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Association of Plasma Clusterin Concentration With Severity, Pathology, and Progression in Alzheimer Disease
Madhav Thambisetty, MD, PhD;
Andrew Simmons, PhD;
Latha Velayudhan, DNB (Psychiatry);
Abdul Hye, PhD;
James Campbell, PhD;
Yi Zhang, MD;
Lars-Olof Wahlund, MD;
Eric Westman, PhD;
Anna Kinsey, PhD;
Andreas Güntert, PhD;
Petroula Proitsi, PhD;
John Powell, PhD;
Mirsada Causevic, PhD;
Richard Killick, PhD;
Katie Lunnon, PhD;
Steven Lynham, MSc;
Martin Broadstock, PhD;
Fahd Choudhry, PhD;
David R. Howlett, PhD;
Robert J. Williams, PhD;
Sally I. Sharp, PhD;
Cathy Mitchelmore, PhD;
Catherine Tunnard, BSc;
Rufina Leung, BSc;
Catherine Foy, PhD;
Darragh O’Brien, MSc;
Gerome Breen, PhD;
Simon J. Furney, PhD;
Malcolm Ward, MSc;
Iwona Kloszewska, MD;
Patrizia Mecocci, MD;
Hilkka Soininen, MD;
Magda Tsolaki, MD;
Bruno Vellas, MD;
Angela Hodges, PhD;
Declan G. M. Murphy, MB BS, FRCPsych;
Sue Parkins, PhD;
Jill C. Richardson, PhD;
Susan M. Resnick, PhD;
Luigi Ferrucci, MD, PhD;
Dean F. Wong, MD, PhD;
Yun Zhou, PhD;
Sebastian Muehlboeck, MSc;
Alan Evans, PhD;
Paul T. Francis, PhD;
Christian Spenger, PhD;
Simon Lovestone, MRC Psych, PhD
Arch Gen Psychiatry. 2010;67(7):739-748. doi:10.1001/archgenpsychiatry.2010.78
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.
Author Affiliations: King's College London, Institute of Psychiatry, London, England (Drs Thambisetty, Simmons, Velayudhan, Hye, Kinsey, Güntert, Proitsi, Powell, Causevic, Killick, Lunnon, Foy, Breen, Furney, Hodges, Murphy, and Lovestone; Mssrs Lynham and O’Brien; and Mss Tunnard and Leung); Proteome Sciences, Cobham, England (Dr Campbell; and Mssrs O’Brien and Ward); Department of Neurobiology, Care Sciences and Society, Section of Clinical Geriatrics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden (Drs Zhang, Wahlund, and Westman); King's College London, Wolfson Centre for Age Related Disorders, London (Drs Broadstock, Choudhry, Howlett, Williams, Sharp, and Francis); Eucaryotic Cell Biology Research Group, Department of Science, Roskilde University, Roskilde, Denmark (Dr Mitchelmore); Department of Old Age Psychiatry & Psychotic Disorders, Medical University of Lodz, Lodz, Poland (Dr Kloszewska); Section of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy (Dr Mecocci); Department of Neurology, Kuopio University and University Hospital, Kuopio, Finland (Dr Soininen); Department of Neurology, Aristotle University, Thessaloniki, Greece (Dr Tsolaki); Department of Internal and Geriatrics Medicine, Hôpitaux de Toulouse, Toulouse, France (Dr Vellas); Neurosciences CEDD, GlaxoSmithKline, North Frontiers Science Park, Harlow, England (Dr Parkins); Synaptic Plasticity and Neural Network Dynamics DPU, Neurosciences CEDD, GlaxoSmithKline, North Frontiers Science Park, Harlow, England (Dr Richardson); Laboratory of Personality and Cognition (Dr Resnick), and Longitudinal Studies Section, Clinical Research Branch (Dr Ferrucci), Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore (Drs Wong and Zhou); Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada (Mr Muehlboeck and Dr Evans); and Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm (Dr Spenger). Dr Thambisetty is now with the Laboratory of Personality and Cognition, Intramural Research Program, National Institute on Aging, National Institutes of Health; and Dr Parkins is now with NHS London, London.
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