Dataset Information

Proteome-based plasma markers of brain amyloid-? deposition in non-demented older individuals.

ABSTRACT: Blood-based markers reflecting core pathological features of Alzheimer's disease (AD) in pre-symptomatic individuals are likely to accelerate the development of disease-modifying treatments. Our aim was to discover plasma proteins associated with brain amyloid-? (A?) burden in non-demented older individuals. We performed discovery-phase experiments using two dimensional gel electrophoresis (2DGE) and mass spectrometry-based proteomic analysis of plasma in combination with 11C-PiB PET imaging of the brain in samples collected 10 years prior to the PET scans. Confirmatory studies used ELISA assays in a separate set of blood samples obtained within a year of the PET scans. We observed that a panel of 18 2DGE plasma protein spots effectively discriminated between individuals with high and low brain A?. Mass spectrometry identified these proteins, many of which have established roles in A? clearance, including a strong signal from apolipoprotein-E (ApoE). In validation-phase studies, we observed a strong association between plasma ApoE concentration and A? burden in the medial temporal lobe. Targeted voxel-based analysis localized this association to the hippocampus and entorhinal cortex. APOE ?4 carriers also showed greater A? levels in several brain regions relative to ?4 non-carriers. These results suggest that both peripheral concentration of ApoE protein and APOE genotype are related to early neuropathological changes in brain regions vulnerable to AD pathology even in the non-demented elderly. Our strategy combining proteomics with in vivo brain amyloid imaging holds promise for the discovery of biologically relevant peripheral markers in those at risk for AD.

SUBMITTER: Thambisetty M

PROVIDER: S-EPMC3125970 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Proteome-based plasma markers of brain amyloid-β deposition in non-demented older individuals.

Thambisetty Madhav M Tripaldi Romina R Riddoch-Contreras Joanna J Hye Abdul A An Yang Y Campbell James J Sojkova Jitka J Kinsey Anna A Lynham Steven S Zhou Yun Y Ferrucci Luigi L Wong Dean F DF Lovestone Simon S Resnick Susan M SM

Journal of Alzheimer's disease : JAD 20100101 4

Blood-based markers reflecting core pathological features of Alzheimer's disease (AD) in pre-symptomatic individuals are likely to accelerate the development of disease-modifying treatments. Our aim was to discover plasma proteins associated with brain amyloid-β (Aβ) burden in non-demented older individuals. We performed discovery-phase experiments using two dimensional gel electrophoresis (2DGE) and mass spectrometry-based proteomic analysis of plasma in combination with 11C-PiB PET imaging of ...[more]

PMID: 20930274

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Project description:BackgroundBrain inflammation has been increasingly associated with early amyloid accumulation in Alzheimer's disease models; however, evidence of its occurrence in humans remains scarce. To elucidate whether amyloid deposition is associated with neuroinflammation and cognitive deficits, we studied brain inflammatory cytokine expression and cognitive decline in non-demented elderly individuals with and without cerebral amyloid-beta deposition.MethodsGlobal cognition, episodic, working, and semantic memory, perceptual speed, visuospatial ability, and longitudinal decline (5.7 ± 3.6 years) in each cognitive domain were compared between elderly individuals (66-79 years) with and without cerebral amyloid-beta deposition. The expression of 20 inflammatory cytokines was analyzed in frozen temporal, parietal, and frontal cortices and compared between older individuals with and without amyloid-beta deposition in each brain region. Correlation analyses were performed to analyze associations between amyloid-beta load, cytokine expression, and cognitive decline.ResultsIndividuals with cortical amyloid-beta deposition displayed deficits and a faster rate of cognitive decline in perceptual speed as compared with those individuals without amyloid-beta. This decline was positively associated with cortical amyloid-beta levels. Elderly individuals with amyloid-beta deposition had higher levels of IL-1β, IL-6, and eotaxin-3 in the temporal cortex accompanied by an increase in MCP-1 and IL-1β in the parietal cortex and a trend towards higher levels of IL-1β and MCP-1 in the frontal cortex as compared with age-matched amyloid-free individuals. Brain IL-1β levels displayed a positive association with cortical amyloid burden in each brain region. Finally, differential cytokine expression in each cortical region was associated with cognitive decline.ConclusionsElderly individuals with amyloid-beta neuropathology but no symptomatic manifestation of dementia, exhibit cognitive decline and increased brain cytokine expression. Such observations suggest that increased cytokine expression might be an early event in the Alzheimer's continuum.

Project description:BackgroundLight to moderate alcohol consumption has been variably associated with lower or higher risk of dementia, but effects on Alzheimer's disease pathology are less clear.ObjectiveWe determined whether late-life alcohol consumption was associated with Alzheimer's disease pathology among older adults.MethodsWe assessed the associations of alcohol consumption self-reported in 2000-2002 with brain amyloid-β deposition on PET scans, and white matter lesion and hippocampal volume on MRIs measured 7-9 years later in 189 participants of the Ginkgo Evaluation of Memory Study (age 75-87 years at baseline) who were free of clinical dementia, using multivariable-adjusted and inverse probability-weighted robust linear regression models.ResultsAlcohol consumption was not statistically significantly associated with amyloid-β deposition (standardized uptake value ratio difference per drink: -0.013 [95% CI: -0.027, 0.002]). Both non-drinkers and participants consuming ≥1 drink(s)/week had higher white matter lesion volume (% intracranial volume) than did the reference group of those consuming <1 drink/week (differences: 0.25 % [95% CI: 0.01, 0.50]; 0.26 % [95% CI: 0.02, 0.50]). The association of alcohol consumption and hippocampal volume was modified by age (p = 0.02). Among participants younger than 77 years, participants consuming 1-7 drinks/week had larger hippocampal volume compared with participants consuming <1 drink/week.ConclusionsAlcohol consumption was not statistically significantly associated with amyloid-β deposition 7-9 years later. Non-drinking and greater alcohol consumption were associated with higher white matter lesion volume compared with drinking <1 drink/week. Moderate drinking was associated with higher hippocampal volume in younger individuals. Given the selective nature of this population and adverse health effects of excessive alcohol consumption, these findings warrant further investigation, but cannot be translated into clinical recommendations.

Dataset Information

Proteome-based plasma markers of brain amyloid-? deposition in non-demented older individuals.

Publications

Proteome-based plasma markers of brain amyloid-β deposition in non-demented older individuals.

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