Longitudinal Risk Factor Changes and Early Recognition of Cerebral Small Vessel Disease

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Cerebral small vessel disease (CSVD) is strongly related to Alzheimer’s disease (AD), related dementias (ADRD), stroke, and vascular cognitive impairment,1 is severe in 30–50% of patients with AD,2 and contributes to about 30% of all dementia cases.3 CSVD remains in subclinical stages for years to decades and can be readily assessed using clinical brain MRI. CSVD is most frequently the consequence of long-term exposure to modifiable risk factors, but such risk factors as well as healthy behaviors change within and between individuals over a lifetime and are further altered by treatments. These changing relations with CSVD burden remain to be fully elucidated, which is critical to understand the duration of vascular risk factor exposure that could lead to irreversible brain injury and should prompt assessment of CSVD burden to enhance preventive efforts. Using novel applications of functional data analysis we will leverage the richly characterized long-term data acquired over up to 7 decades of follow-up in the prospective Framingham Heart Study, and readily available traditional MRI (available in clinical practice) to relate trends and duration of exposure to vascular risk factors, American Heart Association (AHA) life’s essential 8 and preventive treatment use to a total CSVD score (T-CSVD) that provides a comprehensive assessment of CSVD manifestations in individuals. We will further study the role of T-CSVD scores for prediction of dementia and stroke using traditional assessments of individual CSVD measures (covert brain infarcts, white matter hyperintensities, cerebral microbleeds, cortical superficial siderosis and enlarged perivascular spaces), and contrast with novel scores incorporating sensitive measures of white matter injury based on diffusion tensor imaging, and molecular imaging based on amyloid and Tau PET measures available in a subset of participants. Success of our exploratory application will provide a practical assessment of total cerebral small vessel disease in relation to incident stroke and dementia, using CSVD measures available in clinical care, and much needed insight into: i) the age at which assessment of CSVD burden should be considered in clinical practice, and/or ii) the duration of exposure to risk factors that should lead to consideration of CSVD burden assessment. If our application is successful, it may change clinical practice to promote assessment of CSVD burden in subclinical stages for early implementation of preventive treatments.