White Matter Hyperintensity-Associated Blood-Brain Barrier Disruption and Vascular Risk Factors
Introduction
The clinical significance and pathogenesis of white matter hyperintensities (WMH), detected on T2-weighted magnetic resonance imaging (MRI) sequences, remain unclear. WMH occur with normal aging; when progressive, they are associated with cognitive decline.1 WMH are also associated with vascular risk factors (VRF)2; untreated hypertension (HTN) is associated with WMH progression.3 However, VRF account for only a small fraction of WMH pathogenesis,4 suggesting WMH may be a final common pathway for multiple etiologies. A recent consensus statement on subcortical small vessel disease drew a distinction between WMH caused by recurrent lacunar stroke and WMH that accumulates as part of an insidious process.5
In some patients, WMH are associated with blood–brain barrier (BBB) disruption.6 Such BBB disruption is often found at the edge of the WMH involving the normal appearing white matter (NAWM).7 It has been hypothesized that BBB disruption reflects an active chronic inflammatory process and may precede WMH progression.8 The relationship between VRF and BBB disruption is not known. Therefore, the purpose of this study was to examine a cohort of stroke patients with WMH to look for associations between VRF and BBB disruption.
Section snippets
Population
Pretreatment MRIs of patients presenting with acute ischemic stroke who were enrolled in the Institutional Review Board approved NIH Natural History of Stroke Study from 1999 to 2009 were reviewed for the presence of WMH on fluid-attenuated inversion recovery (FLAIR) sequences. MRIs of untreated patients during that time period were also reviewed if their NIH stroke scale was greater than 3. Patients were included in this study if: (1) their FLAIR scan demonstrated confluent WMH and (2) they
Results
Of the 1193 patients screened for this study, 247 had confluent WMH. Of those patients 92 had PWI source images. Of those patients, 65 had adequate BBB modeling (average r2 >.85) and were included in the study. The mean age of the cohort was 79, and it was predominantly female (78%). The median National Institutes of Health Stroke Scale was 8, and 26% of them were treated with intravenous tissue plasminogen activator. Of note, MRI scans used for this analysis were all obtained prior to any
Discussion
We screened several VRF to see if they were associated with an increase in BBB disruption in stroke patients with WMH. We found no positive associations; however, in this population of patients selected due to the presence of WMH, BBB disruption was less severe in patients with a history of HTN. Patients with a history of HTN also had a different distribution of WMH, with greater involvement of the periventricular regions than patients without HTN.
These findings are exploratory and need further
Acknowledgment
This research was possible because of contributions from the NIH Natural History of Stroke Investigators: Richard T. Benson, Amie W. Hsia, Lawrence L. Latour, Richard Leigh, Marie Luby, John K. Lynch, Jose G. Merino, Zurab Nadareishvili, and Steven J. Warach.
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Grant support: All of the authors are supported by the Intramural Program of NIH, NINDS.
Conflict of interest: The authors have nothing to disclose.