title: Parenchymal cystatin C focal deposits and glial scar formation around brain arteries in Hereditary Cystatin C Amyloid Angiopathy.
abstract: Hereditary Cystatin C Amyloid Angiopathy (HCCAA) is an amyloid disorder in Icelandic families caused by an autosomal dominant mutation in the cystatin C gene. Mutant cystatin C forms amyloid deposits in brain arteries and arterioles which are associated with changes in the arterial wall structure, notably deposition of extracellular matrix proteins. In this post-mortem study we examined the neuroinflammatory response relative to the topographical distribution of cystatin C deposition, and associated haemorrhages, in the leptomeninges, cerebrum, cerebellum, thalamus, and midbrain of HCCAA patients. Cystatin C was deposited in all brain areas, grey and white matter alike, most prominently in arteries and arterioles; capillaries and veins were not, or minimally, affected. We also observed perivascular deposits and parenchymal focal deposits proximal to affected arteries. This study shows for the first time, that cystatin C does not exclusively form CAA and perivascular amyloid but also focal deposits in the brain parenchyma. Haemorrhages were observed in all patients and occurred in all brain areas, variable between patients. Microinfarcts were observed in 34.6% of patients. The neuroinflammatory response was limited to the close vicinity of affected arteries and perivascular as well as parenchymal focal deposits. Taken together with previously reported arterial accumulation of extracellular matrix proteins in HCCAA, our results indicate that the central nervous system pathology of HCCAA is characterised by the formation of a glial scar within and around affected arteries.
authors.affiliation: Institute for Experimental Pathology at Keldur, University of Iceland, Reykjavik, Iceland.
authors.forename: Asbjorg
authors.initials: A
authors.lastname: Osk Snorradottir
authors.affiliation: Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Helgi J
authors.initials: HJ
authors.lastname: Isaksson
authors.affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; DZNE, German Centre for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Kaeser
authors.affiliation: DZNE, German Centre for Neurodegenerative Diseases, Tübingen, Germany; Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Angelos A
authors.initials: AA
authors.lastname: Skodras
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; BioMedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland.
authors.forename: Astridur
authors.initials: A
authors.lastname: Palsdottir
authors.affiliation: Institute for Experimental Pathology at Keldur, University of Iceland, Reykjavik, Iceland; BioMedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Iceland. Electronic address: birkirbr@hi.is.
authors.forename: Birkir
authors.initials: B
authors.lastname: Thor Bragason
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D020520:Brain Infarction / Q000473:pathology / Q000503:physiopathology; D002135:Calcium-Binding Proteins; D028243:Cerebral Amyloid Angiopathy, Familial / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000473:pathology; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology*; D055316:Cystatin C / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D009457:Neuroglia / Q000473:pathology*; D015213:Neuroimmunomodulation / Q000502:physiology; D055815:Young Adult; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D055316:Cystatin C; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; C112986:AIF1 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C525030:CST3 protein, human
keywords: Cystatin C distribution; Focal deposits; Glial scar; Hereditary Cystatin C Amyloid Angiopathy; Neuroinflammation