• Deposition of collagen IV and aggrecan in leptomeningeal arteries of hereditary brain haemorrhage with amyloidosis.

      Snorradottir, Asbjorg Osk; Isaksson, Helgi J; Kaeser, Stephan A; Skodras, Angelos A; Olafsson, Elias; Palsdottir, Astridur; Bragason, Birkir Thor; Univ Iceland, Inst Expt Pathol Keldur, IS-112 Reykjavik, Iceland, Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland, Univ Tubingen, Hertie Inst Clin Brain Res, Dept Cellular Neurol, Tubingen, Germany, German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany, Univ Iceland, Fac Med, IS-112 Reykjavik, Iceland, Landspitali Univ Hosp, Dept Neurol, Reykjavik, Iceland (Elsevier Science BV, 2013-10-16)
      Hereditary Cystatin C Amyloid Angiopathy (HCCAA) is a rare genetic disease in Icelandic families caused by a mutation in the cystatin C gene, CST3. HCCAA is classified as a cerebral amyloid angiopathy and mutant cystatin C forms amyloid deposits in cerebral arteries resulting in fatal haemorrhagic strokes in young adults. The aetiology of HCCAA pathology is not clear and there is, at present, no animal model of the disease. The aim of this study was to increase understanding of the cerebral vascular pathology of HCCAA patients with an emphasis on structural changes within the arterial wall of affected leptomeningeal arteries. Examination of post-mortem samples revealed extensive changes in the walls of affected arteries characterised by deposition of extracellular matrix constituents, notably collagen IV and the proteoglycan aggrecan. Other structural abnormalities were thickening of the laminin distribution, intimal thickening concomitant with a frayed elastic layer, and variable reduction in the integrity of endothelia. Our results show that excess deposition of extracellular matrix proteins in cerebral arteries of HCCAA is a prominent feature of the disease and may play an important role in its pathogenesis.
    • Parenchymal cystatin C focal deposits and glial scar formation around brain arteries in Hereditary Cystatin C Amyloid Angiopathy.

      Osk Snorradottir, Asbjorg; Isaksson, Helgi J; Kaeser, Stephan A; Skodras, Angelos A; Olafsson, Elias; Palsdottir, Astridur; Thor Bragason, Birkir; [ 1 ] Univ Iceland, Inst Expt Pathol, Keldur, IS-112 Reykjavik, Iceland [ 2 ] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland [ 3 ] Univ Tubingen, Dept Cellular Neurol, Hertie Inst Clin Brain Res, Tubingen, Germany [ 4 ] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany [ 5 ] Univ Iceland, Fac Med, IS-112 Reykjavik, Iceland [ 6 ] Landspitali Univ Hosp, Dept Neurol, Reykjavik, Iceland [ 7 ] Univ Iceland, Fac Med, Sch Hlth Sci, Biomed Ctr, IS-112 Reykjavik, Iceland (Elsevier Science BV, 2015-10-05)
      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.