Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment
Highlights
► Plasma clusterin concentration is associated with rate of brain atrophy in MCI. ► Plasma clusterin levels reflect its concentration in brain regions with AD pathology. ► Peripheral concentration of clusterin reflects its role in early AD pathology.
Introduction
The identification of peripheral biomarkers associated with core pathological features of Alzheimer's disease (AD) may accelerate the development of disease-modifying treatments (Lyketsos et al., 2008). In pre-symptomatic subjects at risk for subsequent development of AD, blood-based analytes reflecting neuropathology may help in effective targeting of treatments in those most likely to benefit from early intervention (Song et al., 2009). Similarly, peripheral markers of disease pathology in incipient stages of AD may be useful as surrogate end points in clinical trials of novel therapies (Cummings et al., 2007). However, the standard paradigm for biomarker discovery in AD is based upon identification of signals that provide binary discrimination between groups, i.e. AD or mild cognitive impairment (MCI) versus age-matched controls. Given that a significant proportion of elderly control subjects without cognitive impairment already harbor AD pathology, such as Aβ deposition in the brain (Savva et al., 2009), it is unlikely that this strategy will yield biomarkers accurately reflecting early neuropathology. Moreover, this approach also ignores the considerable heterogeneity in the rate of disease progression in patients with established AD (Kraemer et al., 1994).
To overcome some of these limitations, we have recently used proteomic analyses to identify plasma proteins primarily on the basis of their association with established neuroimaging endophenotypes of AD pathology such as brain atrophy and amyloid deposition. Using this approach, we found that higher plasma concentration of clusterin, also known as apolipoprotein-J (apoJ), is associated with greater severity and faster rate of clinical progression in patients with AD (Thambisetty et al., 2010). Our finding of an association between plasma clusterin concentration and disease severity in AD was recently replicated in an independent study by Schrijvers et al.(2011). Together with recent genome-wide association studies (GWAS) demonstrating associations between polymorphic variation in the clusterin gene (CLU) and risk of AD (Harold et al., 2009, Lambert et al., 2009, Seshadri et al., 2010), these findings suggest a potential role for both the CLU gene and clusterin protein in AD pathogenesis. We also recently reported that specific brain regions show accelerated longitudinal tissue loss in individuals with mild cognitive impairment (MCI) (Driscoll et al., 2009). In the current study, our aim was to investigate whether plasma clusterin concentration is related to these longitudinal changes in brain volume in MCI as well as normal individuals. We addressed this question in the neuroimaging cohort of the Baltimore Longitudinal Study of Aging (BLSA), taking advantage of annual volumetric MRI assessments in this group of healthy control and MCI individuals. This rich longitudinal dataset acquired over a mean 6 year interval in each individual contained more than 900 MRI observations in total. We asked two main questions in this neuroimaging study:
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Are there inter-group (MCI versus control) differences in the association between baseline plasma clusterin concentration and longitudinal changes in brain volumes?
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Within each group (MCI and control separately), are there significant associations between baseline plasma clusterin concentration and rates of change in brain volumes?
Subsequently, in an independent analysis of autopsy samples from patients with AD and healthy control individuals, we asked whether plasma clusterin concentration was also related to its concentration within regions vulnerable to AD pathology.
Section snippets
Participants
The neuroimaging study included 139 individuals (ages 57–87 years) from the neuroimaging substudy of the Baltimore Longitudinal Study of Aging (BLSA) who were free of a clinical diagnosis of dementia at the baseline evaluation and received annual brain MRI scans over a mean follow-up interval of 6 years. Sixteen participants were diagnosed with MCI during the course of the study, of whom seven went on to develop dementia. The diagnosis of MCI was made according to Petersen criteria (Petersen, 2004
Sample characteristics
In the neuroimaging study, participants diagnosed with MCI were significantly older than cognitively healthy controls and also had lower MMSE scores at baseline. Baseline performance scores on other cognitive tests in the two groups are shown in Supplementary Table 1. As expected, the MCI group performed worse than the control group on many of the cognitive tests. The groups did not differ significantly in sex, duration of follow-up, or number of years of education (Table 1A). The duration of
Discussion
We investigated whether plasma clusterin concentration predicts subsequent rates of change in brain volumes in MCI and control individuals. To test whether peripheral clusterin concentration was related to progression of early pathological changes in incipient stages of the disease, we first determined whether associations between plasma clusterin concentration at baseline and longitudinal changes in brain volumes differed between MCI and cognitively normal participants from the neuroimaging
Acknowledgments
This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging and by Research and Development Contract N01-AG-3-2124 together with funding from the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust (SLaM) and Institute of Psychiatry, King's College London. Partial support was also through a R&D contract with MedStar Research Institute. We are grateful
References (32)
- et al.
ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo
Neuron
(2004) - et al.
Clusterin: a forgotten player in Alzheimer's disease
Brain Res. Rev.
(2009) - et al.
Plasma biomarkers for mild cognitive impairment and Alzheimer's disease
Brain Res. Rev.
(2009) - et al.
Temporoparietal atrophy: a marker of AD pathology independent of clinical diagnosis
Neurobiol. Aging
(2011) - et al.
Evolution of Alzheimer's disease related cortical lesions
J. Neural Transm. Suppl.
(1998) - et al.
Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults
J. Neurosci.
(2011) - et al.
Apolipoprotein J (clusterin) and Alzheimer's disease
Microsc. Res. Tech.
(2000) - et al.
Disease-modifying therapies for Alzheimer disease: challenges to early intervention
Neurology
(2007) - et al.
Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease
Proc. Natl. Acad. Sci. U.S.A.
(2002) - et al.
Longitudinal pattern of regional brain volume change differentiates normal aging from MCI
Neurology
(2009)
The mini-mental state examination
Arch. Gen. Psychiatry
Human clusterin gene expression is confined to surviving cells during in vitro programmed cell death
J. Clin. Invest.
Possible neuroprotective role of clusterin in Alzheimer's disease: a quantitative immunocytochemical study
Acta Neuropathol.
An image-processing system for qualitative and quantitative volumetric analysis of brain images
J. Comput. Assist. Tomogr.
Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease
Nat. Genet.
Maximum-likelihood estimation for the mixed analysis of variance model
Biometrika
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These authors contributed equally to the manuscript.