Cerebral Small Vessel Disease (SVD) is an important, potentially modifiable factor for clinical dementia. Recent data suggest that the age-specific incidence of dementia may be decreasing, partly as a result of better management of vascular risk factors, lending urgency to dementia prevention trials but a major impediment is the absence of circulating biomarkers for tracking onset and progression of SVD. Brain MRI imaging markers are the current gold standard for SVD but are too expensive and burdensome for repeated assessments. Recent genetic studies, including from the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) consortium, implicate microglial inflammation and astroglia in the biology of SVD and dementia. We propose to measure 2 circulating biomarkers of microglial inflammation (sCD-14 and YKL-40) and a marker of astroglial injury (GFAP) in ~17,000 persons (including 4000 minority participants, 6000 with >2 MRI) across 5 CHARGE population-based cohorts. Specifcally, we will (1) examine the association of the novel biomarkers with (a) previously collected MRI-defined SVD (white matter hyperintensities, lacunar infarcts and cerebral microbleeds), and in persons under age 70, sensitive MRI measures of early, preclinical SVD such as fractional anisotropy on diffusion- weighted imaging, regional cortical thinning and perivascular spaces; (b) previously collected measures of cognitive function; and (c) neurocognitive and vascular consequences of SVD (dementia and stroke). We will use a Mendelian Randomization framework and existing genetic data to examine causal relationships between the novel biomarkers and MRI, neurocognitive, and clinical outcomes. (2) We will assess the incremental predictive utility of the novel biomarkers over (a) vascular risk factor profiles such as the Framingham Stroke Risk Prediction score; (b) over a panel of previously measured `candidate' biomarkers for SVD including CRP, IL6, TNF-alpha, fibrinogen, BNP, urine albumin, tHcy, ST2, GDF15, TnI, BDNF, VEGF, MMP-9, beta-amyloid, clusterin and APOE and (c) we will identify a parsimonious set of biomarkers that best predict presence of SVD and risk of cognitive decline, stroke and dementia. (3) We will (a) validate the prediction models developed in Aim 2 in independent samples, (b) extend the biological associations and improve clinical prediction models through hypothesis-free exploration of multi-dimensional omics (whole genome, GWAS, epigenetic and gene expression) and (c) investigate the added predictive value of risk models that combine genetic, epigenetic, transcriptomic information over models that consider only risk factor and serum biomarker information. In summary we propose to leverage extensive available data to identify and validate a novel circulating biomarker profile of glial cell dysfunction that will improve our understanding of SVD biology and help in the prediction of SVD and its associated adverse neurological outcomes.

Public Health Relevance

To develop novel predictive biomarkers of cerebral small vessel disease (SVD), we propose to measure two circulating biomarkers of microglial inflammation (sCD-14 and YKL-40) and a marker of astroglial injury (GFAP) in ~17,000 persons from 5 population-based cohorts. We will examine the causal relationships of these biomarkers with MRI-defined SVD and its associated neurocognitive and neurovascular outcomes and we will assess the incremental predictive utility of the novel biomarkers over previously established clinical and risk factor data. We will incorporate genetic, epigenetic, transcriptomic information to improve our understanding of the role of glial cell dysfunction in SVD biology and develop improved prediction models of SVD risk and development of adverse neurological outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
Project #
1UH2NS100605-01
Application #
9272153
Study Section
Special Emphasis Panel (ZNS1-SRB-T (19))
Program Officer
Mcgavern, Linda
Project Start
2016-09-30
Project End
2021-08-31
Budget Start
2016-09-30
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$1,037,671
Indirect Cost
$60,271
Name
Boston University
Department
Neurology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Pase, Matthew P; Seshadri, Sudha; Jacques, Paul F (2017) Response by Pase et al to Letter Regarding Article, ""Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia: A Prospective Cohort Study"". Stroke 48:e181
Pase, Matthew P; Himali, Jayandra J; Seshadri, Sudha et al. (2017) Response by Pase et al to Letter Regarding Article, ""Sweetened Beverages and the Risks of Incident Stroke and Dementia"". Stroke 48:e269
Lin, Honghuang; Satizabal, Claudia; Xie, Zhijun et al. (2017) Whole blood gene expression and white matter Hyperintensities. Mol Neurodegener 12:67
Pase, Matthew P; Himali, Jayandra J; Beiser, Alexa S et al. (2017) Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia: A Prospective Cohort Study. Stroke 48:1139-1146
Saber, Hamidreza; Himali, Jayandra J; Beiser, Alexa S et al. (2017) Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study. Stroke 48:1760-1765
Pase, Matthew P; Satizabal, Claudia L; Seshadri, Sudha (2017) Role of Improved Vascular Health in the Declining Incidence of Dementia. Stroke 48:2013-2020
Pase, Matthew P; Himali, Jayandra J; Beiser, Alexa et al. (2017) Response by Pase et al to Letters Regarding Article, ""Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia. A Prospective Cohort Study"". Stroke :
Adams, Shayna; Conner, Sarah; Himali, Jayandra J et al. (2017) Vascular risk factor burden and new-onset depression in the community. Prev Med :