Description (from grant): 

Small vessel disease (SVD) manifests as age-related diffuse white matter hyperintensities (WMHs) on T2-weighted brain MRI scans. SVD is believed to be a common cause of vascular cognitive impairment in the elderly. We will characterize the underlying vascular pathophysiological changes of WMHs using non-invasive and multimodal MRI measures and follow them over a period of 2.5 years in an elderly population with diverse WMH burdens. Such in vivo and quantitative information at baseline and follow up is crucial for the mechanistic understanding of WMHs and SVD pathology during normal and abnormal aging processes.

Although WMHs have been thought to play a significant role in vascular cognitive impairment and dementia, much remains to be discovered about their pathophysiological cause, cognitive outcome, and progression over time. Much of what is known about the underlying pathophysiology of WMHs is derived predominately from post-mortem studies, which mainly reveal demyelination and axonal degeneration. Due to the limitations of such one-shot in vitro exams at the end-stage of the disease, postmortem studies lack the critical data needed to characterize the hemodynamic and functional correlates of WMHs. Utilizing an in vivo study will thus be more useful in understanding the pathophysiological characteristics that underpin microcirculation and microstructural changes associated with development and evolution of WMHs. The main objective of this study is to use recently developed multimodal advanced MRI techniques to non-invasively characterize and monitor the vascular pathophysiological changes associated with WMHs over time in the elderly, including cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebrovascular reactivity (CVR), as well as blood-brain barrier (BBB) water exchange disruption. We hypothesize that the novel quantitative information integrated from this study will help understand relevant microvascular components related to the possible causes of WMHs and are markers for their progression over time. Aim 1: Determine hemodynamic profiles (i.e., CBF, CBV, and CVR) in the core and periphery of both deep and periventricular WMHs as well as NAWM and correlate these vascular measurements with microstructural indices such as fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging (DTI). Aim 2: Examine the associations between the local measures of WMHs (i.e., volume and Fazekas score) and global measures of BBB exchange rate (BBB-x) and neural activity (i.e. cerebral metabolic rate of oxygen or CMRO2) of whole brain (i.e. tissues outside the WMH). Aim 3: Conduct a 30-month (2.5-year) follow-up study of the cohort. We will examine whether increasing WMH burden and worsening clinical symptoms are accompanied by deterioration of physiological parameters such as BBB-x and CMRO2. We will also determine which vascular parameter(s) can predict the conversion from tissue at risk in the periphery (“penumbra”) or NAWM to WMH over the follow-up period. If successful, this study will provide comprehensive, and newly uncovered, in vivo insights into the microvascular links to formation and progression of WMHs.


Lin Z, Li Y, Su P, Mao D, Wei Z, Pillai JJ, Moghekar A, van Osch M, Ge Y, Lu H. Non-contrast MR imaging of blood-brain barrier permeability to water. Magn Reson Med. 2018 Oct;80(4):1507-1520.