Association of MRI Visible Perivascular Spaces and Neurofilament Light Chain: The Framingham Heart Study

Background: Neurofilament light chain (NfL) is a marker of neuronal injury. Perivascular spaces (PVS) visible on magnetic resonance imaging (MRI) represent cerebral small vessel disease (CSVD) but their role as markers of neuronal injury needs further clarification. Objective: To relate PVS burden according to brain topography and plasma NfL. Methods: Framingham Heart Study (FHS) participants with brain MRI and NfL measurements were included. PVS were rated in the basal ganglia (BG) and centrum semiovale (CSO) using validated methods and categorized based on counts. A mixed region variable representing high burden PVS in either BG or CSO was assessed. Multivariable linear regression analyses were used to relate PVS burden to log-transformed NfL levels in models adjusted for age, sex, FHS cohort, time between MRI and clinic exam, and image view (model 1), vascular risk factors (model 2), and white matter hyperintensity volume, covert brain infarcts, and cerebral microbleeds (model 3). Results: Among 1,457 participants (68.1 +/- 8.5 years, 45% males), NfL levels increased with higher PVS burden. Multivariable analysis showed an association of high PVS burden strictly in BG with NfL (beta = 0.117, 95% CI 0.014-0.221; p = 0.027), but attenuated in model 3. The associations were mainly in participants >= 65 years (beta = 0.122, 95% CI 0.015-0.229, p = 0.026), women (beta = 0.156, 95% CI 0.024-0.288, p = 0.021), and APOE epsilon 4 non-carriers (beta = 0.140, 95% CI 0.017-0.263, p = 0.026). Conclusions: The association of strictly BG high PVS burden with NfL suggests a role for PVS as markers of neuroaxonal injury, but our results are hypothesis generating and require further replication.