%0 Journal Article %J J Alzheimers Dis %D 2023 %T Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings. %A Gonzalez, Christopher %A Mimmack, Kayden J %A Amariglio, Rebecca E %A Becker, J Alex %A Chhatwal, Jasmeer P %A Fitzpatrick, Colleen D %A Gatchel, Jennifer R %A Johnson, Keith A %A Katz, Zoe S %A Kuppe, Madeline K %A Locascio, Joseph J %A Udeogu, Onyinye J %A Papp, Kathryn V %A Premnath, Pranitha %A Properzi, Michael J %A Rentz, Dorene M %A Schultz, Aaron P %A Sperling, Reisa A %A Vannini, Patrizia %A Wang, Sharon %A Marshall, Gad A %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Amyloid %K Amyloid beta-Peptides %K Amyloidogenic Proteins %K Cognitive Dysfunction %K Entorhinal Cortex %K Humans %K Positron-Emission Tomography %K tau Proteins %X

BACKGROUND: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical.

OBJECTIVE: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults.

METHODS: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid.

RESULTS: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone.

CONCLUSION: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

%B J Alzheimers Dis %V 94 %P 217-226 %8 2023 %G eng %N 1 %R 10.3233/JAD-220885 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Cross-Sectional Analysis of Periodontal Disease and Cognitive Impairment Conducted in a Memory Clinic: The Pearl Study. %A Saji, Naoki %A Ishihara, Yuichi %A Murotani, Kenta %A Uchiyama, Akira %A Takeda, Akinori %A Sakurai, Takashi %A Matsushita, Kenji %X

BACKGROUND: Periodontal disease (PeD) is a risk factor of Alzheimer's disease and is associated with cognitive decline in older adults. However, the relationships between subitems of neuropsychological tests and PeD have not been fully clarified.

OBJECTIVE: To evaluate associations between PeD and subitems of neuropsychological tests.

METHODS: We performed a cross-sectional analysis of data of 183 participants (women: 50% , mean age: 79 years) from a clinical study. We enrolled patients who visited our memory clinic and assessed demographics, dementia-related risk factors, neuropsychological tests, brain magnetic resonance images, and a dental screening check. We evaluated the relationships between cognitive function and PeD using multivariable logistic regression analyses.

RESULTS: Participants with dementia were less likely to make periodical visits to the dentist, had fewer teeth, had less frequent tooth brushing habits, and were more likely to have PeD. Impaired cognitive function was significantly associated with an increasing degree of PeD. In multivariable logistic regression analyses, impaired visuospatial function and attention were associated with twice the risk of moderate or severe PeD compared with individuals with preserved visuospatial function and attention (odds ratio: 2.11, 95% confidence interval: 1.04-4.29, p = 0.037). Impaired word recall and recognition and following commands were associated with increased risk of PeD (odds ratio: 2.80, 95% confidence interval: 1.41-5.32, p = 0.003).

CONCLUSIONS: Cognitive decline, such as impaired visuospatial function, attention, word recall and recognition, and inability to follow commands were independently and strongly associated with PeD. These items can be assessed easily on a daily basis.

%B J Alzheimers Dis %V 96 %P 369-380 %8 2023 Oct 24 %G eng %N 1 %R 10.3233/JAD-230742 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Effects of Brain Pathologies on Spatiotemporal Gait Parameters in Patients with Mild Cognitive Impairment. %A Lindh-Rengifo, Magnus %A Jonasson, Stina B %A Ullén, Susann %A Palmqvist, Sebastian %A van Westen, Danielle %A Stomrud, Erik %A Mattsson-Carlgren, Niklas %A Nilsson, Maria H %A Hansson, Oskar %X

BACKGROUND: Impaired gait can precede dementia. The associations between gait parameters and brain pathologies are therefore of interest.

OBJECTIVE: To explore how different brain pathologies (i.e., vascular and Alzheimer's) are associated with specific gait parameters from various gait components in persons with mild cognitive impairment (MCI), who have an increased risk of developing dementia.

METHODS: This cross-sectional study included 96 patients with MCI (mean 72, ±7.5 years; 52% women). Gait was evaluated by using an electronic walkway, GAITRite®. Four gait parameters (step velocity variability; step length; step time; stance time asymmetry) were used as dependent variables in multivariable linear regression analyses. Independent variables included Alzheimer's disease pathologies (amyloid-β and tau) by using PET imaging and white matter hyperintensities (WMH) by using MRI. Covariates included age, sex, comorbidities (and intracranial volume in analyses that includedWMH).

RESULTS: Increased tau-PET (Braak I-IV region of interest [ROI]) was associated with step velocity variability (standardized regression coefficient, β= 0.383, p < 0.001) and step length (β= 0.336, p < 0.001), which remained significant when using different Braak ROIs (I-II, III-IV, V-VI). The associations remained significant when adjusting for WMH (p < 0.001). When also controlling for gait speed, tau was no longer significantly (p = 0.168) associated with an increased step length. No significant associations between gait and Aβ-PET load or WMH were identified.

CONCLUSIONS: The results indicate that one should pay specific attention to assess step velocity variability when targeting single task gait in patients with MCI. Future studies should address additional gait variability measures and dual tasking in larger cohorts.

%B J Alzheimers Dis %V 96 %P 161-171 %8 2023 Oct 24 %G eng %N 1 %R 10.3233/JAD-221303 %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 Patterns of Aging Changes in Bodyweight May Predict Alzheimer's Disease. %A Ukraintseva, Svetlana %A Duan, Hongzhe %A Holmes, Rachel %A Bagley, Olivia %A Wu, Deqing %A Yashkin, Arseniy %A Kulminski, Alexander %A Akushevich, Igor %A Whitson, Heather %A Stallard, Eric %A Yashin, Anatoliy %A Arbeev, Konstantin %X

Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ∼10 years younger AgeMax, compared to AD-free women. APOE4 carriers had younger AgeMax and steeper slope. Older AgeMax and flatter slope predicted lower AD risk. Premature decline in weight could be a sign of accelerated physical aging contributing to AD.

%B J Alzheimers Dis %V 97 %P 163-170 %8 2024 Jan 02 %G eng %N 1 %R 10.3233/JAD-220998 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Plasma ApoE4 Levels Are Lower than ApoE2 and ApoE3 Levels, and Not Associated with Plasma Aβ 40/42 Ratio as a Biomarker of Amyloid-β Amyloidosis in Alzheimer's Disease. %A Nakamura, Takumi %A Kawarabayashi, Takeshi %A Ueda, Tetsuya %A Shimomura, Sachiko %A Hoshino, Masaki %A Itoh, Ken %A Ihara, Kazushige %A Nakaji, Shigeyuki %A Takatama, Masamitsu %A Ikeda, Yoshio %A Shoji, Mikio %X

BACKGROUND: APOE4 is the strongest risk factor for Alzheimer's disease (AD). However, limited information is currently available on APOE4 and the pathological role of plasma apolipoprotein E (ApoE) 4 remains unclear.

OBJECTIVE: The aims of the present study were to measure plasma levels of total ApoE (tE), ApoE2, ApoE3, and ApoE4 using mass spectrometry and elucidate the relationships between plasma ApoE and blood test items.

METHODS: We herein examined plasma levels of tE, ApoE2, ApoE3, and ApoE4 in 498 subjects using liquid chromatograph-mass spectrometry (LC-MS/MS).

RESULTS: Among 498 subjects, mean age was 60 years and 309 were female. tE levels were distributed as ApoE2/E3 = ApoE2/E4 >ApoE3/E3 = ApoE3/E4 >ApoE4/E4. In the heterozygous group, ApoE isoform levels were distributed as ApoE2 >ApoE3 >ApoE4. ApoE levels were not associated with aging, the plasma amyloid-β (Aβ) 40/42 ratio, or the clinical diagnosis of AD. Total cholesterol levels correlated with the level of each ApoE isoform. ApoE2 levels were associated with renal function, ApoE3 levels with low-density lipoprotein cholesterol and liver function, and ApoE4 levels with triglycerides, high-density lipoprotein cholesterol, body weight, erythropoiesis, and insulin metabolism.

CONCLUSION: The present results suggest the potential of LC-MS/MS for the phenotyping and quantitation of plasma ApoE. Plasma ApoE levels are regulated in the order of ApoE2 >ApoE3 >ApoE4 and are associated with lipids and multiple metabolic pathways, but not directly with aging or AD biomarkers. The present results provide insights into the multiple pathways by which peripheral ApoE4 influences the progression of AD and atherosclerosis.

%B J Alzheimers Dis %V 93 %P 333-348 %8 2023 May 02 %G eng %N 1 %R 10.3233/JAD-220996 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Risk Factors for Longer-Term Mortality in Discharged Patients with Dementia and SARS-CoV-2 Infection: A Matched Case-Control Study. %A Chen, Shanquan %A Cardinal, Rudolf N %A Gräf, Stefan %A O'Brien, John T %A Underwood, Benjamin R %X

BACKGROUND: Persisting symptoms and increased mortality after SARS-CoV-2 infection has been described in COVID-19 survivors.

OBJECTIVE: We examined longer-term mortality in patients with dementia and SARS-CoV-2 infection.

METHODS: A retrospective matched case-control study of 165 patients with dementia who survived an acute hospital admission with COVID-19 infection, and 1325 patients with dementia who survived a hospital admission but without SARS-CoV-2 infection. Potential risk factors investigated included socio-demographic factors, clinical features, and results of investigations. Data were fitted using a Cox proportional hazard model.

RESULTS: Compared to patients with dementia but without SARS-CoV-2 infection, people with dementia and SARS-CoV-2 infection had a 4.4-fold risk of death (adjusted hazard ratio [aHR] = 4.44, 95% confidence interval [CI] 3.13-6.30) even beyond the acute phase of infection. This excess mortality could be seen up to 125 days after initial recovery but was not elevated beyond this time. Risk factors for COVID-19-associated mortality included prescription of antipsychotics (aHR = 3.06, 95% CI 1.40-6.69) and benzodiazepines (aHR = 3.00, 95% CI 1.28-7.03). Abnormalities on investigation associated with increased mortality included high white cell count (aHR = 1.21, 95% CI 1.04-1.39), higher absolute neutrophil count (aHR = 1.28, 95% CI 1.12-1.46), higher C-reactive protein (aHR = 1.01, 95% CI 1.00-1.02), higher serum sodium (aHR = 1.09, 95% CI 1.01-1.19), and higher ionized calcium (aHR = 1.03, 95% CI 1.00-1.06). The post-acute COVID mortality could be modeled for the first 120 days after recovery with a balanced accuracy of 87.2%.

CONCLUSION: We found an increased mortality in patients with dementia beyond the acute phase of illness. We identified several investigation results associated with increased mortality, and increased mortality in patients prescribed antipsychotics or benzodiazepines.

%B J Alzheimers Dis %V 92 %P 295-309 %8 2023 Mar 07 %G eng %N 1 %R 10.3233/JAD-221093 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Urinary Amino Acid-Conjugated Acrolein and Taurine as New Biomarkers for Detection of Dementia. %A Yoshida, Madoka %A Uemura, Takeshi %A Mizoi, Mutsumi %A Waragai, Masaaki %A Sakamoto, Akihiko %A Terui, Yusuke %A Kashiwagi, Keiko %A Igarashi, Kazuei %X

BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the serious diseases at advanced age, and its early detection is important for maintaining quality of life (QOL).

OBJECTIVE: In this study, we sought novel biomarkers for dementia in urine.

METHODS: Samples of urine were collected from 57 control subjects without dementia, 62 mild cognitive impairment (MCI) patients, and 42 AD patients. Mini-Mental State Examination (MMSE) was evaluated when subjects were examined by medical doctors. Urinary amino acid (lysine)-conjugated acrolein (AC-Acro) was measured using N ɛ -(3-formyl-3, 4-dehydropiperidine) lysine (FDP-Lys) ELISA kit, and taurine content was measured using a taurine assay kit. Values were normalized by creatinine content which was measured with the colorimetric assay kit.

RESULTS: We found that urinary amino acid (lysine)-conjugated acrolein (AC-Acro) and taurine negatively correlated with MMSE score and are significantly lower in dementia patients compared to the normal subjects. When AC-Acro and taurine were evaluated together with age using an artificial neural network model, median relative risk values for subjects with AD, subjects with mild cognitive impairment, and control subjects were 0.96, 0.53, and 0.06, respectively.

CONCLUSION: Since urine is relatively easy to collect, our findings provide a novel biomarker for dementia without invasiveness.

%B J Alzheimers Dis %V 92 %P 361-369 %8 2023 Mar 07 %G eng %N 1 %R 10.3233/JAD-220912 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Impaired Experience-Dependent Refinement of Place Cells in a Rat Model of Alzheimer's Disease. %A Broussard, John I %A Redell, John B %A Maynard, Mark E %A Zhao, Jing %A Moore, Anthony %A Mills, Rachel W %A Hood, Kimberly N %A Underwood, Erica %A Roysam, Badrinath %A Dash, Pramod K %X

BACKGROUND: Hippocampal place cells play an integral role in generating spatial maps. Impaired spatial memory is a characteristic pathology of Alzheimer's disease (AD), yet it remains unclear how AD influences the properties of hippocampal place cells.

OBJECTIVE: To record electrophysiological activity in hippocampal CA1 neurons in freely-moving 18-month-old male TgF344-AD and age-matched wild-type (WT) littermates to examine place cell properties.

METHODS: We implanted 32-channel electrode arrays into the CA1 subfield of 18-month-old male WT and TgF344-AD (n = 6/group) rats. Ten days after implantation, single unit activity in an open field arena was recorded across days. The spatial information content, in-field firing rate, and stability of each place cell was compared across groups. Pathology was assessed by immunohistochemical staining, and a deep neural network approach was used to count cell profiles.

RESULTS: Aged TgF344-AD rats exhibited hippocampal amyloid-β deposition, and a significant increase in Iba1 immunoreactivity and microglia cell counts. Place cells from WT and TgF344-AD rat showed equivalent spatial information, in-field firing rates, and place field stability when initially exposed to the arena. However, by day 3, the place cells in aged WT rats showed characteristic spatial tuning as evidenced by higher spatial information content, stability, and in-field firing rates, an effect not seen in TgF344-AD rats.

CONCLUSION: These findings support the notion that altered electrophysiological properties of place cells may contribute to the learning and memory deficits observed in AD.

%B J Alzheimers Dis %V 86 %P 1907-1916 %8 2022 Apr 19 %G eng %N 4 %R 10.3233/JAD-215023 %0 Journal Article %J J Alzheimers Dis %D 2022 %T The Role of Amyloid-β, Tau, and α-Synuclein Proteins as Putative Blood Biomarkers in Patients with Cerebral Amyloid Angiopathy. %A Piccarducci, Rebecca %A Caselli, Maria Chiara %A Zappelli, Elisa %A Ulivi, Leonardo %A Daniele, Simona %A Siciliano, Gabriele %A Ceravolo, Roberto %A Mancuso, Michelangelo %A Baldacci, Filippo %A Martini, Claudia %X

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β protein (Aβ) within brain blood vessels that develops in elderly people and Alzheimer's disease (AD) patients. Therefore, the investigation of biomarkers able to differentiate CAA patients from AD patients and healthy controls (HC) is of great interest, in particular in peripheral fluids.

OBJECTIVE: The current study aimed to detect the neurodegenerative disease (ND)-related protein (i.e., Aβ 1 - 40, Aβ 1 - 42, tau, and α-synuclein) levels in both red blood cells (RBCs) and plasma of CAA patients and HC, evaluating their role as putative peripheral biomarkers for CAA.

METHODS: For this purpose, the proteins' concentration was quantified in RBCs and plasma by homemade immunoenzymatic assays in an exploratory cohort of 20 CAA patients and 20 HC.

RESULTS: The results highlighted a significant increase of Aβ 1 - 40 and α-synuclein concentrations in both RBCs and plasma of CAA patients, while higher Aβ 1 - 42 and t-tau levels were detected only in RBCs of CAA individuals compared to HC. Moreover, Aβ 1 - 42/Aβ 1 - 40 ratio increased in RBCs and decreased in plasma of CAA patients. The role of these proteins as candidate peripheral biomarkers easily measurable with a blood sample in CAA needs to be confirmed in larger studies.

CONCLUSION: In conclusion, we provide evidence concerning the possible use of blood biomarkers for contributing to CAA diagnosis and differentiation from other NDs.

%B J Alzheimers Dis %V 89 %P 1039-1049 %8 2022 Sep 27 %G eng %N 3 %R 10.3233/JAD-220216 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Association of White Matter Hyperintensity Progression with Cognitive Decline in Patients with Amnestic Mild Cognitive Impairment. %A Hirao, Kentaro %A Yamashita, Fumio %A Tsugawa, Akito %A Haime, Rieko %A Fukasawa, Raita %A Sato, Tomohiko %A Kanetaka, Hidekazu %A Umahara, Takahiko %A Sakurai, Hirofumi %A Hanyu, Haruo %A Shimizu, Soichiro %X

BACKGROUND: White matter hyperintensities (WMH) on MRI have been reported to increase the risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). However, effects of the progression of WMH on the cognition of patients with MCI remains unclear to date.

OBJECTIVE: To investigate the association between WMH progression and cognitive decline in amnestic MCI patients.

METHODS: Thirty-eight subjects with amnestic MCI were analyzed prospectively every year for 2 years. Fourteen MCI subjects dropped out on the final visit, and therefore 24 subjects with MCI were analyzed for the entire duration. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 FLAIR using the 3D-slicer. The associations between PVH/DWMH progression and cognitive decline were investigated.

RESULTS: An increase in DWMH volume significantly correlated with changes in Mini-Mental State Examination and category verbal fluency scores, whereas an increase in PVH volume did not correlate with changes in any item.

CONCLUSION: DWMH progression was closely associated with a decline in frontal lobe function and semantic memory, suggesting that WMH progression might affect some AD pathophysiologies in amnestic MCI patients.

%B J Alzheimers Dis %V 80 %P 877-883 %8 2021 March 23 %G eng %N 2 %R 10.3233/JAD-201451 %0 Journal Article %J J Alzheimers Dis %D 2021 %T The Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS II): Optimization and Further Validation. %A Dekker, Alain D %A Ulgiati, Aurora M %A Groen, Henk %A Boxelaar, Vincent A %A Sacco, Silvia %A Falquero, Ségolène %A Carfi, Angelo %A di Paola, Antonella %A Benejam, Bessy %A Valldeneu, Silvia %A Fopma, Roelie %A Oosterik, Marjo %A Hermelink, Marloes %A Beugelsdijk, Gonny %A Schippers, Mieke %A Henstra, Hepie %A Scholten-Kuiper, Martine %A Willink-Vos, Judith %A de Ruiter, Lisa %A Willems, Liesbeth %A Loonstra-de Jong, Anneke %A Coppus, Antonia M W %A Tollenaere, Marleen %A Fortea, Juan %A Onder, Graziano %A Rebillat, Anne-Sophie %A Van Dam, Debby %A De Deyn, Peter P %K Adult %K Aged %K Anxiety %K Dementia %K Down Syndrome %K Female %K Humans %K Irritable Mood %K Male %K Middle Aged %K Reproducibility of Results %K Symptom Assessment %X

BACKGROUND: People with Down syndrome (DS) are at high risk to develop Alzheimer's disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior.

OBJECTIVE: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population.

METHODS: Optimization was based on item irrelevance and clinical experiences obtained in the initial study. Using the shortened and refined BPSD-DS II, informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113).

RESULTS: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising.

CONCLUSION: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment.

%B J Alzheimers Dis %V 81 %P 1505-1527 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33967040?dopt=Abstract %R 10.3233/JAD-201427 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Longitudinally Increasing Elevated Asymmetric Flortaucipir Binding in a Cognitively Unimpaired Amyloid-Negative Older Individual. %A Schwarz, Christopher G %A Knopman, David S %A Ramanan, Vijay K %A Lowe, Val J %A Wiste, Heather J %A Cogswell, Petrice M %A Utianski, Rene L %A Senjem, Matthew L %A Gunter, Jeffrey R %A Vemuri, Prashanthi %A Petersen, Ronald C %A Jack, Clifford R %X

We present the case of a cognitively unimpaired 77-year-old man with elevated, asymmetric, and longitudinally increasing Flortaucipir tau PET despite normal (visually negative) amyloid PET. His atypical tau PET signal persisted and globally increased in a follow-up scan five years later. Across eight years of observations, temporoparietal atrophy was observed consistent with tau PET patterns, but he retained the cognitively unimpaired classification. Altogether, his atypical tau PET signal is not explained by any known risk factors or alternative pathologies, and other imaging findings were not remarkable. He remains enrolled for further observation.

%B J Alzheimers Dis %V 85 %P 59-64 %8 2022 Jan 04 %G eng %N 1 %R 10.3233/JAD-215052 %0 Journal Article %J J Alzheimers Dis %D 2021 %T A Novel Cognitive Function Scale Using Functional Near-Infrared Spectroscopy for Evaluating Cognitive Dysfunction. %A Nakamura, Shin %A Yomota, Satoshi %A Ito, Hitomi %A Akinaga, Nobuyuki %A Hori, Ayaka %A Chinomi, Kenta %A Suzuki, Hideaki %A Uchida, Kazuhiko %A Asada, Takashi %X

BACKGROUND: Maintaining cognitive function is integral to a healthy social life in the aged. Although neuropsychological tests and brain imaging methods can assess cognitive dysfunction, these techniques are subjective, psychologically burdensome, and cannot be conducted easily.

OBJECTIVE: We sought to develop an objective, low-burden novel cognitive function scale based on functional near-infrared spectroscopy (fNIRS) of hemodynamic changes in the cerebral cortex during daily task performance.

METHODS: A total of 63 participants (aged 60-80 years) identified as non-dementia controls (NDC) or with mild cognitive impairment (MCI) were recruited and randomly assigned to training and test data sets. Explanatory variables were hemodynamic responses during low-burden sensory and simple tasks without higher-order brain functioning.

RESULTS: A logistic regression analysis of the fNIRS index in NDCs and MCI patients revealed area under the curve, sensitivity, specificity, and holdout results of 0.98, 94%, 88%, and 62% respectively. Correlation between fNIRS index and MCI odds showed positive linearity (R2 = 0.96).

CONCLUSION: Positive correlation between the fNIRS index and MCI odds indicated effectiveness of this fNIRS measurement. Although additional experiments are necessary, the fNIRS index representing degree of cognitive decline can be an onsite monitoring tool to assess cognitive status.

%B J Alzheimers Dis %V 81 %P 1579-1588 %8 2021 Jun 15 %G eng %N 4 %R 10.3233/JAD-210072 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Research Attitudes and Interest Among Elderly Latinxs: The Impact of a Collaborative Video and Community Peers. %A Sewell, Margaret C %A Neugroschl, Judith %A Umpierre, Mari %A Chin, Shehan %A Zhu, Carolyn W %A Velasco, Nelly %A Gonzalez, Sabrina %A Acabá-Berrocal, Alexandra %A Bianchetti, Luca %A Silva, Gabriela %A Collazo, Alma %A Sano, Mary %X

BACKGROUND: Latinx elders are underrepresented in dementia research. In a previous study we assessed research attitudes in urban minority elders and found a significant minority expressed neutral to negative attitudes relating to trust, safety, and personal responsibility to help research.

OBJECTIVE: To assess the impact of a composite intervention on attitudes toward research and research participation among elderly Latinx. The intervention was a collaboratively produced research participation video shown during presentations with our elderly community advisory board (CAB) as co-presenters.

METHODS: The video was created by the ADRC and CAB. All senior center attendees were eligible to participate. Afterwards, the Research Attitudes Questionnaire (RAQ) and a brief questionnaire on the impact of the video were administered. Using Wilcoxon Rank Sum Tests, Chi Square, and OLS regressions, RAQ responses were compared to those from a historical cohort from similar centers.

RESULTS: 74 in the "Historical Cohort 1" and 104 in "Intervention Cohort 2" were included. RAQ total score was higher in Cohort 2 than Cohort 1 (28.5 versus 26.1, p <  0.05) after controlling for age, education, and country of origin. In response to the question "Has the video influenced your willingness and interest to participate in research", 88.7%of the participants in Cohort 2 reported being "more" or "much more" interested in research.

CONCLUSION: Tailoring community research recruitment programs to include relatable peers using novel recruitment techniques may have positive implications for improving enrollment of diverse elderly individuals in research.

%B J Alzheimers Dis %V 82 %P 771-779 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-210027 %0 Journal Article %J J Alzheimers Dis %D 2020 %T A Community-Based Study Identifying Metabolic Biomarkers of Mild Cognitive Impairment and Alzheimer's Disease Using Artificial Intelligence and Machine Learning. %A Yilmaz, Ali %A Ustun, Ilyas %A Ugur, Zafer %A Akyol, Sumeyya %A Hu, William T %A Fiandaca, Massimo S %A Mapstone, Mark %A Federoff, Howard %A Maddens, Michael %A Graham, Stewart F %X

BACKGROUND: Currently, there is no objective, clinically available tool for the accurate diagnosis of Alzheimer's disease (AD). There is a pressing need for a novel, minimally invasive, cost friendly, and easily accessible tool to diagnose AD, assess disease severity, and prognosticate course. Metabolomics is a promising tool for discovery of new, biologically, and clinically relevant biomarkers for AD detection and classification.

OBJECTIVE: Utilizing artificial intelligence and machine learning, we aim to assess whether a panel of metabolites as detected in serum can be used as an objective and clinically feasible tool for the diagnosis of mild cognitive impairment (MCI) and AD.

METHODS: Using a community-based sample cohort acquired from different sites across the US, we adopted an approach combining Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR), Liquid Chromatography coupled with Mass Spectrometry (LC-MS). and various machine learning statistical approaches to identify a biomarker panel capable of identifying those patients with AD and MCI from healthy controls.

RESULTS: Of the 212 measured metabolites, 5 were identified as optimal to discriminate between controls, and individuals with MCI or AD. Our models performed with AUC values in the range of 0.72-0.76, with the sensitivity and specificity values ranging from 0.75-0.85 and 0.69-0.81, respectively. Univariate and pathway analysis identified lipid metabolism as the most perturbed biochemical pathway in MCI and AD.

CONCLUSION: A comprehensive method of acquiring metabolomics data, coupled with machine learning techniques, has identified a strong panel of diagnostic biomarkers capable of identifying individuals with MCI and AD. Further, our data confirm what other groups have reported in that lipid metabolism is significantly perturbed in those individuals suffering with dementia. This work may provide additional insight into AD pathogenesis and encourage more in-depth analysis of the AD lipidome.

%B J Alzheimers Dis %V 78 %P 1381-1392 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200305 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Costs and Resource Use Associated with Community-Dwelling Patients with Alzheimer's Disease in Japan: Baseline Results from the Prospective Observational GERAS-J Study. %A Nakanishi, Miharu %A Igarashi, Ataru %A Ueda, Kaname %A Brnabic, Alan J M %A Treuer, Tamas %A Sato, Masayo %A Kahle-Wrobleski, Kristin %A Meguro, Kenichi %A Yamada, Masahito %A Mimura, Masaru %A Arai, Heii %X

BACKGROUND: As the Japanese population ages, caring for people with Alzheimer's disease (AD) dementia is becoming a major socioeconomic issue.

OBJECTIVE: To determine the contribution of patient and caregiver costs to total societal costs associated with AD dementia.

METHODS: Baseline data was used from the longitudinal, observational GERAS-J study. Using the Mini-Mental State Examination (MMSE) score, patients routinely visiting memory clinics were stratified into three groups based on AD severity. Health care resource utilizationwas recorded using the Resource Utilization in Dementia questionnaire. Total monthly societal costs were estimated using Japan-specific unit costs of services and products (patient direct health care use, patient social care use, and informal caregiving time). Uncertainty around mean costs was estimated using bootstrapping methods.

RESULTS: Overall, 553 community-dwelling patients withADdementia (28.3% mild[MMSE21-26], 37.8% moderate[MMSE 15-20], and 34.0% moderately severe/severe [MMSE < 14]) and their caregivers were enrolled. Patient characteristics were: mean age 80.3 years, 72.7% female, and 13.6% living alone. Caregiver characteristics were: mean age 62.1 years, 70.7% female, 78.8% living with patient, 49.0% child of patient, and 39.2% sole caregiver. Total monthly societal costs of AD dementia (Japanese yen) were: 158,454 (mild), 211,301 (moderate), and 294,224 (moderately severe/severe). Informal caregiving costs comprised over 50% of total costs.

CONCLUSION: Baseline results of GERAS-J showed that total monthly societal costs associated with AD dementia increased with AD severity. Caregiver-related costs were the largest cost component. Interventions are needed to decrease informal costs and decrease caregiver burden.

%B J Alzheimers Dis %V 74 %P 127-138 %8 2020 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31985460?dopt=Abstract %R 10.3233/JAD-190811 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Individual Differences in the Effects of Physical Activity on Cognitive Function in People with Mild to Moderate Dementia. %A Uijen, Iris L %A Aaronson, Justine A %A Karssemeijer, Esther G A %A Olde Rikkert, Marcel G M %A Kessels, Roy P C %X

The aim of this study was to investigate whether the effect of physical activity on cognitive function in persons with dementia is moderated by patient characteristics as Apolipoprotein E and dementia type. We included 101 individuals with dementia and calculated the reliable change index to determine the change in global cognition, executive function, episodic memory, working memory, and processing speed before and after a 12-week exercise training. We found a higher treatment-related benefit in episodic memory in persons with non-Alzheimer's disease compared to persons with Alzheimer's disease, and in executive function in individuals with better baseline cognitive function.

%B J Alzheimers Dis %V 74 %P 435-439 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/32039840?dopt=Abstract %R 10.3233/JAD-190606 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Synaptic Vesicle Protein 2B Negatively Regulates the Amyloidogenic Processing of AβPP as a Novel Interaction Partner of BACE1. %A Miyamoto, Masakazu %A Kuzuya, Akira %A Noda, Yasuha %A Ueda, Sakiho %A Asada-Utsugi, Megumi %A Ito, Shinji %A Fukusumi, Yoshiyasu %A Kawachi, Hiroshi %A Takahashi, Ryosuke %A Kinoshita, Ayae %X

BACKGROUND: Given that amyloid-β (Aβ) peptide is produced and released at synapses, synaptic Aβ is one of the promising therapeutic targets to prevent synaptic dysfunction in Alzheimer's disease (AD). Although Aβ production begins with the cleavage of the amyloid-β protein precursor (AβPP) by β-site AβPP cleaving enzyme 1 (BACE1), the mechanism on how BACE1 is involved in AβPP processing at synapses remains unclear.

OBJECTIVE: This study aimed to identify novel BACE1 interacting proteins regulating Aβ production at the synapse.

METHODS: BACE1 interacting proteins were pulled down using a mass spectrometry-based proteomics of wild-type (WT) rat brain synaptoneurosome lysates utilizing anti-BACE1 antibody. Then, a novel BACE1 interactor was identified and characterized using experimental systems that utilized transfected cells and knockout (KO) mice.

RESULTS: Synaptic vesicle protein 2B (SV2B) was identified as a novel presynaptic interaction partner of BACE1. In HEK293 cells, co-overexpression of SV2B with BACE1 significantly reduced the sAβPPβ and Aβ levels released in the media; thus, SV2B overexpression negatively affected the AβPP cleavage by BACE1. Compared with those of WT mice, the hippocampal lysates of SV2B knockout mice had significantly elevated Aβ levels, whereas the β-secretase activity and the AβPP and BACE1 protein levels remained unchanged. Finally, a fractionation assay revealed that BACE1 was mislocalized in SV2B KO mice; hence, SV2B may be involved in BACE1 trafficking downregulating the amyloidogenic pathway of AβPP.

CONCLUSION: SV2B has a novel role of negatively regulating the amyloidogenic processing of AβPP at the presynapses.

%B J Alzheimers Dis %V 75 %P 173-185 %8 2020 May 05 %G eng %N 1 %R 10.3233/JAD-200071 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Waist Circumference and Domain-Specific Cognitive Function Among Non-Demented Japanese Older Adults Stratified by Sex: Results from the Takashima Cognition Study. %A Waki, Takashi %A Tanaka-Mizuno, Sachiko %A Takashima, Naoyuki %A Takechi, Hajime %A Hayakawa, Takehito %A Miura, Katsuyuki %A Ueshima, Hirotsugu %A Kita, Yoshikuni %A Dodge, Hiroko H %X

BACKGROUND: While being obese in mid-life is associated with an increased risk of dementia and cognitive decline in late-life, being obese in late-life is shown to be associated with a lower risk of these outcomes in some studies. This phenomenon is known as the "obesity paradox", but the underlying reasons and potential sex difference have not been well understood.

OBJECTIVE: To investigate the association between cognition and waist circumference (WC), an alternative measure of body fat which can be measured easier than body mass index (BMI), among older adults in each generation of late-life for men and women separately.

METHODS: Three hundred thirty-five participants were used in the current study who were identified by random sampling of residents aged 65-74, 75-84, and 85 + years in Takashima County, Shiga Prefecture, Japan during 2005-2006. Associations between WC and domain-specific cognitive functions measured by 12 neuropsychological tests were examined using multivariable linear regression models with covariates: age, education, and hypertension.

RESULTS: Larger WC was associated with better attention/working memory among 65-74-year old women and with better learning/acquisition among 65-74-year-old men, while larger WC was associated with worse learning/acquisition, memory, attention/working memory, and language/fluency among 75-84-year old men.

CONCLUSION: We found age and sex differences in the association between WC and domain-specific cognitive functions. Among older old men (age 75-84) larger WC had negative effects on various domains including memory, attention, language, and executive functions, while we did not find any negative effects of larger WC on cognition among women in any age groups.

%B J Alzheimers Dis %V 73 %P 887-896 %8 2020 Feb 04 %G eng %N 3 %R 10.3233/JAD-190395 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Cerebral Microbleeds Are Associated with Cerebral Hypoperfusion in Patients with Alzheimer's Disease. %A Hatada, Yutaka %A Hashimoto, Mamoru %A Shiraishi, Shinya %A Ishikawa, Tomohisa %A Fukuhara, Ryuji %A Yuki, Seiji %A Tanaka, Hibiki %A Miyagawa, Yusuke %A Kitajima, Mika %A Uetani, Hiroyuki %A Tsunoda, Naoko %A Koyama, Asuka %A Ikeda, Manabu %X

BACKGROUND: Although cerebral microbleeds (CMBs) are commonly observed in patients with Alzheimer's disease (AD), their clinical relevance for AD remains unclear.

OBJECTIVE: We investigated the significance of CMBs in AD by examining the relationship between CMBs and cerebral blood flow (CBF) in patients with AD.

METHODS: Thirty-four patients (aged 77.9±7.6 years; 17 men) with probable AD and multiple (≥8) CMBs were selected from 394 consecutive patients. For each lobe of the brain, the correlation between the number of CMBs observed on susceptibility-weighted images and the decrease in CBF observed on single-photon emission computed tomography was assessed.

RESULTS: The number of microbleeds was significantly correlated with the severity of decrease in the occipital lobe (Spearman's r = 0.531, p <  0.001) and temporal lobe (r = 0.437, p <  0.001) but not in the frontal lobe (r = 0.201, p = 0.101) and parietal lobe (r = 0.178, p = 0.146). These results were unchanged in the partial correlational analysis after controlling the effect of other small vessel disease such as lacunars and white matter hyperintensities.

CONCLUSION: Multiple CMBs are associated with cerebral hypoperfusion in AD. The effects of CMBs on CBF differed according to brain location, possibly reflecting different distributions of the underlying cerebral amyloid angiopathy and AD-related histopathology, such as neurofibrillary tangles.

%B J Alzheimers Dis %V 71 %P 273-280 %8 2019 Sep 3 %G eng %N 1 %R 10.3233/JAD-190272 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Mild Cognitive Impairment and Dementia Involving Multiple Cognitive Domains in Mexican Urbanites. %A Calderón-Garcidueñas, Lilian %A Mukherjee, Partha S %A Kulesza, Randy J %A Torres-Jardón, Ricardo %A Hernández-Luna, Jacqueline %A Ávila-Cervantes, Rodrigo %A Macías-Escobedo, Edgar %A González-González, Oscar %A González-Maciel, Angelica %A García-Hernández, Kevin %A Hernández-Castillo, Ariatna %A Villarreal-Ríos, Rodolfo %X

Exposures to fine particulate matter PM2.5 and ozone O3 are associated with Alzheimer's disease (AD) risk. Mexico City residents have lifetime exposures to PM2.5 and O3 above annual USEPA standards and their brains contain high redox, combustion, and friction-derived magnetite nanoparticles. AD pathological changes with subcortical pre-tangle stages in infancy and cortical tau pre-tangles, NFT Stages I-II, and amyloid phases 1-2 are identified by the 2nd decade. Given their AD continuum, a reliable identification of cognitive impairment is of utmost importance. The Montreal Cognitive Assessment (MoCA) was administered to 517 urbanites, age 21.60±5.88 years, with 13.69±1.28 formal education years, in Mexican PM2.5 polluted cities. MoCA score was 23.92±2.82, and 24.7% and 30.3% scored ≤24 and ≤22, respectively (MCI≤24, AD≤22). Cognitive deficits progressively targeted Visuospatial, Executive, Language, and Memory domains, body mass index (BMI) impacting total scores negatively (p = 0.0008), aging driving down Executive, Visuospatial, and Language index scores (p <  0.0001, 0.0037, and 0.0045), and males performing better in Executive tasks. Average age for AD MoCA scores was 22.38±7.7 years. Residency in polluted cities is associated with progression of multi-domain cognitive impairment affecting 55% of Mexican seemingly healthy youth. Normal BMI ought to be a neuroprotection goal. MoCA provides guidance for further mandatory neuropsychological testing in young populations. Identifying and lowering key neurotoxicants impacting neural risk trajectories in the developing brain and monitoring cognitive performance would greatly facilitate multidisciplinary early diagnosis and prevention of AD in high risk young populations. Cognitive deficits hinder development of those representing the force moving the country in future years.

%B J Alzheimers Dis %V 68 %P 1113-1123 %8 2019 Apr 8 %G eng %N 3 %R 10.3233/JAD-181208 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Two Year Outcomes, Cognitive and Behavioral Markers of Decline in Healthy, Cognitively Normal Older Persons with Global Deterioration Scale Stage 2 (Subjective Cognitive Decline with Impairment). %A Reisberg, Barry %A Torossian, Carol %A Shulman, Melanie B %A Monteiro, Isabel %A Boksay, Istvan %A Golomb, James %A Guillo Benarous, Francoise %A Ulysse, Anaztasia %A Oo, Thet %A Vedvyas, Alok %A Rao, Julia A %A Marsh, Karyn %A Kluger, Alan %A Sangha, Jaspreet %A Hassan, Mudasar %A Alshalabi, Munther %A Arain, Fauzia %A Shaikh, Naveed %A Buj, Maja %A Kenowsky, Sunnie %A Masurkar, Arjun V %A Rabin, Laura %A Noroozian, Maryam %A Sánchez-Saudinós, Mar A Belén %A Blesa, Rafael %A Auer, Stefanie %A Zhang, Yian %A de Leon, Mony %A Sadowski, Martin %A Wisniewski, Thomas %A Gauthier, Serge %A Shao, Yongzhao %X

BACKGROUND: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2.

OBJECTIVE: Two-year interval behavioral markers were investigated herein.

METHODS: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years.

RESULTS: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01).

CONCLUSION: SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

%B J Alzheimers Dis %V 67 %P 685-705 %8 2019 Jan 22 %G eng %N 2 %R 10.3233/JAD-180341 %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 Dementia Care Competence Among Care Professionals and Reduced Challenging Behavior of Home-Dwelling Persons with Dementia: A Pre- and Post-Intervention Data Analysis. %A Nakanishi, Miharu %A Hirooka, Kayo %A Imai, Yasuaki %A Inoue, Shintaro %A Yukari, Yukio %A Katayama, Chie %A Miyamoto, Yuki %A Shindo, Yumi %A Ueno, Hideki %A Toya, Junichiro %A Takano, Yosuke %A Nishida, Atsushi %X

BACKGROUND: We developed a psychosocial dementia care program to help care managers and professional caregivers manage challenging behavior in home-dwelling persons with dementia in Japan. The program consists of a web-based tool for ongoing monitoring and assessment for challenging behavior, and multi-agency discussion meetings. Results of a cluster-randomized controlled trial indicate a reduction in challenging behavior through this program.

OBJECTIVES: The present study aimed to identify a key component of the developed program that is associated with a reduction in challenging behavior.

METHODS: We used consecutive data of the intervention and examined the association between challenging behavior in home-dwelling persons with dementia, professionals' competence, and the frequency of revision of action plans. Challenging behavior was assessed using the total score of the Neuropsychiatric Inventory. A baseline and follow-up questionnaire was completed by care professionals using a Japanese version of the Sense of Competence in Dementia Care Staff scale.

RESULTS: A total of 86 care professionals completed a 6-month intervention with 219 persons with dementia. The 86 care professionals significantly improved in their dementia care competence. Challenging behavior was significantly reduced among the 219 persons with dementia at follow-up regardless of the level of professionals' competence or the frequency of revision of action plans. Less pain was significantly related to the lower levels of challenging behavior.

CONCLUSION: The ongoing multi-agency discussion meetings, with a focus on challenging behavior, may have been the key component in the psychosocial dementia care program. Pain management should be emphasized in action plans for challenging behavior.

%B J Alzheimers Dis %V 64 %P 515-523 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29914021?dopt=Abstract %R 10.3233/JAD-171077 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Early Stage Alterations in CA1 Extracellular Region Proteins Indicate Dysregulation of IL6 and Iron Homeostasis in the 5XFAD Alzheimer's Disease Mouse Model. %A Gurel, Busra %A Cansev, Mehmet %A Sevinc, Cansu %A Kelestemur, Seda %A Ocalan, Busra %A Cakir, Aysen %A Aydin, Sami %A Kahveci, Nevzat %A Ozansoy, Mehmet %A Taskapilioglu, Ozlem %A Ulus, Ismail Hakki %A Başar, Merve Karayel %A Sahin, Betul %A Tuzuner, Mete Bora %A Baykal, Ahmet Tarik %K Alzheimer Disease %K Animals %K CA1 Region, Hippocampal %K Chromatography, Liquid %K Disease Models, Animal %K Female %K Homeostasis %K Interleukin-6 %K Iron %K Mice %K Mice, Transgenic %K Proteomics %K Tandem Mass Spectrometry %X

In recent years, an increasing number of research papers revealed that the compositional and volumetric alterations in the extracellular matrix are the consequences of aging and may be related to Alzheimer's disease (AD). In this study, we aimed to demonstrate the alterations in hippocampal extracellular fluid proteins in vivo using the 5XFAD mouse model. Samples were obtained from hippocampi of 5XFAD mice (n = 6) and their non-transgenic littermates by intracerebral push-pull perfusion technique at 3 months of age, representing the pre-pathological stage of the AD. Proteins in the hippocampal perfusates were analyzed by Ultra Performance Liquid Chromatography-Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry (UPLC-ESI-qTOF-MS/MS). 178 proteins were identified and 19 proteins of them were found to be statistically significantly altered (p≤0.05, fold change ≥40%, unique peptide count ≥3) in the hippocampal CA1 extracellular fluid of the 5XFAD mouse model. Ingenuity pathway analysis of the protein expression results identified IL6 as an upstream regulator. The upregulation of IL6 was validated by immunohistochemical staining of the hippocampus and cortex of the 5XFAD mice prior to Aβ plaque formation. Furthermore, the iron level in the hippocampus was measured by inductively coupled plasma-mass spectrometry as IL6 is mentioned in several studies to take part in iron homeostasis and inflammation and found to be increased in 5XFAD mice hippocampus. Alterations in extracellular matrix proteins in addition to increasing amount of hippocampal IL6 and iron in the early stages of AD may reveal inflammation-mediated iron dyshomeostasis in the early stages of neurodegeneration.

%B J Alzheimers Dis %V 61 %P 1399-1410 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376847?dopt=Abstract %R 10.3233/JAD-170329 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Effects of Composite Supplement Containing Astaxanthin and Sesamin on Cognitive Functions in People with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Trial. %A Ito, Naoki %A Saito, Hitomi %A Seki, Shinobu %A Ueda, Fumitaka %A Asada, Takashi %X

BACKGROUND: Dementia and its first or transitional stage, mild cognitive impairment (MCI), is a major concern for the aging Japanese society. Thus, the use of dietary supplements to improve or maintain cognitive function has become a topic of public interest.

OBJECTIVE: In this study, we evaluated the effects of a composite supplement containing food-derived antioxidants, specifically astaxanthin and sesamin (AS), on cognitive function in people with MCI.

METHOD: Twenty-one healthy participants with MCI were recruited in our double-blind placebo-controlled pilot study. They were assigned to either an AS group, who received ingestible capsules containing AS, or a placebo group, who received identical placebo capsules. To assess cognitive functions, we performed the Japanese version of the Central Nervous System Vital Signs (CNSVS) test and the Alzheimer's Disease Assessment Scale-Cog test at baseline, after 6 weeks, and after 12 weeks of dietary supplementation.

RESULTS: The CNSVS test revealed significant improvements in psychomotor speed and processing speed in the AS group compared with the placebo group, suggesting that the daily supplementation of AS improved cognitive functions related to the ability to comprehend, and perform complex tasks quickly and accurately.

CONCLUSION: Our results provide support for the use of AS as a dietary supplementation for improving cognitive functions.

%B J Alzheimers Dis %V 62 %P 1767-1775 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614679?dopt=Abstract %R 10.3233/JAD-170969 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Establishing a New Screening System for Mild Cognitive Impairment and Alzheimer's Disease with Mental Rotation Tasks that Evaluate Visuospatial Function. %A Suzuki, Ayuko %A Shinozaki, Jun %A Yazawa, Shogo %A Ueki, Yoshino %A Matsukawa, Noriyuki %A Shimohama, Shun %A Nagamine, Takashi %K Aged %K Aged, 80 and over %K Agnosia %K Alzheimer Disease %K Case-Control Studies %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Early Diagnosis %K Eye Movements %K Female %K Humans %K Male %K Mental Status Schedule %K Reaction Time %K ROC Curve %X

BACKGROUND: The mental rotation task is well-known for the assessment of visuospatial function; however, it has not been used for screening of dementia patients.

OBJECTIVE: The aim of this study was to create a simple screening test for patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by focusing on non-amnestic symptoms.

METHODS: Age-matched healthy controls (age 75.3±6.8), patients with MCI (76.5±5.5), and AD (78.2±5.0) participated in this study. They carried out mental rotation tasks targeting geometric graphics or alphabetical characters with three rotating angles (0°, 90°, and 180°) and indicated the correct answer. Response accuracy and reaction time were recorded along with their eye movements using an eye tracker. To quantify their visual processing strategy, the run count ratio (RC ratio) was calculated by dividing the mean number of fixations in incorrect answers by that in correct answers.

RESULTS: AD patients showed lower accuracy and longer reaction time than controls. They also showed a significantly greater number of fixation and smaller saccade amplitude than controls, while fixation duration did not differ significantly. The RC ratio was higher for AD, followed by MCI and control groups. By setting the cut-off value to 0.47 in the 180° rotating angle task, we could differentiate MCI patients from controls with a probability of 80.0%.

CONCLUSIONS: We established a new screening system for dementia patients by evaluating visuospatial function. The RC ratio during a mental rotation task is useful for discriminating MCI patients from controls.

%B J Alzheimers Dis %V 61 %P 1653-1665 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376869?dopt=Abstract %R 10.3233/JAD-170801 %0 Journal Article %J J Alzheimers Dis %D 2018 %T INDEL Length and Haplotypes in the β-Synuclein Gene: A Key to Differentiate Dementia with Lewy Bodies? %A Gámez-Valero, Ana %A Canet-Pons, Julia %A Urbizu, Aintzane %A Anillo, Ana %A Santos, Cristina %A Ariza, Aurelio %A Beyer, Katrin %X

Lewy body diseases (LBD) include Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer's disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB, perform haplotype analysis for SNCB, and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB, determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher's exact, chi-square, ANOVA tests, and the ΔΔCt method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB.

%B J Alzheimers Dis %V 65 %P 207-219 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30040713?dopt=Abstract %R 10.3233/JAD-180074 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Influence of the Val66Met Polymorphism of Brain-Derived Neurotrophic Factor on Neurological Function after Traumatic Brain Injury. %A Finan, John D %A Udani, Shreya V %A Patel, Vimal %A Bailes, Julian E %X

Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results.

%B J Alzheimers Dis %V 65 %P 1055-1064 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149456?dopt=Abstract %R 10.3233/JAD-180585 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Neuroprotective Effects of Ferruginol, Jatrophone, and Junicedric Acid Against Amyloid-β Injury in Hippocampal Neurons. %A Zolezzi, Juan M %A Lindsay, Carolina B %A Serrano, Felipe G %A Ureta, Roxana C %A Theoduloz, Cristina %A Schmeda-Hirschmann, Guillermo %A Inestrosa, Nibaldo C %X

Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aβ peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aβ oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aβ oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aβ oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.

%B J Alzheimers Dis %V 63 %P 705-723 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29660932?dopt=Abstract %R 10.3233/JAD-170701 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration. %A Piaceri, Irene %A Imperiale, Daniele %A Ghidoni, Enrico %A Atzori, Cristiana %A Bagnoli, Silvia %A Ferrari, Camilla %A Ungari, Silvana %A Ambrogio, Luca %A Sorbi, Sandro %A Nacmias, Benedetta %X

BACKGROUND: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's disease or psychiatric disorders, jeopardizing care and research.

OBJECTIVE: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein).

METHODS: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s.

RESULTS: Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature.

CONCLUSION: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.

%B J Alzheimers Dis %V 62 %P 1683-1689 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614680?dopt=Abstract %R 10.3233/JAD-170989 %0 Journal Article %J J Alzheimers Dis %D 2018 %T The Price of Stress: High Bedtime Salivary Cortisol Levels Are Associated with Brain Atrophy and Cognitive Decline in Stroke Survivors. Results from the TABASCO Prospective Cohort Study. %A Tene, Oren %A Hallevi, Hen %A Korczyn, Amos D %A Shopin, Ludmila %A Molad, Jeremy %A Kirschbaum, Clemens %A Bornstein, Natan M %A Shenhar-Tsarfaty, Shani %A Kliper, Efrat %A Auriel, Eitan %A Usher, Sali %A Stalder, Tobias %A Ben Assayag, Einor %X

BACKGROUND AND OBJECTIVE: Previous studies suggest that excessive cortisol levels after stroke are associated with cognitive dysfunction. However, limited data exist regarding associations between post-stroke cortisol levels, brain abnormalities, genetic factors, and cognitive outcome. We sought to study these issues in a longitudinal stroke survivors cohort.

METHODS: Data from 182 cognitively intact ischemic stroke patients from the TABASCO study were available. Saliva cortisol levels (bedtime and post-awakening) and cognitive assessments were obtained on admission, and 6, 12, and 24 months thereafter. During hospitalization, patients underwent 3T MRI scans and APOE genotyping.

RESULTS: Higher bedtime cortisol levels immediately post-stroke were associated with larger neurological deficits (p < 0.001), brain atrophy (p = 0.025), worse white matter integrity (p = 0.003), and worse cognitive results up to 24 months post-stroke. These findings remained significant when adjusted for age, gender, education, smoking, stroke severity, apolipoprotein E4 (ApoE4) status, and body mass index. ApoE4 negatively modified the relation between cortisol and memory. As a group, participants who presented with high admission bedtime cortisol levels continued to present relatively elevated bedtime levels across all examined time-points, and this group had inferior memory and executive functioning scores compared to the lower cortisol group 24 months post-stroke (p = 0.05, p = 0.035, respectively). Post-awakening cortisol levels were not associated with neuroimaging findings or cognitive scores.

CONCLUSIONS: High bedtime salivary cortisol levels post-stroke may provide information about dysregulation of diurnal HPA-axis activity under acute challenge conditions, and predict worse cognitive outcome. ApoE4 genotype might modify this association. These findings call for specific stress management interventions in stroke survivors.

%B J Alzheimers Dis %V 65 %P 1365-1375 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30149451?dopt=Abstract %R 10.3233/JAD-180486 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Reduced Cerebrovascular Reserve Capacity as a Biomarker of Microangiopathy in Alzheimer's Disease and Mild Cognitive Impairment. %A Urbanova, Barbora Soukupova %A Schwabova, Jaroslava Paulasova %A Magerova, Hana %A Jansky, Petr %A Marková, Hana %A Vyhnálek, Martin %A Laczó, Jan %A Hort, Jakub %A Tomek, Ales %X

BACKGROUND: Cerebral microangiopathy in Alzheimer's disease (AD) causes chronic hypoperfusion and probably accelerates neurodegenerative changes.

OBJECTIVE: We hypothesize microvascular impairment could be present already in mild cognitive impairment (MCI) and can be revealed using transcranial color-coded sonography (TCCS) and the breath-holding maneuver.

METHODS: Three groups of subjects (AD in the stage of dementia, MCI, and cognitively normal controls) with detailed neuropsychological testing and low cerebrovascular burden (no history of stroke, no intra- or extracranial artery stenoses, and no severe vascular lesions on brain MRI), underwent a TCCS assessment of peak systolic (PSV), mean flow (MFV), and end diastolic velocities (EDV) and resistance and pulsatility indices (RI, PI) in large intracranial vessels bilaterally. Cerebrovascular reserve capacity was assessed using the breath-holding index (BHI) in middle cerebral artery (MCA) bilaterally. The ultrasound parameters were compared between the groups, correlated with neuropsychological tests, and compared between amnestic and non-amnestic MCI subtypes.

RESULTS: Fourteen AD (3 males, 67.9±11.1 years, MMSE 18.0±4.6), 24 MCI (13 males, 71.9±7.3 years, MMSE 28.0±1.6), and 24 risk factor-matched controls (14 males, 67.8±6.4 years, MMSE 29.1±1.2) were enrolled. Significant differences were found between AD and controls in MFV, EDV, RI, PI in right MCA after breath holding, in PSV, MFV, EDV in left MCA after breath holding, and in BHI on the left side. The left BHI correlated positively with verbal memory test.

CONCLUSION: Results show decreased cerebrovascular reserve capacity in AD as a sign of impaired cerebral hemodynamic status without severe underlying atherosclerosis. This can be identified using TCCS and BHI.

%B J Alzheimers Dis %V 63 %P 465-477 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614647?dopt=Abstract %R 10.3233/JAD-170815 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer's Disease and Brain Aging. %A Hasegawa, Yu %A Toyama, Kensuke %A Uekawa, Ken %A Ichijo, Hidenori %A Kim-Mitsuyama, Shokei %K Aging %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Aspartic Acid Endopeptidases %K Avoidance Learning %K Disease Models, Animal %K Gene Expression Regulation %K MAP Kinase Kinase Kinase 5 %K MAP Kinase Signaling System %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Presenilin-1 %K Reaction Time %X

To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aβ, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging.

%B J Alzheimers Dis %V 61 %P 259-263 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154282?dopt=Abstract %R 10.3233/JAD-170645 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Separating Symptomatic Alzheimer's Disease from Depression based on Structural MRI. %A Klöppel, Stefan %A Kotschi, Maria %A Peter, Jessica %A Egger, Karl %A Hausner, Lucrezia %A Frölich, Lutz %A Förster, Alex %A Heimbach, Bernhard %A Normann, Claus %A Vach, Werner %A Urbach, Horst %A Abdulkadir, Ahmed %X

Older patients with depression or Alzheimer's disease (AD) at the stage of early dementia or mild cognitive impairment may present with objective cognitive impairment, although the pathology and thus therapy and prognosis differ substantially. In this study, we assessed the potential of an automated algorithm to categorize a test set of 65 T1-weighted structural magnetic resonance images (MRI). A convenience sample of elderly individuals fulfilling clinical criteria of either AD (n = 28) or moderate and severe depression (n = 37) was recruited from different settings to assess the potential of the pattern recognition method to assist in the differential diagnosis of AD versus depression. We found that our algorithm learned discriminative patterns in the subject's grey matter distribution reflected by an area under the receiver operator characteristics curve of up to 0.83 (confidence interval ranged from 0.67 to 0.92) and a balanced accuracy of 0.79 for the separation of depression from AD, evaluated by leave-one-out cross validation. The algorithm also identified consistent structural differences in a clinically more relevant scenario where the data used during training were independent from the data used for evaluation and, critically, which included five possible diagnoses (specifically AD, frontotemporal dementia, Lewy body dementia, depression, and healthy aging). While the output was insufficiently accurate to use it directly as a means for classification when multiple classes are possible, the continuous output computed by the machine learning algorithm differed between the two groups that were investigated. The automated analysis thus could complement, but not replace clinical assessments.

%B J Alzheimers Dis %V 63 %P 353-363 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29614658?dopt=Abstract %R 10.3233/JAD-170964 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Tau Protein Dysfunction after Brain Ischemia. %A Pluta, Ryszard %A Ułamek-Kozioł, Marzena %A Januszewski, Sławomir %A Czuczwar, Stanisław J %X

Brain ischemia comprises blood-brain barrier, glial, and neuronal cells. The blood-brain barrier controls permeability of different substances and the composition of the neuronal cells 'milieu', which is required for their physiological functioning. Recent evidence indicates that brain ischemia itself and ischemic blood-brain barrier dysfunction is associated with the accumulation of neurotoxic molecules within brain tissue, e.g., different parts of amyloid-β protein precursor and changed pathologically tau protein. All these changes due to ischemia can initiate and progress neurodegeneration of the Alzheimer's disease-type. This review presents brain ischemia and ischemic blood-brain barrier as a trigger for tau protein alterations. Thus, we hypothesize that the changes in pattern of phosphorylation of tau protein are critical to microtubule function especially in neurons, and contribute to the neurodegeneration following brain ischemia-reperfusion episodes with Alzheimer's disease phenotype.

%B J Alzheimers Dis %V 66 %P 429-437 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30282370?dopt=Abstract %R 10.3233/JAD-180772 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Time Trends in the Prevalence of Neurocognitive Disorders and Cognitive Impairment in the United States: The Effects of Disease Severity and Improved Ascertainment. %A Akushevich, Igor %A Yashkin, Arseniy P %A Kravchenko, Julia %A Ukraintseva, Svetlana %A Stallard, Eric %A Yashin, Anatoliy I %X

BACKGROUND: Trends in the prevalence of cognitive impairment (CI) based on cognitive assessment instruments are often inconsistent with those of neurocognitive disorders (ND) based on Medicare claims records.

OBJECTIVE: We hypothesized that improved ascertainment and resulting decrease in disease severity at the time of diagnosis are responsible for this phenomenon.

METHODS: Using Medicare data linked to the Health and Retirement Study (1992-2012), we performed a joint analysis of trends in CI and ND to test our hypothesis.

RESULTS: We identified two major contributors to the divergent directions in CI and ND trends: reductions in disease severity explained more than 60% of the differences between CI and ND prevalence over the study period; the remaining 40% was explained by a decrease in the fraction of undiagnosed individuals.

DISCUSSION: Improvements in the diagnoses of ND diseases were a major contributor to reported trends in ND and CI. Recent forecasts of CI and ND trends in the U.S. may be overly pessimistic.

%B J Alzheimers Dis %V 64 %P 137-148 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29865067?dopt=Abstract %R 10.3233/JAD-180060 %0 Journal Article %J J Alzheimers Dis %D 2018 %T TREM1 mRNA Expression in Leukocytes and Cognitive Function in Japanese Patients with Alzheimer's Disease. %A Sao, Tomoko %A Yoshino, Yuta %A Yamazaki, Kiyohiro %A Ozaki, Yuki %A Mori, Yoko %A Ochi, Shinichiro %A Yoshida, Taku %A Mori, Takaaki %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) activates the innate immune system, promotes phagocytosis by microglia, and is associated with Alzheimer's disease (AD). The possible role of a related molecule, TREM1, in AD remains unknown.

OBJECTIVE: We investigated a possible role for TREM1 in AD by determining the gene expression and methylation levels of TREM1 in leukocytes from AD patients.

METHODS: Fifty patients with AD and 50 age-matched healthy controls were enrolled. AD patients underwent a battery of neuropsychiatric tests. Peripheral blood samples were obtained from each participant, RNA and DNA were extracted, and samples were assessed for TREM1 mRNA expression and methylation rates at three CpG sites in the TREM1 promoter.

RESULTS: TREM1 mRNA expression levels in AD patients were significantly higher than those in controls (p = 0.008). TREM1 mRNA expression levels were not correlated with sex, age, duration of illness, APOE genotype, donepezil treatment, or scores of most neuropsychiatric tests. TREM1 mRNA expression levels in AD patients were correlated with the total score of the Montgomery-Åsberg Depression Rating Scale (p = 0.047, r = - 0.344). Methylation rates at the three CpG sites were significantly lower in AD patients than in controls. We also found a significant correlation between TREM1 mRNA expression and TREM1 DNA methylation rates (p < 0.001).

CONCLUSION: TREM1 may be associated with the immune responses in AD, and along with hypomethylation at CpG sites in the TREM1 promoter, may become part of a biomarker panel for AD pathogenesis.

%B J Alzheimers Dis %V 64 %P 1275-1284 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/30010135?dopt=Abstract %R 10.3233/JAD-180418 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Abnormalities of Cerebral Deep Medullary Veins on 7 Tesla MRI in Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease: A Pilot Study. %A Bouvy, Willem H %A Kuijf, Hugo J %A Zwanenburg, Jaco J M %A Koek, Huiberdina L %A Kappelle, L Jaap %A Luijten, Peter R %A Ikram, M Kamran %A Biessels, Geert Jan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Brain %K Cerebral Small Vessel Diseases %K Cognitive Dysfunction %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %X

Cerebral small vessel disease (SVD) contributes to cognitive impairment and dementia. SVD may affect veins, but veins are difficult to detect with 1.5 and 3T MRI. We compared deep medullary veins (DMVs) visualized on 7T-MRI between patients with early Alzheimer's disease (eAD; n = 17) or amnestic MCI (aMCI; n = 12) and controls (n = 40). The number and density of DMVs was similar in patients and controls, but tortuosity was higher in eAD (Cohen's d = 0.7, 95% CI: 0.1-1.2, p = 0.02) and aMCI (Cohen's d = 0.8, 95% CI: 0.2-1.5, p = 0.01), independent of brain atrophy. Venous changes provide a new perspective on vascular involvement in dementia.

%B J Alzheimers Dis %V 57 %P 705-710 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28282806?dopt=Abstract %R 10.3233/JAD-160952 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Biomarkers and Functional Decline in Prodromal Alzheimer's Disease. %A Robb, Catherine %A Udeh-Momoh, Chinedu %A Wagenpfeil, Stefan %A Schöpe, Jakob %A Alexopoulos, Panagiotis %A Perneczky, Robert %X

BACKGROUND: Little is known of possible associations between Alzheimer's disease (AD) biomarkers and instrumental activities of daily living (IADL) change over time.

OBJECTIVE: The present study seeks to identify relationships between baseline imaging and fluid biomarker profiles, and decline in IADL utilizing data collated from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.

METHODS: Generalized estimating equations analysis, adjusted for cognitive deterioration, was applied to a cohort of 509 individuals from all stages of ADNI, including 156 healthy controls, 189 early mild cognitive impairment (MCI) patients and 164 MCI patients.

RESULTS: A significant correlation was found between baseline biomarkers, specifically CSF Aβ and FDG PET, and IADL change over a 3-year period in individuals with MCI. Importantly, comparable correlations between presence of pathological biomarker levels and temporal decline in both functional and cognitive performance were also noted.

DISCUSSION: We show that distinct baseline biomarkers may predict latent changes in IADL. Our results necessitate a revision of the commonly held view upholding cognitive changes as the predominant endpoint measure associated with presence of abnormal baseline biomarkers.

%B J Alzheimers Dis %V 58 %P 69-78 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372331?dopt=Abstract %R 10.3233/JAD-161162 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team. %A Arnerić, Stephen P %A Batrla-Utermann, Richard %A Beckett, Laurel %A Bittner, Tobias %A Blennow, Kaj %A Carter, Leslie %A Dean, Robert %A Engelborghs, Sebastiaan %A Genius, Just %A Gordon, Mark Forrest %A Hitchcock, Janice %A Kaplow, June %A Luthman, Johan %A Meibach, Richard %A Raunig, David %A Romero, Klaus %A Samtani, Mahesh N %A Savage, Mary %A Shaw, Leslie %A Stephenson, Diane %A Umek, Robert M %A Vanderstichele, Hugo %A Willis, Brian %A Yule, Susan %X

Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

%B J Alzheimers Dis %V 55 %P 19-35 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27662307?dopt=Abstract %R 10.3233/JAD-160573 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Cortical Cerebral Microinfarcts on 3 Tesla MRI in Patients with Vascular Cognitive Impairment. %A Ferro, Doeschka A %A van Veluw, Susanne J %A Koek, Huiberdina L %A Exalto, Lieza G %A Biessels, Geert Jan %X

BACKGROUND: Cerebral microinfarcts (CMIs) are small ischemic lesions that are a common neuropathological finding in patients with stroke or dementia. CMIs in the cortex can now be detected in vivo on 3 Tesla MRI.

OBJECTIVE: To determine the occurrence of CMIs and associated clinical features in patients with possible vascular cognitive impairment (VCI).

METHOD: 182 memory-clinic patients (mean age 71.4±10.6, 55% male) with vascular injury on brain MRI (i.e., possible VCI) underwent a standardized work-up including 3 Tesla MRI and cognitive assessment. A control group consisted of 70 cognitively normal subjects (mean age 70.6±4.7, 60% male). Cortical CMIs and other neuroimaging markers of vascular brain injury were rated according to established criteria.

RESULT: Occurrence of CMIs was higher (20%) in patients compared to controls (10%). Among patients, the presence of CMIs was associated with male sex, history of stroke, infarcts, and white matter hyperintensities. CMI presence was also associated with a diagnosis of vascular dementia and reduced performance in multiple cognitive domains.

CONCLUSION: CMIs on 3 Tesla MRI are common in patients with possible VCI and co-occur with imaging markers of small and large vessel disease, likely reflecting a heterogeneous etiology. CMIs are associated with worse cognitive performance, independent of other markers of vascular brain injury.

%B J Alzheimers Dis %V 60 %P 1443-1450 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29036822?dopt=Abstract %R 10.3233/JAD-170481 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Decrease of Amyloid-β Levels by Curcumin Derivative via Modulation of Amyloid-β Protein Precursor Trafficking. %A Kotani, Rina %A Urano, Yasuomi %A Sugimoto, Hachiro %A Noguchi, Noriko %X

The abnormal production and deposition of amyloid-β (Aβ) peptides is a pathologic hallmark of Alzheimer's disease. Aβ is generated from amyloid-β protein precursor (AβPP) by two sequential proteolytic cleavage steps involving β- and γ-secretases in the trans-Golgi network and endosomes. Since direct inhibition of secretase could induce undesirable side-effects due to inadvertent inhibition of unrelated secretase substrates, it is important to establish methods for inhibiting Aβ production that do not affect secretase activity. It has been suggested that curcumin may have potent anti-amyloidogenic effect. In the present study, we evaluate the effect of curcumin derivatives on Aβ production in human neuroblastoma SH-SY5Y cells and in CHO cells which stably express human AβPP (CHO-AβPP). We found that the curcumin derivative CU6 was more effective than curcumin itself in reducing Aβ secretion. We further found that in SH-SY5Y cells CU6 inhibited neither β- nor γ-secretase activity, and that increased amounts of immature forms of AβPP accumulated in the endoplasmic reticulum (ER). We also found that CU6 induced expression of the ER chaperone glucose-regulated protein 78 (GRP78), and enhanced formation of the AβPP/GRP78 complex. These results suggest that CU6 downregulates intracellular AβPP trafficking, resulting in suppression of Aβ production independently of secretase activity.

%B J Alzheimers Dis %V 56 %P 529-542 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27983550?dopt=Abstract %R 10.3233/JAD-160794 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Effect of APOE ε4 Genotype on Metabolic Biomarkers in Aging and Alzheimer's Disease. %A Morris K, Jill %A Uy, Roxanne Adeline Z %A Vidoni, Eric D %A Wilkins, Heather M %A Archer, Ashley E %A Thyfault, John P %A Miles, John M %A Burns, Jeffrey M %X

Alzheimer's disease (AD) may have heterogeneous pathophysiological underpinnings, with risk factors including apolipoprotein rmvarep4 (APOE4) genotype and insulin resistance. We hypothesized that distinct phenotypes exist within AD. We examined APOE4 and metabolic biomarkers in 338 subjects (n = 213 nondemented (ND), n = 125 AD). We further characterized steady state free fatty acid (FFA) levels in a subset of 45 participants who had also participated in a hyperinsulinemic-euglycemic clamp. Insulin resistance (HOMA-IR) was elevated in AD versus ND (p = 0.04) and in APOE4 noncarriers versus carriers (p < 0.01). This was driven by increased fasting insulin in AD versus ND (p < 0.01) and in APOE4 non-carriers versus carriers (p = 0.01). Fasting glucose was not different. In subjects who underwent a clamp, there was a group x genotype interaction on FFA levels during hyperinsulinemia (p = 0.03). APOE4 non-carriers with AD had higher FFA levels, while APOE4 carriers with AD exhibited lower FFA levels. Metabolic dysfunction is overrepresented in individuals with AD dementia who do not carry the APOE4 allele. This suggests that important subsets of AD phenotypes may exist that diverge metabolically.

%B J Alzheimers Dis %V 58 %P 1129-1135 %G eng %N 4 %R 10.3233/JAD-170148 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Gene Expression and Methylation Analysis of ABCA7 in Patients with Alzheimer's Disease. %A Yamazaki, Kiyohiro %A Yoshino, Yuta %A Mori, Takaaki %A Yoshida, Taku %A Ozaki, Yuki %A Sao, Tomoko %A Mori, Yoko %A Ochi, Shinichiro %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

BACKGROUND/OBJECTIVE: The aim of this study was to examine the blood gene expression and methylation of ATP-binding cassette sub-family A member 7 gene (ABCA7) as a biological marker of AD.

METHODS: AD subjects (n = 50; 11 males, 77.7±6.05 years old) and age- and sex-matched healthy controls (n = 50) were recruited. A single nucleotide polymorphism in ABCA7 (rs3764650), methylation rates of CpG sites in the ABCA7 promoter region, and ABCA7 mRNA expression levels in peripheral blood were examined.

RESULTS: The distribution of the rs3764650 polymorphism in AD subjects was not different from that of controls. Although the methylation rates of AD subjects were not significantly different from those of controls, the ABCA7 mRNA expression level in AD subjects was significantly higher than that in controls. Additionally, the ABCA7 mRNA expression level in AD subjects was significantly correlated with Mini-Mental State Examination recall, the Alzheimer's Disease Assessment Scale total score, and the Clinical Dementia Rating score. We also found a significant correlation between the ABCA7 mRNA expression level and duration of illness.

CONCLUSION: The ABCA7 mRNA expression level in peripheral blood may be a marker for early stages of AD and disease progression regardless of rs3764650 and the methylation rate of its promoter.

%B J Alzheimers Dis %V 57 %P 171-181 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28222527?dopt=Abstract %R 10.3233/JAD-161195 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes. %A van Waalwijk van Doorn, Linda J C %A Gispert, Juan D %A Kuiperij, H Bea %A Claassen, Jurgen A H R %A Arighi, Andrea %A Baldeiras, Ines %A Blennow, Kaj %A Bozzali, Marco %A Castelo-Branco, Miguel %A Cavedo, Enrica %A Emek-Savaş, Derya D %A Eren, Erden %A Eusebi, Paolo %A Farotti, Lucia %A Fenoglio, Chiara %A Ormaechea, Juan Fortea %A Freund-Levi, Yvonne %A Frisoni, Giovanni B %A Galimberti, Daniela %A Genc, Sermin %A Greco, Viviana %A Hampel, Harald %A Herukka, Sanna-Kaisa %A Liu, Yawu %A Lladó, Albert %A Lleo, Alberto %A Nobili, Flavio M %A Oguz, Kader K %A Parnetti, Lucilla %A Pereira, João %A Picco, Agnese %A Pikkarainen, Maria %A de Oliveira, Catarina Resende %A Saka, Esen %A Salvadori, Nicola %A Sánchez-Valle, Raquel %A Santana, Isabel %A Scarpini, Elio %A Scheltens, Philip %A Soininen, Hilkka %A Tarducci, Roberto %A Teunissen, Charlotte %A Tsolaki, Magda %A Urbani, Andrea %A Vilaplana, Eduard %A Visser, Pieter Jelle %A Wallin, Asa K %A Yener, Görsev %A Molinuevo, José L %A Meulenbroek, Olga %A Verbeek, Marcel M %X

Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.

%B J Alzheimers Dis %V 56 %P 543-555 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28059783?dopt=Abstract %R 10.3233/JAD-160668 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Individual Correspondence of Amyloid-β and Intrinsic Connectivity in the Posterior Default Mode Network Across Stages of Alzheimer's Disease. %A Pasquini, Lorenzo %A Benson, Gloria %A Grothe, Michel J %A Utz, Lukas %A Myers, Nicholas E %A Yakushev, Igor %A Grimmer, Timo %A Scherr, Martin %A Sorg, Christian %X

In Alzheimer's disease (AD), amyloid-β (Aβ) pathology and intrinsic functional connectivity (iFC) interact. Across stages of AD, we expected individual spatial correspondence of Aβ and iFC to reveal both Aβ accumulation and its detrimental effects on iFC. We used resting-state functional magnetic imaging and Aβ imaging in a cross-sectional sample of 90 subjects across stages of AD and healthy older adults. Global and local correspondence of Aβ and iFC were assessed within the posterior default mode network (pDMN) by within-subject voxel-wise correlations. Beginning at preclinical stages, global Aβ-iFC correspondence was positive for the whole pDMN, showing that Aβ accumulates in areas of high connectivity, and reached a plateau at prodromal stages. Starting at preclinical stages, local correspondence was negative in network centers, indicating that Aβ reduces connectivity of the pDMN as a function of local plaque concentration, and peaked at prodromal stages. Positive global correspondence suggests that Aβ accumulation progresses along iFC, with this effect starting in preclinical stages, and being constant along clinical periods. Negative local correspondence suggests detrimental effects of Aβ on iFC in network centers, starting at preclinical stages, and peaking when first symptoms appear. Data reveal a complex trajectory of Aβ and iFC correspondence, affecting both Aβ accumulation and iFC impairments.

%B J Alzheimers Dis %V 58 %P 763-773 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482640?dopt=Abstract %R 10.3233/JAD-170096 %0 Journal Article %J J Alzheimers Dis %D 2017 %T INPP5D mRNA Expression and Cognitive Decline in Japanese Alzheimer's Disease Subjects. %A Yoshino, Yuta %A Yamazaki, Kiyohiro %A Ozaki, Yuki %A Sao, Tomoko %A Yoshida, Taku %A Mori, Takaaki %A Mori, Yoko %A Ochi, Shinichiro %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

Microglial dysfunction and inflammation have recently been shown to be related to the development of Alzheimer's disease (AD). Inositol polyphosphate-5-phosphatase (INPP5D) functions broadly as a negative regulator of immune signaling, and its locus was associated with development of AD in a large-scale genome-wide association study. Thus, we examined INPP5D mRNA expression and methylation rates of the CpG sites in the upstream region of INPP5D exon 1 in peripheral leukocytes in 50 AD and age- and sex-matched control subjects. INPP5D mRNA expression in AD subjects was significantly higher than that in control subjects (1.16±0.39 versus 1.0±0.23, p = 0.049) and was correlated with the Mini-Mental State Examination score (p = 0.002, r = 0.426) and the total score of the Alzheimer's Disease Assessment Scale (p < 0.001, r = -0.697). Methylation rates in the upstream region of INPP5D exon 1 were not significantly different between AD and control subjects (average rate: 3.5±3.0 versus 2.8±1.3, p = 0.551). Our results suggested that INPP5D mRNA expression was elevated in the early stage and decreased with cognitive decline in AD. INPP5D mRNA expression in leukocytes may be a useful biomarker for the early stage of AD.

%B J Alzheimers Dis %V 58 %P 687-694 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28482637?dopt=Abstract %R 10.3233/JAD-161211 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Kynurenine Pathway Metabolites in Alzheimer's Disease. %A Giil, Lasse Melvaer %A Midttun, Øivind %A Refsum, Helga %A Ulvik, Arve %A Advani, Rajiv %A Smith, A David %A Ueland, Per Magne %X

BACKGROUND: Metabolites of tryptophan, produced via the kynurenine pathway (kynurenines), have been linked to Alzheimer's disease (AD) in small cohorts with conflicting results.

OBJECTIVE: To compare differences in plasma kynurenine levels between AD and controls and identify potential associations with cognition.

METHODS: The study included 65 histopathologically-confirmed AD patients and 65 cognitively-screened controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Cognition was assessed using the Cambridge Cognitive Examination (CamCog). Tryptophan, kynurenines, neopterin, and vitamin B6 forms were measured in plasma by liquid chromatography-tandem mass spectrometry. Non-parametric statistics, logistic regression and standardized robust regressions were applied with a false discovery rate of 0.05.

RESULTS: Tryptophan, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid were lower in AD (Odds ratios (ORs) 0.24 -0.47; p-values <0.001 -0.01). Pyridoxal 5'phosphate did not differ between AD and controls. Kynurenine, anthranilic acid, quinolinic acid, and markers of immune activation (neopterin, kynurenine/tryptophan ratio, and the PAr index (Pyridoxic acid/(Pyridoxal 5'phosphate + Pyridoxal)) increased with age (β 0.31 -0.51; p-values <0.001 -0.006). Xanthurenic acid decreased with age (β: -0.42, p < 0.001). Elderly AD patients with high quinolinic acid performed worse on the CamCog test, indicated by a significant age*quinolinic acid interaction (β 0.21, p < 0.001).

CONCLUSION: Plasma concentrations of several kynurenines were lower in patients with AD compared to controls. Low xanthurenic acid occurred in both AD and with aging. Inflammation-related markers were associated with age, but not AD. However, elevated QA was associated with poor cognition in older AD patients.

%B J Alzheimers Dis %V 60 %P 495-504 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869479?dopt=Abstract %R 10.3233/JAD-170485 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Normal Vitamin Levels and Nutritional Indices in Alzheimer's Disease Patients with Mild Cognitive Impairment or Dementia with Normal Body Mass Indexes. %A Ulstein, Ingun %A Bøhmer, Thomas %X

Evidence supports an association between vitamin deficiencies and cognitive decline in Alzheimer's disease (AD). If vitamin deficiencies are causative for AD development, they should be detectable during very early stages of AD. Here we investigated nutritional factors among home-living patients diagnosed with mild cognitive impairment (MCI) or mild dementia due to AD, compared to healthy controls. Our study included 73 patients with AD (25 with MCI, 48 with dementia) and 63 cognitively intact age-matched controls. All participants underwent cognitive testing, somatic examination, and measurements of vitamins A, B1, B6, folate, B12, C, D, and E, and F2-α-isoprostane. Results are given as mean (SD). MMSE scores were 29.1 (1.0) for healthy controls, 27.4 (1.8) for patients with MCI, and 24.3 (3.2) for patients with dementia. Vitamin concentrations for the these groups, respectively, were as follows: B1 (nmol/l), 157 (29), 161 (35), and 161 (32); B6 (nmol/l), 57 (63), 71 (104), and 58 (44); folate (mmol/l), 23 (9), 26 (10), and 23 (11); B12 (pmol/l), 407 (159), 427 (116), and 397 (204); C (μmol/l), 63 (18), 61 (16), and 63 (29); A (μmol/l), 2.3 (0.6), 2.2 (0.5), and 2.3(0.5); E (μmol/l), 36 (6.3), 36 (6.9), and 36 (8.2); 25-OH vitamin D (nmol/l), 65 (18), 61 (19), and 65 (20); and 8-iso-PGFα (pg/ml), 64 (27); 60 (19), and 66 (51). These concentrations did not significantly differ (p≤0.05) between the three groups. Our results do not support the hypothesis that vitamin deficiencies play a causative role in the development of early cognitive impairment.

%B J Alzheimers Dis %V 55 %P 717-725 %8 2016 Oct 5 %G eng %N 2 %R 10.3233/JAD-160393 %0 Journal Article %J J Alzheimers Dis %D 2017 %T PE859, A Novel Curcumin Derivative, Inhibits Amyloid-β and Tau Aggregation, and Ameliorates Cognitive Dysfunction in Senescence-Accelerated Mouse Prone 8. %A Okuda, Michiaki %A Fujita, Yuki %A Hijikuro, Ichiro %A Wada, Mei %A Uemura, Takuya %A Kobayashi, Yukako %A Waku, Tomonori %A Tanaka, Naoki %A Nishimoto, Takaaki %A Izumi, Yasuhiko %A Kume, Toshiaki %A Akaike, Akinori %A Takahashi, Takashi %A Sugimoto, Hachiro %X

Aggregation of amyloid-β (Aβ) and tau plays a crucial role in the onset and progression of Alzheimer's disease (AD). Therefore, the inhibition of Aβ and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aβ and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on Aβ aggregationin vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aβ and tau aggregation in vivo. PE859 inhibited Aβ aggregation in vitro and protected cultured cells from Aβ-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aβ and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD.

%B J Alzheimers Dis %V 59 %P 313-328 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28598836?dopt=Abstract %R 10.3233/JAD-161017 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Selenoprotein S Reduces Endoplasmic Reticulum Stress-Induced Phosphorylation of Tau: Potential Role in Selenate Mitigation of Tau Pathology. %A Rueli, Rachel H L H %A Torres, Daniel J %A Dewing, Andrea S T %A Kiyohara, Arlene C %A Barayuga, Stephanie M %A Bellinger, Miyoko T %A Uyehara-Lock, Jane H %A White, Lon R %A Moreira, Paula I %A Berry, Marla J %A Perry, George %A Bellinger, Frederick P %X

Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer's disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer's disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer's disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer's disease and potentially other neurodegenerative disorders.

%B J Alzheimers Dis %V 55 %P 749-762 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27802219?dopt=Abstract %R 10.3233/JAD-151208 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Three-Repeat Tau with Grain-Like Structures and Distribution in an 83-Year-Old Man. %A Kasahata, Naoki %A Sato, Tomohide %A Onishi, Iichiroh %A Kitagawa, Masanobu %A Uchihara, Toshiki %A Hirokawa, Katsuiku %X

We encountered an 83-year-old man with 3-repeat dominant grain-like tau deposition. Tau-positive lesions exhibited apparent similarity to argyrophilic grains in terms of their distribution in the ambient gyrus, amygdala, and dorsomedial temporal tip and the characteristic comma-like morphology. The abundant oligodendroglial tau immunoreactivities were 3-repeat dominant. Tuft-shaped astrocytes showed partial 3-repeat tau immnoreactivities. These grain-like structures, as well as tuft-shaped astrocytes and oligodendroglia, exhibited predominant 3-repeat tau immunoreactivity, suggesting that grain-like structures and their characteristic distribution are mutually linked and not unique to 4-repeat tau deposition. pTDP immunoreactivity, extensive macrophage infiltration, and spongiosis were associated with these 3-repeat tau deposits.

%B J Alzheimers Dis %V 58 %P 681-685 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28453470?dopt=Abstract %R 10.3233/JAD-160672 %0 Journal Article %J J Alzheimers Dis %D 2017 %T TOMM40 and APOE Gene Expression and Cognitive Decline in Japanese Alzheimer's Disease Subjects. %A Mise, Ayano %A Yoshino, Yuta %A Yamazaki, Kiyohiro %A Ozaki, Yuki %A Sao, Tomoko %A Yoshida, Taku %A Mori, Takaaki %A Mori, Yoko %A Ochi, Shinichiro %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

BACKGROUND: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE), andis reported in several genome-wide association studies to be associated with Alzheimer's disease (AD).

OBJECTIVE: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD.

METHODS: We examined TOMM40, PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (PARK2), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40exon 1 in peripheral leukocytes and TOMM40523 polyT genotypes in 60 AD and age- and sex-matched control subjects.

RESULTS: TOMM40 mRNA expression was significantly lower in AD subjects (0.87±0.18 versus 1.0±0.23, p = 0.005), and PINK1 mRNA expression was higher in AD subjects (1.5±0.61 versus 1.0±0.52, p < 0.001). TOMM40 mRNA expression was significantly correlated with the Mini-Mental State Examination total score (r = 0.290, p = 0.027). There was no expressional change in peripheral APOE mRNA in either AD or control subjects (p = 0.32). Methylation rates in the upstream region of TOMM40exon 1 were not different between AD and control subjects (average rate: 1.37±0.99 versus 1.39±1.20, p = 0.885), and TOMM40523 polyT genotypes were also not different between AD and control subjects (p = 0.67).

CONCLUSION: TOMM40 mRNA expression was lower in AD subjects and was correlated with cognitive decline. Significant changes in both TOMM40 and PINK1 mRNA may be related to mitochondrial dysfunction.

%B J Alzheimers Dis %V 60 %P 1107-1117 %8 2017 %G eng %N 3 %R 10.3233/JAD-170361 %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 Attitudes and Perceptions of Research in Aging and Dementia in an Urban Minority Population. %A Neugroschl, Judith %A Sewell, Margaret %A De La Fuente, Angelica %A Umpierre, Mari %A Luo, Xiaodong %A Sano, Mary %X

In dementia trials, minority participation is low. We assessed attitudes toward research in a community based urban poor minority sample of elderly adults attending senior center talks using the 7-item Research Attitudes Questionnaire (RAQ). Presentations on cognitive aging were given at senior centers, and 123 attendees completed the RAQ-7. On trust and safety questions, a significant minority (42-48%) responded neutrally or negatively. Encouragingly, on questions concerning the importance of research, 72-81% answered positively. More work can be done to capitalize on these findings to engage and foster trust, and this can be a focus of outreach.

%B J Alzheimers Dis %V 53 %P 69-72 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128368?dopt=Abstract %R 10.3233/JAD-151072 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Cognitive Change Index as a Measure of Self and Informant Perception of Cognitive Decline: Relation to Neuropsychological Tests. %A Rattanabannakit, Chatchawan %A Risacher, Shannon L %A Gao, Sujuan %A Lane, Kathleen A %A Brown, Steven A %A McDonald, Brenna C %A Unverzagt, Frederick W %A Apostolova, Liana G %A Saykin, Andrew J %A Farlow, Martin R %K Adult %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cognitive Dysfunction %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Perception %K Self Report %X

BACKGROUND: The perception of cognitive decline by individuals and those who know them well ("informants") has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms.

OBJECTIVE: We investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms.

METHODS: 267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models.

RESULTS: CCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant.

CONCLUSION: Self- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome.

%B J Alzheimers Dis %V 51 %P 1145-55 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923008?dopt=Abstract %R 10.3233/JAD-150729 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cognitive Reserve in Alzheimer's Dementia: Diagnostic Accuracy of a Testing-the-Limits Paradigm. %A Küster, Olivia C %A Kösel, Jonas %A Spohn, Stephanie %A Schurig, Niklas %A Tumani, Hayrettin %A von Arnim, Christine A F %A Uttner, Ingo %X

Individuals with higher cognitive reserve are more able to cope with pathological brain alterations, potentially due to the application of more efficient cognitive strategies. The extent to which an individual's cognitive performance can be increased by advantageous conditions differs substantially between patients with Alzheimer's dementia (AD) and healthy older adults and can be assessed with the Testing-the-Limits (TtL) approach. Thus, TtL has been proposed as a tool for the early diagnosis of AD. Here, we report the diagnostic accuracy of a memory TtL paradigm to discriminate between AD patients and controls. The TtL paradigm was administered to 57 patients with clinically diagnosed AD and 94 controls. It consisted of a pre-test condition, representing baseline cognitive performance, the presentation of an encoding strategy, and two subsequent post-test conditions, representing learning potential. Receiver operating characteristic (ROC) curves were analyzed for each condition in order to receive optimal cutoff points along with their sensitivity and specificity and to compare the diagnostic accuracy of the conditions. Differentiation between AD patients and controls, indicated by the area under the ROC curve, increased significantly for the TtL post-test and total error scores compared to the pre-test score. The combined error score in the two post-tests could differentiate between AD patients and controls with a sensitivity of 0.93 and a specificity of 0.80. The presented approach can be carried out in 25 minutes and thus constitutes a time- and cost-effective way to diagnose AD with high accuracy.

%B J Alzheimers Dis %V 52 %P 519-28 %8 2016 Mar 29 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031485?dopt=Abstract %R 10.3233/JAD-151141 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics. %A Lelental, Natalia %A Brandner, Sebastian %A Kofanova, Olga %A Blennow, Kaj %A Zetterberg, Henrik %A Andreasson, Ulf %A Engelborghs, Sebastiaan %A Mroczko, Barbara %A Gabryelewicz, Tomasz %A Teunissen, Charlotte %A Mollenhauer, Brit %A Parnetti, Lucilla %A Chiasserini, Davide %A Molinuevo, José Luis %A Perret-Liaudet, Armand %A Verbeek, Marcel M %A Andreasen, Niels %A Brosseron, Frederic %A Bahl, Justyna M C %A Herukka, Sanna-Kaisa %A Hausner, Lucrezia %A Frölich, Lutz %A Labonte, Anne %A Poirier, Judes %A Miller, Anne-Marie %A Zilka, Norbert %A Kovacech, Branislav %A Urbani, Andrea %A Suardi, Silvia %A Oliveira, Catarina %A Baldeiras, Ines %A Dubois, Bruno %A Rot, Uros %A Lehmann, Sylvain %A Skinningsrud, Anders %A Betsou, Fay %A Wiltfang, Jens %A Gkatzima, Olymbia %A Winblad, Bengt %A Buchfelder, Michael %A Kornhuber, Johannes %A Lewczuk, Piotr %K Amyloid beta-Peptides %K Animals %K Anti-Bacterial Agents %K Biomarkers %K Cattle %K Clinical Chemistry Tests %K Dementia %K Humans %K Peptide Fragments %K Quality Control %K Reference Standards %K Serum Albumin, Bovine %K Sodium Azide %K tau Proteins %K Time Factors %K Tissue Preservation %X

BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples.

OBJECTIVE: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers.

METHODS: Three matrices were validated in this study: (A) human pooled CSF, (B) Aβ peptides spiked into human prediluted plasma, and (C) Aβ peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study.

RESULTS: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80°C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects.

CONCLUSION: Our results suggest that it is possible to replace self-made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter-laboratory QC schedules for NDD measurements.

%B J Alzheimers Dis %V 52 %P 51-64 %8 2016 03 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967210?dopt=Abstract %R 10.3233/JAD-150883 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia. %A Pluta, Ryszard %A Kocki, Janusz %A Ułamek-Kozioł, Marzena %A Petniak, Alicja %A Gil-Kulik, Paulina %A Januszewski, Sławomir %A Bogucki, Jacek %A Jabłoński, Mirosław %A Brzozowska, Judyta %A Furmaga-Jabłońska, Wanda %A Bogucka-Kocka, Anna %A Czuczwar, Stanisław J %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Brain Ischemia %K Disease Models, Animal %K Down-Regulation %K Female %K Rats %K Rats, Wistar %K Temporal Lobe %K Time Factors %X

Brain ischemia may be causally related with Alzheimer's disease. Presumably, β-secretase and amyloid-β protein precursor gene expression changes may be associated with Alzheimer's disease neuropathology. Consequently, we have examined quantitative changes in both β-secretase and amyloid-β protein precursor genes in the medial temporal lobe cortex with the use of quantitative rtPCR analysis following 10-min global brain ischemia in rats with survival of 2, 7, and 30 days. The greatest significant overexpression of β-secretase gene was noted on the 2nd day, while on days 7-30 the expression of this gene was only modestly downregulated. Amyloid-β protein precursor gene was downregulated on the 2nd day, but on days 7-30 postischemia, there was a significant reverse tendency. Thus, the demonstrated alterations indicate that the considerable changes of expression of β-secretase and amyloid-β protein precursor genes may be connected with a response of neurons in medial temporal lobe cortex to transient global brain ischemia. Finally, the ischemia-induced gene changes may play a key role in a late and slow onset of Alzheimer-type pathology.

%B J Alzheimers Dis %V 51 %P 1023-31 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890784?dopt=Abstract %R 10.3233/JAD-151102 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Dysregulation of Autophagy, Mitophagy, and Apoptotic Genes in the Medial Temporal Lobe Cortex in an Ischemic Model of Alzheimer's Disease. %A Ułamek-Kozioł, Marzena %A Kocki, Janusz %A Bogucka-Kocka, Anna %A Petniak, Alicja %A Gil-Kulik, Paulina %A Januszewski, Sławomir %A Bogucki, Jacek %A Jabłoński, Mirosław %A Furmaga-Jabłońska, Wanda %A Brzozowska, Judyta %A Czuczwar, Stanisław J %A Pluta, Ryszard %X

Ischemic brain damage is a pathological incident that is often linked with medial temporal lobe cortex injury and finally its atrophy. Post-ischemic brain injury associates with poor prognosis since neurons of selectively vulnerable ischemic brain areas are disappearing by apoptotic program of neuronal death. Autophagy has been considered, after brain ischemia, as a guardian against neurodegeneration. Consequently, we have examined changes in autophagy (BECN 1), mitophagy (BNIP 3), and apoptotic (caspase 3) genes in the medial temporal lobe cortex with the use of quantitative reverse-transcriptase PCR following transient 10-min global brain ischemia in rats with survival 2, 7, and 30 days. The intense significant overexpression of BECN 1 gene was noted on the 2nd day, while on days 7-30 the expression of this gene was still upregulated. BNIP 3 gene was downregulated on the 2nd day, but on days 7-30 post-ischemia, there was a significant reverse tendency. Caspase 3 gene, associated with apoptotic neuronal death, was induced in the same way as BNIP 3 gene after brain ischemia. Thus, the demonstrated changes indicate that the considerable dysregulation of expression of BECN 1, BNIP 3, and caspase 3 genes may be connected with a response of neuronal cells in medial temporal lobe cortex to transient complete brain ischemia.

%B J Alzheimers Dis %V 54 %P 113-21 %8 2016 Jul 27 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27472881?dopt=Abstract %R 10.3233/JAD-160387 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Elevated mRNA Expression and Low Methylation of SNCA in Japanese Alzheimer's Disease Subjects. %A Yoshino, Yuta %A Mori, Takaaki %A Yoshida, Taku %A Yamazaki, Kiyohiro %A Ozaki, Yuki %A Sao, Tomoko %A Funahashi, Yu %A Iga, Jun-Ichi %A Ueno, Shu-Ichi %X

Despite the continuing debate about the amyloid hypothesis in Alzheimer's disease (AD), the precise pathogenesis is still unclear. Mixed pathology is common and multiple different protein aggregates are seen in human postmortem brains. Aggregates consisting of the alpha-synuclein protein encoded by the Synuclein Alpha gene (SCNA) are common in both dementia with Lewy bodies and AD. We examined SNCA mRNA expression and methylation rates of the CpG island at intron 1 of SNCA in peripheral leukocytes in 50 AD and age- and sex-matched control subjects to verify whether alpha-synuclein pathology affects the AD pathogenesis. SNCA mRNA expression in AD subjects was significantly higher than that in control subjects (1.62±0.73 versus 0.98±0.50, p < 0.001). We found significant differences between AD and control subjects at seven CpG sites (average rate; 8.8±2.7 versus 9.5±2.5, respectively: p = 0.027). The methylation rates tended to be lower in AD subjects at all CpG sites. We conclude that mRNA expression and methylation of SNCA intron 1 are altered in AD, which may be caused by Lewy body pathology in AD.

%B J Alzheimers Dis %V 54 %P 1349-1357 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567856?dopt=Abstract %R 10.3233/JAD-160430 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. %A Chouraki, Vincent %A Reitz, Christiane %A Maury, Fleur %A Bis, Joshua C %A Bellenguez, Celine %A Yu, Lei %A Jakobsdottir, Johanna %A Mukherjee, Shubhabrata %A Adams, Hieab H %A Choi, Seung Hoan %A Larson, Eric B %A Fitzpatrick, Annette %A Uitterlinden, Andre G %A De Jager, Philip L %A Hofman, Albert %A Gudnason, Vilmundur %A Vardarajan, Badri %A Ibrahim-Verbaas, Carla %A van der Lee, Sven J %A Lopez, Oscar %A Dartigues, Jean-François %A Berr, Claudine %A Amouyel, Philippe %A Bennett, David A %A van Duijn, Cornelia %A DeStefano, Anita L %A Launer, Lenore J %A Ikram, M Arfan %A Crane, Paul K %A Lambert, Jean-Charles %A Mayeux, Richard %A Seshadri, Sudha %X

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

%B J Alzheimers Dis %V 53 %P 921-32 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract %R 10.3233/JAD-150749 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Feasibility of a Memory Clinic-Based Physical Activity Prescription Program. %A Vidoni, Eric D %A Watts, Amber S %A Burns, Jeffrey M %A Greer, Colby S %A Graves, Rasinio S %A Van Sciver, Angela %A Black, Jessica R %A Cooper, Sarah K %A Nagely, Allison C %A Uphoff, Elaine %A Volmer, Jennifer M %A Bieberle, Natalie A %X

BACKGROUND: Effective programs for promoting physical activity are needed for those with cognitive impairment.

OBJECTIVE: To test the feasibility of mobile Health (mHealth) technology-supported physical activity prescription from a tertiary care memory clinic.

METHODS: This feasibility study was designed as a 16-week randomized, crossover trial of a physical activity prescription: 8 weeks of intervention, 8 weeks of baseline or maintenance phase data collection. We recruited 2 cohorts: 21 individuals with Alzheimer-related cognitive impairment (mean age 72.3 (5.2), 9 females), and 9 individuals with normal cognition (mean age 69.6 (5.8), 8 females). We gave each cohort an mHealth accelerometer-based physical activity prescription to double number of steps taken. Our primary outcomes were feasibility and safety. Our secondary outcomes were change in weekly steps taken, Dementia Quality of Life Scale, Self-efficacy Scale, 6-minute Walk, and mini-Physical Performance Test.

RESULTS: Set-up and use of the device was not a barrier to participation. However, only 62% of participants with cognitive impairment completed the intervention. The cohort with cognitive impairment did not change their weekly step count above Week 1. All participants in the cohort with normal cognition were able to set up and use their device and increased their weekly step count above Week 1. There were no differences between Week 1 and Week 8 for any secondary measures in either cohort.

CONCLUSIONS: Setup and daily use of mHealth technology appears to be feasible for a person with cognitive impairment with the help of a partner, but increasing daily step counts over 8 weeks was not achieved. Future work needs to assess alternative activity prescription goals or additional support for patients and their partners.

%B J Alzheimers Dis %V 53 %P 161-70 %8 2016 Apr 21 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27104905?dopt=Abstract %R 10.3233/JAD-160158 %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 Intracerebroventricular Infusion of Angiotensin-(1-7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer's Disease. %A Uekawa, Ken %A Hasegawa, Yu %A Senju, Satoru %A Nakagata, Naomi %A Ma, Mingjie %A Nakagawa, Takashi %A Koibuchi, Nobutaka %A Kim-Mitsuyama, Shokei %X

This work was performed to test our hypothesis that angiotensin-(1-7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimer's disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1-7), or (3) angiotensin-(1-7)+A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1-7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1-7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1-7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimer's disease.

%B J Alzheimers Dis %V 53 %P 127-33 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128367?dopt=Abstract %R 10.3233/JAD-150642 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuropsychological Features of Microbleeds and Cortical Microinfarct Detected by High Resolution Magnetic Resonance Imaging. %A Ueda, Yukito %A Satoh, Masayuki %A Tabei, Ken-Ichi %A Kida, Hirotaka %A Ii, Yuichiro %A Asahi, Masaru %A Maeda, Masayuki %A Sakuma, Hajime %A Tomimoto, Hidekazu %X

BACKGROUND: Lobar microbleeds (MBs) and cortical microinfarct (CMI) are caused by cerebral amyloid angiopathy in the elderly and increase in number in Alzheimer's disease.

OBJECTIVE: The aim of this study is to elucidate the effects of lobar MBs and CMIs on cognitive function.

METHODS: The subjects were outpatients who visited the memory clinic of Mie University Hospital. Among 120 subjects, 109 patients fulfilled the inclusion criteria. We quantitatively estimated MBs and CMIs using double inversion recovery and 3D FLAIR images of 3T MRI. Neuropsychological assessments included intellectual, memory, constructional, and frontal lobe function.

RESULTS: Of the 109 patients, MBs and CMIs were observed in 68 (62%) and 17 (16%) subjects, respectively. Of the 68 patients with MBs, lobar MBs were found in 28, deep MBs in 8 and mixed MBs in 31. In each age group, the number of MBs increased in patients with CMI (CMI+ group) than those without CMI (CMI- group), and MBs and CMIs additively decreased MMSE scores. In psychological screens, the MBs+ group with more than 10 MBs showed significantly lower scores of category- and letter-WF than MB- group. The CMI+ group showed significantly worse scores than CMI- group in Japanese Raven's coloured progressive matrices, Trail Making Test-A, category- and letter-word fluency and copy and drawing of figures.

CONCLUSION: Lobar MBs and CMIs in the elderly frequently coexisted with each other and additively contributed to cognitive impairment, which is mainly predisposed to frontal lobe function.

%B J Alzheimers Dis %V 53 %P 315-25 %8 2016 May 07 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27163803?dopt=Abstract %R 10.3233/JAD-151008 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer's Dementia. %A Hirni, Daniela I %A Kivisaari, Sasa L %A Krumm, Sabine %A Monsch, Andreas U %A Berres, Manfred %A Oeksuez, Fatma %A Reinhardt, Julia %A Ulmer, Stephan %A Kressig, Reto W %A Stippich, Christoph %A Taylor, Kirsten I %X

Neurofibrillary pathology in Alzheimer's dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8-13.4 years and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD.

%B J Alzheimers Dis %V 52 %P 573-80 %8 2016 Mar 26 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031465?dopt=Abstract %R 10.3233/JAD-150158 %0 Journal Article %J J Alzheimers Dis %D 2016 %T N-Terminal Pro-B-Type Natriuretic Peptide and Risk of Future Cognitive Impairment in the REGARDS Cohort. %A Cushman, Mary %A Callas, Peter W %A McClure, Leslie A %A Unverzagt, Frederick W %A Howard, Virginia J %A Gillett, Sarah R %A Thacker, Evan L %A Wadley, Virginia G %X

BACKGROUND: Improved understanding of the etiology of cognitive impairment is needed to develop effective preventive interventions. Higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac dysfunction associated with risk of cardiovascular diseases and stroke in apparently healthy people.

OBJECTIVE: To study the association of NT-proBNP with risk of incident cognitive impairment.

METHODS: The Reasons for Geographic and Racial Differences in Stroke is a national cohort study of 30,239 black and white Americans age 45 and older at baseline, enrolled in 2003-7. Among participants without prebaseline stroke or cognitive impairment, baseline NT-proBNP was measured in 470 cases of incident cognitive impairment and 557 controls. Cases were participants scoring below the 6th percentile of demographically-adjusted means on at least 2 of 3 serially administered tests (word list learning, word list recall and semantic fluency) over 3.5 years follow-up.

RESULTS: Adjusting for age, gender, race, region of residence, education, and income, there was an increased odds ratio of incident cognitive impairment with increasing NT-proBNP; participants in the 4th versus 1st quartile (>127 versus ≤33 pg/ml) had a 1.69-fold increased odds (95% CI 1.11-2.58). Adjustment for cardiovascular risk factors and presence of an apolipoprotein E4 allele had no substantial impact on the odds ratio. Results did not differ by age, race, gender, or presence of an apolipoprotein E4 allele.

CONCLUSION: Higher NT-pro-BNP was associated with incident cognitive impairment in this prospective study, independent of atherogenic and Alzheimer's disease risk factors. Future work should clarify pathophysiologic connections of NT-proBNP and cognitive dysfunction.

%B J Alzheimers Dis %V 54 %P 497-503 %8 2016 Sep 06 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567834?dopt=Abstract %R 10.3233/JAD-160328 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Nutritional Status of Patients with Alzheimer's Disease and Their Caregivers. %A Tombini, Mario %A Sicari, Maura %A Pellegrino, Giovanni %A Ursini, Francesca %A Insardá, Pasqualina %A Di Lazzaro, Vincenzo %X

BACKGROUND: Malnutrition is one of the most important conditions that negatively affects the health of elder people, particularly in patients with dementia.

OBJECTIVE: To provide an assessment of nutritional status of patients affected by Alzheimer's disease (AD) living at home and of their caregivers by means of Mini Nutritional Assessment (MNA), and to explore the influence of different factors on nutrition.

METHODS: 90 patients affected by AD living at home and 90 age- and sex-matched caregivers were enrolled. Patients and caregivers, coming from an urban-rural fringe of Southern Italy, were assessed using full MNA, Mini-Mental State Examination, Geriatric Depression Scale- short form, Activity of Daily Living, and Instrumental Activities of Daily Living scales.

RESULTS: Malnutrition was found with high prevalence in patients affected by AD of different severity (more than 95% of patients were malnourished or at risk of malnutrition), and associated with reduced functional status. An altered nutrition was also recognized with high rate in the group of caregivers (23.3% were malnourished and 41.1% at risk of malnutrition) and the worse nutritional condition was correlated with higher age and lower functional and cognitive status and education. A positive correlation between MNA score of AD patients and caregivers was found.

CONCLUSION: Corrective measures should be taken in order to early identify nutritional deficiencies and risk of malnutrition observed with high rate in both groups of AD patients and their caregivers; in these subjects a nutrition education program and intervention policies are mandatory to restore nutritional status.

%B J Alzheimers Dis %V 54 %P 1619-1627 %8 2016 Oct 18 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27636839?dopt=Abstract %R 10.3233/JAD-160261 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Possible Involvement of Adiponectin, the Anti-Diabetes Molecule, in the Pathogenesis of Alzheimer's Disease. %A Waragai, Masaaki %A Adame, Anthony %A Trinh, Ivy %A Sekiyama, Kazunari %A Takamatsu, Yoshiki %A Une, Kaori %A Masliah, Eliezer %A Hashimoto, Makoto %X

Adiponectin (APN) is protective in animal models of neurodegenerative diseases, but the role of APN in human brain has not been established. Using an enzyme-linked immunosorbent assay, we found that APN was significantly decreased in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), compared to those in patients with mild cognitive impairment (MCI) and in normal controls (NC), despite elevation of APN in serum of patients with MCI and AD compared to that in NC. The discrepancy of CSF APN from serum APN in AD may suggest some critical actions of APN in the pathogenesis of AD. Indeed, it was histologically observed that APN was co-localized with tau in neurofibrillary tangles and immunoblot analysis showed that the functional trimers of APN were significantly decreased in AD compared to those in NC. Collectively, a loss of function of APN may be involved in the pathogenesis of AD.

%B J Alzheimers Dis %V 52 %P 1453-9 %8 2016 Apr 08 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27079710?dopt=Abstract %R 10.3233/JAD-151116 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Relative Alterations in Blood-Based Levels of Sestrin in Alzheimer's Disease and Mild Cognitive Impairment Patients. %A Rai, Nitish %A Kumar, Rahul %A Desai, Gaurav Rajesh %A Venugopalan, G %A Shekhar, Shashank %A Chatterjee, Prasun %A Tripathi, Manjari %A Upadhyay, Ashish Datt %A Dwivedi, Sadanand %A Dey, Aparajit B %A Dey, Sharmistha %X

Sestrins (sesn) are highly conserved proteins that play an important neuroprotective role, in part as a consequence of their antioxidative capacity, which prevents reactive oxygen species formation. In this study, we evaluated the concentrations of sesn1 and sesn2 in the serum of 41 Alzheimer's disease (AD) patients, 27 mild cognitive impairment (MCI), and 60 elderly controls, by surface plasmon resonance, which was validated by using western blot. Moreover, the mRNA level of sestrins in all the study groups was determined by real time polymerase chain reaction. The results showed significant overexpression of serum sesn2 protein and mRNA levels in the AD group compared to MCI and elderly control groups. A difference in serum sesn2 concentration between MCI and the control group was also evident. ROC analysis showed highly sensitive, selective cutoff values for sens2 in the differentiation of AD, MCI, and controls. No significant difference in sesn1 level was observed among the study groups. This study highlights the important role of sesn2 in the progression of the AD, indicating its potential utility as a protein marker in this devastating disease.

%B J Alzheimers Dis %V 54 %P 1147-1155 %8 2016 Oct 04 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27567861?dopt=Abstract %R 10.3233/JAD-160479 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Role of Physical Fitness in the Neurocognitive Performance of Task Switching in Older Persons with Mild Cognitive Impairment. %A Tsai, Chia-Liang %A Pai, Ming-Chyi %A Ukropec, Jozef %A Ukropcová, Barbara %X

Although elderly people with amnestic mild cognitive impairment (aMCI) have been found to show impaired behavioral performance in task switching, no research has yet explored the electrophysiological mechanisms and the potential correlation between physical fitness and neurocognitive (i.e., behavioral and electrophysiological) performance in aMCI. The present study was thus aimed to examine whether there are differences in electrophysiological (i.e., event-related potential) performance between aMCI participants and controls when performing a task-switching paradigm, and to investigate the role of physical fitness in the relationship between neurocognitive performance and aMCI. Sixty participants were classified into aMCI (n = 30) and control (n = 30) groups, and performed a task-switching paradigm with concomitant electrophysiological recording, as well as underwent senior functional physical fitness tests. The aMCI group showed comparable scores on most parts of the physical fitness tests, but reduced lower body flexibility and VO2max as compared to the control group. When performing the task-switching paradigm, the aMCI group showed slower reaction times in the heterogeneous condition and larger global switching costs, although no significant difference was observed in accuracy rates between the two groups. In addition, the aMCI group showed significantly prolonged P3 latencies in the homogeneous and heterogeneous conditions, and a smaller P3 amplitude only in the heterogeneous condition. The level of cardiorespiratory fitness was significantly correlated with P3 amplitude in the aMCI group, particularly in the heterogeneous condition of the task-switching paradigm. These results show that the aMCI group exhibited abnormalities in their neurocognitive performance when performing the task-switching paradigm and such a deficit was likely associated with reduced cardiorespiratory fitness, which was shown to be the important predictor of neurocognitive performance.

%B J Alzheimers Dis %V 53 %P 143-59 %8 2016 Apr 23 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27128369?dopt=Abstract %R 10.3233/JAD-151093 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vitamin D and Memory Decline: Two Population-Based Prospective Studies. %A Kuźma, Elżbieta %A Soni, Maya %A Littlejohns, Thomas J %A Ranson, Janice M %A van Schoor, Natasja M %A Deeg, Dorly J H %A Comijs, Hannie %A Chaves, Paulo H M %A Kestenbaum, Bryan R %A Kuller, Lewis H %A Lopez, Oscar L %A Becker, James T %A Langa, Kenneth M %A Henley, William E %A Lang, Iain A %A Ukoumunne, Obioha C %A Llewellyn, David J %K Humans %K Memory Disorders %K Netherlands %K Prospective Studies %K United States %K Vitamin D %K Vitamin D Deficiency %X

BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown.

OBJECTIVE: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline.

METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey's Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively.

RESULTS: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34).

CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.

%B J Alzheimers Dis %V 50 %P 1099-108 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836174?dopt=Abstract %R 10.3233/JAD-150811 %0 Journal Article %J J Am Geriatr Soc %D 2014 %T Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. %A Rebok, George W %A Ball, Karlene %A Guey, Lin T %A Jones, Richard N %A Kim, Hae-Young %A King, Jonathan W %A Marsiske, Michael %A Morris, John N %A Tennstedt, Sharon L %A Unverzagt, Frederick W %A Willis, Sherry L %K Activities of Daily Living %K Aged %K Aged, 80 and over %K Aging %K Cognition Disorders %K Cognitive Therapy %K Female %K Follow-Up Studies %K Humans %K Independent Living %K Male %K Memory Disorders %K Mental Processes %K Single-Blind Method %K United States %X

OBJECTIVES: To determine the effects of cognitive training on cognitive abilities and everyday function over 10 years.

DESIGN: Ten-year follow-up of a randomized, controlled single-blind trial (Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE)) with three intervention groups and a no-contact control group.

SETTING: Six U.S. cities.

PARTICIPANTS: A volunteer sample of 2,832 persons (mean baseline age 73.6; 26% African American) living independently.

INTERVENTION: Ten training sessions for memory, reasoning, or speed of processing; four sessions of booster training 11 and 35 months after initial training.

MEASUREMENTS: Objectively measured cognitive abilities and self-reported and performance-based measures of everyday function.

RESULTS: Participants in each intervention group reported less difficulty with instrumental activities of daily living (IADLs) (memory: effect size = 0.48, 99% confidence interval (CI) = 0.12-0.84; reasoning: effect size = 0.38, 99% CI = 0.02-0.74; speed of processing: effect size = 0.36, 99% CI = 0.01-0.72). At a mean age of 82, approximately 60% of trained participants, versus 50% of controls (P < .05), were at or above their baseline level of self-reported IADL function at 10 years. The reasoning and speed-of-processing interventions maintained their effects on their targeted cognitive abilities at 10 years (reasoning: effect size = 0.23, 99% CI = 0.09-0.38; speed of processing: effect size = 0.66, 99% CI = 0.43-0.88). Memory training effects were no longer maintained for memory performance. Booster training produced additional and durable improvement for the reasoning intervention for reasoning performance (effect size = 0.21, 99% CI = 0.01-0.41) and the speed-of-processing intervention for speed-of-processing performance (effect size = 0.62, 99% CI = 0.31-0.93).

CONCLUSION: Each Advanced Cognitive Training for Independent and Vital Elderly cognitive intervention resulted in less decline in self-reported IADL compared with the control group. Reasoning and speed, but not memory, training resulted in improved targeted cognitive abilities for 10 years.

%B J Am Geriatr Soc %V 62 %P 16-24 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24417410?dopt=Abstract %R 10.1111/jgs.12607 %0 Journal Article %J Nat Med %D 2014 %T Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. %A Villeda, Saul A %A Plambeck, Kristopher E %A Middeldorp, Jinte %A Castellano, Joseph M %A Mosher, Kira I %A Luo, Jian %A Smith, Lucas K %A Bieri, Gregor %A Lin, Karin %A Berdnik, Daniela %A Wabl, Rafael %A Udeochu, Joe %A Wheatley, Elizabeth G %A Zou, Bende %A Simmons, Danielle A %A Xie, Xinmin S %A Longo, Frank M %A Wyss-Coray, Tony %K Age Factors %K Aging %K Animals %K Blood Transfusion %K Blotting, Western %K Cell Line %K Cognition Disorders %K Cyclic AMP Response Element-Binding Protein %K DNA Primers %K Hippocampus %K Immunohistochemistry %K Mice %K Mice, Inbred C57BL %K Microarray Analysis %K Neuronal Plasticity %K Parabiosis %K Polymerase Chain Reaction %X

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

%B Nat Med %V 20 %P 659-63 %8 2014 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24793238?dopt=Abstract %R 10.1038/nm.3569 %0 Journal Article %J Cell Stem Cell %D 2013 %T Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. %A Kondo, Takayuki %A Asai, Masashi %A Tsukita, Kayoko %A Kutoku, Yumiko %A Ohsawa, Yutaka %A Sunada, Yoshihide %A Imamura, Keiko %A Egawa, Naohiro %A Yahata, Naoki %A Okita, Keisuke %A Takahashi, Kazutoshi %A Asaka, Isao %A Aoi, Takashi %A Watanabe, Akira %A Watanabe, Kaori %A Kadoya, Chie %A Nakano, Rie %A Watanabe, Dai %A Maruyama, Kei %A Hori, Osamu %A Hibino, Satoshi %A Choshi, Tominari %A Nakahata, Tatsutoshi %A Hioki, Hiroyuki %A Kaneko, Takeshi %A Naitoh, Motoko %A Yoshikawa, Katsuhiro %A Yamawaki, Satoko %A Suzuki, Shigehiko %A Hata, Ryuji %A Ueno, Shu-Ichi %A Seki, Tsuneyoshi %A Kobayashi, Kazuhiro %A Toda, Tatsushi %A Murakami, Kazuma %A Irie, Kazuhiro %A Klein, William L %A Mori, Hiroshi %A Asada, Takashi %A Takahashi, Ryosuke %A Iwata, Nobuhisa %A Yamanaka, Shinya %A Inoue, Haruhisa %K Alzheimer Disease %K Amyloid beta-Peptides %K Cell Differentiation %K Cerebral Cortex %K Docosahexaenoic Acids %K Humans %K Induced Pluripotent Stem Cells %K Intracellular Space %K Models, Biological %K Mutant Proteins %K Neurons %K Oxidative Stress %K Phenotype %K Protein Structure, Quaternary %X

Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.

%B Cell Stem Cell %V 12 %P 487-96 %8 2013 Apr 4 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/23434393?dopt=Abstract %R 10.1016/j.stem.2013.01.009