title: Pathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy.
abstract: Hereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.
authors.affiliation: Institute for Experimental Pathology at Keldur, University of Iceland, Reykjavik, Iceland.|Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Asbjorg Osk
authors.initials: AO
authors.lastname: Snorradottir
authors.affiliation: Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Helgi J
authors.identifier: 0000-0002-1024-686X
authors.initials: HJ
authors.lastname: Isaksson
authors.affiliation: Stem Cell Research Unit, Biomedical Center, University of Iceland, Reykjavik, Iceland.|Department of Laboratory Haematology, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Saevar
authors.initials: S
authors.lastname: Ingthorsson
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Department of Neurology, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Elias
authors.initials: E
authors.lastname: Olafsson
authors.affiliation: Institute for Experimental Pathology at Keldur, University of Iceland, Reykjavik, Iceland.
authors.forename: Astridur
authors.initials: A
authors.lastname: Palsdottir
authors.affiliation: Institute for Experimental Pathology at Keldur, University of Iceland, Reykjavik, Iceland.
authors.forename: Birkir Thor
authors.initials: BT
authors.lastname: Bragason
mesh_terms: D000328:Adult; D000368:Aged; D001485:Basement Membrane / Q000378:metabolism* / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism*; D024141:Collagen Type IV / Q000378:metabolism; D003238:Connective Tissue / Q000378:metabolism* / Q000473:pathology; D055316:Cystatin C / Q000235:genetics / Q000378:metabolism*; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D024141:Collagen Type IV; D055316:Cystatin C