Plasma Clusterin and the CLU Gene rs11136000 Variant Are Associated with Mild Cognitive Impairment in Type 2 Diabetic Patients

Objective: Type 2 diabetes mellitus (T2DM) is related to an elevated risk of mild cognitive impairment (MCI). Plasma clusterin is reported associated with the early pathology of Alzheimer's disease (AD) and longitudinal brain atrophy in subjects with MCI. The rs11136000 single nucleotide polymorphism within the clusterin (CLU) gene is also associated with the risk of AD. We aimed to investigate the associations among plasma clusterin, rs11136000 genotype and T2DM-associated MCI. Methods: A total of 231 T2DM patients, including 126 MCI and 105 cognitively healthy controls were enrolled in this study. Demographic parameters were collected and neuropsychological tests were conducted. Plasma clusterin and CLU rs11136000 genotype were examined.Results: Plasma clusterin was significantly higher in MCI patients than in control group (p=0.007). In subjects with MCI, plasma clusterin level was negatively correlated with Montreal cognitive assessment and auditory verbal learning test_delayed recall scores (p=0.027 and p=0.020, respectively). After adjustment for age, educational attainment, and gender, carriers of rs11136000 TT genotype demonstrated reduced risk for MCI compared with the CC genotype carriers (OR=0.158, χ2=4.113, p=0.043). Multivariable regression model showed that educational attainment, duration of diabetes, HDL-c, and plasma clusterin levels are associated with MCI in T2DM patients.Conclusions: Plasma clusterin was associated with MCI and may reflect a protective response in T2DM patients. TT genotype exhibited a reduced risk of MCI compared to CC genotype. Further investigations should be conducted to determine the role of clusterin in cognitive decline

Plasma proteins predict conversion to dementia from prodromal disease.

PublishedJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tBACKGROUND: The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia. METHODS: Three multicenter cohorts of cognitively healthy elderly, mild cognitive impairment (MCI), and AD participants with standardized clinical assessments and structural neuroimaging measures were used. Twenty-six candidate proteins were quantified in 1148 subjects using multiplex (xMAP) assays. RESULTS: Sixteen proteins correlated with disease severity and cognitive decline. Strongest associations were in the MCI group with a panel of 10 proteins predicting progression to AD (accuracy 87%, sensitivity 85%, and specificity 88%). CONCLUSIONS: We have identified 10 plasma proteins strongly associated with disease severity and disease progression. Such markers may be useful for patient selection for clinical trials and assessment of patients with predisease subjective memory complaints.Medical Research Council (MRC)Alzheimer’s Research UKThe National Institute for Health Research (NIHR) Biomedical Research CentreBiomedical Research Unit for DementiaAddNeuroMed through the EU FP6 programInnovative Medicines Initiative Joint Undertaking under an EMIF grantEuropean Union’s Seventh Framework Programme (FP7/2007-2013

Plasma Apolipoprotein Levels Are Associated with Cognitive Status and Decline in a Community Cohort of Older Individuals

<div><h3>Objectives</h3><p>Apolipoproteins have recently been implicated in the etiology of Alzheimer’s disease (AD). In particular, Apolipoprotein J (ApoJ or clusterin) has been proposed as a biomarker of the disease at the pre-dementia stage. We examined a group of apolipoproteins, including ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH and ApoJ, in the plasma of a longitudinal community based cohort.</p> <h3>Methods</h3><p>664 subjects (257 with Mild Cognitive Impairment [MCI] and 407 with normal cognition), mean age 78 years, from the Sydney Memory and Aging Study (MAS) were followed up over two years. Plasma apolipoprotein levels at baseline (Wave 1) were measured using a multiplex bead fluorescence immunoassay technique.</p> <h3>Results</h3><p>At Wave 1, MCI subjects had lower levels of ApoA1, ApoA2 and ApoH, and higher levels of ApoE and ApoJ, and a higher ApoB/ApoA1 ratio. Carriers of the apolipoprotein E ε4 allele had significantly lower levels of plasma ApoE, ApoC3 and ApoH and a significantly higher level of ApoB. Global cognitive scores were correlated positively with ApoH and negatively with ApoJ levels. ApoJ and ApoE levels were correlated negatively with grey matter volume and positively with cerebrospinal fluid (CSF) volume on MRI. Lower ApoA1, ApoA2 and ApoH levels, and higher ApoB/ApoA1 ratio, increased the risk of cognitive decline over two years in cognitively normal individuals. ApoA1 was the most significant predictor of decline. These associations remained after statistically controlling for lipid profile. Higher ApoJ levels predicted white matter atrophy over two years.</p> <h3>Conclusions</h3><p>Elderly individuals with MCI have abnormal apolipoprotein levels, which are related to cognitive function and volumetric MRI measures cross-sectionally and are predictive of cognitive impairment in cognitively normal subjects. ApoA1, ApoH and ApoJ are potential plasma biomarkers of cognitive decline in non-demented elderly individuals.</p> </div

Plasma apolipoprotein J as a potential biomarker for Alzheimer\u27s disease: Australian Imaging, Biomarkers and Lifestyle study of aging

Introduction: For early detection of Alzheimer\u27s disease (AD), the field needs biomarkers that can be used to detect disease status with high sensitivity and specificity. Apolipoprotein J (ApoJ, also known as clusterin) has long been associated with AD pathogenesis through various pathways. The aim of this study was to investigate the potential of plasma apoJ as a blood biomarker for AD. Methods: Using the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the present study assayed plasma apoJ levels over baseline and 18 months in 833 individuals. Plasma ApoJ levels were analyzed with respect to clinical classification, age, gender, apolipoprotein E (APOE) ε4 allele status, mini-mental state examination score, plasma amyloid beta (Aβ), neocortical Aβ burden (as measured by Pittsburgh compound B-positron emission tomography), and total adjusted hippocampus volume. Results: ApoJ was significantly higher in both mild cognitive impairment (MCI) and AD groups as compared with healthy controls (HC; P \u3c .0001). ApoJ significantly correlated with both standardized uptake value ratio (SUVR) and hippocampus volume and weakly correlated with the plasma Aβ1-42/Aβ1-40 ratio. Plasma apoJ predicted both MCI and AD from HC with greater than 80% accuracy for AD and greater than 75% accuracy for MCI at both baseline and 18-month time points. Discussion: Mean apoJ levels were significantly higher in both MCI and AD groups. ApoJ was able to differentiate between HC with high SUVR and HC with low SUVR via APOE ε4 allele status, indicating that it may be included in a biomarker panel to identify AD before the onset of clinical symptoms. © 2016 The Authors

Complement biomarkers as predictors of disease progression in Alzheimer's disease

There is a critical unmet need for reliable markers of disease and disease course in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). The growing appreciation of the importance of inflammation in early AD has focused attention on inflammatory biomarkers in cerebrospinal fluid or plasma; however, non-specific inflammation markers have disappointed to date. We have adopted a targeted approach, centered on an inflammatory pathway already implicated in the disease. Complement, a core system in innate immune defense and potent driver of inflammation, has been implicated in pathogenesis of AD based on a confluence of genetic, histochemical, and model data. Numerous studies have suggested that measurement of individual complement proteins or activation products in cerebrospinal fluid or plasma is useful in diagnosis, prediction, or stratification, but few have been replicated. Here we apply a novel multiplex assay to measure five complement proteins and four activation products in plasma from donors with MCI, AD, and controls. Only one complement analyte, clusterin, differed significantly between control and AD plasma (controls, 295 mg/l; AD, 388 mg/l: p < 10- 5). A model combining clusterin with relevant co-variables was highly predictive of disease. Three analytes (clusterin, factor I, terminal complement complex) were significantly different between MCI individuals who had converted to dementia one year later compared to non-converters; a model combining these three analytes with informative co-variables was highly predictive of conversion. The data confirm the relevance of complement biomarkers in MCI and AD and build the case for using multi-parameter models for disease prediction and stratification

Plasma Biomarkers of Brain Atrophy in Alzheimer's Disease

Peripheral biomarkers of Alzheimer's disease (AD) reflecting early neuropathological change are critical to the development of treatments for this condition. The most widely used indicator of AD pathology in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with brain atrophy in AD. Using gel based proteomics we previously identified seven plasma proteins that were significantly associated with hippocampal volume in a combined cohort of subjects with AD (N = 27) and MCI (N = 17). In the current report, we validated this finding in a large independent cohort of AD (N = 79), MCI (N = 88) and control (N = 95) subjects using alternative complementary methods—quantitative immunoassays for protein concentrations and estimation of pathology by whole brain volume. We confirmed that plasma concentrations of five proteins, together with age and sex, explained more than 35% of variance in whole brain volume in AD patients. These proteins are complement components C3 and C3a, complement factor-I, γ-fibrinogen and alpha-1-microglobulin. Our findings suggest that these plasma proteins are strong predictors of in vivo AD pathology. Moreover, these proteins are involved in complement activation and coagulation, providing further evidence for an intrinsic role of these pathways in AD pathogenesis

Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology

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Identification and evaluation of biomarkers for Huntington’s disease

Huntington’s disease (HD) is a devastating, incurable inherited neurodegenerative disorder that commonly affects adults in mid-life. Despite encouraging results from in vitro and animal trials, disease-modifying therapeutic trials in HD are limited by a lack of tools to track disease progression. HD is clinically heterogeneous, and current clinical rating scales lack sensitivity and specificity, particularly over relatively short time periods. Improvements in the precision of objective measurement of disease progression in HD could lead to state markers (biomarkers) better able to predict onset, detect progression and measure the effects of therapeutic intervention. Biomarkers capable of detecting disease-related changes in premanifest gene carriers will be essential for clinical trials of treatments to delay onset. Imaging, clinical and cognitive assessment as well as laboratory markers have all been proposed as biomarkers, but few measures have been quantified over short time intervals or shown to be predictive of clinical change over longer periods. A robust panel of biomarkers from a number of modalities will be necessary to progress to interventional clinical trials of disease-modifying therapies in HD, using biomarkers to measure the success or failure of an intervention. Such cross-validation requires simultaneous multimodal biomarker evaluation within a suitable cohort of subjects studied longitudinally. This thesis describes a multi-modal approach to the discovery and evaluation of potential biomarkers for Huntington's disease in a large cohort of human volunteers. After reviewing the relevant features of Huntington's disease and current state of biomarker research in Huntington's disease, several approaches to, and outcomes from, biomarker discovery and evaluation are described, including proteomic profiling, targeted ELISA, multiplex inflammatory profiling and measurement of whole-brain atrophy by longitudinal magnetic resonance imaging. The thesis draws together these different approaches and summarises the contributions to both biomarker research and our understanding of the neurobiology of HD that the work has generated

No diagnostic value of plasma clusterin in Alzheimer's disease.

There is an urgent need for biomarkers to enable early diagnosis of Alzheimer's disease (AD). It has recently been shown that a variant within the clusterin gene is associated with increased risk of AD and plasma levels of clusterin have been found to be associated with the risk of AD. We, therefore, investigated the diagnostic value of clusterin by quantifying clusterin using an ELISA in plasma from 171 controls, 127 patients with AD, 82 patients with other dementias and 30 patients with depression. We observed similar plasma clusterin levels in controls, AD patients and patients with other dementias, suggesting that plasma clusterin levels have no diagnostic value for AD. There was a slight, but significant, increase in plasma clusterin in patients with depression compared to all other groups tested, which may warrant further investigation

Serum neuronal exosomes predict and differentiate Parkinson's disease from atypical parkinsonism

ObjectiveParkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies.MethodsWe performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.ResultsMean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression.ConclusionsIncreased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism