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

2010; American Medical Association; Volume: 67; Issue: 7 Linguagem: Inglês

10.1001/archgenpsychiatry.2010.78

1538-3636

Madhav Thambisetty, Andrew Simmons, Latha Velayudhan, Abdul Hye, James Campbell, Yi Zhang, Lars‐Olof Wahlund, Eric Westman, Anna Kinsey, Andreas Güntert, Petroula Proitsi, John Powell, Mirsada Čaušević, Richard Killick, Katie Lunnon, Steven Lynham, Martin Broadstock, Fahd Choudhry, David Howlett, Robert J. Williams, Sally I. Sharp, Cathy Mitchelmore, Catherine Tunnard, Rufina Leung, Catherine Foy, Darragh P. O’Brien, Gerome Breen, Simon J. Furney, Malcolm Ward, Iwona Kłoszewska, Patrizia Mecocci, Hilkka Soininen, Magda Tsolaki, Bruno Vellas, Angela Hodges, Declan Murphy, Sue Parkins, Jill Richardson, Susan M. Resnick, Luigi Ferrucci, Dean F. Wong, Yun Zhou, Sebastian Muehlboeck, Alan C. Evans, Paul T. Francis, Christian Spenger, Simon Lovestone,

S100 Proteins and Annexins

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-β 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 well as amyloid and clusterin colocalization in plaques. Conclusions These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.