MICROVASCULAR DEGENERATION IN HEREDITARY CYSTATIN-C AMYLOID ANGIOPATHY OF THE BRAIN

Hereditary cystatin C amyloid angiopathy (HCCAA), an autosomal dominan t form of cerebral amylold angiopathy (CAA) occurring primarily in Ice land, is characterized by a variant cystatin C amyloid deposition in t he walls of cerebral parenchymal and leptomeningeal vessels. Cystatin C is also found to colocalize with amyloid beta/A4 protein in cerebral Vessel walls of patients with Alzheimer's disease (AD), sporadic CAA, and hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHW AD). The abundance of cystatin C deposition in cerebral blood vessel w alls suggests that cellular elements of the vessel wall itself may pla y a role in its deposition. Microvascular changes in the brains of HCC AA patients were investigated by single- and double-label immunohistoc hemistry. We found that cystatin C amyloid immunoreactivity was presen t not only in cerebral cortical and leptomeningeal vessels, but also i n white matter parenchymal vessels. Cystatin C deposition was more pro minent in the media of parenchymal vessels and in the adventitia of le ptomeningeal vessels. Smooth muscle (sm) cells were few or could not b e identified within vessel walls showing extensive cystatin C depositi on, suggesting progressive loss of these cells as cystatin C accumulat es. However, in less severely affected vessels, cystatin C was present in cells that also had the phenotype of sm, suggesting that sm cells synthesize or process cystatin C. Cystatin C immunoreactivity was in a ddition, detected in some neuronal cell bodies throughout the cortex i n patients with HCCAA and AD-related CAA. Our results indicate that ce llular components of the Vessel walls may play an important role in cy statin C deposition, as they do in beta/A4 deposition in AD-related CA A. Cystatin C deposition within the vascular media and adventitia, wit h associated vessel wall injury as manifested by sm cell loss, represe nts microvascular degeneration that leads to cerebral hemorrhage.