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Relative contributions of biomarkers in Alzheimer's disease.

ABSTRACT: To assess relationships between biomarkers for Alzheimer's disease (AD) and their potential contributions to AD.Biomarkers and cognitive evaluations were assessed longitudinally in 179 patients with mild cognitive impairment, from the Alzheimer's Disease Neuroimaging Initiative from 2003 to 2006, and were used to examine, at any given time, the joint contributions of hippocampal volume, whole brain volume, and brain glucose metabolism on clinical AD progression, using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Marginal structural models were applied, and an inverse-probability of treatment weight estimation was used to account for time-dependent confounding between study variables.At any given time, population-level differences (e.g., 1-standard deviation [SD] increase) in brain glucose metabolism (-1.036; 95% confidence interval [95% CI], -1.608, -0.464) and hippocampal volume (-1.537; 95% CI, -2.399, -0.674) independently reduced mean (ADAS-Cog), whereas a 1-SD increase in whole brain volume did not (0.372; 95% CI, -0.283, 1.027). The effects of brain glucose metabolism differed in subgroups defined by baseline covariates (e.g., age), but no subgroup effects were observed for hippocampal volume and brain volume.Brain glucose metabolism and hippocampal volume represent relevant biological markers in subjects at risk for AD.

SUBMITTER: Haight TJ

PROVIDER: S-EPMC3510749 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Relative contributions of biomarkers in Alzheimer's disease.

Haight Thaddeus J TJ Jagust William J WJ

Annals of epidemiology 20121024 12

<h4>Purpose</h4>To assess relationships between biomarkers for Alzheimer's disease (AD) and their potential contributions to AD.<h4>Methods</h4>Biomarkers and cognitive evaluations were assessed longitudinally in 179 patients with mild cognitive impairment, from the Alzheimer's Disease Neuroimaging Initiative from 2003 to 2006, and were used to examine, at any given time, the joint contributions of hippocampal volume, whole brain volume, and brain glucose metabolism on clinical AD progression, u ...[more]

PMID: 23102709

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Project description:s synapse degeneration is an early event in Alzheimer’s disease (AD) pathophysiology, a biofluid marker of synapse loss in living patients could be a surrogate marker of disease prognosis and therefore would be an excellent addition to the AD biomarker arsenal. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins that could be potential biomarkers of underlying synapse degeneration. The aim of this study was to identify, verify and evaluate a set of synaptic proteins as surrogate CSF markers of underlying synapse loss in AD patients. In the Discovery Stage, we combined high-throughput shotgun proteomics of the CSF with an exhaustive search of the literature and public databases for proteomic studies of the CSF and synapse. A thorough characterization of the synaptic component of the CSF identified 210 synaptic proteins that are detectable in human CSF. We selected an initial panel of 22 candidate biomarkers for evaluation. In the Verification Stage, 12 proteins were discarded due to poor detection by targeted mass spectrometry (Selected Reaction Monitoring, SRM). We confirmed the expression of the remaining 10 proteins either directly at (Calsynytenin-1, GluR2, GluR4, Neurexins 2A and 3A, Neuroligin-2, Syntaxin-1B, Thy-1 and Vamp-2), or surrounding (Tenascin-R), the human synapse using Array Tomography microscopy and biochemical fractionation methods. We quantified the synaptic panel by SRM in CSF samples from 2 independent clinical cohorts of cognitively normal controls and all clinical stages of AD (n=140). A set of the panel proteins demonstrated a non-linear profile distinct to that of existing biomarkers whereby the CSF levels were decreased at the earliest preclinical stage of AD, reflecting reduced synaptic density in these asymptomatic individuals and elevated at later symptomatic stages when neurodegeneration is widespread. In conclusion, we have identified a set of novel synapse-specific proteins that could have clinical value for assessing disease progression in individuals at-risk for AD and potentially in other neurological disorders characterized by early synapse loss.

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Relative contributions of biomarkers in Alzheimer's disease.

Publications

Relative contributions of biomarkers in Alzheimer's disease.

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