoon %A Cirrito, John R %A Stewart, Floy R %A Raichle, Marcus E %A Lee, Jin-Moo %A Holtzman, David M %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cerebral Cortex %K Disease Models, Animal %K Extracellular Fluid %K Female %K Lactic Acid %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Microdialysis %K Neurons %K Plaque, Amyloid %K Sensory Deprivation %K Somatosensory Cortex %X

Amyloid-β (Aβ) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Aβ deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ, which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Aβ, and unilateral vibrissal deprivation decreased ISF Aβ and lactate, in contralateral barrel cortex. Long-term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in Alzheimer's disease.

%B Nat Neurosci %V 14 %P 750-6 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21532579?dopt=Abstract %R 10.1038/nn.2801 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2011 %T Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. %A Jin, Ming %A Shepardson, Nina %A Yang, Ting %A Chen, Gang %A Walsh, Dominic %A Selkoe, Dennis J %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Blotting, Western %K Chromatography, Gel %K Dimerization %K Genetic Vectors %K Hippocampus %K Humans %K Immunohistochemistry %K Immunoprecipitation %K In Situ Nick-End Labeling %K Lentivirus %K Microscopy, Confocal %K Microtubules %K Neurites %K Phosphorylation %K Rats %K Rats, Sprague-Dawley %K tau Proteins %X

Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.

%B Proc Natl Acad Sci U S A %V 108 %P 5819-24 %8 2011 Apr 5 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/21421841?dopt=Abstract %R 10.1073/pnas.1017033108 %0 Journal Article %J Neurology %D 2011 %T Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. %A Li, J %A Wang, Y J %A Zhang, M %A Xu, Z Q %A Gao, C Y %A Fang, C Q %A Yan, J C %A Zhou, H D %K Aged %K Alzheimer Disease %K Cerebrovascular Disorders %K Cognition Disorders %K Disease Progression %K Female %K Humans %K Incidence %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Peptides %K Regression Analysis %K Residence Characteristics %K Retrospective Studies %K Risk Factors %K Statistics, Nonparametric %X

OBJECTIVE: Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia.

METHODS: A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion.

RESULTS: At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion.

CONCLUSION: VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.

%B Neurology %V 76 %P 1485-91 %8 2011 Apr 26 %G eng %N 17 %1 http://www.ncbi.nlm.nih.gov/pubmed/21490316?dopt=Abstract %R 10.1212/WNL.0b013e318217e7a4 %0 Journal Article %J Neurology %D 2010 %T Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. %A Petersen, R C %A Aisen, P S %A Beckett, L A %A Donohue, M C %A Gamst, A C %A Harvey, D J %A Jack, C R %A Jagust, W J %A Shaw, L M %A Toga, A W %A Trojanowski, J Q %A Weiner, M W %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biomarkers %K Cross-Sectional Studies %K Diagnostic Imaging %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Middle Aged %X

BACKGROUND: Neuroimaging measures and chemical biomarkers may be important indices of clinical progression in normal aging and mild cognitive impairment (MCI) and need to be evaluated longitudinally.

OBJECTIVE: To characterize cross-sectionally and longitudinally clinical measures in normal controls, subjects with MCI, and subjects with mild Alzheimer disease (AD) to enable the assessment of the utility of neuroimaging and chemical biomarker measures.

METHODS: A total of 819 subjects (229 cognitively normal, 398 with MCI, and 192 with AD) were enrolled at baseline and followed for 12 months using standard cognitive and functional measures typical of clinical trials.

RESULTS: The subjects with MCI were more memory impaired than the cognitively normal subjects but not as impaired as the subjects with AD. Nonmemory cognitive measures were only minimally impaired in the subjects with MCI. The subjects with MCI progressed to dementia in 12 months at a rate of 16.5% per year. Approximately 50% of the subjects with MCI were on antidementia therapies. There was minimal movement on the Alzheimer's Disease Assessment Scale-Cognitive Subscale for the normal control subjects, slight movement for the subjects with MCI of 1.1, and a modest change for the subjects with AD of 4.3. Baseline CSF measures of Abeta-42 separated the 3 groups as expected and successfully predicted the 12-month change in cognitive measures.

CONCLUSION: The Alzheimer's Disease Neuroimaging Initiative has successfully recruited cohorts of cognitively normal subjects, subjects with mild cognitive impairment (MCI), and subjects with Alzheimer disease with anticipated baseline characteristics. The 12-month progression rate of MCI was as predicted, and the CSF measures heralded progression of clinical measures over 12 months.

%B Neurology %V 74 %P 201-9 %8 2010 Jan 19 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/20042704?dopt=Abstract %R 10.1212/WNL.0b013e3181cb3e25 %0 Journal Article %J Ann Neurol %D 2010 %T APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. %A Morris, John C %A Roe, Catherine M %A Xiong, Chengjie %A Fagan, Anne M %A Goate, Alison M %A Holtzman, David M %A Mintun, Mark A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Aniline Compounds %K Apolipoprotein E2 %K Apolipoprotein E4 %K Apolipoproteins E %K Brain %K Female %K Follow-Up Studies %K Genotype %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Peptide Fragments %K Phosphorylation %K Plaque, Amyloid %K tau Proteins %K Thiazoles %X

OBJECTIVE: To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging.

METHODS: Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta(42) (Abeta(42)), tau, and phosphorylated tau (ptau(181)). All individuals were genotyped for APOE.

RESULTS: The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181).

INTERPRETATION: Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.

%B Ann Neurol %V 67 %P 122-31 %8 2010 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/20186853?dopt=Abstract %R 10.1002/ana.21843