Vascular Contributors to Blood Brain Barrier Permeability and Regional White Matter Hyperintensity Progression in Young Asymptomatic People

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Project Summary: White matter hyperintensities (WMHs) of the brain are a phenotype of cerebrovascular small vessel disease (cSVD) and estimated to represent 40% of the cSVD disease burden . The WMH phenotype is closely associated with damage to the neurovascular unit and is thought to contribute to cognitive impairment, deficits in motor control, and stroke. Understanding how WMHs are affected by vascular risk factors and progress over time is a part of a national research priority of understanding vascular contributions that influence cognitive decline and dementia (VCID). There is a knowledge gap about how WMHs progress in younger age groups (age 40-50). This study addresses two issues of significance regarding early progression: (i) how periventricular WMHs (PVWMHs) and subcortically located deep WMHs (DWMHs) progress independently and influence different clinical outcomes and (ii) how increasing blood–brain barrier (BBB) permeability and microvascular changes are associated with lesion expansion. This study adds to the understanding of the pathophysiology of WMH progression, supporting the development of earlier prevention and mitigation. GeneSTAR is a vascular study of asymptomatic younger (age 40-50) siblings of patients with premature coronary artery disease enriched for WMH. The GeneSTAR population is deeply phenotyped for vascular properties, has a high prevalence of asymptomatic WMHs, and is relatively young at the time of first MRI. We will leverage these features and our experience studying PVWMH, DWMH, and BBB permeability by recalling these participants and repeating the 3T MRI volumetrics with adding two independent measures of BBB permeability. This study will include relatively young African American and European American adults (n=500) with a mean age of 50.8±10.4 at baseline in GeneSTAR and will now reimage them at age 61.9±10.5 years. We will relate any changes in WMH volume to: (i) vascular risk factors (hypertension, diabetes, blood lipids, smoking), (ii) changes in vascular function (carotid artery wall stiffness, pulse pressure, and brachial arterial diameter), and (iii) changes in cognitive function (immediate memory, working memory, information retrieval, multi-domain cognitive skills, and motor function). We also will recall 130 of our proposed participants in years 4 and 5 to study the relationship between WMH progression and increases in BBB permeability and mean transit time (MTT) using serial imaging. This second MRI at year 3 or 4 has the goal of measuring the interval change in all MRI phenotypes measured at year 1 and relate WMH volume progression to BBB permeability and mean transit time measured in year 1 to that at years 4 or 5. We will study how changes in BBB permeability and perfusion are: (i) related to WMH volume changes, (ii) affected by vascular risk factors, and (iii) associated with cognitive changes.