Elsevier

NeuroImage

Volume 59, Issue 1, 2 January 2012, Pages 212-217
NeuroImage

Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment

https://doi.org/10.1016/j.neuroimage.2011.07.056Get rights and content

Abstract

Recent genetic and proteomic studies demonstrate that clusterin/apolipoprotein-J is associated with risk, pathology, and progression of Alzheimer's disease (AD). Our main aim was to examine associations between plasma clusterin concentration and longitudinal changes in brain volume in normal aging and mild cognitive impairment (MCI). A secondary objective was to examine associations between peripheral concentration of clusterin and its concentration in the brain within regions that undergo neuropathological changes in AD. Non-demented individuals (N = 139; mean baseline age 70.5 years) received annual volumetric MRI (912 MRI scans in total) over a mean six-year interval. Sixteen participants (92 MRI scans in total) were diagnosed during the course of the study with amnestic MCI. Clusterin concentration was assayed by ELISA in plasma samples collected within a year of the baseline MRI. Mixed effects regression models investigated whether plasma clusterin concentration was associated with rates of brain atrophy for control and MCI groups and whether these associations differed between groups. In a separate autopsy sample of individuals with AD (N = 17) and healthy controls (N = 4), we examined the association between antemortem clusterin concentration in plasma and postmortem levels in the superior temporal gyrus, hippocampus and cerebellum. The associations of plasma clusterin concentration with rates of change in brain volume were significantly different between MCI and control groups in several volumes including whole brain, ventricular CSF, temporal gray matter as well as parahippocampal, superior temporal and cingulate gyri. Within the MCI but not control group, higher baseline concentration of plasma clusterin was associated with slower rates of brain atrophy in these regions. In the combined autopsy sample of AD and control cases, representing a range of severity in AD pathology, we observed a significant association between clusterin concentration in the plasma and that in the superior temporal gyrus. Our findings suggest that clusterin, a plasma protein with roles in amyloid clearance, complement inhibition and apoptosis, is associated with rate of brain atrophy in MCI. Furthermore, peripheral concentration of clusterin also appears to reflect its concentration within brain regions vulnerable to AD pathology. These findings in combination suggest an influence of this multi-functional protein on early stages of progression in AD pathology.

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:

  • 1.

    Are there inter-group (MCI versus control) differences in the association between baseline plasma clusterin concentration and longitudinal changes in brain volumes?

  • 2.

    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

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