Plasma Biomarkers of Brain Atrophy in Alzheimer's Disease

TY - JOUR

T1 - Plasma Biomarkers of Brain Atrophy in Alzheimer's Disease

AU - Thambisetty, Madhav

AU - Simmons, Andrew

AU - Hye, Abdul

AU - Campbell, James

AU - Westman, Eric

AU - Zhang, Yi

AU - Wahlund, Lars-Olof

AU - Kinsey, Anna

AU - Causevic, Mirsada

AU - Killick, Richard

AU - Kloszewska, Iwona

AU - Mecocci, Patrizia

AU - Soininen, Hilkka

AU - Tsolaki, Magda

AU - Vellas, Bruno

AU - Spenger, Christian

AU - Lovestone, Simon

PY - 2011

Y1 - 2011

N2 - Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods-quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, gamma-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis.

AB - Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods-quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, gamma-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis.

KW - Blood Proteins

KW - Reproducibility of Results

KW - Humans

KW - Alzheimer Disease

KW - Brain

KW - Least-Squares Analysis

KW - Aged

KW - Atrophy

KW - Organ Size

KW - Male

KW - Female

KW - Biological Markers

U2 - 10.1371/journal.pone.0028527

DO - 10.1371/journal.pone.0028527

M3 - Article

C2 - 22205954

SN - 1932-6203

VL - 6

JO - PL o S One

JF - PL o S One

IS - 12

M1 - e28527

ER -