Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease

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 Causevic; Richard Killick; Katie Lunnon; Steven Lynham; Martin Broadstock; Fahd Choudhry; David R Howlett; Robert J Williams; Sally I Sharp; Cathy Mitchelmore; Catherine Tunnard; Rufina Leung; Catherine Foy; Darragh O'Brien; Gerome Breen; Simon J Furney; Malcolm Ward; Iwona Kloszewska; Patrizia Mecocci; Hilkka Soininen; Magda Tsolaki; Bruno Vellas; Angela Hodges; Declan G M Murphy; Sue Parkins; Jill C Richardson; Susan M Resnick; Luigi Ferrucci; Dean F Wong; Yun Zhou; Sebastian Muehlboeck; Alan Evans; Paul T Francis; Christian Spenger; Simon Lovestone

doi:10.1001/archgenpsychiatry.2010.78

Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease

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 Causevic, Richard Killick, Katie Lunnon, Steven Lynham, Martin Broadstock, Fahd Choudhry, David R Howlett, Robert J WilliamsSally I Sharp, Cathy Mitchelmore, Catherine Tunnard, Rufina Leung, Catherine Foy, Darragh O'Brien, Gerome Breen, Simon J Furney, Malcolm Ward, Iwona Kloszewska, Patrizia Mecocci, Hilkka Soininen, Magda Tsolaki, Bruno Vellas, Angela Hodges, Declan G M Murphy, Sue Parkins, Jill C Richardson, Susan M Resnick, Luigi Ferrucci, Dean F Wong, Yun Zhou, Sebastian Muehlboeck, Alan Evans, Paul T Francis, Christian Spenger, Simon Lovestone

King's College London

Research output: Contribution to journal › Article › peer-review

346 Citations (Scopus)

Abstract

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 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.

Original language	English
Pages (from-to)	739-48
Number of pages	10
Journal	Archives of General Psychiatry
Volume	67
Issue number	7
DOIs	https://doi.org/10.1001/archgenpsychiatry.2010.78
Publication status	Published - Jul 2010

Keywords

Aged
Aging
Alzheimer Disease
Amyloid beta-Peptides
Animals
Atrophy
Brain
Clusterin
Cognition Disorders
Disease Models, Animal
Disease Progression
Entorhinal Cortex
Female
Gene Expression
Genotype
Humans
Longitudinal Studies
Male
Mice
Mice, Transgenic
Molecular Chaperones
Polymorphism, Single Nucleotide
Proteomics
Severity of Illness Index
Comparative Study
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1001/archgenpsychiatry.2010.78

Cite this

Thambisetty, M., Simmons, A., Velayudhan, L., Hye, A., Campbell, J., Zhang, Y., Wahlund, L.-O., Westman, E., Kinsey, A., Güntert, A., Proitsi, P., Powell, J., Causevic, M., Killick, R., Lunnon, K., Lynham, S., Broadstock, M., Choudhry, F., Howlett, D. R., ... Lovestone, S. (2010). Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Archives of General Psychiatry, 67(7), 739-48. https://doi.org/10.1001/archgenpsychiatry.2010.78

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title = "Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease",

abstract = "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 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.",

keywords = "Aged, Aging, Alzheimer Disease, Amyloid beta-Peptides, Animals, Atrophy, Brain, Clusterin, Cognition Disorders, Disease Models, Animal, Disease Progression, Entorhinal Cortex, Female, Gene Expression, Genotype, Humans, Longitudinal Studies, Male, Mice, Mice, Transgenic, Molecular Chaperones, Polymorphism, Single Nucleotide, Proteomics, Severity of Illness Index, Comparative Study, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't",

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

year = "2010",

month = jul,

doi = "10.1001/archgenpsychiatry.2010.78",

language = "English",

volume = "67",

pages = "739--48",

journal = "Archives of General Psychiatry",

issn = "1538-3636",

publisher = "American Medical Association",

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Thambisetty, M , Simmons, A , Velayudhan, L , Hye, A, Campbell, J, Zhang, Y, Wahlund, L-O, Westman, E, Kinsey, A, Güntert, A, Proitsi, P , Powell, J , Causevic, M , Killick, R , Lunnon, K , Lynham, S , Broadstock, M , Choudhry, F, Howlett, DR, Williams, RJ , Sharp, SI, Mitchelmore, C, Tunnard, C , Leung, R , Foy, C , O'Brien, D , Breen, G , Furney, SJ , Ward, M, Kloszewska, I, Mecocci, P, Soininen, H, Tsolaki, M, Vellas, B, Hodges, A , Murphy, DGM, Parkins, S, Richardson, JC, Resnick, SM, Ferrucci, L, Wong, DF, Zhou, Y, Muehlboeck, S, Evans, A, Francis, PT, Spenger, C & Lovestone, S 2010, 'Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease', Archives of General Psychiatry, vol. 67, no. 7, pp. 739-48. https://doi.org/10.1001/archgenpsychiatry.2010.78

TY - JOUR

T1 - Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease

AU - Thambisetty, Madhav

AU - Simmons, Andrew

AU - Velayudhan, Latha

AU - Hye, Abdul

AU - Campbell, James

AU - Zhang, Yi

AU - Wahlund, Lars-Olof

AU - Westman, Eric

AU - Kinsey, Anna

AU - Güntert, Andreas

AU - Proitsi, Petroula

AU - Powell, John

AU - Causevic, Mirsada

AU - Killick, Richard

AU - Lunnon, Katie

AU - Lynham, Steven

AU - Broadstock, Martin

AU - Choudhry, Fahd

AU - Howlett, David R

AU - Williams, Robert J

AU - Sharp, Sally I

AU - Mitchelmore, Cathy

AU - Tunnard, Catherine

AU - Leung, Rufina

AU - Foy, Catherine

AU - O'Brien, Darragh

AU - Breen, Gerome

AU - Furney, Simon J

AU - Ward, Malcolm

AU - Kloszewska, Iwona

AU - Mecocci, Patrizia

AU - Soininen, Hilkka

AU - Tsolaki, Magda

AU - Vellas, Bruno

AU - Hodges, Angela

AU - Murphy, Declan G M

AU - Parkins, Sue

AU - Richardson, Jill C

AU - Resnick, Susan M

AU - Ferrucci, Luigi

AU - Wong, Dean F

AU - Zhou, Yun

AU - Muehlboeck, Sebastian

AU - Evans, Alan

AU - Francis, Paul T

AU - Spenger, Christian

AU - Lovestone, Simon

PY - 2010/7

Y1 - 2010/7

N2 - 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 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.

AB - 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 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.

KW - Aged

KW - Aging

KW - Alzheimer Disease

KW - Amyloid beta-Peptides

KW - Animals

KW - Atrophy

KW - Brain

KW - Clusterin

KW - Cognition Disorders

KW - Disease Models, Animal

KW - Disease Progression

KW - Entorhinal Cortex

KW - Female

KW - Gene Expression

KW - Genotype

KW - Humans

KW - Longitudinal Studies

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Molecular Chaperones

KW - Polymorphism, Single Nucleotide

KW - Proteomics

KW - Severity of Illness Index

KW - Comparative Study

KW - Journal Article

KW - Multicenter Study

KW - Research Support, Non-U.S. Gov't

U2 - 10.1001/archgenpsychiatry.2010.78

DO - 10.1001/archgenpsychiatry.2010.78

M3 - Article

C2 - 20603455

SN - 1538-3636

VL - 67

SP - 739

EP - 748

JO - Archives of General Psychiatry

JF - Archives of General Psychiatry

IS - 7

ER -

Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease

Abstract

Keywords

UN SDGs

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