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

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

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

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

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

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

%B J Alzheimers Dis %V 97 %P 635-648 %8 2024 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/38160360?dopt=Abstract %R 10.3233/JAD-230934 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Association of Influenza Vaccination and Dementia Risk: A Meta-Analysis of Cohort Studies. %A Sun, Huimin %A Liu, Min %A Liu, Jue %K Aged %K Aged, 80 and over %K Cohort Studies %K Dementia %K Humans %K Influenza, Human %K Vaccination %X

BACKGROUND: Dementia is a critical global public health problem. Previous cohort studies have found that influenza vaccination can decrease the risk of dementia.

OBJECTIVE: This meta-analysis aimed to systematically examine the relationship between influenza vaccination and dementia risk.

METHODS: We searched PubMed, Embase, Web of Science, ScienceDirect, medRxiv, and bioRxiv for studies investigating dementia risk based on influenza vaccination status, up to September 14, 2022. Relative risks (RRs) and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Subgroup analyses and sensitivity analyses were conducted as well.

RESULTS: Of the 4,087 articles initially reviewed, 6 cohort studies were included in the final meta-analysis, and all eligible studies were at low risk of bias. There were 2,087,195 participants without dementia at baseline (mean age: 61.8-75.5 years, 57.05% males), and 149,804 (7.18%) cases of dementia occurred during 4.00-13.00 years of follow-up. Pooled analysis of adjusted RRs found that influenza vaccination could reduce dementia risk by 31% (RR = 0.69, 95% CI: 0.57-0.83). Subgroup analyses showed that in the study with a mean age of 75-80 years or 75%-100% males, the association was generally weakened compared with studies with a mean age of 60-75 years or 25%-50% males. The results were stable in the sensitivity analyses, and no publication bias was observed.

CONCLUSION: Influenza vaccination in older adults was markedly associated with a decreased risk of dementia. More mechanistic studies and epidemiological studies are needed to clarify the association between influenza vaccination and decreased dementia risk.

%B J Alzheimers Dis %V 92 %P 667-678 %8 2023 %G eng %N 2 %R 10.3233/JAD-221036 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Observed Improvement in Cognition During a Personalized Lifestyle Intervention in People with Cognitive Decline. %A Sandison, Heather %A Callan, Nini G L %A Rao, Rammohan V %A Phipps, John %A Bradley, Ryan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K California %K Cognition %K Cognitive Dysfunction %K Diet, Healthy %K Dietary Supplements %K Disease Progression %K Exercise %K Feasibility Studies %K Female %K Healthy Lifestyle %K Humans %K Infections %K Male %K Memory %K Middle Aged %K Nutritional Status %K Pragmatic Clinical Trials as Topic %K Reproducibility of Results %K Stress, Psychological %K Time Factors %K Treatment Outcome %K Verbal Behavior %X

BACKGROUND: Alzheimer's disease (AD) is a chronic condition marked by progressive objective cognitive impairment (OCI). No monotherapy has substantially altered disease progression, suggesting the disease is multifactorial and may require a multimodal therapeutic approach.

OBJECTIVE: We sought to determine if cognitive function in a sample with OCI would change in response to a multimodal, individualized care plan based on potential contributors to cognitive decline (e.g., nutritional status, infection, etc.).

METHODS: Participants (n = 34) were recruited from the San Diego, CA area. The multimodal intervention included lifestyle changes (i.e., movement, diet, and stress management), nutraceutical support, and medications. It was delivered pragmatically over four clinical visits, and outcome measures were gathered at four study visits, occurring at baseline, one, three, and six months (primary endpoint). Study participants received weekly phone calls for nutrition support throughout study participation. Outcome measures included the Cambridge Brain Sciences (CBS) battery, and the Montreal Cognitive Assessment (MoCA).

RESULTS: At 6 months, mean MoCA scores improved from 19.6±3.1 to 21.7±6.2 (p = 0.013). Significant improvement was observed in mean scores of the CBS memory domain [25.2 (SD 23.3) to 35.8 (SD 26.9); p < 0.01] and CBS overall composite cognition score [24.5 (SD 16.1) to 29.7 (SD 20.5); p = 0.02]. All CBS domains improved.

CONCLUSION: Multiple measures of cognitive function improved after six months of intervention. Our results support the feasibility and impact of a multimodal, individualized treatment approach to OCI, warranting further research.

%B J Alzheimers Dis %V 94 %P 993-1004 %8 2023 %G eng %N 3 %R 10.3233/JAD-230004 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Phonological and Semantic Fluency in Alzheimer's Disease: A Systematic Review and Meta-Analysis. %A Olmos-Villaseñor, Rocio %A Sepulveda-Silva, Consuelo %A Julio-Ramos, Teresa %A Fuentes-Lopez, Eduardo %A Toloza-Ramirez, David %A Santibañez, Rodrigo A %A Copland, David A %A Mendez-Orellana, Carolina %K Alzheimer Disease %K Humans %K Linguistics %K Neuropsychological Tests %K Semantics %K Verbal Behavior %X

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

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

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

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

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

%B J Alzheimers Dis %V 95 %P 1-12 %8 2023 %G eng %N 1 %R 10.3233/JAD-221272 %0 Journal Article %J J Alzheimers Dis %D 2023 %T Vacuolar Protein-Sorting Proteins Are Reduced Even Before Cognitive Decline in a Mouse Model of Alzheimer's Disease. %A Shinagawa, Hijiri %A Ohuchi, Kazuki %A Goto, Yuya %A Hashimoto, Kohei %A Kijima, Hideki %A Maekawa, Shogo %A Kurita, Hisaka %A Inden, Masatoshi %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Cognitive Dysfunction %K Humans %K Mice %K Protein Transport %K Vesicular Transport Proteins %X

Currently, interventions from the preclinical stage are considered necessary for the treatment of Alzheimer's disease (AD). Previous studies have reported that vacuolar protein-sorting protein (VPS), a retromer construct, is involved in the pathogenic mechanisms of AD and Parkinson's disease. This study evaluated VPS26, VPS29, and VPS35 before and after the onset of cognitive decline in an App knock-in mouse model of AD that more closely resembles the human pathology than previous AD models. The results showed that the expression of VPS26 and VPS35 decreased before the onset of cognitive decline, suggesting the possibility of anti-amyloid-β disease-modifying treatment targeting these proteins.

%B J Alzheimers Dis %V 96 %P 1011-1017 %8 2023 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/37980668?dopt=Abstract %R 10.3233/JAD-230686 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Association Between Serum Vitamins and the Risk of Alzheimer's Disease in Chinese Population. %A Liu, Xi-Xi %A Wu, Peng-Fei %A Liu, Ying-Zi %A Jiang, Ya-Ling %A Wan, Mei-Dan %A Xiao, Xue-Wen %A Yang, Qi-Jie %A Jiao, Bin %A Liao, Xin-Xin %A Wang, Jun-Ling %A Liu, Shao-Hui %A Zhang, Xuewei %A Shen, Lu %K Activities of Daily Living %K Aged %K Alzheimer Disease %K Case-Control Studies %K China %K Female %K Folic Acid %K Humans %K Logistic Models %K Male %K Mental Status and Dementia Tests %K Middle Aged %K Riboflavin %K Risk %K Vitamin B 12 %K Vitamin D %K Vitamin E %X

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

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

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

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

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

%B J Alzheimers Dis %V 85 %P 829-836 %8 2022 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34864672?dopt=Abstract %R 10.3233/JAD-215104 %0 Journal Article %J J Alzheimers Dis %D 2022 %T Risk of Alzheimer's Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching. %A Bukhbinder, Avram S %A Ling, Yaobin %A Hasan, Omar %A Jiang, Xiaoqian %A Kim, Yejin %A Phelps, Kamal N %A Schmandt, Rosemarie E %A Amran, Albert %A Coburn, Ryan %A Ramesh, Srivathsan %A Xiao, Qian %A Schulz, Paul E %K Adult %K Aged %K Alzheimer Disease %K Chronic Disease %K Cohort Studies %K Female %K Humans %K Influenza, Human %K Male %K Middle Aged %K Propensity Score %K Vaccination %X

BACKGROUND: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer's disease (AD) risk in a general cohort of older US adults has not been characterized.

OBJECTIVE: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database.

METHODS: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year look-back period and≥65 years old by the start of follow-up. Propensity-score matching (PSM) was used to create flu-vaccinated and flu-unvaccinated cohorts with similar baseline demographics, medication usage, and comorbidities. Relative risk (RR) and absolute risk reduction (ARR) were estimated to assess the effect of influenza vaccination on AD risk during the 4-year follow-up.

RESULTS: From the unmatched sample of eligible patients (n = 2,356,479), PSM produced a sample of 935,887 flu-vaccinated-unvaccinated matched pairs. The matched sample was 73.7 (SD, 8.7) years of age and 56.9% female, with median follow-up of 46 (IQR, 29-48) months; 5.1% (n = 47,889) of the flu-vaccinated patients and 8.5% (n = 79,630) of the flu-unvaccinated patients developed AD during follow-up. The RR was 0.60 (95% CI, 0.59-0.61) and ARR was 0.034 (95% CI, 0.033-0.035), corresponding to a number needed to treat of 29.4.

CONCLUSION: This study demonstrates that influenza vaccination is associated with reduced AD risk in a nationwide sample of US adults aged 65 and older.

%B J Alzheimers Dis %V 88 %P 1061-1074 %8 2022 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/35723106?dopt=Abstract %R 10.3233/JAD-220361 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Is the Frontal Lobe the Primary Target of SARS-CoV-2? %A Toniolo, Sofia %A Di Lorenzo, Francesco %A Scarioni, Marta %A Frederiksen, Kristian Steen %A Nobili, Flavio %K Acute Febrile Encephalopathy %K Biomarkers %K COVID-19 %K Delirium %K Electroencephalography %K Frontal Lobe %K Humans %K Magnetic Resonance Imaging %K Nerve Net %K SARS-CoV-2 %K Virulence %X

Acute delirium and other neuropsychiatric symptoms have frequently been reported in COVID-19 patients and are variably referred to as acute encephalopathy, COVID-19 encephalopathy, SARS-CoV-2 encephalitis, or steroid-responsive encephalitis. COVID-19 specific biomarkers of cognitive impairment are currently lacking, but there is some evidence that SARS-CoV-2 could preferentially and directly target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET imaging. We suggest that an inflammatory parainfectious process targeting preferentially the frontal lobes (and/or frontal networks) could be the underlying cause of these shared clinical, neurophysiological, and imaging findings in COVID-19 patients. We explore the biological mechanisms and the clinical biomarkers that might underlie such disruption of frontal circuits and highlight the need of standardized diagnostic procedures to be applied when investigating patients with these clinical findings. We also suggest the use of a unique label, to increase comparability across studies.

%B J Alzheimers Dis %V 81 %P 75-81 %8 2021 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33720900?dopt=Abstract %R 10.3233/JAD-210008 %0 Journal Article %J J Alzheimers Dis %D 2021 %T One-Year Aerobic Exercise Reduced Carotid Arterial Stiffness and Increased Cerebral Blood Flow in Amnestic Mild Cognitive Impairment. %A Tomoto, Tsubasa %A Liu, Jie %A Tseng, Benjamin Y %A Pasha, Evan P %A Cardim, Danilo %A Tarumi, Takashi %A Hynan, Linda S %A Munro Cullum, C %A Zhang, Rong %K Aged %K Brain %K Cardiorespiratory Fitness %K Carotid Arteries %K Cerebrovascular Circulation %K Cognitive Dysfunction %K Exercise %K Humans %K Magnetic Resonance Imaging %K Neuropsychological Tests %K Vascular Stiffness %X

BACKGROUND: Central arterial stiffness and brain hypoperfusion are emerging risk factors of Alzheimer's disease (AD). Aerobic exercise training (AET) may improve central arterial stiffness and brain perfusion.

OBJECTIVE: To investigate the effects of AET on central arterial stiffness and cerebral blood flow (CBF) in patients with amnestic mild cognitive impairment (MCI), a prodromal stage of AD.

METHODS: This is a proof-of-concept, randomized controlled trial that assigned 70 amnestic MCI patients into a 12-month program of moderate-to-vigorous AET or stretching-and-toning (SAT) intervention. Carotid β-stiffness index and CBF were measured by color-coded duplex ultrasonography and applanation tonometry. Total CBF was measured as the sum of CBF from both the internal carotid and vertebral arteries, and divided by total brain tissue mass assessed with MRI to obtain normalized CBF (nCBF). Episodic memory and executive function were assessed using standard neuropsychological tests (CVLT-II and D-KEFS). Changes in cardiorespiratory fitness were measured by peak oxygen uptake (VO2peak).

RESULTS: Total 48 patients (29 in SAT and 19 in AET) were completed one-year training. AET improved VO2peak, decreased carotid β-stiffness index and CBF pulsatility, and increased nCBF. Changes in VO2peak were associated positively with changes in nCBF (r = 0.388, p = 0.034) and negatively with carotid β-stiffness index (r = -0.418, p = 0.007) and CBF pulsatility (r = -0.400, p = 0.014). Decreases in carotid β-stiffness were associated with increases in cerebral perfusion (r = -0.494, p = 0.003). AET effects on cognitive performance were minimal compared with SAT.

CONCLUSION: AET reduced central arterial stiffness and increased CBF which may precede its effects on neurocognitive function in patients with MCI.

%B J Alzheimers Dis %V 80 %P 841-853 %8 2021 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33579857?dopt=Abstract %R 10.3233/JAD-201456 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Reliability of Telephone and Videoconference Methods of Cognitive Assessment in Older Adults with and without Dementia. %A Hunter, Matthew B %A Jenkins, Natalie %A Dolan, Clare %A Pullen, Hannah %A Ritchie, Craig %A Muniz-Terrera, Graciela %K Aged %K Aged, 80 and over %K Cognition %K Cognitive Dysfunction %K Dementia %K Geriatric Assessment %K Humans %K Neuropsychological Tests %K Remote Consultation %K Reproducibility of Results %K Telephone %K Videoconferencing %X

BACKGROUND: Telephone and videoconference administration of cognitive tests introduce additional sources of variance compared to in-person testing. Reviews of test-retest reliability have included mixed neurocognitive and psychiatric populations with limited consideration of methodological and statistical contributions.

OBJECTIVE: We reviewed reliability estimates from comparison studies of older adults with and without dementia, considering test-retest analyses and study methods.

METHODS: Medline, Embase, PsycINFO, and Web of Science were systematically searched from 1 January 2000 to 9 June 2020 for original articles comparing telephone or videoconference administered cognitive instruments to in-person administration in older adults with and without dementia or mild cognitive impairment.

RESULTS: Of 4,125 articles, 23 were included: 11 telephone (N = 2 dementia cohorts) and 12 videoconference (N = 4 dementia cohorts). Telephone administered subtest scores trended in the same direction as in-person with comparable means. Person-level data were scarce. Data on dementia was only available for MMSE, with resulting subtle modality bias. MMSE, SMMSE, Letter Fluency, and HVLT-R in healthy to mild-moderate Alzheimer's disease were particularly reliable for videoconference administration. Other tests show promise but require more observations and comprehensive analyses. Most studies used high-speed stable videoconferencing hardware resulting in a lack of ecological validity for home administration.

CONCLUSION: Remote administration is often consistent with in-person administration but variable and limited at the person/test level. Improved statistical design and inclusion of dementia related cohorts in telephone studies is recommended. Reliability evidence is stronger for videoconferencing but with limited applicability to home administration and severe dementia. Improved reporting of administrative procedures is recommended.

%B J Alzheimers Dis %V 81 %P 1625-1647 %8 2021 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/33967052?dopt=Abstract %R 10.3233/JAD-210088 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Circulating Vitamin D Levels and Alzheimer's Disease: A Mendelian Randomization Study in the IGAP and UK Biobank. %A Wang, Longcai %A Qiao, Yanchun %A Zhang, Haihua %A Zhang, Yan %A Hua, Jiao %A Jin, Shuilin %A Liu, Guiyou %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Biological Specimen Banks %K Cognition Disorders %K Databases, Factual %K Female %K Genome-Wide Association Study %K Humans %K Hydroxycholecalciferols %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Nutritional Status %K United Kingdom %K Vitamin D %K Vitamin D Deficiency %X

Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer's disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk in individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents.

%B J Alzheimers Dis %V 73 %P 609-618 %8 2020 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31815694?dopt=Abstract %R 10.3233/JAD-190713 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Age-Related Changes in the Spatial Frequency Threshold of Male and Female 3xTg-AD Mice Using OptoMotry. %A King, Jillian L %A Wong, Aimée A %A Brown, Richard E %K Aging %K Alzheimer Disease %K Animals %K Disease Models, Animal %K Female %K Humans %K Male %K Maze Learning %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Sex Characteristics %K tau Proteins %K Vision, Ocular %X

Visual impairments and retinal abnormalities occur in patients with Alzheimer's disease (AD) and in mouse models of AD. It is important to know the visual ability of mouse models of AD to ensure that age-related cognitive deficits are not confounded by visual impairments. Using OptoMotry, the spatial frequency thresholds of male and female 3xTg-AD mice did not differ from their B6129SF2 wildtype controls between 1-18 months of age, but females had higher spatial frequency thresholds than males. However, the differences were quite small, and the visual ability of all mice was comparable to that of C57BL/6 mice.

%B J Alzheimers Dis %V 62 %P 591-596 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480178?dopt=Abstract %R 10.3233/JAD-170805 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Cerebrospinal Fluid, MRI, and Florbetaben-PET in Cerebral Amyloid Angiopathy-Related Inflammation. %A Renard, Dimitri %A Collombier, Laurent %A Demattei, Christophe %A Wacongne, Anne %A Charif, Mahmoud %A Ayrignac, Xavier %A Azakri, Souhayla %A Gaillard, Nicolas %A Boudousq, Vincent %A Lehmann, Sylvain %A Menjot de Champfleur, Nicolas %A Thouvenot, Eric %K Aged %K Aged, 80 and over %K Amyloid beta-Peptides %K Aniline Compounds %K Biomarkers %K Brain %K Cerebral Amyloid Angiopathy %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Positron-Emission Tomography %K Prospective Studies %K Stilbenes %K tau Proteins %K Vasculitis, Central Nervous System %X

BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by fibrillar amyloid-β (Aβ) imaging (using 11C-Pittsburgh compound B and 18F-florbetapir, but not 18F-florbetaben).

OBJECTIVE: To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients.

METHODS: CSF levels of total tau, phosphorylated tau, Aβ1-42, and Aβ1-40, MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET (using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA-ri patients.

RESULTS: A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Aβ1-40 levels (rho = -0.83, p = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = -0.63, p = 0.076; phosphorylated tau, rho = -0.68, p = 0.05; Aβ1-42, rho = -0.59, p = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = -0.50, p = 0.18) was observed between CSF Aβ1-40 levels and cerebral microbleed numbers.

CONCLUSION: In CAA-ri, CSF Aβ1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Aβ1-40 as an in vivo marker for CAA and CAA-ri.

%B J Alzheimers Dis %V 61 %P 1107-1117 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254099?dopt=Abstract %R 10.3233/JAD-170843 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Homocysteine and Dementia: An International Consensus Statement. %A Smith, A David %A Refsum, Helga %A Bottiglieri, Teodoro %A Fenech, Michael %A Hooshmand, Babak %A McCaddon, Andrew %A Miller, Joshua W %A Rosenberg, Irwin H %A Obeid, Rima %K Cognition %K Cognitive Dysfunction %K Consensus %K Dementia %K Dietary Supplements %K Homocysteine %K Humans %K Meta-Analysis as Topic %K Review Literature as Topic %K Risk Factors %K Vitamin B Complex %X

Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.

%B J Alzheimers Dis %V 62 %P 561-570 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad171042?id=journal-of-alzheimers-disease%2Fjad171042 %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480200?dopt=Abstract %R 10.3233/JAD-171042 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Impact of a Virtual Dementia Experience on Medical and Pharmacy Students' Knowledge and Attitudes Toward People with Dementia: A Controlled Study. %A Gilmartin-Thomas, Julia F-M %A McNeil, John %A Powell, Anne %A Malone, Daniel T %A Wolfe, Rory %A Larson, Ian C %A O'Reilly, Claire L %A Kirkpatrick, Carl M %A Kipen, Eva %A Petrovich, Tanya %A Bell, J Simon %K Australia %K Curriculum %K Dementia %K Female %K Health Knowledge, Attitudes, Practice %K Humans %K Male %K Students, Medical %K Students, Pharmacy %K Virtual Reality %K Young Adult %X

BACKGROUND: Clinical practice guidelines for dementia highlight the importance of providing patient-centered care. This can be achieved by improving health professionals' attitudes and knowledge toward people with dementia.

OBJECTIVE: Quantitatively evaluate the impact of a virtual dementia experience on medical and pharmacy students' knowledge and attitudes toward people with dementia.

METHODS: A non-randomized controlled study from September-October 2016. The intervention group received a 1.5-hour multisensory, virtual simulation of light, sound, color, and visual content to experience the cognitive and perceptual difficulties faced by people with dementia. Controls participated in the standard curriculum only. All students were invited to complete the 20-item Dementia Attitudes Scale (DAS) pre- and post-intervention.

RESULTS: A total of 278 students (n = 64 medical, n = 214 pharmacy) were analyzed (n = 80 intervention, n = 198 control). The majority of students were female (n = 184, 66.2%), with an average age of 22.5 years. The intervention improved the DAS total score and subdomains of comfort and knowledge (p < 0.001).

CONCLUSION: The intervention had a positive impact on medical and pharmacy students' knowledge and attitudes toward people with dementia.

%B J Alzheimers Dis %V 62 %P 867-876 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480198?dopt=Abstract %R 10.3233/JAD-170982 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Nutrition: Review on the Possible Treatment for Alzheimer's Disease. %A Botchway, Benson O A %A Moore, Masania K %A Akinleye, Faith O %A Iyer, Ishwari C %A Fang, Marong %K Alzheimer Disease %K Curcumin %K Diet, Mediterranean %K Dietary Supplements %K Humans %K Nutritional Status %K Risk Factors %K Vitamins %X

Since its discovery some hundred years ago, Alzheimer's disease (AD), a neurodegenerative disease and an eminent cause of most dementia, continues to pose problems for affected families and society, especially in developed countries. With the approved medications by the Food and Drugs Administration in the United States, effectual treatment of AD apropos to the complete eradication of the disease continues to be elusive due to complexities relating to the pathophysiology of the disease. Nutrition has and continues to play a salient role in the survival of living organisms with no exception for human beings. Herein, we report the connection between nutrition and AD with particular attention to vitamins, curcumin, and the Mediterranean diet.

%B J Alzheimers Dis %V 61 %P 867-883 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254101?dopt=Abstract %R 10.3233/JAD-170874 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. %A Power, Rebecca %A Coen, Robert F %A Beatty, Stephen %A Mulcahy, Riona %A Moran, Rachel %A Stack, Jim %A Howard, Alan N %A Nolan, John M %K Adult %K Cognition %K Dietary Supplements %K Double-Blind Method %K Executive Function %K Female %K Healthy Volunteers %K Humans %K Lutein %K Macular Pigment %K Male %K Memory, Episodic %K Middle Aged %K Retina %K Vision Tests %K Zeaxanthins %X

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

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

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

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

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

%B J Alzheimers Dis %V 61 %P 947-961 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332050?dopt=Abstract %R 10.3233/JAD-170713 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Ubisol-Q10 (a Nanomicellar Water-Soluble Formulation of CoQ10) Treatment Inhibits Alzheimer-Type Behavioral and Pathological Symptoms in a Double Transgenic Mouse (TgAPEswe, PSEN1dE9) Model of Alzheimer's Disease. %A Muthukumaran, Krithika %A Kanwar, Annie %A Vegh, Caleb %A Marginean, Alexandra %A Elliott, Austin %A Guilbeault, Nicholas %A Badour, Alexander %A Sikorska, Marianna %A Cohen, Jerome %A Pandey, Siyaram %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Disease Models, Animal %K Male %K Maze Learning %K Memory %K Memory Disorders %K Mice %K Mice, Transgenic %K Microglia %K Mutation %K Nerve Tissue Proteins %K Peptide Fragments %K Presenilin-1 %K Ubiquinone %K Vitamins %X

 Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.

%B J Alzheimers Dis %V 61 %P 221-236 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154270?dopt=Abstract %R 10.3233/JAD-170275 %0 Journal Article %J J Alzheimers Dis %D 2018 %T VEGFR1 and VEGFR2 in Alzheimer's Disease. %A Harris, Rachel %A Miners, James Scott %A Allen, Shelley %A Love, Seth %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Case-Control Studies %K Endothelial Cells %K Female %K Gene Expression Regulation %K Humans %K Male %K Middle Aged %K Neovascularization, Pathologic %K RNA, Messenger %K Signal Transduction %K Vascular Endothelial Growth Factor A %K Vascular Endothelial Growth Factor Receptor-1 %K Vascular Endothelial Growth Factor Receptor-2 %X

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-β, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.

%B J Alzheimers Dis %V 61 %P 741-752 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226875?dopt=Abstract %R 10.3233/JAD-170745 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Vestibular Loss Predicts Poorer Spatial Cognition in Patients with Alzheimer's Disease. %A Wei, Eric X %A Oh, Esther S %A Harun, Aisha %A Ehrenburg, Matthew %A Agrawal, Yuri %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Bilateral Vestibulopathy %K Cognitive Dysfunction %K Cross-Sectional Studies %K Female %K Humans %K Linear Models %K Male %K Multivariate Analysis %K Neuropsychological Tests %K Prospective Studies %K Spatial Navigation %K Vestibular Function Tests %X

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

%B J Alzheimers Dis %V 61 %P 995-1003 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254098?dopt=Abstract %R 10.3233/JAD-170751 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Word and Picture Version of the Free and Cued Selective Reminding Test (FCSRT): Is There Any Difference? %A Arighi, Andrea %A Carandini, Tiziana %A Mercurio, Matteo %A Carpani, Giovanni %A Pietroboni, Anna Margherita %A Fumagalli, Giorgio %A Ghezzi, Laura %A Basilico, Paola %A Calvi, Alberto %A Scarioni, Marta %A De Riz, Milena %A Fenoglio, Chiara %A Scola, Elisa %A Triulzi, Fabio %A Galimberti, Daniela %A Scarpini, Elio %K Aged %K Aged, 80 and over %K Association Learning %K Cognitive Dysfunction %K Cues %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Recall %K Middle Aged %K Neuropsychological Tests %K Photic Stimulation %K Vocabulary %X

The Free and Cued Selective Reminding Test (FCSRT) is the most commonly used neuropsychological test to evaluate episodic memory. Two variants of FCSRT exist, using the recall of words (FCSRT-w) or pictures (FCSRT-p). Fourteen patients with mild cognitive impairment underwent neuropsychological evaluation and brain magnetic resonance. We found differences in FCSRT-w and FCSRT-p variants scores. FCSRT-p was correlated with atrophy in areas involved in visual stimuli processing while FCSRT-w was correlated to hippocampal atrophy. Our study suggests that FCSRT-w and FCSRT-p scores are not equivalent, but a larger cohort of patients is needed to validate these results.

%B J Alzheimers Dis %V 61 %P 47-52 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125489?dopt=Abstract %R 10.3233/JAD-170712 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Apolipoprotein ɛ4 is Associated with Dementia and Cognitive Impairment Predominantly Due to Alzheimer's Disease and Not with Vascular Cognitive Impairment: A Singapore-Based Cohort. %A Chai, Yuek Ling %A Yeo, Hazel Kai-Hui %A Wang, Jiehao %A Hilal, Saima %A Ikram, Mohammad Kamran %A Venketasubramanian, Narayanaswamy %A Wong, Boon-Seng %A Chen, Christopher Li-Hsian %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Analysis of Variance %K Apolipoprotein E4 %K Cognition Disorders %K Cohort Studies %K Dementia %K Female %K Genetic Association Studies %K Genotype %K Humans %K Male %K Middle Aged %K Neuroimaging %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Singapore %K Vascular Diseases %X

BACKGROUND AND OBJECTIVE: While the association for apolipoprotein ɛ4 allele (APOE4) with Alzheimer's disease (AD) has been consistently confirmed, the association with vascular cognitive impairment (VCI) is unclear. We therefore explored the relationship of APOE with both AD and cerebrovascular disease (CeVD) by examining the prevalence of APOE4 in AD, AD with CeVD and vascular dementia (VaD), as well as in cognitive impairment no dementia (CIND) with and without CeVD.

METHODS: We performed a case-control study with subjects recruited from memory clinics and the community. All subjects underwent standardized brain neuroimaging, clinical and neuropsychological assessments, following which they were classified using research criteria.

RESULTS: A total of 411 subjects; 92 controls with no cognitive impairment (NCI), 77 CIND without CeVD, 87 CIND with CeVD, 55 AD without CeVD, 68 AD with CeVD, and 32 VaD patients were recruited. Compared to NCI (16.3%), the prevalence of APOE4 carriers was significantly higher only in CIND (37.7%) and AD in the absence of CeVD (45.5%), but not in the three subgroups of VCI, namely CIND with CeVD (20.7%), AD with CeVD (27.9%) and VaD (25.0%). Logistic regression analyses also showed that APOE4 carriers were more likely to have CIND without CeVD (Odds Ratio [OR]: 3.34; 95% Confidence Interval [CI]: 1.59-7.03) and AD without CeVD (OR: 7.21; 95% CI: 2.74-18.98), but no such association was observed in the VCI subgroups.

CONCLUSION: APOE4 is significantly associated with dementia and CIND due to AD pathology, but not with VCI.

%B J Alzheimers Dis %V 51 %P 1111-8 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923016?dopt=Abstract %R 10.3233/JAD-150902 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study. %A Karakis, Ioannis %A Pase, Matthew P %A Beiser, Alexa %A Booth, Sarah L %A Jacques, Paul F %A Rogers, Gail %A DeCarli, Charles %A Vasan, Ramachandran S %A Wang, Thomas J %A Himali, Jayandra J %A Annweiler, Cedric %A Seshadri, Sudha %K Adult %K Aging %K Brain %K Cohort Studies %K Dementia %K Female %K Humans %K Incidence %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Multivariate Analysis %K Neuropsychological Tests %K Regression Analysis %K Risk %K Sensitivity and Specificity %K Vitamin D %X

BACKGROUND: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts.

OBJECTIVE: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer's disease (AD), MRI markers of brain aging, and neuropsychological function.

METHODS: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10 ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n = 1663), multiple neuropsychological tests (n = 1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n = 1139).

RESULTS: In adjusted models, participants with vitamin D deficiency (n = 104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β= -0.03 to -0.05±0.02) and the Hooper Visual Organization Test (β= -0.09 to -0.12±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β= -0.01±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD.

CONCLUSIONS: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.

%B J Alzheimers Dis %V 51 %P 451-61 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890771?dopt=Abstract %R 10.3233/JAD-150991 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Cerebral Amyloid Angiopathy (CAA)-Related Inflammation: Comparison of Inflammatory CAA and Amyloid-β-Related Angiitis. %A Chu, Shuguang %A Xu, Feijia %A Su, Ya %A Chen, Hong %A Cheng, Xin %K Apolipoproteins E %K Cerebral Amyloid Angiopathy %K Headache %K Humans %K Inflammation %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Seizures %K Vasculitis, Central Nervous System %X

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a relatively rare syndrome of reversible encephalopathy and could be divided into two subtypes of inflammatory CAA (ICAA) and amyloid-β-related angiitis (ABRA) according to histopathology. We present a case of pathologically proved ABRA with partial seizures and headache, and a focal lesion in the right temporal lobes on magnetic resonance imaging. Summarized from previous 139 ABRA and ICAA cases, ABRA is preferred when the lesion is enhanced on MRI and requires combination drug therapy, while ICAA is highly suspected with ApoE genotype of ɛ4/ɛ4. More clinical markers for diagnosis of CAA-ri warrant further researches.

%B J Alzheimers Dis %V 51 %P 525-32 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890776?dopt=Abstract %R 10.3233/JAD-151036 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Decreased Levels of VAMP2 and Monomeric Alpha-Synuclein Correlate with Duration of Dementia. %A Vallortigara, Julie %A Whitfield, David %A Quelch, William %A Alghamdi, Amani %A Howlett, David %A Hortobágyi, Tibor %A Johnson, Mary %A Attems, Johannes %A O'Brien, John T %A Thomas, Alan %A Ballard, Clive G %A Aarsland, Dag %A Francis, Paul T %K Aged %K Aged, 80 and over %K alpha-Synuclein %K Amyloid beta-Peptides %K Analysis of Variance %K Cognition Disorders %K Dementia %K Female %K Humans %K Male %K Mental Status Schedule %K Neuropsychological Tests %K Regression Analysis %K Synaptophysin %K tau Proteins %K Vesicle-Associated Membrane Protein 2 %X

Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), but are also frequently present in Alzheimer's disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key 'SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor' (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p <  0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

%B J Alzheimers Dis %V 50 %P 101-10 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639969?dopt=Abstract %R 10.3233/JAD-150707 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Membrane Toxicity of Amyloid-β Fragments by Pore Forming Mechanisms. %A Peters, Christian %A Bascuñán, Denisse %A Opazo, Carlos %A Aguayo, Luis G %K Amyloid beta-Peptides %K Animals %K Calcium %K Cell Membrane %K Cells, Cultured %K Fluorescent Antibody Technique %K HEK293 Cells %K Hippocampus %K Humans %K Microscopy, Electron, Transmission %K Neurons %K Patch-Clamp Techniques %K Peptide Fragments %K Porosity %K Rats, Sprague-Dawley %K Voltage-Sensitive Dye Imaging %X

A major characteristic of Alzheimer's disease (AD) is the presence of amyloid-β peptide (Aβ) oligomers and aggregates in the brain. It is known that Aβ oligomers interact with the neuronal membrane and induce perforations that cause an influx of calcium ions and enhance the release of synaptic vesicles leading to a delayed synaptic failure by vesicle depletion. To better understand the mechanism by which Aβ exerts its effect on the plasma membrane, we evaluated three Aβ fragments derived from different regions of Aβ(1-42); Aβ(1-28) from the N-terminal region, Aβ(25-35) from the central region, and Aβ(17-42) from the C-terminal region. The neuronal activities of these fragments were examined with patch clamp, immunofluorescence, transmission electron microscopy, aggregation assays, calcium imaging, and MTT reduction assays. The present results indicate that the fragment Aβ(1-28) contributes to aggregation, an increase in intracellular calcium and synaptotoxicity, but is not involved in membrane perforation; Aβ(25-35) is important for membrane perforation, calcium increase, and synaptotoxicity; and Aβ(17-42) induced mitochondrial toxicity similar to the full length Aβ(1-42), but was unable to induce membrane perforation and calcium increase, supporting the idea that it is less toxic in the non-amyloidogenic pathway.

%B J Alzheimers Dis %V 51 %P 689-99 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890761?dopt=Abstract %R 10.3233/JAD-150896 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Drivers: A Biologically Contextualized, Cross-Inferential View of the Epidemiology of Neurodegenerative Disorders. %A de Pedro-Cuesta, Jesús %A Martínez-Martín, Pablo %A Rábano, Alberto %A Alcalde-Cabero, Enrique %A José García López, Fernando %A Almazán-Isla, Javier %A Ruiz-Tovar, María %A Medrano, Maria-José %A Avellanal, Fuencisla %A Calero, Olga %A Calero, Miguel %K Age Factors %K Aging %K Amyloid Precursor Protein Secretases %K Apolipoproteins E %K Aspartic Acid Endopeptidases %K Creutzfeldt-Jakob Syndrome %K Environment %K Female %K Humans %K Incidence %K Male %K Neurodegenerative Diseases %K Personality %K Risk Factors %K Vascular Diseases %X

BACKGROUND: Sutherland et al. (2011) suggested that, instead of risk factors for single neurodegenerative disorders (NDDs), there was a need to identify specific "drivers", i.e., risk factors with impact on specific deposits, such as amyloid-β, tau, or α-synuclein, acting across entities.

OBJECTIVES AND METHODS: Redefining drivers as "neither protein/gene- nor entity-specific features identifiable in the clinical and general epidemiology of conformational NDDs (CNDDs) as potential footprints of templating/spread/transfer mechanisms", we conducted an analysis of the epidemiology of ten CNDDs, searching for patterns.

RESULTS: We identified seven potential drivers, each of which was shared by at least two CNDDs: 1) an age-at-exposure-related susceptibility to Creutzfeldt-Jakob disease (CJD) and several late-life CNDDs; 2) a relationship between age at onset, survival, and incidence; 3) shared genetic risk factors for CJD and late-life CNNDs; 4) partly shared personal (diagnostic, educational, behavioral, and social risk factors) predating clinical onset of late-life CNDDs; 5) two environmental risk factors, namely, surgery for sporadic CJD and amyotrophic lateral sclerosis, and Bordetella pertussis infection for Parkinson's disease; 6) reticulo-endothelial system stressors or general drivers (andropause or premenopausal estrogen deficiency, APOEɛ4, and vascular risk factors) for late-life CNDDs such as dementia/Alzheimer's disease, type-2 diabetes mellitus, and some sporadic cardiac and vascular degenerative diseases; and 7) a high, invariant incidence ratio of sporadic to genetic forms of mid- and late-life CNDDs, and type-2 diabetes mellitus.

CONCLUSION: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-β, tau, Langerhans islet peptide, and transthyretin) or established combinations of these.

%B J Alzheimers Dis %V 51 %P 1003-22 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923014?dopt=Abstract %R 10.3233/JAD-150884 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Anserine/Carnosine Supplementation on Verbal Episodic Memory in Elderly People. %A Hisatsune, Tatsuhiro %A Kaneko, Jun %A Kurashige, Hiroki %A Cao, Yuan %A Satsu, Hideo %A Totsuka, Mamoru %A Katakura, Yoshinori %A Imabayashi, Etsuko %A Matsuda, Hiroshi %K Adult %K Aged %K Aging %K Anserine %K Brain %K Carnosine %K Cytokines %K Dietary Supplements %K Double-Blind Method %K Female %K Gene Expression Regulation %K Humans %K Image Processing, Computer-Assisted %K Male %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Oligonucleotide Array Sequence Analysis %K Verbal Learning %X

Our goal in this study was to determine whether or not anserine/carnosine supplementation (ACS) is capable of preserving cognitive function of elderly people. In a double-blind randomized controlled trial, volunteers were randomly assigned to an ACS or placebo group at a 1:1 ratio. The ACS group took 1.0 g of an anserine/carnosine (3:1) formula daily for 3 months. Participants were evaluated by psychological tests before and after the 3-month supplementation period. Thirty-nine healthy elderly volunteers (60-78 years old) completed the follow-up tests. Among the tests, delayed recall verbal memory assessed by the Wechsler Memory Scale-Logical Memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0128). Blood analysis revealed a decreased secretion of inflammatory cytokines, including CCL-2 and IL-8, in the ACS group. MRI analysis using arterial spin labeling showed a suppression in the age-related decline in brain blood flow in the posterior cingulate cortex area in the ACS group, compared to the placebo group (p = 0.0248). In another randomized controlled trial, delayed recall verbal memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0202). These results collectively suggest that ACS may preserve verbal episodic memory and brain perfusion in elderly people, although further study is needed.

%B J Alzheimers Dis %V 50 %P 149-59 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682691?dopt=Abstract %R 10.3233/JAD-150767 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Functional Connectivity of Ventral and Dorsal Visual Streams in Posterior Cortical Atrophy. %A Migliaccio, Raffaella %A Gallea, Cécile %A Kas, Aurélie %A Perlbarg, Vincent %A Samri, Dalila %A Trotta, Laura %A Michon, Agnès %A Lacomblez, Lucette %A Dubois, Bruno %A Lehéricy, Stéphane %A Bartolomeo, Paolo %K Aged %K Alzheimer Disease %K Atrophy %K Case-Control Studies %K Cerebral Cortex %K Female %K Humans %K Image Processing, Computer-Assisted %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Oxygen %K Visual Pathways %X

BACKGROUND: Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC).

OBJECTIVES: To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer's disease (AD) pathology.

METHODS: Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy.

RESULTS: PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls.

CONCLUSIONS: FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.

%B J Alzheimers Dis %V 51 %P 1119-30 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923019?dopt=Abstract %R 10.3233/JAD-150934 %0 Journal Article %J J Alzheimers Dis %D 2016 %T JNK: A Putative Link Between Insulin Signaling and VGLUT1 in Alzheimer's Disease. %A Rodriguez-Perdigon, Manuel %A Solas, Maite %A Ramirez, Maria Javier %K Aged %K Alzheimer Disease %K Animals %K Brain %K Corticosterone %K Disease Models, Animal %K Female %K Humans %K Insulin %K Insulin Resistance %K Male %K MAP Kinase Kinase 4 %K Mice, Inbred C57BL %K Mitogen-Activated Protein Kinase 1 %K Neuroprotective Agents %K RNA, Messenger %K Vesicular Glutamate Transport Protein 1 %X

In the present work, the involvement of JNK in insulin signaling alterations and its role in glutamatergic deficits in Alzheimer's disease (AD) has been studied. In postmortem cortical tissues, pJNK levels were increased, while insulin signaling and the expression of VGLUT1 were decreased. A significant correlation was found between reduced expression of insulin receptor and VGLUT1. The administration of a JNK inhibitor reversed the decrease in VGLUT1 expression found in a mice model of insulin resistance. It is suggested that activation of JNK in AD inhibits insulin signaling which could lead to a decreased expression of VGLUT1, therefore contributing to the glutamatergic deficit in AD.

%B J Alzheimers Dis %V 50 %P 963-7 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836159?dopt=Abstract %R 10.3233/JAD-150659 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Linguistic Features Identify Alzheimer's Disease in Narrative Speech. %A Fraser, Kathleen C %A Meltzer, Jed A %A Rudzicz, Frank %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Diagnosis, Computer-Assisted %K Factor Analysis, Statistical %K Female %K Humans %K Language Disorders %K Linguistics %K Logistic Models %K Machine Learning %K Male %K Mental Status Schedule %K Middle Aged %K Narration %K Photic Stimulation %K Speech %K Verbal Behavior %X

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

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

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

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

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

%B J Alzheimers Dis %V 49 %P 407-22 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484921?dopt=Abstract %R 10.3233/JAD-150520 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer's Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open-Label Study. %A Remington, Ruth %A Bechtel, Cynthia %A Larsen, David %A Samar, Annemarie %A Page, Robert %A Morrell, Christopher %A Shea, Thomas B %K Aged %K Aged, 80 and over %K alpha-Tocopherol %K Alzheimer Disease %K Cognition Disorders %K Dietary Supplements %K Disease Progression %K Female %K Folic Acid %K Follow-Up Studies %K Humans %K Male %K Mood Disorders %K Neuropsychological Tests %K Psychiatric Status Rating Scales %K Time Factors %K Vitamin B 12 %X

Nutritional interventions have shown varied efficacy on cognitive performance during Alzheimer's disease (AD). Twenty-four individuals diagnosed with AD received a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) under open-label conditions (ClinicalTrials.gov NCT01320527). Primary outcome was cognitive performance. Secondary outcomes were behavioral and psychological symptoms of dementia (BPSD) and activities of daily living. Participants maintained their baseline cognitive performance and BPSD over 12 months. These findings are consistent with improvement in cognitive performance and BPSD in prior placebo-controlled studies with NF, and contrast with the routine decline for participants receiving placebo.

%B J Alzheimers Dis %V 51 %P 991-5 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26967219?dopt=Abstract %R 10.3233/JAD-151098 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. %A Oulhaj, Abderrahim %A Jernerén, Fredrik %A Refsum, Helga %A Smith, A David %A de Jager, Celeste A %K Aged %K Aged, 80 and over %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Fatty Acids, Omega-3 %K Female %K Humans %K Male %K Neuropsychological Tests %K Treatment Outcome %K Vitamin B Complex %X

A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.

%B J Alzheimers Dis %V 50 %P 547-57 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757190?dopt=Abstract %R 10.3233/JAD-150777 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Patients with Mild Alzheimer's Disease Fail When Using Their Working Memory: Evidence from the Eye Tracking Technique. %A Fernández, Gerardo %A Manes, Facundo %A Politi, Luis E %A Orozco, David %A Schumacher, Marcela %A Castro, Liliana %A Agamennoni, Osvaldo %A Rotstein, Nora P %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Eye Movements %K Female %K Humans %K Linear Models %K Magnetic Resonance Imaging %K Male %K Memory Disorders %K Memory, Short-Term %K Mental Recall %K Mental Status Schedule %K Predictive Value of Tests %K Semantics %K Verbal Learning %X

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

%B J Alzheimers Dis %V 50 %P 827-38 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836011?dopt=Abstract %R 10.3233/JAD-150265 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Protective Effect of Amyloid-β Peptides Against Herpes Simplex Virus-1 Infection in a Neuronal Cell Culture Model. %A Bourgade, Karine %A Le Page, Aurélie %A Bocti, Christian %A Witkowski, Jacek M %A Dupuis, Gilles %A Frost, Eric H %A Fülöp, Tamás %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Cell Line, Tumor %K Coculture Techniques %K Culture Media, Conditioned %K Herpes Simplex %K Herpesvirus 1, Human %K Humans %K Interferon-alpha %K Interleukin-1beta %K Neuroglia %K Neurons %K Peptide Fragments %K Tumor Necrosis Factor-alpha %K Virus Replication %X

Senile amyloid plaques are one of the main hallmarks of Alzheimer's disease (AD). They correspond to insoluble deposits of amyloid-β peptides (Aβ) and are responsible for the inflammatory response and neurodegeneration that lead to loss of memory. Recent data suggest that Aβ possess antimicrobial and anti-viral activity in vitro. Here, we have used cocultures of neuroglioma (H4) and glioblastoma (U118-MG) cells as a minimal in vitro model to investigate whether Aβ is produced by neuroglioma cells and whether this could result in protective anti-viral activity against HSV-1 infection. Results showed that H4 cells secreted Aβ42 in response to HSV-1 challenge and that U118-MG cells could rapidly internalize Aβ42. Production of pro-inflammatory cytokines TNFα and IL-1β by H4 and U118-MG cells occurred under basal conditions but infection of the cells with HSV-1 did not significantly upregulate production. Both cell lines produced low levels of IFNα. However, extraneous Aβ42 induced strong production of these cytokines. A combination of Aβ42 and HSV-1 induced production of pro-inflammatory cytokines TNFα and IL-1β, and IFNα in the cell lines. The reported anti-viral protection of Aβ42 was revealed in transfer experiments involving conditioned medium (CM) of HSV-1-infected H4 cells. CM conferred Aβ-dependent protection against HSV-1 replication in de novo cultures of H4 cells challenged with HSV-1. Type 1 interferons did not play a role in these assays. Our data established that H4 neuroglioma cells produced Aβ42 in response to HSV-1 infection thus inhibiting secondary replication. This mechanism may play a role in the etiology of AD.

%B J Alzheimers Dis %V 50 %P 1227-41 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836158?dopt=Abstract %R 10.3233/JAD-150652 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Reversible Mild Cognitive Impairment: The Role of Comorbidities at Baseline Evaluation. %A Grande, Giulia %A Cucumo, Valentina %A Cova, Ilaria %A Ghiretti, Roberta %A Maggiore, Laura %A Lacorte, Eleonora %A Galimberti, Daniela %A Scarpini, Elio %A Clerici, Francesca %A Pomati, Simone %A Vanacore, Nicola %A Mariani, Claudio %K Analysis of Variance %K Cognitive Dysfunction %K Cohort Studies %K Comorbidity %K Female %K Humans %K Male %K Memory %K Mental Status Schedule %K Neuropsychological Tests %K Reference Values %K Verbal Learning %X

The prognostic value of mild cognitive impairment (MCI) is being questioned, with some MCI subjects reverting to normal cognition (NC). The reversion rate varies mostly depending on the study design, the setting, and both MCI and NC definitions. Previous studies have focused on the profile of subjects who revert to NC, but the role of comorbidities has not been entirely investigated. We aimed to evaluate the proportion of MCI subjects who revert to NC in a memory clinic context, focusing on the role of comorbidities. Between 2004 and 2013, 374 MCI subjects were recruited. During a mean time of 32 ± 25.5 months, 21 subjects (5.6%) reverted to NC. Subjects who reverted to NC were younger (p = 0.0001), more educated (p = 0.0001), had a better global cognition (p = 0.0001), as assessed by the Mini-Mental State Examination (MMSE) and suffered from more comorbidities (p = 0.002), as assessed by Cumulative Illness Rating Scale (CIRS) than those who developed dementia. The Cox Regression Model, constructed to adjust for the confounders, showed that the higher were the MMSE (HR = 1.83, CI 95%: 1.07-3.11) and the CIRS score (HR = 1.3, CI 95% 0.88-1.92) at baseline, the higher was the probability of returning to NC than developing dementia, though the last association was not significant. Subjects who reverted to NC were more frequently affected by respiratory (p = 0.002), urologic (p = 0.012), and psychiatric (p = 0.012) diseases. The cognitive performance of subjects with medical comorbidities could benefit from preventive strategies aimed at treating the underlying diseases.

%B J Alzheimers Dis %V 51 %P 57-67 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836169?dopt=Abstract %R 10.3233/JAD-150786 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vascular Health Indices and Cognitive Domain Function: Singapore Longitudinal Ageing Studies. %A Lim, Shir Lynn %A Gao, Qi %A Nyunt, Ma Shwe Zin %A Gong, Lingli %A Lunaria, Josephine B %A Lim, May Li %A Ling, Audrey %A Lam, Carolyn Su-Ping %A Richards, Arthur Mark %A Ling, Lieng Hsi %A Ng, Tze Pin %K Aged %K Blood Flow Velocity %K Blood Pressure %K Cardiovascular Diseases %K Carotid Intima-Media Thickness %K Cognitive Aging %K Female %K Humans %K Longitudinal Studies %K Male %K Mental Status Schedule %K Middle Aged %K Neuropsychological Tests %K Singapore %K Vascular Stiffness %X

BACKGROUND: Few studies have comprehensively evaluated the relationship between vascular disease and cognition of older adults without cardiac disease.

OBJECTIVE: We explored the associations of structural atherosclerosis, vascular stiffness, and reactivity with global, memory, attention, language, visuospatial ability, and executive function in community-dwelling, non-demented older Asians without cardiac diseases.

METHODS: Cognition was assessed by Mini-Mental State Examination (MMSE) (n = 308) and detailed neuropsychological tests (n = 155). Vascular measures included carotid intima-media thickness; aortic stiffness [carotid-femoral pulse wave velocity (CFPWV), aortic augmentation index (AI), and aortic pulse pressure (PP)]; carotid stiffness [elasticity modulus (Ep), beta index (β), arterial compliance (AC), carotid AI]; and endothelial function [reactive hyperemia index (RHI)]. Multivariable analyses controlled for potential confounding by demographics, apolipoprotein E genotype and cardiovascular risk factors.

RESULTS: The participants' mean age was 63.0 ± 6.1 years. Inverse associations with MMSE were found for AC (β= 0.128, p = 0.019), Ep (β= -0.151, p = 0.008), β index (β= -0.122, p = 0.029), carotid stiffness z-score (β= -0.154, p = 0.007); with executive function for CFPWV (β= -0.209, p = 0.026), AC (β= 0.214, p = 0.005), Ep (β= -0.160, p = 0.050), β index (β= -0.165, p = 0.041), and both aortic (β= -0.229, p = 0.010) and carotid (β= -0.208, p = 0.010) stiffness z-scores; with verbal memory for AI (β= -0.229, p = 0.004) and aortic (β= -0.263, p = 0.004) stiffness z-score; with language for AI (β= -0.155, p = 0.025), aortic stiffness z-score (β= -0.196, p = 0.011). RHI positively correlated with visuospatial ability (β= 0.195, p = 0.013) and executive function (β= 0.151, p = 0.045).

CONCLUSION: The results support a link between systemic vascular health and neurocognitive function in older Asian adults. Subclinical noninvasive measures of arterial stiffness and reactivity may identify individuals vulnerable to cognitive impairment.

%B J Alzheimers Dis %V 50 %P 27-40 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639958?dopt=Abstract %R 10.3233/JAD-150516 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Vascular Risk Factors and Cognition in Parkinson's Disease. %A Pilotto, Andrea %A Turrone, Rosanna %A Liepelt-Scarfone, Inga %A Bianchi, Marta %A Poli, Loris %A Borroni, Barbara %A Alberici, Antonella %A Premi, Enrico %A Formenti, Anna %A Bigni, Barbara %A Cosseddu, Maura %A Cottini, Elisabetta %A Berg, Daniela %A Padovani, Alessandro %K Age of Onset %K Aged %K Attention %K Disability Evaluation %K Educational Status %K Executive Function %K Female %K Humans %K Male %K Motor Activity %K Neuropsychological Tests %K Parkinson Disease %K Prevalence %K Risk Factors %K Sex Factors %K Time Factors %K Vascular Diseases %X

Vascular risk factors have been associated with cognitive deficits and incident dementia in the general population, but their role on cognitive dysfunction in Parkinson's disease (PD) is still unclear. The present study addresses the single and cumulative effect of vascular risk factors on cognition in PD patients, taking clinical confounders into account. Standardized neuropsychological assessment was performed in 238 consecutive PD patients. We evaluated the association of single and cumulative vascular risk factors (smoking, diabetes, hypercholesterolemia, hypertension, and heart disease), with the diagnosis of PD normal cognition (PDNC, n = 94), mild cognitive impairment (PD-MCI, n = 111), and dementia (PDD, n = 33). The association between single neuropsychological tests and vascular risk factors was evaluated with covariance analyses adjusted for age at onset, educational levels, gender, disease duration, and motor performance. Age, educational levels, disease duration, and motor function were significantly different between PDNC, PD-MCI, and PDD. Heart disease was the only vascular factor significantly more prevalent in PDD compared with PDNC in adjusted analyses. Performance of tests assessing executive and attention functions were significantly worse in patients with hypertension, heart disease, and/or diabetes (p <  0.05). Heart disease is associated with dementia in PD, suggesting a potential window of intervention. Vascular risk factors act especially on attention and executive functions in PD. Vascular risk stratification may be useful in order to identify PD patients with a greater risk of developing dementia. These findings need to be verified in longitudinal studies.

%B J Alzheimers Dis %V 51 %P 563-70 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890741?dopt=Abstract %R 10.3233/JAD-150610 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Ventilatory Response to Hypercapnia Predicts Dementia with Lewy Bodies in Late-Onset Major Depressive Disorder. %A Takahashi, Sho %A Mizukami, Katsuyoshi %A Arai, Tetsuaki %A Ogawa, Ryoko %A Kikuchi, Norihiro %A Hattori, Satoshi %A Darby, David %A Asada, Takashi %K 3-Iodobenzylguanidine %K Aged %K Aged, 80 and over %K Depressive Disorder, Major %K Follow-Up Studies %K Heart Rate %K Humans %K Hypercapnia %K Hypotension, Orthostatic %K Kaplan-Meier Estimate %K Lewy Body Disease %K Middle Aged %K Partial Pressure %K Psychiatric Status Rating Scales %K Retrospective Studies %K Ventilators, Mechanical %X

BACKGROUND: Studies have shown that developing major depressive disorder (MDD) at 50 years of age or older can predict dementia. Depression is particularly common in dementia with Lewy bodies (DLB), and occasionally occurs before the onset of extrapyramidal symptoms. Moreover, systemic autonomic dysfunction, including an abnormal ventilatory response to hypercapnia (VRH), is common in patients with DLB.

OBJECTIVE: Here, we aimed to determine whether the VRH is useful for distinguishing depression that is predictive of DLB from other types of MDD.

METHODS: Participants were 35 consecutive patients with first onset MDD at 50 years or older with bradykinesia. After diagnosing the clinical subtype of MDD according to DSM-IV criteria, each subject underwent a battery of psychological tests, autonomic examinations including VRH, brain magnetic resonance imaging, and 123I-meta-iodobenzylguanidine scintigraphy.

RESULTS: Longitudinal follow-up showed that all 18 patients with abnormal VRH results developed DLB, whereas none of the 17 patients with normal VRH results converted to DLB within the study period (sensitivity: 100% , specificity: 100%). Additionally, over half of the DLB converters showed abnormalities on other autonomic examinations. For converters, the most common MDD subtype had psychotic and melancholic features simultaneously. The frequency of hypersensitivity to psychotropics was higher in converters than it was in non-converters.

CONCLUSION: In the present study, patients with abnormal VRH results were very likely to develop DLB. Thus, for patients with late-onset MDD accompanied by bradykinesia, the VRH in combination with the clinical subtype of MDD or hypersensitivity to psychotropics may be useful for diagnosing prodromal DLB.

%B J Alzheimers Dis %V 50 %P 751-8 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757183?dopt=Abstract %R 10.3233/JAD-150507 %0 Journal Article %J J Alzheimers Dis %D 2016 %T 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 Neurology %D 2011 %T Report of the task force on designing clinical trials in early (predementia) AD. %A Aisen, P S %A Andrieu, S %A Sampaio, C %A Carrillo, M %A Khachaturian, Z S %A Dubois, B %A Feldman, H H %A Petersen, R C %A Siemers, E %A Doody, R S %A Hendrix, S B %A Grundman, M %A Schneider, L S %A Schindler, R J %A Salmon, E %A Potter, W Z %A Thomas, R G %A Salmon, D %A Donohue, M %A Bednar, M M %A Touchon, J %A Vellas, B %K Advisory Committees %K Alzheimer Disease %K Amyloidogenic Proteins %K Biomarkers %K Clinical Trials as Topic %K Cognition %K Consensus %K Disease Progression %K Drug Industry %K Early Diagnosis %K Europe %K Humans %K Indans %K International Cooperation %K Nootropic Agents %K Outcome Assessment (Health Care) %K Patient Selection %K Piperidines %K Positron-Emission Tomography %K Research Design %K Treatment Outcome %K United States %K United States Food and Drug Administration %K Vitamin E %X

BACKGROUND: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia.

METHOD: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD.

RESULTS: General consensus was reached on key principles involving the scope of the AD diagnosis, the selection of subjects for trials, outcome measures, and analytical methods.

CONCLUSION: A consensus has been achieved in support of the testing of candidate treatments in the early (predementia) AD population.

%B Neurology %V 76 %P 280-6 %8 2011 Jan 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21178097?dopt=Abstract %R 10.1212/WNL.0b013e318207b1b9