Neuropathological assessment of cerebrovascular integrity in Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy neuropathological change (CTE-NC) is defined by perivascular deposits of phosphorylated tau, with lesions preferentially located at sulcal depths. We investigated whether CTE-NC is associated with structural changes to perivascular spaces (PVSs) or microvascular degeneration. Post-mortem middle frontal gyrus tissue from 11 CTE-NC cases and 11 age-matched controls was examined using immunohistochemistry. All CTE-NC cases exhibited pathognomonic lesions in this region. We quantified PVS width along with vessel lumen and PVS area, string vessel burden, pericyte density, and aquaporin-4 (AQP4) polarisation to the astrocytic endfoot. Total PVS width did not differ significantly between the groups in grey matter (P = 0.543) nor white matter (P = 0.468). Neither PVS area (sulcal depth, P = 0.097; gyral crest, P = 0.645) nor PVS-to-lumen area ratio (sulcal depth, P = 0.454; gyral crest, P = 0.307) differed significantly. Similarly, there were no significant differences in total microvascular length (p = 0.693), string vessel burden (p = 0.128), pericyte density (p = 0.589), or AQP4 endfoot enrichment (p = 0.538). We therefore found no evidence of large-scale PVS enlargement, lumen narrowing, capillary degeneration, pericyte loss, or altered AQP4 endfoot enrichment in CTE-NC at the locations and spatial scales investigated. Taken together, these findings suggest that the pathognomonic perivascular tau lesion is not associated with a classical small vessel degenerative phenotype in CTE-NC. However, that does not exclude more subtle molecular, functional, or ultrastructural changes at the interface between vessels, the perivascular space, and surrounding brain tissue.