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Risk of developing cerebral ?-amyloid plaques with posttranslational modification among HIV-infected adults.

ABSTRACT: OBJECTIVES:Evidence of accelerated brain aging among HIV-infected adults argues for the increased risk of developing cerebral ?-amyloid (A?) plaques. We compared the frequency of A? plaque-bearing cases in our HIV cohort with that in a general cohort reported by Braak et al. We explored posttranslationally modified A? forms (N3pE, E22P, phospho-Ser8) in plaques and E22P-A? in the postmortem cerebrospinal fluid (CSF) in the HIV cohort. DESIGN:Clinicopathological study of HIV-infected adults. METHODS:To assess frontal A? plaque deposition, we conducted immunohistochemistry for generic A? (4G8) and three modified A? forms. We determined CSF E22P-A? levels by ELISA. RESULTS:We found 4G8-A? plaques in 29% of 279 HIV-infected cases. Within the age range of 31-70 years, the frequency of 4G8-A? plaque-bearing cases was higher in our HIV cohort (n?=?273) compared with the general cohort (n?=?1110) overall (29.3 vs. 25.8%) and across four age groups by decade (odds ratio 2.35, P?

SUBMITTER: Umlauf A

PROVIDER: S-EPMC6852888 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Risk of developing cerebral β-amyloid plaques with posttranslational modification among HIV-infected adults.

Umlauf Anya A Soontornniyomkij Benchawanna B Sundermann Erin E EE Gouaux Ben B Ellis Ronald J RJ Levine Andrew J AJ Moore David J DJ Soontornniyomkij Virawudh V

AIDS (London, England) 20191101 14

<h4>Objectives</h4>Evidence of accelerated brain aging among HIV-infected adults argues for the increased risk of developing cerebral β-amyloid (Aβ) plaques. We compared the frequency of Aβ plaque-bearing cases in our HIV cohort with that in a general cohort reported by Braak et al. We explored posttranslationally modified Aβ forms (N3pE, E22P, phospho-Ser8) in plaques and E22P-Aβ in the postmortem cerebrospinal fluid (CSF) in the HIV cohort.<h4>Design</h4>Clinicopathological study of HIV-infect ...[more]

PMID: 31688040

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Project description:Accumulating data suggest that cerebrovascular disease contributes to Alzheimer's disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of β-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer's disease pathology in the ageing brain and increases the risk of Alzheimer's disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal β-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical-pathological cohort studies: the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic β-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline = 80.2 ± 7.1 years; age at death = 89.5 ± 6.7 years; 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal β-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimer's disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimer's disease clinical trials and therapeutic development.

Project description:Fatigue is a common symptom in the elderly and has also been associated with impaired cognition in older adults. Hence, we sought to explore the cross-sectional relationship between fatigue and cerebral ?-amyloid (A?) in 269 elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial. Standard uptake value ratios (SUVRs) were generated by [18F] florbetapir positron emission tomography (PET) using the cerebellum as a reference. Cortical-to-cerebellar SUVRs (cortical-SUVRs) were obtained using the mean signal from the frontal cortex, temporal cortex, parietal cortex, precuneus, anterior cingulate, and posterior cingulate. Other brain regions independently assessed were the anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval center, and temporal cortex. Fatigue was defined according to two questions retrieved from the Center for Epidemiological Studies-Depression scale. Chronic fatigue was defined as meeting fatigue criteria at two consecutive clinical visits 6 months apart between study baseline and 1 year (visits were performed at baseline, 6 months and 1 year then annually). Cross-sectional associations between fatigue variables and cerebral A? were explored using fully adjusted multiple linear regression models. We found no statistically significant cross-sectional associations between fatigue assessed at the clinical visit closest to PET and A? in any brain region. Similarly, chronic fatigue was not significantly associated with A? load. Sensitivity analysis in subjects with a Clinical Dementia Rating of 0.5 showed that fatigue reported at the clinical visit closest to PET was, however, weakly associated with increased A? in the hippocampus (B-coefficient: 0.07, 95% CI: 0.01, 0.12, p?=?0.016). These preliminary results suggest that fatigue might be associated with A? in brain regions associated with Alzheimer's disease in subjects in the early stages of disease.

Dataset Information

Risk of developing cerebral ?-amyloid plaques with posttranslational modification among HIV-infected adults.

Publications

Risk of developing cerebral β-amyloid plaques with posttranslational modification among HIV-infected adults.

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