Blood-Brain Barrier Permeability and Inflammation in Cerebral Small Vessel Disease
University of Cambridge
Doctor of Philosophy (PhD)
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Walsh, J. (2020). Blood-Brain Barrier Permeability and Inflammation in Cerebral Small Vessel Disease (Doctoral thesis). https://doi.org/10.17863/CAM.50869
Introduction: Cerebral small vessel disease (SVD) is responsible for a third of strokes and is the most common cause of vascular dementia. It is characterised by white matter lesions and more diffuse damage outside of the lesions. Despite its importance, the mechanisms causing white matter damage are incompletely understood. Both increased blood-brain barrier (BBB) permeability and inflammation have been suggested to play a role. We hypothesised that BBB permeability and microglia activation would be increased in SVD and explored the relationship between these processes and other imaging, cognitive and blood markers. Methods: A PET/MR system was used to acquire simultaneous dynamic contrast enhanced MRI with Patlak modelling to measure BBB leakage, and [C11]PK-11195 PET to assess microglia activation. We recruited 20 sporadic SVD patients, 20 monogenic SVD patients (CADASIL) and 20 healthy controls to this study. Results: BBB permeability in the white matter of the sporadic SVD group was significantly higher than control (p=0.001), with a significantly higher volume of focal hotspots (p=0.010). The focal hotspots of activated microglia also had a significantly higher mean in the white matter (p<0.001). The role of BBB permeability and PK binding in CADASIL was less clear, with no difference in permeability but a significantly higher mean of focal hotspot of activated microglia in the CADASIL white matter, compared to control (p=0.015). In the sporadic SVD and CADASIL groups, the number of voxels containing both significant permeability and microglia activation was significantly lower than expected (p<0.001). Conclusion: Areas of focal increase in both BBB permeability and microglia activation occur in SVD and therefore may have a role in the pathophysiology of white matter damage. In this cross-sectional dataset, the two processes were spatially independent of one-another. However, we cannot exclude a temporal relationship, where one process may precede another, without follow-up data. Further research is needed to see if these markers predict white matter damage in longitudinal studies, and whether they can be altered therapeutically.
Small Vessel Disease, Blood-Brain Barrier, CADASIL, Stroke, Inflammation, MRI, PET, Imaging, Neuroimaging
Funded by British Heart Foundation Clinical Research Excellence non-clinical PhD Studentship and Medical Research Council Experimental Medicine grant.
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This record's DOI: https://doi.org/10.17863/CAM.50869
All rights reserved, Licensee: University of Cambridge Order Date: Oct 16, 2019 Order Number: 4690890201468 Publication: The Lancet Neurology Title: Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration Type of Use: reuse in a thesis/dissertation Licensee: University of Cambridge Order Date: Oct 16, 2019 Order Number: 4690881088032 Publication: The Lancet Neurology Title: Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges Type of Use: reuse in a thesis/dissertation Licensee: University of Cambridge Order Date: Oct 16, 2019 Order Number: 4690890838360 Publication: Journal of Neurochemistry Title: Binswanger's disease: biomarkers in the inflammatory form of vascular cognitive impairment and dementia Type of Use: Dissertation/Thesis Licensee: University of Cambridge Order Date: Oct 16, 2019 Order Number: 4690891290785 Publication: Neurobiology of Disease Title: Structure and function of the blood–brain barrier Type of Use: reuse in a thesis/dissertation