Global Blood-Brain Barrier Disruption and Post-Stroke Cognitive Decline

Project Summary/Abstract This study is focused on expanding our understanding of post-stroke cognitive impairment and dementia (PSCID). Studies have found that patients who suffer a stroke are at increased risk for developing subsequent cognitive decline. While this has been demonstrated epidemiologically, the mechanism by which this occurs is not known. PSCID is a form of vascular cognitive impairment and dementia (VCID). VCID has been linked to progressive changes in the white matter, referred to as white matter hyperintensities (WMH), that are readily seen on magnetic resonance imaging (MRI). It has been hypothesized that disruption of the blood-brain barrier (BBB) precedes the development of WMH. Thus, imaging the BBB may be a way to determine who is at risk for developing VCID. It is the central hypothesis of this proposal that PSCID is due to acceleration of VCID brought on by the acute ischemic event and is characterized by global disruption of the BBB which precedes the development of WMH. Thus we aim to: 1) Test if BBB disruption detected on routine clinical MRI scans of the brain is predictive of PSCID, 2) Study the mechanism of progressive WMH in post-stroke patients using serial research MRI scans to measure BBB disruption of normal appearing white matter before it progresses to WMH, and 3) Translate a novel MRI method into the clinical setting that uses arterial spin labeling (ASL) to measure BBB disruption without the administration of exogenous contrast. To achieve these objectives patients will be recruited from hospitals in the Johns Hopkins Health System. Patients will be followed with serial cognitive testing to detect cognitive decline over a 3-year period. BBB measurements will be extracted from the MRI scans done at the time of the evaluation for acute stroke. A subset of patients will be followed with serial research MRIs. Research MRIs will be used to track the progression of NAWM to WMH and its relationship to BBB disruption. These research MRIs will also implement a novel ASL method for measuring BBB permeability to determine if this method could be used instead of contrast-based methods. The long-term goal of this research is to validate a biomarker for the pathogenesis of PSCID such that patients at risk can be identified for therapeutic trials and potential therapeutics can be screened for their effect on the pathology.