Blood-brain barrier leakage and perivascular inflammation in cerebral amyloid angiopathy

Cerebral amyloid angiopathy is a small vessel disease associated with cortical microbleeds and lobar intracerebral haemorrhage due to amyloid-β deposition in the walls of leptomeningeal and cortical arterioles. The mechanisms of cerebral amyloid angiopathy-related haemorrhage remain largely unknown. Recent work has demonstrated that ruptured blood vessels have limited (or no) amyloid-β at the site of bleeding and evidence of local vascular remodelling. We hypothesized that blood-brain barrier leakage and perivascular inflammation may be involved in this remodelling process. This study examined cortical arterioles at various stages of cerebral amyloid angiopathy-related vascular pathology (without evidence of microhaemorrhage) in autopsy tissue from seven cases with definite cerebral amyloid angiopathy. We included temporo-occipital sections with microbleeds guided by ex vivo MRI from two cases with severe cerebral amyloid angiopathy and systematically sampled occipital sections from five consecutive cases with varying cerebral amyloid angiopathy severity. Haematoxylin and eosin stains and immunohistochemistry against amyloid-β, fibrin(ogen), smooth muscle actin, reactive astrocytes (glial fibrillary acidic protein) and activated microglia (cluster of differentiation 68) were performed. Arterioles were graded using a previously proposed scale of individual vessel cerebral amyloid angiopathy severity, and a blinded assessment for blood-brain barrier leakage, smooth muscle actin and perivascular inflammation was performed. Blood-brain barrier leakage and smooth muscle actin loss were observed in significantly more vessels with mild amyloid-β deposition (Grade 1 vessels; P = 0.044 and P = 0.012, respectively) as compared to vessels with no amyloid-β (Grade 0), and blood-brain barrier leakage was observed in 100% of vessels with evidence of vessel remodelling (Grades 3 and 4). Perivascular inflammation in the form of reactive astrocytes and activated microglia was observed predominantly surrounding arterioles at later stages of vessel pathology (Grades 2-4) and consistently around vessels with the same morphological features as ruptured vessel segments (Grade 4). These findings suggest a role for blood-brain barrier leakage and perivascular inflammation leading to arteriolar remodelling and haemorrhage in cerebral amyloid angiopathy, with early blood-brain barrier leakage as a potential trigger for subsequent perivascular inflammation.