Perivascular space dysfunction in cerebral small vessel disease is related to neuroinflammation

Enlarged perivascular spaces are a feature of cerebral small vessel disease, and it has been hypothesized that they may reflect impaired glymphatic drainage. The mechanisms underlying perivascular spaces enlargement are not fully understood, but both increased inflammation and blood brain barrier permeability have been hypothesized to play a role. We investigated the relationship between perivascular spaces and both CNS and peripheral inflammation, as well as blood brain barrier permeability, in cerebral small vessel disease. Fifty-four symptomatic sporadic cerebral small vessel disease patients were studied. perivascular spaces were quantified using both a visual rating scale, and by measurement of perivascular spaces volume, in both the white matter and basal ganglia. PET-MRI was used to simultaneously measure microglial activation using the radioligand 11C-PK11195, and blood brain barrier permeability was acquired using dynamic contrast enhanced MRI. We determined 11C-PK11195 binding and blood brain barrier permeability in the local vicinity of individual perivascular spaces in concentric shells surrounding perivascular spaces. In addition, both mean 11C-PK11195 binding and blood brain barrier permeability in both the white matter and basal ganglia were determined. To assess systemic inflammation a panel of 93 blood biomarkers relating to cardiovascular disease, inflammation and endothelial activation were measured. Within the white matter tissue in closest proximity to perivascular spaces displayed greater 11C-PK11195 binding (p < 0.001), in the vicinity of perivascular spaces. Higher white matter perivascular spaces burden on the visual rating scale was associated with higher white matter 11C-PK11195 binding (rho = 0.469, FDR-p =0.009); values for perivascular spaces volume showed a similar trend. In contrast there were no associations between basal ganglia perivascular spaces burden and 11C-PK11195 binding. No perivascular spaces marker correlated with blood brain barrier permeability. There was no association between perivascular spaces markers and systemic inflammation blood biomarkers. Our findings demonstrate that white matter perivascular spaces are associated with increased 11C-PK11195 binding, consistent with neuroinflammation playing a role in white matter perivascular spaces enlargement. Further longitudinal and intervention studies and required to determine whether the relationship between neuroinflammation with enlarged perivascular spaces is causal.