Association of Plasma Clusterin Concentration With Severity, Pathology, and Progression in Alzheimer Disease

作者：Madhav Thambisetty, Andrew D. Simmons, Latha Velayudhan, Abdul Hye, James Campbell, Yi Zhang, Lars‐Olof Wahlund, Eric Westman, Anna M. Kinsey, Andreas Güntert, Petroula Proitsi, John Powell, Mirsada Čaušević, Richard Killick, Katie Lunnon, Steven Lynham, Martin Broadstock, Fahd Choudhry, David R Howlett, Robert J. Williams, Sally Isabel Sharp, Cathy Mitchelmore, Catherine Tunnard, Rufina Leung, Catherine Foy, Darragh Patrick O'Brien, Gerome D. Breen, Simon J. Furney, Malcolm Andrew Ward, Iwona Kłoszewska, Patrizia Mecocci, Hilkka S. Soininen, Magda Tsolaki, Bruno J. Vellas, Angela Hodges, Declan Murphy, Sue Parkins, Jill C. Richardson, Susan M. Resnick, Luigi Ferrucci, Dean Foster Wong, Yun Zhou, Sebastian Muehlboeck, Alan Charles Evans, Paul T. Francis, Christian Spenger, Simon Lovestone · 发表于：Archives of General Psychiatry · 年份：2010 · DOI：10.1001/archgenpsychiatry.2010.78 · 被引用次数：409 · 研究领域：Clusterin in disease pathology、Alzheimer's disease research and treatments、Advanced Proteomics Techniques and Applications

CONTEXT: Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD). OBJECTIVE: To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. DESIGN: Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model. SETTING: A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging. PARTICIPANTS: Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging. MAIN OUTCOME MEASURES: Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid. RESULTS: Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as ...