GeneSTAR Research Center - Genetic Studies of Atherosclerosis Risk
Small Vessel Cerebrovascular Disease Cognition and Vascular Aging 
  
Our work in brain vascular disease is represented by a series of studies in GeneSTAR participants using brain magnetic resonance imaging (3 Tesla) to examine pre-clinical small vessel cerebrovascular disease in high risk European and American families. Done in concert with the Departments of Neurology and Neuroradiology, the GeneSTAR studies are ongoing and more recently include gadolinium imaging for evaluation  of the blood brain barrier and a search for novel biomarkers of premature aging in the brain, or precursors to cognitive decline. .We have a particular interst in serial measures of white matter hyperintensities, brain atrophy, and functional  cognitive measures. 
 
Small vessel cerebrovascular disease (SVCD) is generally silent and is identified by white matter hyperintensities and small focal brain infarcts on magnetic resonance imaging (MRI). These lesions double the risk of subsequent stroke. We found a markedly increased prevalence of silent SVCD (73-90%) on MRI in  apparently healthy middle-aged siblings of probands with known premature coronary artery disease (CAD). Siblings also underwent exercise perfusion tomography to detect occult CAD. Of subjects with occult CAD, 88% had any SVCD, and 62% had significant SVCD on MRI, while only 5.5% without occult CAD had these findings.There is a relationship between vascular disease in the brain nad in the heart.
 
Our discovery that occult CAD and SVCD appear to co-occur in premature CAD families provided an opportunity to study models for pre-clinical small vessel disease in the brain and heart. In both clinically manifest strokes and CAD, classical risk factor models markedly underestimate incident events, suggesting that other factors, including genetic susceptibility, may be contributory. In addition, there is strong clustering of both cerebrovascular disease and CAD in families, consistent with a genetic contribution to the disease process.
 
 
To determine potential shared and unique mechanism-derived biomarkers and known risk factors related to pre-clinical vascular disease in the brain and the heart, and the contribution of attendant mechanism-specific genes, we are conducting a series of cross-sectional and  longitudinal  epidemiologic studies of the of  SVCD using MRI determination of white matter hyperintensity volumes and ratios, lacunar infarcts, and occult CAD using stress sestamibi tomography of the hear as well as CT angiogrpahy.
 
We have used novel biological models of vascular disease to select measurements of mechanism-derived inflammatory (IL-6, TNF-α, hs-CRP, sVCAM-1, sICAM1, and MCP-1) and prothrombotic factors (PAI-1, Lp(a) and fibrinogen), endothelium dependent vascular reactivity of the brachial artery, and traditional vascular disease risk factors. More recently our work has included studies of monocytes and inflammation.
 
We are examining examine biomarkers in 800 apparently healthy 35-80 year old siblings and adult offspring from GeneSTAR families with documented premature CAD. We will also examine associations between genetic variants and SVCD using candidate genes. WGS, and GWAS. 
 

This study is the first to examine small vessel disease in the brain and concommitantly  the heart in high risk family members who are notably susceptible to coronary heart disease and cerebrovascular disease. The study also includes extensive characterization of cognitive function and measures of mental well being, as well as comorbid events that may predispose to the neurocognitive decline associated with aging.  The study is spearheaded by Dr. Paul A. Nyquist.  MRI analysis  support is provided by Dr.Jerry Prince William B. Kouwenhoven Professor of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University. 
 
 
 
Paul A. Nyquist, MD
Associate Professor, Neurology
Principal Investigator



Collaborators 

Jerry L. Prince, Ph.D
William B. Kouwenhoven Professor Elictrical and Computer Engineering
Joint appointments, Radiology and Biomedical Engineering

Norman Haughey, PhD
Professor and Vice Chair of Reserach Department of Neurology

Peter C.M. Van Zijl, Ph.D.
Department of Radiology and Radiological Science