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Comparative Study

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

Madhav Thambisetty et al. Arch Gen Psychiatry.

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.

Figures

Figure-1
Figure-1. Study design
Schematic diagram of the design of A) Discovery and B) Validation-phase studies for the identification of blood-based AD biomarkers associated with both in vivo disease pathology as well as rate of disease progression. C) Association of plasma clusterin concentration with brain amyloid burden was tested in both non-demented older humans and a transgenic mouse model of AD.
Figure-2
Figure-2. Gel based proteomic discovery phase studies
Proteomic identification of plasma proteins associated with hippocampal volume in AD+MCI subjects (top panel) and those associated with fast AD progressors (bottom panel). A representative 2DGE gel is shown with spots outlined in green denoting proteins associated with hippocampal volume in AD+MCI and those in red highlighting proteins associated with fast AD progression.
Figure-3
Figure-3. Increased concentration of plasma clusterin is associated with rate of clinical progression in AD
AD patients with a rapid progression rate, measured A) Prior to blood sampling (Rapid progressors; N=219, Slow progressors; N=125) and B) One year after blood sampling (Rapid progressors; N=115, Slow progressors; N=122) have significantly increased clusterin concentration relative to slow progressors. C) High levels of clusterin are associated with a significantly greater risk of accelerated cognitive decline subsequent to blood sampling. AD patients (N= 204) were assigned a prognostic index derived as their plasma clusterin concentration multiplied by its corresponding regression coefficient (β) in a Cox proportional regression analysis. The figure shows the cumulative hazard functions for the effect of the `prognostic factor' (i.e. plasma clusterin concentration) on the `survival probability' i.e. maintaining a non-aggressive clinical course (decline in MMSE≤ 2 points/year). The cumulative survival functions represent estimated survival probabilities for three representative AD patients with the lowest (5.87ng/ml), median (76.84 ng/ml) and highest plasma clusterin (159 ng/ml) concentrations showing that an AD patient with the highest clusterin concentration has the lowest probability of maintaining a non-aggressive clinical course one year after sampling. The reported hazard ratio for a 10 ng/ml rise in plasma clusterin concentration for risk of becoming a rapid AD decliner was 1.071, 95%CI (1–1.147), p=0.05.
Figure-4
Figure-4. Clusterin expression is associated with amyloid pathology
A) Clusterin is an antecedent biomarker of in vivo fibrillar amyloid burden in the entorhinal cortex in non-demented older individuals (N=60). SPM analysis shows correlation between plasma clusterin concentration and 11C-PiB uptake controlling for age and sex, p < 0.05; uncorrected. Highlighted areas denote regions in the ERC of both hemispheres that show significant association with plasma clusterin concentration 10 years prior to the PiB-PET scans. B) Gene expression of clusterin is altered in AD. Clusterin mRNA levels are significantly elevated in blood cells from AD patients (N=182) relative to healthy controls (N=179, ** p<0.001) and MCI subjects (N=207, ** p=0.008) after correcting for age. C) Transgenic TASTPM mice (N=10) overexpressing both human APP and PS1 genes have significantly higher plasma concentration of clusterin relative to wild type littermates (N=10) at 6 months of age (p=0.02). Inset shows hippocampal and cortical amyloid plaques in a 6-month old TASTPM mouse stained by a monoclonal antibody against Aβ1–42. Wild type mice show no amyloid pathology at this age (not shown). D) Representative photomicrograph of cortical amyloid plaques in 6-month old TASTPM mouse. A close association is observed between Aβ within amyloid plaques (black arrows – monoclonal antibody to Aβ42; grey-black labelling with diaminobenzidine) and clusterin (white arrows – polyclonal antibody, R&D Systems; brown labelled with Novared). Colours have been slightly enhanced digitally for illustrative purposes. Scale bar represents 25 microns. E) TASTPM mice show age-dependent increases in cortical Aβ (1E8, pan- Aβ; dashed line) and clusterin (solid line) load as determined by quantitative image analysis of immunohistochemical labelling. N=9–11 at each timepoint, mixed male and female mouse population. Quantitative estimates of amyloid burden and clusterin deposition were derived using Image J software. F) TASTPM mice demonstrate a highly significant (p<0.0001) correlation between Aβ and clusterin load (N=39, male and female mice, 8–30 weeks of age). X and Y axes represent Aβ and clusterin load (percentage area labelled) respectively.

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