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Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease

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Abstract

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid β-protein (Aβ) within cerebral vessels. The involvement of different brain areas in CAA follows a hierarchical sequence similar to that of Alzheimer-related senile plaques. Alzheimer’s disease patients frequently exhibit CAA. The expansion of CAA in AD often shows the pattern of full-blown CAA. The deposition of Aβ within capillaries distinguishes two types of CAA. One with capillary Aβ-deposition is characterized by a strong association with the apolipoprotein E (APOE) ε4 allele and by its frequent occurrence in Alzheimer’s disease cases whereas the other one lacking capillary Aβ-deposits is not associated with APOE ε4. Capillary CAA can be seen in every stage of CAA or AD-related Aβ-deposition. AD cases with capillary CAA show more widespread capillary Aβ-deposition than non-demented cases as well as capillary occlusion. In a mouse model of CAA, capillary CAA was associated with capillary occlusion and cerebral blood flow disturbances. Thus, blood flow alterations with subsequent hypoperfusion induced by CAA-related capillary occlusion presumably point to a second mechanism in which Aβ adversely affects the brain in AD in addition to its direct neurotoxic effects.

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References

  1. Akiyama H, Schwab C, Kondo H, Mori H, Kametani F, Ikeda K, McGeer PL (1996) Granules in glial cells of patients with Alzheimer’s disease are immunopositive for C-terminal sequences of beta-amyloid protein. Neurosci Lett 206:169–172

    PubMed  CAS  Google Scholar 

  2. Anders KH, Wang ZZ, Kornfeld M, Gray F, Soontornniyomkij V, Reed LA, Hart MN, Menchine M, Secor DL, Vinters HV (1997) Giant cell arteritis in association with cerebral amyloid angiopathy: immunohistochemical and molecular studies. Hum Pathol 28:1237–1246

    PubMed  CAS  Google Scholar 

  3. Arriagada PV, Marzloff K, Hyman BT (1992) Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology 42:1681–1688

    PubMed  CAS  Google Scholar 

  4. Attems J, Jellinger KA (2004) Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study. Acta Neuropathol (Berl) 107:83–90

    Google Scholar 

  5. Attems J, Lintner F, Jellinger KA (2004) Amyloid beta peptide 1–42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology. Acta Neuropathol (Berl) 107:283–291

    CAS  Google Scholar 

  6. Attems J, Lauda F, Jellinger KA (2008) Unexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy: an autopsy study. J Neurol 255:70–76

    PubMed  Google Scholar 

  7. Bacskai BJ, Frosch MP, Freeman SH, Raymond SB, Augustinack JC, Johnson KA, Irizarry MC, Klunk WE, Mathis CA, Dekosky ST, Greenberg SM, Hyman BT, Growdon JH (2007) Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report. Arch Neurol 64:431–434

    PubMed  Google Scholar 

  8. Benson MD (1996) Leptomeningeal amyloid and variant transthyretins. Am J Pathol 148:351–354

    PubMed  CAS  Google Scholar 

  9. Blomqvist ME, Chalmers K, Andreasen N, Bogdanovic N, Wilcock GK, Cairns NJ, Feuk L, Brookes AJ, Love S, Blennow K, Kehoe PG, Prince JA (2005) Sequence variants of IDE are associated with the extent of beta-amyloid deposition in the Alzheimer’s disease brain. Neurobiol Aging 26:795–802

    PubMed  CAS  Google Scholar 

  10. Bornebroek M, Haan J, Maat-Schieman ML, Van Duinen SG, Roos RA (1996) Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D): I—a review of clinical, radiologic and genetic aspects. Brain Pathol 6:111–114

    PubMed  CAS  Google Scholar 

  11. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259

    PubMed  CAS  Google Scholar 

  12. Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351–357

    PubMed  CAS  Google Scholar 

  13. Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C, Sommer B, Staufenbiel M, Jucker M (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci U S A 96:14088–14093

    PubMed  CAS  Google Scholar 

  14. Capetillo-Zarate E, Staufenbiel M, Abramowski D, Haass C, Escher A, Stadelmann C, Yamaguchi H, Wiestler OD, Thal DR (2006) Selective vulnerability of different types of commissural neurons for amyloid beta-protein induced neurodegeneration in APP23 mice correlates with dendritic tree morphology. Brain 129:2992–3005

    PubMed  Google Scholar 

  15. Christie R, Yamada M, Moskowitz M, Hyman B (2001) Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. Am J Pathol 158:1065–1071

    PubMed  CAS  Google Scholar 

  16. de Leon MJ, Mosconi L, Logan J (2007) Seeing what Alzheimer saw. Nat Med 13:129–131

    PubMed  Google Scholar 

  17. Eng JA, Frosch MP, Choi K, Rebeck GW, Greenberg SM (2004) Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 55:250–256

    PubMed  Google Scholar 

  18. Foster NL, Chase TN, Mansi L, Brooks R, Fedio P, Patronas NJ, Di Chiro G (1984) Cortical abnormalities in Alzheimer’s disease. Ann Neurol 16:649–654

    PubMed  CAS  Google Scholar 

  19. Gardner EP, Kandel ER (2000) Touch. In: Kandel ER, Schwartz JH, Jessel TM (eds) Principles of neural science, 4th edn. McGraw-Hill, New York, pp 451–471

    Google Scholar 

  20. Garzuly F, Vidal R, Wisniewski T, Brittig F, Budka H (1996) Familial meningocerebrovascular amyloidosis, Hungarian type, with mutant transthyretin (TTR Asp18Gly). Neurology 47:1562–1567

    PubMed  CAS  Google Scholar 

  21. Ghetti B, Piccardo P, Spillantini MG, Ichimiya Y, Porro M, Perini F, Kitamoto T, Tateishi J, Seiler C, Frangione B, Bugiani O, Giaccone G, Prelli F, Goedert M, Dlouhy SR, Tagliavini F (1996) Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. Proc Natl Acad Sci U S A 93:744–748

    PubMed  CAS  Google Scholar 

  22. Ghiso JA, Holton J, Miravalle L, Calero M, Lashley T, Vidal R, Houlden H, Wood N, Neubert TA, Rostagno A, Plant G, Revesz T, Frangione B (2001) Systemic amyloid deposits in familial British dementia. J Biol Chem 276:43909–43914

    PubMed  CAS  Google Scholar 

  23. Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890

    PubMed  CAS  Google Scholar 

  24. Gomez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16:4491–4500

    PubMed  CAS  Google Scholar 

  25. Greenberg SM (1997) Handbook of neurosurgery. Greenberg Graphics, Lakeland

    Google Scholar 

  26. Greenberg SM, Vonsattel JP (1997) Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke 28:1418–1422

    PubMed  CAS  Google Scholar 

  27. Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ (1992) Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357:500–503

    PubMed  CAS  Google Scholar 

  28. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Selkoe DJ (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322–325

    PubMed  CAS  Google Scholar 

  29. Haltia M, Ghiso J, Prelli F, Gallo G, Kiuru S, Somer H, Palo J, Frangione B (1990) Amyloid in familial amyloidosis, Finnish type, is antigenically and structurally related to gelsolin. Am J Pathol 136:1223–1228

    PubMed  CAS  Google Scholar 

  30. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    PubMed  CAS  Google Scholar 

  31. Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Sturchler-Pierrat C, Burki K, van Duinen SG, Maat-Schieman ML, Staufenbiel M, Mathews PM, Jucker M (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7:954–960

    PubMed  CAS  Google Scholar 

  32. Higgins LS, Murphy GM Jr, Forno LS, Catalano R, Cordell B (1996) P3 beta-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer’s disease brain. Am J Pathol 149:585–596

    PubMed  CAS  Google Scholar 

  33. Holton JL, Lashley T, Ghiso J, Braendgaard H, Vidal R, Guerin CJ, Gibb G, Hanger DP, Rostagno A, Anderton BH, Strand C, Ayling H, Plant G, Frangione B, Bojsen-Moller M, Revesz T (2002) Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta. J Neuropathol Exp Neurol 61:254–267

    PubMed  CAS  Google Scholar 

  34. Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC (2000) Identification of the major Abeta1–42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6:143–150

    PubMed  CAS  Google Scholar 

  35. Iwatsubo T, Saido TC, Mann DM, Lee VM, Trojanowski JQ (1996) Full-length amyloid-beta (1–42(43)) and amino-terminally modified and truncated amyloid-beta 42(43) deposit in diffuse plaques. Am J Pathol 149:1823–1830

    PubMed  CAS  Google Scholar 

  36. Jellinger KA (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109:813–836

    PubMed  CAS  Google Scholar 

  37. Joachim CL, Morris JH, Selkoe DJ (1988) Clinically diagnosed Alzheimer’s disease: autopsy results in 150 cases. Ann Neurol 24:50–56

    PubMed  CAS  Google Scholar 

  38. Johnson KA, Gregas M, Becker JA, Kinnecom C, Salat DH, Moran EK, Smith EE, Rosand J, Rentz DM, Klunk WE, Mathis CA, Price JC, Dekosky ST, Fischman AJ, Greenberg SM (2007) Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol 62:229–234

    PubMed  Google Scholar 

  39. Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ, Gorno-Tempini ML, Schuff N (2005) Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 234:851–859

    PubMed  Google Scholar 

  40. Kalback W, Watson MD, Kokjohn TA, Kuo YM, Weiss N, Luehrs DC, Lopez J, Brune D, Sisodia SS, Staufenbiel M, Emmerling M, Roher AE (2002) APP transgenic mice Tg2576 accumulate Abeta peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer’s disease senile plaques. Biochemistry 41:922–928

    PubMed  CAS  Google Scholar 

  41. Kida S, Pantazis A, Weller RO (1993) CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol 19:480–488

    PubMed  CAS  Google Scholar 

  42. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ (2003) Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A 100:6382–6387

    PubMed  CAS  Google Scholar 

  43. Kinnecom C, Lev MH, Wendell L, Smith EE, Rosand J, Frosch MP, Greenberg SM (2007) Course of cerebral amyloid angiopathy-related inflammation. Neurology 68:1411–1416

    PubMed  CAS  Google Scholar 

  44. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32

    PubMed  CAS  Google Scholar 

  45. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–1126

    PubMed  CAS  Google Scholar 

  46. Levy E, Haltia M, Fernandez-Madrid I, Koivunen O, Ghiso J, Prelli F, Frangione B (1990) Mutation in gelsolin gene in Finnish hereditary amyloidosis. J Exp Med 172:1865–1867

    PubMed  CAS  Google Scholar 

  47. Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, Beach T, Sue L, Sabbagh M, Cai H, Wong P, Price D, Shen Y (2004) Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci U S A 101:3632–3637

    PubMed  CAS  Google Scholar 

  48. Maat-Schieman ML, van Duinen SG, Bornebroek M, Haan J, Roos RA (1996) Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D): II—a review of histopathological aspects. Brain Pathol 6:115–120

    PubMed  CAS  Google Scholar 

  49. Mandybur TI (1986) Cerebral amyloid angiopathy: the vascular pathology and complications. J Neuropathol Exp Neurol 45:79–90

    PubMed  CAS  Google Scholar 

  50. Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T (2001) Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer’s disease. Am J Pathol 158:2165–2175

    PubMed  CAS  Google Scholar 

  51. Mazur-Kolecka B, Dickson D, Frackowiak J (2005) Induction of vascular amyloidosis-beta by oxidative stress depends on APOE genotype. Neurobiol Aging 27:804–814

    PubMed  Google Scholar 

  52. Meguro K, Blaizot X, Kondoh Y, Le Mestric C, Baron JC, Chavoix C (1999) Neocortical and hippocampal glucose hypometabolism following neurotoxic lesions of the entorhinal and perirhinal cortices in the non-human primate as shown by PET. Implications for Alzheimer’s disease. Brain 122(Pt 8):1519–1531

    PubMed  Google Scholar 

  53. Miller BC, Eckman EA, Sambamurti K, Dobbs N, Chow KM, Eckman CB, Hersh LB, Thiele DL (2003) Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc Natl Acad Sci U S A 100:6221–6226

    PubMed  CAS  Google Scholar 

  54. Mueggler T, Baumann D, Rausch M, Staufenbiel M, Rudin M (2003) Age-dependent impairment of somatosensory response in the amyloid precursor protein 23 transgenic mouse model of Alzheimer’s disease. J Neurosci 23:8231–8236

    PubMed  CAS  Google Scholar 

  55. Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res 541:163–166

    PubMed  CAS  Google Scholar 

  56. Niwa K, Carlson GA, Iadecola C (2000) Exogenous A beta1–40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. J Cereb Blood Flow Metab 20:1659–1668

    PubMed  CAS  Google Scholar 

  57. Niwa K, Younkin L, Ebeling C, Turner SK, Westaway D, Younkin S, Ashe KH, Carlson GA, Iadecola C (2000) Abeta 1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci U S A 97:9735–9740

    PubMed  CAS  Google Scholar 

  58. Ohm TG, Muller H, Braak H, Bohl J (1995) Close-meshed prevalence rates of different stages as a tool to uncover the rate of Alzheimer’s disease-related neurofibrillary changes. Neuroscience 64:209–217

    PubMed  CAS  Google Scholar 

  59. Olichney JM, Hansen LA, Hofstetter CR, Grundman M, Katzman R, Thal LJ (1995) Cerebral infarction in Alzheimer’s disease is associated with severe amyloid angiopathy and hypertension. Arch Neurol 52:702–708

    PubMed  CAS  Google Scholar 

  60. Olichney JM, Hansen LA, Hofstetter CR, Lee JH, Katzman R, Thal LJ (2000) Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein E4. Arch Neurol 57:869–874

    PubMed  CAS  Google Scholar 

  61. Palsdottir A, Abrahamson M, Thorsteinsson L, Arnason A, Olafsson I, Grubb A, Jensson O (1988) Mutation in cystatin C gene causes hereditary brain haemorrhage. Lancet 2:603–604

    PubMed  CAS  Google Scholar 

  62. Popp J, Thal DR, Lewczuk P, Wiltfang J, Jessen F (2007) Histologically confirmed amyloid deposition and low CSF Abeta (42) in a cognitively normal subject. J Neurol 254:970–971

    PubMed  Google Scholar 

  63. Price JL, Davis PB, Morris JC, White DL (1991) The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging 12:295–312

    PubMed  CAS  Google Scholar 

  64. Reid AH, Maloney AF (1974) Giant cell arteritis and arteriolitis associated with amyloid angiopathy in an elderly mongol. Acta Neuropathol (Berl) 27:131–137

    CAS  Google Scholar 

  65. Revesz T, Ghiso J, Lashley T, Plant G, Rostagno A, Frangione B, Holton JL (2003) Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol 62:885–898

    PubMed  CAS  Google Scholar 

  66. Revesz T, Ghiso J, Plant G, Lashley T, Rostagno A, Frangione B, Holton JL (2005) Cerebral amyloid angiopathy. In: Kalimo H (ed) Pathology & genetics: cerebrovascular diseases. ISN Neuropath Press, Basel, pp 94–102

    Google Scholar 

  67. Roher AE, Lowenson JD, Clarke S, Wolkow C, Wang R, Cotter RJ, Reardon IM, Zurcher-Neely HA, Heinrikson RL, Ball MJ, Greenberg BD (1993) Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer’s disease. J Biol Chem 268:3072–3083

    PubMed  CAS  Google Scholar 

  68. Roher AE, Lowenson JD, Clarke S, Woods AS, Cotter RJ, Gowing E, Ball MJ (1993) Beta-amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci U S A 90:10836–10840

    PubMed  CAS  Google Scholar 

  69. Russo C, Saido TC, DeBusk LM, Tabaton M, Gambetti P, Teller JK (1997) Heterogeneity of water-soluble amyloid beta-peptide in Alzheimer’s disease and Down’s syndrome brains. FEBS Lett 409:411–416

    PubMed  CAS  Google Scholar 

  70. Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Marky A, Lenting PJ, Wu Z, Zarcone T, Goate A, Mayo K, Perlmutter D, Coma M, Zhong Z, Zlokovic BV (2007) Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med 13:1029–1031

    PubMed  CAS  Google Scholar 

  71. Saido TC, Yamao-Harigaya W, Iwatsubo T, Kawashima S (1996) Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett 215:173–176

    PubMed  CAS  Google Scholar 

  72. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177

    PubMed  CAS  Google Scholar 

  73. Schlote W (1965) Die Amyloidnatur der kongophilen, drusigen Entartung der Hirnarterien (Scholz) im Senium. Acta Neuropathol 4:449–468

    Google Scholar 

  74. Schober R, Birkenmeier GP, Thal DR (1998) The 515kD and 85kD subunits of the alpha2-macroglobulin receptor/LDL receptor-related protein in cerebral amyloid angiopathy. Neuropathology 18(Suppl.):251

    Google Scholar 

  75. Scholz W (1938) Studien zur Pathologie der Hirngefäße. II. Die drusige Entartung der Hirnarterien und -capillaren. (Eine Form seniler Gefäßerkrankung). Z ges Neurol Psychiatr 4:694–715

    Article  Google Scholar 

  76. Shin HK, Jones PB, Garcia-Alloza M, Borrelli L, Greenberg SM, Bacskai BJ, Frosch MP, Hyman BT, Moskowitz MA, Ayata C (2007) Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy. Brain 130:2310–2319

    PubMed  Google Scholar 

  77. Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, Lavretsky H, Burggren AC, Cole GM, Vinters HV, Thompson PM, Huang SC, Satyamurthy N, Phelps ME, Barrio JR (2006) PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 355:2652–2663

    PubMed  CAS  Google Scholar 

  78. St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D, Growdon J, Bruni A, Foncin JF, Salmon D, Frommelt P, Amaducci L, Sorbi S, Piacentini S, Stewart GD, Hobbs WJ, Conneally PM, Gusella JF (1987) The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235:885–890

    PubMed  CAS  Google Scholar 

  79. Stopa EG, Butala P, Salloway S, Johanson CE, Gonzalez L, Tavares R, Hovanesian V, Hulette CM, Vitek MP, Cohen RA (2008) Cerebral cortical arteriolar angiopathy, vascular beta-amyloid, smooth muscle actin, Braak stage, and APOE genotype. Stroke 39:814–821

    PubMed  Google Scholar 

  80. Surbek B (1961) L’angiopathie dyshorique (Morel) de l’écorce cérébrale. Etude anatomo-clinique et statistique, aspect génétique. Acta Neuropathol 1:168–197

    Google Scholar 

  81. Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987) Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235:880–884

    PubMed  CAS  Google Scholar 

  82. Tekirian TL, Saido TC, Markesbery WR, Russell MJ, Wekstein DR, Patel E, Geddes JW (1998) N-terminal heterogeneity of parenchymal and cerebrovascular Abeta deposits. J Neuropathol Exp Neurol 57:76–94

    PubMed  CAS  Google Scholar 

  83. Terry RD, Peck A, DeTeresa R, Schechter R, Horoupian DS (1981) Some morphometric aspects of the brain in senile dementia of the Alzheimer type. Ann Neurol 10:184–192

    PubMed  CAS  Google Scholar 

  84. Thal DR, Rüb U, Schultz C, Sassin I, Ghebremedhin E, Del Tredici K, Braak E, Braak H (2000) Sequence of Abeta-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol 59:733–748

    PubMed  CAS  Google Scholar 

  85. Thal DR, Schultz C, Dehghani F, Yamaguchi H, Braak H, Braak E (2000) Amyloid beta-protein (Abeta)-containing astrocytes are located preferentially near N-terminal-truncated Abeta deposits in the human entorhinal cortex. Acta Neuropathol (Berl) 100:608–617

    CAS  Google Scholar 

  86. Thal DR, Ghebremedhin E, Rüb U, Yamaguchi H, Del Tredici K, Braak H (2002) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293

    PubMed  Google Scholar 

  87. Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Abeta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    PubMed  Google Scholar 

  88. Thal DR, Ghebremedhin E, Orantes M, Wiestler OD (2003) Vascular pathology in Alzheimer’s disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62:1287–1301

    PubMed  Google Scholar 

  89. Thal DR, Del Tredici K, Braak H (2004) Neurodegeneration in normal brain aging and disease. Sci Aging Knowledge Environ 2004:PE26

    PubMed  Google Scholar 

  90. Thal DR, Capetillo-Zarate E, Schultz C, Rüb U, Saido TC, Yamaguchi H, Haass C, Griffin WST, Del Tredici K, Braak H, Ghebremedhin E (2005) Apolipoprotein E co-localizes with newly formed amyloid beta-protein (Abeta)-deposits lacking immunoreactivity against N-terminal epitopes of Abeta in a genotype-dependent manner. Acta Neuropathol 110:459–471

    PubMed  CAS  Google Scholar 

  91. Thal DR, Capetillo-Zarate E, Del Tredici K, Braak H (2006) The development of amyloid beta protein deposits in the aged brain. Sci Aging Knowledge Environ 2006:re1

    PubMed  Google Scholar 

  92. Thal DR, Larionov S, Abramowski D, Wiederhold KH, Van Dooren T, Yamaguchi H, Haass C, Van Leuven F, Staufenbiel M, Capetillo-Zarate E (2007) Occurrence and co-localization of amyloid beta-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice. Neurobiol Aging 28:1221–1230

    PubMed  CAS  Google Scholar 

  93. Thal DR, Capetillo-Zarate E, Larionov S, Staufenbiel M, Zurbruegg S, Beckmann N (2008) Cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiol Aging doi:10.1016/j.neurobiolaging.2008.01.017

  94. The National Institute on Aging (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2

    Google Scholar 

  95. Trembath D, Ervin JF, Broom L, Szymanski M, Welsh-Bohmer K, Pieper C, Hulette CM (2007) The distribution of cerebrovascular amyloid in Alzheimer’s disease varies with ApoE genotype. Acta Neuropathol 113:23–31

    PubMed  CAS  Google Scholar 

  96. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741

    PubMed  CAS  Google Scholar 

  97. Vidal R, Garzuly F, Budka H, Lalowski M, Linke RP, Brittig F, Frangione B, Wisniewski T (1996) Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTRD 18 G). Am J Pathol 148:361–366

    PubMed  CAS  Google Scholar 

  98. Vidal R, Frangione B, Rostagno A, Mead S, Revesz T, Plant G, Ghiso J (1999) A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399:776–781

    PubMed  CAS  Google Scholar 

  99. Vinters HV, Gilbert JJ (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14:924–928

    PubMed  CAS  Google Scholar 

  100. Vinters HV (1992) Cerebral amyloid angiopathy. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM (eds) Stroke. Pathophysiology, diagnosis and management. Churchill Livingstone, New York, pp 821–858

    Google Scholar 

  101. Vinters HV, Wang ZZ, Secor DL (1996) Brain parenchymal and microvascular amyloid in Alzheimer’s disease. Brain Pathol 6:179–195

    PubMed  CAS  Google Scholar 

  102. Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EP Jr (1991) Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 30:637–649

    PubMed  CAS  Google Scholar 

  103. Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE (1998) Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am J Pathol 153:725–733

    PubMed  CAS  Google Scholar 

  104. Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M, Jucker M (2001) Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci 21:1619–1627

    PubMed  CAS  Google Scholar 

  105. Wisniewski HM, Wegiel J, Wang KC, Lach B (1992) Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer’s disease. Acta Neuropathol (Berl) 84:117–127

    CAS  Google Scholar 

  106. Wisniewski HM, Frackowiak J, Mazur-Kolecka B (1995) In vitro production of beta-amyloid in smooth muscle cells isolated from amyloid angiopathy-affected vessels. Neurosci Lett 183:120–123

    PubMed  CAS  Google Scholar 

  107. Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9:453–457

    PubMed  CAS  Google Scholar 

  108. Yamada M, Itoh Y, Shintaku M, Kawamura J, Jensson O, Thorsteinsson L, Suematsu N, Matsushita M, Otomo E (1996) Immune reactions associated with cerebral amyloid angiopathy. Stroke 27:1155–1162

    PubMed  CAS  Google Scholar 

  109. Yamaguchi H, Yamazaki T, Lemere CA, Frosch MP, Selkoe DJ (1992) Beta amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer’s disease. An immunoelectron microscopic study. Am J Pathol 141:249–259

    PubMed  CAS  Google Scholar 

  110. Yamaguchi H, Sugihara S, Ogawa A, Saido TC, Ihara Y (1998) Diffuse plaques associated with astroglial amyloid beta protein, possibly showing a disappearing stage of senile plaques. Acta Neuropathol (Berl) 95:217–222

    CAS  Google Scholar 

  111. Zhang-Nunes SX, Maat-Schieman ML, van Duinen SG, Roos RA, Frosch MP, Greenberg SM (2006) The cerebral beta-amyloid angiopathies: hereditary and sporadic. Brain Pathol 16:30–39

    PubMed  CAS  Google Scholar 

  112. Zhang ET, Richards HK, Kida S, Weller RO (1992) Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain. Acta Neuropathol (Berl) 83:233–239

    CAS  Google Scholar 

  113. Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci 28:202–208

    PubMed  CAS  Google Scholar 

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Acknowledgments

The work reviewed here was supported by the DFG: TH624/4-1 (DRT), TH624/4-2 (DRT), GH 12/2-1 (EG), GH 12/2-2 (EG); BONFOR: O-154.0041 (DRT), and the NIH-NIA: AG12411 (WSTG). The authors gratefully acknowledge I. Szász and H. U. Klatt for graphics and artwork. We thank Dr. A. Scheuerle for reading the manuscript.

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  1. Laboratory of Neuropathology, Institute of Pathology, University of Ulm, Albert-Einstein-Allee 7, 89081, Ulm, Germany

    Dietmar Rudolf Thal

  2. Donald W. Reynolds Center on Aging, UAMS, Geriatric Research Education and Clinical Center, Veterans’ Affairs Medical Center, Little Rock, AR, USA

    W. Sue T. Griffin

  3. Laboratorium Pathologie Oost Nederland, Enschede, The Netherlands

    Rob A. I. de Vos

  4. Institute for Clinical Neuroanatomy, J. W. Goethe University, 60590, Frankfurt am Main, Germany

    Estifanos Ghebremedhin

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  1. Dietmar Rudolf Thal
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Correspondence to Dietmar Rudolf Thal.

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Thal, D.R., Griffin, W.S.T., de Vos, R.A.I. et al. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol 115, 599–609 (2008). https://doi.org/10.1007/s00401-008-0366-2

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