scholarly journals Pupillary dilation responses as a midlife indicator of risk for Alzheimer’s Disease: Association with Alzheimer’s disease polygenic risk

2019 ◽  
Author(s):  
William S. Kremen ◽  
Matthew S. Panizzon ◽  
Jeremy A. Elman ◽  
Eric L. Granholm ◽  
Ole A. Andreassen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Locus Coeruleus ◽  
Digit Span ◽  
Pupillary Response ◽  
Pupil Dilation ◽  
Cognitively Normal ◽  
Polygenic Risk ◽  
Pupillary Responses ◽  
Span Tasks

ABSTRACTPathological changes in Alzheimer’s disease (AD) begin decades before dementia onset. Because locus coeruleus tau pathology is the earliest occurring AD pathology, targeting indicators of locus coeruleus (dys)function may improve midlife screening for earlier identification of AD risk. Pupillary responses during cognitive tasks are driven by the locus coeruleus and index cognitive effort. Several findings suggest task-associated pupillary response as an early marker of AD risk. Requiring greater effort suggests being closer to one’s compensatory capacity, and adults with mild cognitive impairment (MCI) have greater pupil dilation during digit span tasks than cognitively normal individuals, despite equivalent task performance. Higher AD polygenic risk scores (AD-PRSs) are associated with increased odds of MCI and tau positivity. We hypothesized that AD-PRSs would be associated with pupillary responses in cognitively normal middle-aged adults. We demonstrated that pupillary responses during digit span tasks were heritable (h2=.30-.36) in 1119 men ages 56-66. We then examined associations between AD-PRSs and pupillary responses in a cognitively normal subset who all had comparable span capacities (n=539). Higher AD-PRSs were associated with greater pupil dilation/effort in a high (9-digit recall) cognitive load condition; Cohen’s d=.36 for the upper versus lower quartile of the AD-PRS distribution. Results held up after controlling for APOE genotype. The results support pupillary response—and by inference, locus coeruleus dysfunction—as a genetically-mediated biomarker of early MCI/AD risk. In some studies, cognition predicted disease progression earlier than biomarkers. Pupillary responses might improve screening and early identification of genetically at-risk individuals even before cognitive performance declines.

scholarly journals P4-496: MYELOID CELL-SPECIFIC ALZHEIMER'S DISEASE POLYGENIC RISK SCORE PREDICTS NEURODEGENERATION AND Aβ-RELATED COGNITIVE DECLINE IN COGNITIVELY NORMAL OLDER ADULTS

2019 ◽  
Vol 15 ◽  
pp. P1503-P1504
Author(s):  
Hyun-Sik Yang ◽  
Tian Ge ◽  
Hilary Finucane ◽  
Philip L. De Jager ◽  
Reisa A. Sperling
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Risk Score ◽  
Myeloid Cell ◽  
Polygenic Risk Score ◽  
Cognitively Normal ◽  
Polygenic Risk

scholarly journals Brainstem substructures and cognition in prodromal Alzheimer’s disease

2021 ◽  
Author(s):  
Shubir Dutt ◽  
◽  
Yanrong Li ◽  
Mara Mather ◽  
Daniel A. Nation
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Locus Coeruleus ◽  
Carrier Status ◽  
Cognitively Normal ◽  
Brainstem Nuclei ◽  
Prodromal Alzheimer’S Disease ◽  
Executive Abilities

AbstractNeuropathological research suggests the tau pathology of Alzheimer’s disease may originate in brainstem nuclei, yet it remains unknown whether tau-mediated degeneration of brainstem nuclei influences cognitive impairment in prodromal Alzheimer’s disease. The present study examined cognitive domains impacted in prodromal Alzheimer’s disease and brainstem substructure volume in cognitively normal older adults (n = 814) and those with mild cognitive impairment (n = 542). Subsamples of cognitively normal (n = 112) and mild cognitive impairment (n = 202) also had cerebrospinal fluid Alzheimer’s disease biomarker characterization. Region-of-interest and voxel-level analyses related whole brainstem, midbrain, pons, and locus coeruleus volumes to cognition with multiple linear regression models corrected for age, sex, education, apolipoprotein-ε4 carrier status, and MRI magnet strength. Within mild cognitive impairment participants, smaller midbrain and locus coeruleus volumes were significantly related to poorer performance on tests of attention and executive function, and the relationship between locus coeruleus volume and executive abilities remained significant in the mild cognitive impairment subsample with biomarker-confirmed Alzheimer’s disease. A brainstem-masked voxel-wise regression further demonstrated an association between locus coeruleus volume and executive abilities. Brainstem volumes were not significantly related to memory processes. Study findings implicate midbrain and locus coeruleus volume in attention and executive deficits in mild cognitive impairment. Together with prior neuropathological studies, our data suggest a link between Alzheimer’s disease-related degeneration of brainstem nuclei and cognitive deficits in prodromal Alzheimer’s disease.

scholarly journals Polygenic Risk Scoring is an Effective Approach to Predict Those Individuals Most Likely to Decline Cognitively Due to Alzheimer’s Disease

2020 ◽  
pp. 1-6
Author(s):  
P. Daunt ◽  
C.G. Ballard ◽  
B. Creese ◽  
G. Davidson ◽  
J. Hardy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Risk Scores ◽  
Cognitively Normal ◽  
Polygenic Risk ◽  
Csf Biomarker ◽  
Risk Scoring

BACKGROUND: There is a clear need for simple and effective tests to identify individuals who are most likely to develop Alzheimer’s Disease (AD) both for the purposes of clinical trial recruitment but also for improved management of patients who may be experiencing early pre-clinical symptoms or who have clinical concerns. OBJECTIVES: To predict individuals at greatest risk of progression of cognitive impairment due to Alzheimer’s Disease in individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) using a polygenic risk scoring algorithm. To compare the performance of a PRS algorithm in predicting cognitive decline against that of using the pTau/Aß1-42 ratio CSF biomarker profile. DESIGN: A longitudinal analysis of data from the Alzheimer’s Disease Neuroimaging Initiative study conducted across over 50 sites in the US and Canada. SETTING: Multi-center genetics study. PARTICPANTS: 515 subjects who upon entry to the study were diagnosed as cognitively normal or with mild cognitive impairment. MEASUREMENTS: Use of genotyping and/or whole genome sequencing data to calculate polygenic risk scores and assess ability to predict subsequent cognitive decline as measured by CDR-SB and ADAS-Cog13 over 4 years. RESULTS: The overall performance for predicting those individuals who would decline by at least 15 ADAS-Cog13 points from a baseline mild cognitive impairment in 4 years was 72.8% (CI:67.9-77.7) AUC increasing to 79.1% (CI: 75.6-82.6) when also including cognitively normal participants. Assessing mild cognitive impaired subjects only and using a threshold of greater than 0.6, the high genetic risk participant group declined, on average, by 1.4 points (CDR-SB) more than the low risk group over 4 years. The performance of the PRS algorithm tested was similar to that of the pTau/Aß1-42 ratio CSF biomarker profile in predicting cognitive decline. CONCLUSION: Calculating polygenic risk scores offers a simple and effective way, using DNA extracted from a simple mouth swab, to select mild cognitively impaired patients who are most likely to decline cognitively over the next four years.

scholarly journals Brainstem Volumetric Integrity in Preclinical and Prodromal Alzheimer’s Disease

2020 ◽  
Vol 77 (4) ◽  
pp. 1579-1594 ◽  
Author(s):  
Shubir Dutt ◽  
Yanrong Li ◽  
Mara Mather ◽  
Daniel A. Nation ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Locus Coeruleus ◽  
Region Of Interest ◽  
Intracranial Volume ◽  
Cognitively Normal ◽  
Normal Individuals ◽  
Prodromal Ad ◽  
Brainstem Nuclei ◽  
Prodromal Alzheimer’S Disease

Background: Neuropathological studies have suggested the tau pathology observed in Alzheimer’s disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker-confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia. Objective: The present study examined whether MRI-based brainstem volumes differ among cognitively normal older adults and those with MCI or dementia due to AD and whether preclinical brainstem volumes predict future progression to dementia. Methods: Alzheimer’s Disease Neuroimaging Initiative participants (N = 1,629) underwent baseline MRI scanning with variable clinical follow-up (6–120 months). Region of interest and voxel-based morphometric methods assessed brainstem volume differences among cognitively normal (n = 814), MCI (n = 542), and AD (n = 273) participants, as well as subsets of cerebrospinal fluid biomarker-confirmed MCI (n = 203) and AD (n = 160) participants. Results: MCI and AD cases showed smaller midbrain volumes relative to cognitively normal participants when normalizing to whole brainstem volume, and showed smaller midbrain, locus coeruleus, pons, and whole brainstem volumes when normalizing to total intracranial volume. Cognitively normal individuals who later progressed to AD dementia diagnosis exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and voxel-wise analyses revealed specific volumetric reduction of the locus coeruleus. Conclusion: Findings are consistent with neuropathological observations of early AD-related pathology in brainstem nuclei and further suggest the clinical relevance of brainstem substructural volumes in preclinical and prodromal AD.

754 Apolipoprotein E ε4 allele and pupillary response to tropicamide in Alzheimer's disease and cognitively normal subjects

1996 ◽  
Vol 17 (4) ◽  
pp. S187 ◽  
Author(s):  
S. Matsushita ◽  
H. Arai ◽  
Y. Hasegawa ◽  
M. Tcrajima ◽  
T. Muramatsu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Normal Subjects ◽  
Pupillary Response ◽  
Cognitively Normal ◽  
Ε4 Allele ◽  
Cognitively Normal Subjects

P4-240: Using polygenic risk score to predict Alzheimer's disease

2015 ◽  
Vol 11 (7S_Part_19) ◽  
pp. P872-P872 ◽  
Author(s):  
Valentina Escott-Price ◽  
Rebecca Sims ◽  
Denise Harold ◽  
Maria Vronskaya ◽  
Peter Holmans ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Polygenic Risk

Impacts of Iron Metabolism Dysregulation on Alzheimer’s Disease

2021 ◽  
Vol 80 (4) ◽  
pp. 1439-1450
Author(s):  
Najla Jouini ◽  
Zakaria Saied ◽  
Samia Ben Sassi ◽  
Fatma Nebli ◽  
Taieb Messaoud ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Antioxidant System ◽  
Plasma Concentrations ◽  
Normal Brain ◽  
Cognitively Normal ◽  
Iron Trafficking ◽  
Major Species ◽  
Normal Brain Function ◽  
Calcium Magnesium

Background: Iron plays an important role in maintaining cell survival, with normal iron trafficking known to be regulated by the ceruloplasmin-transferrin (Cp-Tf) antioxidant system. Disruption to this system is thought to be detrimental to normal brain function. Objective: To determine whether an imbalance of iron and the proteins involved in its metabolism (ceruloplasmin and transferrin) are linked to Alzheimer’s disease (AD) and to the expression of amyloid-beta (Aβ) peptide 1–42 (Aβ1–42), which is a major species of Aβ, and the most toxic. Methods: We evaluated the concentrations of iron, calcium, magnesium, and Aβ1–42 in the cerebrospinal fluid (CSF) of patients with AD and cognitively normal controls. Correlations between the components of the Cp-Tf antioxidant system in plasma were studied to determine the role of peripheral blood in the onset and/or development of AD. We used commercial ELISA immunoassays to measure Aβ1–42, immunoturbidimetry to quantify ceruloplasmin and transferrin, and colorimetry to quantify iron, calcium, and magnesium. Results: We found that the AD group had lower CSF concentrations of Aβ1–42 (p < 0.001) and calcium (p < 0.001), but a higher CSF concentration of iron (p < 0.001). Significantly lower plasma concentrations of ceruloplasmin (p = 0.003), transferrin (mean, p < 0.001), and iron (p < 0.001) were observed in the AD group than in cognitively normal adults. Moreover, we found a strong interdependence between most of these components. Conclusion: Iron dyshomeostasis has a crucial role in the onset of AD and/or its development. Correcting metal misdistribution is an appealing therapeutic strategy for AD.

scholarly journals Financial Capacity and Regional Cerebral Tau in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer’s Disease Dementia

2020 ◽  
pp. 1-10
Author(s):  
Christopher Gonzalez ◽  
Nicole S. Tommasi ◽  
Danielle Briggs ◽  
Michael J. Properzi ◽  
Rebecca E. Amariglio ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Early Stage ◽  
Cognitively Normal ◽  
Financial Capacity ◽  
Posterior Cingulate ◽  
Dorsolateral Prefrontal

Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument –Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p <  0.001; inferior temporal: p <  0.001; dorsolateral prefrontal: p = 0.01; posterior cingulate: p = 0.03; precuneus: p <  0.001; and supramarginal gyrus: p = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p = 0.005; amyloid and posterior cingulate tau interaction: p = 0.005; amyloid and precuneus tau interaction: p <  0.001; and amyloid and supramarginal tau interaction: p = 0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD.

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