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 might reflect impaired glymphatic drainage. The mechanisms underlying enlargement of perivascular spaces are not fully understood, but both increased inflammation and blood-brain barrier (BBB) permeability have been hypothesized to play a role. We investigated the relationship between perivascular spaces and both CNS and peripheral inflammation, in addition to BBB permeability, in cerebral small vessel disease. Fifty-four symptomatic sporadic cerebral small vessel disease patients were studied. Perivascular spaces were quantified both using a visual rating scale and by measurement of the volume of perivascular spaces in the white matter and the basal ganglia. PET-MRI was used to measure microglial activation using the radioligand 11C-PK11195, and simultaneously, BBB permeability was acquired using dynamic contrast-enhanced MRI. We determined 11C-PK11195 binding and BBB permeability in the local vicinity of individual perivascular spaces in concentric shells surrounding the perivascular spaces. In addition, both mean 11C-PK11195 binding and BBB permeability in both the white matter and the 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 (ρ = 0.469, false discovery rate-corrected P = 0.009); values for the volume of perivascular spaces showed a similar trend. In contrast, there were no associations between the burden of basal ganglia perivascular spaces and 11C-PK11195 binding. No marker of perivascular spaces was correlated with blood-brain barrier permeability. There was no association between markers of perivascular spaces and blood biomarkers of systemic inflammation. Our findings demonstrate that white matter perivascular spaces are associated with increased 11C-PK11195 binding, consistent with neuroinflammation playing a role in enlargement of white matter perivascular spaces. Further longitudinal and intervention studies are required to determine whether the relationship between neuroinflammation and enlarged perivascular spaces is causal.