Association of Neighborhood Context, Cognitive Decline, and Cortical Change in an Unimpaired Cohort

Objective:To test the hypothesis that neighborhood-level disadvantage is associated with longitudinal measures of neurodegeneration and cognitive decline in an unimpaired cohort.Methods:Longitudinal MRI and cognitive testing data were collected from 601 cognitively unimpaired participants in the Wisconsin Registry for Alzheimer’s Prevention study and the Wisconsin Alzheimer’s Disease Research Center clinical cohort. Area Deprivation Index was geospatially determined based on participant residence geocode and ranked relative to state of residence. Linear regression models were fitted to test associations between neighborhood-level disadvantage and longitudinal change in cortical thickness and cognitive test performance. Mediation tests were used to assess whether neurodegeneration and cognitive decline were associated with neighborhood-level disadvantage along the same theoretical causal path.Results:In our middle to older aged study population (mean baseline age=59), living in the 20% most disadvantaged neighborhoods (N=19) relative to state of residence was associated with cortical thinning in Alzheimer’s signature regions (p=0.002) and decline in the Preclinical Alzheimer’s disease Cognitive Composite (p=0.04), particularly the Trails-Making Test Part B (p<0.001), but not Rey Auditory Verbal Learning Test (p=0.77) or Story Memory Delayed Recall (p=0.49) subtests. Associations were attenuated but remained significant after controlling for racial and demographic differences between neighborhood-level disadvantage groups. Cortical thinning partially mediated the association between neighborhood-level disadvantage and cognitive decline.Conclusions:In this longitudinal study of cognitively unimpaired adults, living in the most highly disadvantaged neighborhoods was associated with accelerated degeneration in Alzheimer’s signature regions and cognitive decline. This study provides further evidence for neighborhood-level disadvantage as a risk factor for preclinical neurodegeneration and cognitive decline in certain populations. Limitations of the present study, including a small number of participants from highly disadvantaged neighborhoods and a circumscribed geographic setting, should be explored in larger and more diverse study cohorts.

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Automatic Prediction of Cognitive and Functional Decline Can Significantly Decrease the Number of Subjects Required for Clinical Trials in Early Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210664 ◽

2021 ◽

pp. 1-8

Author(s):

Neda Shafiee ◽

Mahsa Dadar ◽

Simon Ducharme ◽

D. Louis Collins ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Cognitive Decline ◽

Functional Decline ◽

Amyloid Β ◽

Cognitive Test ◽

Disease Heterogeneity ◽

Early Alzheimer’S Disease

Background: While both cognitive and magnetic resonance imaging (MRI) data has been used to predict progression in Alzheimer’s disease, heterogeneity between patients makes it challenging to predict the rate of cognitive and functional decline for individual subjects. Objective: To investigate prognostic power of MRI-based biomarkers of medial temporal lobe atrophy and macroscopic tissue change to predict cognitive decline in individual patients in clinical trials of early Alzheimer’s disease. Methods: Data used in this study included 312 patients with mild cognitive impairment from the ADNI dataset with baseline MRI, cerebrospinal fluid amyloid-β, cognitive test scores, and a minimum of two-year follow-up information available. We built a prognostic model using baseline cognitive scores and MRI-based features to determine which subjects remain stable and which functionally decline over 2 and 3-year follow-up periods. Results: Combining both sets of features yields 77%accuracy (81%sensitivity and 75%specificity) to predict cognitive decline at 2 years (74%accuracy at 3 years with 75%sensitivity and 73%specificity). When used to select trial participants, this tool yields a 3.8-fold decrease in the required sample size for a 2-year study (2.8-fold decrease for a 3-year study) for a hypothesized 25%treatment effect to reduce cognitive decline. Conclusion: When used in clinical trials for cohort enrichment, this tool could accelerate development of new treatments by significantly increasing statistical power to detect differences in cognitive decline between arms. In addition, detection of future decline can help clinicians improve patient management strategies that will slow or delay symptom progression.

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Association between plasma exosome neurogranin and brain structure in patients with Alzheimer’s disease: a protocol study

BMJ Open ◽

10.1136/bmjopen-2020-036990 ◽

2020 ◽

Vol 10 (8) ◽

pp. e036990 ◽

Cited By ~ 2

Author(s):

MengFei He ◽

Li Sun ◽

Wenhui Cao ◽

Changhao Yin ◽

Wenqiang Sun ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Rating Scale ◽

Early Stage ◽

Verbal Learning ◽

Blood Collection ◽

Clinical Dementia Rating ◽

Protocol Study ◽

Medical University

IntroductionNeurogranin is known to be significantly elevated in patients with Alzheimer’s disease (AD) and may be an effective clinical predictor of cognitive decline and neurodegeneration. Amnestic mild cognitive impairment (aMCI) is an intermediate disease state between normal cognitive ageing and dementia, the latter of which can easily revert to AD. There remains significant uncertainty regarding the conversion of aMCI to AD, and therefore, elucidating such progression is paramount to the field of cognitive neuroscience. In this protocol study, we therefore aim to investigate the changes in plasma neurogranin in the early stage of AD and the mechanism thereof regarding the cognitive progression towards AD.Methods and analysisIn this study, patients with aMCI and AD patients (n=70 each) will be recruited at the memory clinic of the Department of Neurology of Hongqi Hospital affiliated with the Mudanjiang Medical University of China. Healthy older controls (n=70) will also be recruited from the community. All subjects will undergo neuroimaging and neuropsychological evaluations in addition to blood collection at the first year and the third year. We hope to identify a new biomarker of cognitive decline associated with AD and characterise its behaviour throughout the progression of aMCI to AD. This work will reveal novel targets for the therapeutic prevention, diagnosis and treatment of AD. The primary outcome measures will be (1) neuropsychological evaluation, including Mini-Mental State Examination, Montreal Cognitive Assessment, Clinical Dementia Rating scale, Shape Trail Test-A&B, Auditory Verbal Learning Test-HuaShan version; (2) microstructural alterations and hippocampal features from MRI scans; and (3) neurogranin levels in the neuronal-derived exosomes from peripheral blood samples.Ethics and disseminationThe ethics committee of the Hongqi Hospital affiliated with the Mudanjiang Medical University of China has approved this study protocol. The results will be published in peer-reviewed journals and presented at national or international scientific conferences.Trial registration numberChiCTR2000029055.

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Cognitive Changes associated with Alzheimer’s disease in Down syndrome

10.1101/263095 ◽

2018 ◽

Cited By ~ 3

Author(s):

Nicholas C. Firth ◽

Carla M. Startin ◽

Rosalyn Hithersay ◽

Sarah Hamburg ◽

Peter A. Wijeratne ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Down Syndrome ◽

Cognitive Decline ◽

Sustained Attention ◽

Motor Coordination ◽

Disease Stage ◽

Cognitive Test ◽

Early Assessment ◽

Cognitive Changes

AbstractObjectiveIndividuals with Down syndrome (DS) have an extremely high genetic risk for Alzheimer’s disease (AD) however the course of cognitive decline associated with progression to dementia is ill-defined. Data-driven methods can estimate long-term trends from cross-sectional data while adjusting for variability in baseline ability, which complicates dementia assessment in those with DS.MethodsWe applied an event-based model to cognitive test data and informant-rated questionnaire data from 283 adults with DS (the largest study of cognitive functioning in DS to date) to estimate the sequence of cognitive decline and individuals’ disease stage.ResultsDecline in tests of memory, sustained attention / motor coordination, and verbal fluency occurred early, demonstrating that AD in DS follows a similar pattern of change to other forms of AD. Later decline was found for informant measures. Using the resulting staging model, we showed that adults with a clinical diagnosis of dementia and those with APOE 3:4 or 4:4 genotype were significantly more likely to be staged later, suggesting the model is valid.InterpretationOur results identify tests of memory and sustained attention may be particularly useful measures to track decline in the preclinical/prodromal stages of AD in DS whereas informant-measures may be useful in later stages (i.e. during conversion to dementia, or post-diagnosis). These results have implications for the selection of outcome measures of treatment trials to delay or prevent cognitive decline due to AD in DS. As clinical diagnoses are generally made late into AD progression, early assessment is essential.

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Neuropsychological and neuroanatomical features of patients with behavioral variant Alzheimer's disease (AD): a comparison to behavioral variant frontotemporal dementia and amnestic AD groups

10.1101/2022.01.04.21268578 ◽

2022 ◽

Author(s):

Sophia Dominguez Perez ◽

Jeffrey S Phillips ◽

Catherine Norise ◽

Nikolas G Kinney ◽

Prerana Vaddi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontotemporal Dementia ◽

Verbal Memory ◽

Verbal Learning ◽

Executive Dysfunction ◽

Intracranial Volume ◽

Behavioral Variant Frontotemporal Dementia ◽

Cortical Thinning ◽

Learning Test

An understudied non-amnestic variant of Alzheimer's disease (AD), behavioral variant AD (bvAD) is associated with progressive personality, behavior, or executive dysfunction and frontal atrophy. This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. Subjects included 16 bvAD, 67 bvFTD, and 18 aAD patients, and 26 healthy controls. Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.

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Cognitive Training in Patients with Alzheimer's Disease: Findings of a 12-month Randomized Controlled Trial

Current Alzheimer Research ◽

10.2174/1567205014666171113105044 ◽

2018 ◽

Vol 15 (5) ◽

pp. 452-461 ◽

Cited By ~ 3

Author(s):

Alessandro Trebbastoni ◽

Letizia Imbriano ◽

Livia Podda ◽

Lidia Rendace ◽

Maria Luisa Sacchett ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Cognitive Training ◽

Cognitive Functions ◽

Verbal Learning ◽

Treated Group ◽

Pharmacological Intervention ◽

Randomized Controlled ◽

Over Time

Background: Cognitive training (CT) is a non-pharmacological intervention based on a set of tasks that reflect specific cognitive functions. CT is aimed at improving cognition in patients with cognitive impairment, though no definitive conclusions have yet been drawn on its efficacy in Alzheimer's disease (AD). Objective: To assess the effectiveness of a CT program designed to improve cognition in AD patients. Method: This is a randomized, controlled, single-blind, longitudinal trial with a no-treatment control condition in mild-to-moderate AD. Treated patients received in-group CT twice a week for six months, whereas controls did not. CT consisted of tasks ranging from paper-and-pencil to verbal-learning exercises. Participants' cognitive levels were assessed at baseline, post-intervention and 6 months later by means of a complete neuropsychological test battery. Repeated measures ANOVA was used to analyze the effect of time on the outcome measures, as well as to compare treated and untreated patients over time, with demographic data considered as covariates. Results: Of the 140 patients enrolled, 45 in the treated group and 85 controls concluded the study. The CT significantly improved treated subjects' cognitive functions immediately after the CT. Six months later, some test scores remained stable when compared with those obtained at baseline. The control group performed significantly worse than the treated group at each time-point, displaying a progressive cognitive decline over time. Conclusion: Our results suggest that CT may improve cognitive functions in patients with AD and may help to temporarily slow their cognitive decline.

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The Alzheimer’s Prevention Initiative Composite Cognitive Test: a practical measure for tracking cognitive decline in preclinical Alzheimer’s disease

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00633-2 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Jessica B. Langbaum ◽

Noel N. Ellison ◽

Angelika Caputo ◽

Ronald G. Thomas ◽

Carolyn Langlois ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Cognitive Test ◽

Preclinical Alzheimer’S Disease ◽

Practical Measure

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Predicting Progression & Cognitive Decline in Amyloid-Positive Patients with Alzheimer's Disease

10.21203/rs.3.rs-290530/v1 ◽

2021 ◽

Author(s):

Hákon Valur Dansson ◽

Lena Stempfle ◽

Hildur Egilsdóttir ◽

Alexander Schliep ◽

Erik Portelius ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Disease Progression ◽

Test Scores ◽

Amyloid Β ◽

Cognitive Test ◽

Progression Rate ◽

Specific Level ◽

Clinical Variables

Abstract BackgroundIn Alzheimer’s disease (AD), amyloid- β (Aβ) peptides aggregate in the brain forming amyloid plaques, which are a key pathological hallmark of the disease. However, plaques may also be present in cognitively unimpaired elderly individuals. Therefore, it is of great value to explain the variance in disease progression among patients with Aβ pathology. MethodsA cohort of n= 2293 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database was selected to study heterogeneity in disease progression for individuals with Aβ plaque pathology. The analysis used baseline clinical variables including demographics, genetic markers and neuropsychological data to predict how the cognitive ability and AD diagnosis of subjects progressed using statistical models and machine learning. Due to the limited prevalence of Aβ pathology, models fit only to Aβ-positive subjects were compared to models fit to an extended cohort including subjects without established Aβ pathology, adjusting for covariate differences between the cohorts. ResultsAβ pathology status was determined based the Aβ 42 /Aβ 40 ratio. The best predictive model of change in cognitive test scores for Aβ-positive subjects at the two-year follow-up achieved an R 2 score of 0.388 while the best model predicting adverse changes in diagnosis achieved a weighted F1 score of 0.791. Conforming to expectations, Aβ-positive subjects declined faster on average than those without Aβ pathology, but the specific level of Aβ plaques was not predictive of progression rate. For the four-year prediction task of cognitive score change, the best model achieved an R 2 score of 0.325 and it was found that fitting models to the extended cohort substantially improved performance. Moreover, using all clinical variables outperformed the best model based only on baseline cognitive test scores which achieved an R 2 score of 0.228. ConclusionOur analysis shows that levels of Aβ plaques are not strong predictors of the rate of cognitive decline in Aβ-positive subjects. Baseline assessments of cognitive function accounts for the majority of variance explained in the prediction of two-year decline but is insufficient for achieving optimal results in longer-term predictions. Predicting changes both in cognitive test scores and in diagnosis provides multiple perspectives of the progression of potential AD subjects.

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