Madhav Thambisetty

King's College London, Londinium, England, United Kingdom

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Publications (94)

  • [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease (AD) is the leading cause of dementia and mitigating amyloid-β (Aβ) levels may serve as a rational therapeutic avenue to slow AD progression. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb Aβ levels, and mechanisms that underlie ROCK2's effects on Aβ production are defined. How ROCK1 affects Aβ generation remains a critical barrier. Here, we report that ROCK1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. Aβ42 oligomers marginally increased ROCK1 and ROCK2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 (LIMK1), suggesting that Aβ42 activates ROCKs. RNAi depletion of ROCK1 or ROCK2 suppressed endogenous Aβ40 production in neurons, and Aβ40 levels were reduced in brains of ROCK1 heterozygous knock-out mice compared to wild-type littermate controls. ROCK1 knockdown decreased amyloid precursor protein (APP), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK1. These observations suggest that reduction of ROCK1 diminishes Aβ levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK1 and ROCK2 are therapeutic targets to combat Aβ production in AD. This article is protected by copyright. All rights reserved.
    Article · Jun 2016 · Journal of Neurochemistry
  • Richard A. Goodman · Kimberly A. Lochner · Madhav Thambisetty · [...] · Shari M. Ling
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Rapid growth of the older adult population requires greater epidemiologic characterization of dementia. We developed national prevalence estimates of diagnosed dementia and subtypes in the highest risk U.S. Population: Methods: We analyzed Centers for Medicare & Medicaid administrative enrollment and claims data for 100% of Medicare fee-for-service beneficiaries enrolled during 2011-2013 and age ≥68 years as of December 31, 2013 (n = 21.6 million). Results: Over 3.1 million (14.4%) beneficiaries had a claim for a service and/or treatment for any dementia subtype. Dementia not otherwise specified was the most common diagnosis (present in 92.9%). The most common subtype was Alzheimer's (43.5%), followed by vascular (14.5%), Lewy body (5.4%), frontotemporal (1.0%), and alcohol induced (0.7%). The prevalence of other types of diagnosed dementia was 0.2%. Discussion: This study is the first to document concurrent prevalence of primary dementia subtypes among this U.S. Population: The findings can assist in prioritizing dementia research, clinical services, and caregiving resources.
    Article · May 2016 · Alzheimer's & dementia: the journal of the Alzheimer's Association
  • [Show abstract] [Hide abstract] ABSTRACT: Type II diabetes mellitus (DM) increases risk for cognitive decline and is associated with brain atrophy in older demented and non-demented individuals. We investigated (1) the cross-sectional association between fasting blood glucose level and cortical thickness in a sample of largely middle-aged, cognitively normal adults, and (2) whether these associations were modified by genes associated with both lipid processing and dementia. To explore possible modifications by genetic status, we investigated the interaction between blood glucose levels and the apolipoprotein E (APOE) ϵ4 allele and the translocase of the outer mitochondrial membrane (TOMM) 40 '523 genotype on cortical thickness. Cortical thickness measures were based on mean thickness in a subset of a priori-selected brain regions hypothesized to be vulnerable to atrophy in Alzheimer's disease (AD) (i.e., 'AD vulnerable regions'). Participants included 233 cognitively normal subjects in the BIOCARD study who had a measure of fasting blood glucose and cortical thickness measures, quantified by magnetic resonance imaging (MRI) scans. After adjustment for age, sex, race, education, depression, and medical conditions, higher blood glucose was associated with thinner parahippocampal gyri (B = - 0.002; 95% CI - 0.004, - 0.0004) and temporal pole (B = - 0.002; 95% CI - 0.004, - 0.0001), as well as reduced average thickness over AD vulnerable regions (B = - 0.001; 95% CI - 0.002, - 0.0001). There was no evidence for greater cortical thinning in ϵ4 carriers of the APOE gene or in APOE ϵ3/3 individuals carrying the TOMM40 VL/VL genotypes. When individuals with glucose levels in the diabetic range (≥ 126 mg/dL), were excluded from the analysis, the associations between glucose levels and cortical thickness were no longer significant. These findings suggest that glucose levels in the diabetic range are associated with reduced cortical thickness in AD vulnerable regions as early as middle age.
    Article · Apr 2016 · Journal of the Neurological Sciences
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    [Show abstract] [Hide abstract] ABSTRACT: Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p < 0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q < 0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.
    Full-text Article · Mar 2016 · Journal of Alzheimer's disease: JAD
  • Alexandra M. Kueider · Toshiko Tanaka · Yang An · [...] · Madhav Thambisetty
    [Show abstract] [Hide abstract] ABSTRACT: We investigated whether: 1) serum levels of 25-hydroxyvitamin D [25(OH)D]; and 2) single nucleotide polymorphisms (SNPs) in the group-specific component (GC) gene regulating serum 25(OH)D levels are associated with cognition in older individuals; and 3) whether causal relationships exist between 25(OH)D and cognition during aging. Data from 1207 participants in the Baltimore Longitudinal Study of Aging were analyzed (mean follow-up 10.4 years) to test associations between serum 25(OH)D and cognition. Two GC SNPs were used to derive a composite genetic risk score associated with lower 25(OH)D concentrations. Lower serum 25(OH)D and higher GC composite scores were associated with lower executive function at baseline. Mendelian randomization analyses suggested a causal relationship between lower serum 25(OH)D and poorer executive function and psychomotor speed. The SNP score was also associated with lower performance on measures of visuospatial abilities at baseline but with attenuated declines over time in visuospatial abilities and executive function. Widespread associations between vitamin-D regulatory SNPs and cognition suggest a mechanistic basis for the relationship between serum 25(OH)D levels and cognition during aging.
    Article · Mar 2016 · Neurobiology of aging
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    Ramon Casanova · Sudhir Varma · Brittany Simpson · [...] · Madhav Thambisetty
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Recently, quantitative metabolomics identified a panel of 10 plasma lipids that were highly predictive of conversion to Alzheimer's disease (AD) in cognitively normal older individuals (n = 28, area under the curve [AUC] = 0.92, sensitivity/specificity of 90%/90%). Methods: Quantitative targeted metabolomics in serum using an identical method as in the index study. Results: We failed to replicate these findings in a substantially larger study from two independent cohorts-the Baltimore Longitudinal Study of Aging ([BLSA], n = 93, AUC = 0.642, sensitivity/specificity of 51.6%/65.7%) and the Age, Gene/Environment Susceptibility-Reykjavik Study ([AGES-RS], n = 100, AUC = 0.395, sensitivity/specificity of 47.0%/36.0%). In analyses applying machine learning methods to all 187 metabolite concentrations assayed, we find a modest signal in the BLSA with distinct metabolites associated with the preclinical and symptomatic stages of AD, whereas the same methods gave poor classification accuracies in the AGES-RS samples. Discussion: We believe that ours is the largest blood biomarker study of preclinical AD to date. These findings underscore the importance of large-scale independent validation of index findings from biomarker studies with relatively small sample sizes.
    Full-text Article · Jan 2016 · Alzheimer's and Dementia
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    [Show abstract] [Hide abstract] ABSTRACT: Introduction: For early detection of Alzheimer's 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 < .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.
    Full-text Article · Dec 2015
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    A.M. Kueider · E. Palchamy · T. Tanaka · [...] · M. Thambisetty
    Full-text Conference Paper · Nov 2015
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    [Show abstract] [Hide abstract] ABSTRACT: Longitudinal studies play a key role in various fields, including epidemiology, clinical research, and genomic analysis. Currently, the most popular methods in longitudinal data analysis are model-driven regression approaches, which impose strong prior assumptions and are unable to scale to large problems in the manner of machine learning algorithms. In this work, we propose a novel longitudinal support vector regression (LSVR) algorithm that not only takes the advantage of one of the most popular machine learning methods, but also is able to model the temporal nature of longitudinal data by taking into account observational dependence within subjects. We test LSVR on publicly available data from the DREAM-Phil Bowen ALS Prediction Prize4Life challenge. Results suggest that LSVR is at a minimum competitive with favored machine learning methods and is able to outperform those methods in predicting ALS score one month in advance.
    Full-text Conference Paper · Nov 2015
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    Brittany N Simpson · Min Kim · Yi-Fang Chuang · [...] · Madhav Thambisetty
    [Show abstract] [Hide abstract] ABSTRACT: We recently showed that Alzheimer disease (AD) patients have lower plasma concentrations of the phosphatidylcholines [PC16:0/20:5 (PC1620); PC16:0/22:6 (PC1622); and PC18:0/22:6 (PC1822)] relative to healthy controls. We now extend these findings by examining associations between plasma concentrations of these PCs with cognitive performance and brain function (measured by regional resting state cerebral blood flow; rCBF), in non-demented older individuals. Within the Baltimore Longitudinal Study of Aging neuroimaging substudy, Participants underwent cognitive assessments and brain 15O-Water Positron Emission Tomography(PET). Plasma PC concentrations (PC16:0/20:5, PC16:0/22:6, PC18:0/22:6), cognitive performance [California Verbal Learning Test (CVLT), Trail Making Test A&B, and the Mini-Mental State Examination, Benton Visual Retention, Card Rotation, and Fluencies - Category and Letter], and rCBF were assessed. Lower plasma PC concentrations were associated with lower baseline memory performance (CVLT long delay recall task - PC1620:-2.09-1.30-0.51 p=0.001 [(β with 95% confidence interval subscripts]) and lower rCBF in several brain regions including those associated with memory performance and higher order cognitive processes. Our findings suggest that lower plasma concentrations of PC16:0/20:5, PC16:0/22:6, PC18:0/22:6 are associated with poorer memory performance as well as widespread decreases in brain function during aging. Dysregulation of peripheral PC metabolism may therefore be a common feature of both AD and age-associated differences in cognition
    Full-text Article · Nov 2015 · Journal of Cerebral Blood Flow & Metabolism
  • Alexandra M Kueider · Madhav Thambisetty · Palchamy Elango · [...] · Luigi Ferrucci
    [Show abstract] [Hide abstract] ABSTRACT: Abstract: Background: Although observational studies have shown Vitamin-D deficiency is associated with increased risk of all-cause dementia, Alzheimer’s disease and age-associated cognitive decline, these results may be influenced by confounding and reverse causation. Examining the relationship between genetic variants regulating vitamin-D levels and brain function/structure may overcome some of these limitations. Methods: Data from non-demented participants in the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses (n=848, mean follow-up interval 10.4 years). Serum concentrations of 25-hydroxyvitamin D [25(OH)D] and single nucleotide polymorphisms (SNPs) in the group-specific component (GC) (rs17467825, rs2282679, rs2298850, rs3755967) gene were examined for associations with cognitive performance using linear mixed models. A composite score of the 4 GC SNPs was created. In data from the BLSA neuroimaging substudy (BLSA-NI, n=120, mean follow-up interval 7.8 years), we tested whether GC SNPs influenced changes in brain volumes during aging. Results: As reported previously, GC SNPs were associated with serum concentration of [25(OH)D]. The minor allele of each GC SNP was associated with a 3.68 nmol/L (95% CI -4.72, -2.65) reduction in serum 25(OH)D. Lower serum [25(OH)D] concentration was associated with poorer performance on the clock drawing to command task at baseline (β=0.02, p=.007). At baseline, the composite GC SNP minor alleles were associated with poorer performance on the clock drawing (3:25 (β=-0.74, p=.01), Boston naming (BNT, β=-0.50, p=.01), Wide Range Achievement Test word reading subcomponent (WRAT; β=-0.44, p=.04) and Rey-Osterrieth Complex Figure-total copy (β=-0.85, p=.02) tests. In longitudinal analyses, minor alleles of GC SNPs were associated with attenuated declines on clock drawing, BNT, WRAT and Rey copy tests. Composite GC SNPs were associated with significantly faster rates of decline in volumes of total gray matter, middle occipital and middle frontal gyri, as well as the cuneus. GCs SNPs were marginally associated with faster declines in occipital gray matter. Conclusions: Vitamin-D exerts both state and trait-dependent effects on brain function and structure during aging. The widespread associations between vitamin-D regulatory SNPs and cognition as well as longitudinal rates of brain atrophy, suggests a mechanistic basis for the relationship between vitamin-D and mental health outcomes during aging.
    Conference Paper · Nov 2015
  • Yi-Fang Chuang · Palchamy Elango · Susan M Resnick · Madhav Thambisetty
    [Show abstract] [Hide abstract] ABSTRACT: Abstract ID: 3882 Abstract: Background: Use of anticholinergic (AC) medications is associated with both acute cognitive impairment and risk of Alzheimer’s disease (AD) in older individuals. However, it is unclear how long-term anticholinergic drug use beginning at earlier ages and the severity of their anticholinergic effects affect risk of AD. Similarly, the effect of such exposure on rates of brain atrophy in cognitively normal older adults is not known. Methods: We followed 723 individuals (mean baseline age 52.3 years, mean follow up interval 20.1 years) in the Baltimore Longitudinal Study of Aging (BLSA) who had at least 3 self-reported medication records between 50-65 years of age. 117 participants developed incident AD (n=70) or Mild Cognitive Impairment (MCI) (n=47) during follow up. The Anticholinergic Cognitive Burden Scale (ACB) is an expert based practical index that classifies drugs as “possible” or “definite” AC according to the serum anticholinergic activities assay and clinically relevant negative cognitive effects. Three groups of longitudinal AC medication exposure were identified: Non-users (n=404), ‘Possible AC users’ (n=185) and ‘Definite AC users’ (participants with any ‘definite’ AC use during follow-up irrespective of concomitant ‘possible’ AC drug use; n=134). The neuroimaging sample included 93 participants who remained cognitively normal during imaging (n=93, 724 brain scans, baseline age; 68.6 years). Longitudinal change in cortical thickness was examined using the linear mixed effects Matlab tool within Freesurfer. Results: After adjusting for sex, race, birth year, years of education, follow-up time, smoking status and medical co-mordities, Cox Proportional hazards model indicated that ‘possible’ AC users, but not ‘definite’ AC users, showed increased risk of incident AD compared to non-users (hazard ratio [HR]= 1.67, 95% confidence interval [CI]=(1.04,2.67), P=0.034). Similarly, ‘possible’ AC users also showed greater atrophy rates in total cortical gray matter volume compared to non-users (β=-0.74, 95% CI=(-1.36, -0.12), P=0.018). Vertex-wise analysis revealed that the right posterior cingulate, right middle frontal and left superior temporal gyri were regions showing accelerated cortical thinning over time (Fig. 1). Conclusions: Long-term exposure to medications with mild anticholinergic activity between midlife and early late life is associated with increased risk of AD and accelerated brain atrophy during aging.
    Conference Paper · Nov 2015
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    Full-text Dataset · Sep 2015
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    Full-text Dataset · Sep 2015
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    Full-text Dataset · Sep 2015
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    Full-text Dataset · Sep 2015
  • Y-F Chuang · Yang An · Murat Bilgel · [...] · Madhav Thambisetty
    [Show abstract] [Hide abstract] ABSTRACT: Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD.Molecular Psychiatry advance online publication, 1 September 2015; doi:10.1038/mp.2015.129.
    Article · Sep 2015 · Molecular Psychiatry
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    [Show abstract] [Hide abstract] ABSTRACT: In this exploratory neuroimaging-proteomic study, we aimed to identify CSF proteins associated with AD and test their prognostic ability for disease classification and MCI to AD conversion prediction. Our study sample consisted of 295 subjects with CSF multi-analyte panel data and MRI at baseline downloaded from ADNI. Firstly, we tested the statistical effects of CSF proteins (n = 83) to measures of brain atrophy, CSF biomarkers, ApoE genotype and cognitive decline. We found that several proteins (primarily CgA and FABP) were related to either brain atrophy or CSF biomarkers. In relation to ApoE genotype, a unique biochemical profile characterised by low CSF levels of Apo E was evident in ε4 carriers compared to ε3 carriers. In an exploratory analysis, 3/83 proteins (SGOT, MCP-1, IL6r) were also found to be mildly associated with cognitive decline in MCI subjects over a 4-year period. Future studies are warranted to establish the validity of these proteins as prognostic factors for cognitive decline. For disease classification, a subset of proteins (n = 24) combined with MRI measurements and CSF biomarkers achieved an accuracy of 95.1% (Sensitivity 87.7%; Specificity 94.3%; AUC 0.95) and accurately detected 94.1% of MCI subjects progressing to AD at 12 months. The subset of proteins included FABP, CgA, MMP-2, and PPP as strong predictors in the model. Our findings suggest that the marker of panel of proteins identified here may be important candidates for improving the earlier detection of AD. Further targeted proteomic and longitudinal studies would be required to validate these findings with more generalisability.
    Full-text Article · Aug 2015 · PLoS ONE

Publication Stats

2k Citations

Institutions

  • 2012-2013
    • King's College London
      • Institute of Psychiatry
      Londinium, England, United Kingdom
  • 2008
    • National Institute on Aging
      Baltimore, Maryland, United States