Neuropathologic Features and Grading of Alzheimer-Related and Sporadic CAA

  • Harry V. Vinters
  • Jean-Paul G. Vonsattel


This chapter will consider neuropathologic features of CAA, an approach to grading the severity of CAA using straightforward morphologic criteria, and consequences of CAA in the brain; especially cerebral hemorrhage. Specifically, we will evaluate the relationship between sporadic CAA and that related to Alzheimer disease, unique neuropathologie features of CAA-related brain hemorrhage, and introduce the concept of CAA-associated microangiopathies (CAA-AM, e.g. microaneurysms, secondary angiitis, etc.); lesions that may well be the proximate cause of brain hemorrhage. Approaches to studying CAA pathogenesis and CAA-AM will be discussed in relation to the basic biology of the cerebral microvessel wall and its components, aspects of which are taken up elsewhere in this volume.


Alzheimer Disease Giant Cell Arteritis Cerebral Hemorrhage Cerebral Amyloid Angiopathy Alzheimer Disease Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kosik, K.S. (1992) Alzheimer’s disease: A cell biological perspective, Science 256, 780–783.PubMedCrossRefGoogle Scholar
  2. 2.
    Vinters, H.V., Wang, Z.Z., & Secor, D.L. (1996) Brain parenchymal and microvascular amyloid in Alzheimer’s disease, Brain Pathol. 6, 179–195.PubMedCrossRefGoogle Scholar
  3. 3.
    Cummings, J.L., Vinters, H.V., Cole, G.M., & Khachaturian, Z.S. (1998) Alzheimer’s disease. Etiologies, pathophysiology, cognitive reserve, and treatment opportunities, Neurology 51 (Suppl 1), S2 - S17.PubMedCrossRefGoogle Scholar
  4. 4.
    Selkoe, D.J. (1994) Alzheimer’s disease: A central role for amyloid. J. Neuropathol. Exp. Neurol. 53, 438–447.PubMedCrossRefGoogle Scholar
  5. 5.
    Vinters, H.V. (1998) Alzheimer’s disease: a neuropathologic perspective, Current Diagnostic Pathology 5, 109–117.CrossRefGoogle Scholar
  6. 6.
    Mandybur, T.I. (1975) The incidence of cerebral amyloid angiopathy in Alzheimer’s disease, Neurology 25, 120–126.PubMedCrossRefGoogle Scholar
  7. 7.
    Glenner, G.G. & Wong, C.W. (1984) Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem. Biophys. Res. Commun. 120, 885–890.PubMedCrossRefGoogle Scholar
  8. 8.
    Glenner, G.G. & Wong, C.W. (1984) Alzheimer’s disease and Down’s syndrome: Sharing of a unique cerebrovascular amyloid fibril protein, Biochem. Biophys. Res. Commun. 122, 1131–1135.PubMedCrossRefGoogle Scholar
  9. 9.
    Lendon, C.L., Ashall, F. & Goate, A.M. (1997) Exploring the etiology of Alzheimer disease using molecular genetics, JAMA 277, 825–831.PubMedCrossRefGoogle Scholar
  10. 10.
    Braak, H. & Braak, E. (1991) Neuropathological stageing of Alzheimer-related changes, Acta Neuropathol. 82, 239–259.PubMedCrossRefGoogle Scholar
  11. 11.
    Braak, H., Duyckaerts, C., Braak, E. & Piette, F. (1993) Neuropathological staging of Alzheimer-related changes correlates with psychometrically assessed intellectual status, in Corain, B., Iqbal, K., Nicolini, M., Winblad, B., Wisniewski, H., & Zatta, P. (eds.), Alzheimer’s Disease: Advances in Clinical and Basic Research, John Wiley & Sons, pp. 131–137.Google Scholar
  12. 12.
    Mina, S.S., Heyman, A., McKeel, D., Sumi, S.M., Crain, B.J., Brownlee, L.M., Vogel, F.S., Hughes, J.P., van Belle, G., Berg, L. & Participating CERAD neuropathologists (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologie assessment of Alzheimer’s disease, Neurology 41, 479–486.CrossRefGoogle Scholar
  13. 13.
    Gearing, M., Mina, S.S., Hedreen, J.C., Sumi, S.M., Hansen, L.A. & Heyman, A. (1995) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer’s disease, Neurology 45, 461–466.PubMedCrossRefGoogle Scholar
  14. 14.
    Ellis, R.J., Olichney, J.M., Thal, L.J., Mina, S.S., Morris, J.C., Beekly, D. & Heyman, A. (1996) Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: The CERAD experience, part XV, Neurology 46, 1592–1596.PubMedCrossRefGoogle Scholar
  15. 15.
    Bergeron, C., Ranalli, P.J. & Miceli, P.N. (1987) Amyloid angiopathy in Alzheimer’s disease, Can. J. Neurol. Sci. 14, 564–569.PubMedGoogle Scholar
  16. 16.
    Greenberg, S.M. (1998) Cerebral amyloid angiopathy. Prospects for clinical diagnosis and treatment, Neurology 51, 690–694.PubMedCrossRefGoogle Scholar
  17. 17.
    Greenberg, S.M. & Vonsattel, J-P.G. (1997) Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy, Stroke 28, 1418–1422.PubMedCrossRefGoogle Scholar
  18. 18.
    Vinters, H.V. & Gilbert, J.J. (1983) Cerebral amyloid angiopathy: Incidence and complications in the aging brain II. The distribution of amyloid vascular changes, Stroke 14, 924–928.PubMedCrossRefGoogle Scholar
  19. 19.
    Masuda, J., Tanaka, K., Ueda, K. & Omae, T. (1988) Autopsy study of incidence and distribution of cerebral amyloid angiopathy in Hisayama, Japan, Stroke 19, 205–210.PubMedCrossRefGoogle Scholar
  20. 20.
    Vinters, H.V. (1992) Cerebral amyloid angiopathy and Alzheimer’s disease: two entities or one? J. Neurol. Sci. 112, 1–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Blumenthal, H.T. & Premachandra, B.N. (1990) The aging-disease dichotomy. Cerebral amyloid angiopathy-an independent entity associated with dementia, JAGS 38, 475–482.Google Scholar
  22. 22.
    The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. Neurobiol. Aging 18, Sl-S2.Google Scholar
  23. 23.
    Verbeek, M.M., Eikelenboom, P. & de Waal, R.M.W. (1997) Differences between the pathogenesis of senile plaques and congophilic angiopathy in Alzheimer disease, J. Neuropathol. Exp. Neurol. 56, 751–761.PubMedGoogle Scholar
  24. 24.
    Gudmundsson, G., Hallgrimsson, J., Jonasson, T.A., & Bjarnason, O. (1972) Hereditary cerebral hemorrhage with amyloidosis, Brain 95, 387–404.PubMedCrossRefGoogle Scholar
  25. 25.
    Okazaki, H., Reagan, T.J., & Campbell, R.J. (1979) Clinicopathologic studies of primary cerebral amyloid angiopathy, Mayo Clin. Proc. 54, 22–31.PubMedGoogle Scholar
  26. 26.
    Gilles, C., Brucher, J.M., Khoubesserian, P., & Vanderheagen, J.J. (1984) Cerebral amyloid angiopathy as a cause of multiple intracerebral hemorrhages, Neurology 34, 730–735.PubMedCrossRefGoogle Scholar
  27. 27.
    Torack, R.M. (1975) Congophilic angiopathy complicated by surgery and massive hemorrhage. Light and electron microscopic study, Am. J. Pathol. 81, 349–366.PubMedGoogle Scholar
  28. 28.
    Vonsattel, J.P., Myers, R.H., Hedley-Whyte, E.T., Ropper, A.H., Bird, E.D., & Richardson, E.P. Jr. (1991) Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study, Ann. Neurol. 30, 637–649.PubMedCrossRefGoogle Scholar
  29. 29.
    Russell, D.S. (1954) Discussion: the pathology of spontaneous intracranial hemorrhage, Proc. Royal Soc. Medicine 47, 689–693.Google Scholar
  30. 30.
    Cole, F.M., & Yates, P.O. (1967) The occurrence and significance of intracerebral microaneurysms, J. Pathol. Bacteriol. 93, 393–411.PubMedCrossRefGoogle Scholar
  31. 31.
    Vinters, H.V. (1998) Cerebral amyloid angiopathy, in Barnett, H.J.M., Mohr, J.P., Stein, B.M., & Yatsu, F.M. (eds.), Stroke. Pathophysiology, Diagnosis, and Management, 3/Ed., Churchill Livingstone, New York, pp. 945–962.Google Scholar
  32. 32.
    Vinters, H.V. (1987) Cerebral amyloid angiopathy. A critical review, Stroke 18, 311–324.PubMedCrossRefGoogle Scholar
  33. 33.
    Jellinger, K. (1977) Cerebrovascular amyloidosis with cerebral hemorrhage, J. Neurol. 214, 195–206.PubMedCrossRefGoogle Scholar
  34. 34.
    Vinters, H.V., & Duckwiler, G.R. (1992) Intracranial hemorrhage in the normotensive elderly patient, Neuroimaging Clin. N. America 2, 153–169.Google Scholar
  35. 35.
    Coria, F., & Rubio, I. (1996) Cerebral amyloid angiopathies, Neuropathol. Appl. Neurobiol. 22, 216–227.PubMedCrossRefGoogle Scholar
  36. 36.
    Fountain, N.B., & Eberhard, D.A. (1996) Primary angiitis of the central nervous system associated with cerebral amyloid angiopathy: Report of two cases and review of the literature, Neurology 46, 190–197.PubMedCrossRefGoogle Scholar
  37. 37.
    Ohshima, T., Endo, T., Nukui, H., Ikeda, S-i., Allsop, D., & Onaya, T. (1990) Cerebral amyloid angiopathy as a cause of subarachnoid hemorrhage, Stroke 21, 480–483.PubMedCrossRefGoogle Scholar
  38. 38.
    Gray, F., Dubas, F., Roullet, E., & Escourolle, R. (1985) Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy, Ann. Neurol. 18, 54–59.PubMedCrossRefGoogle Scholar
  39. 39.
    Greenberg, S.M., Vonsattel, J.P.G., Stakes, J.W., Gruber, M., & Finklestein, S.P. (1993) The clinical spectrum of cerebral amyloid angiopathy: Presentations without lobar hemorrhage, Neurology 43, 2073–2079.PubMedCrossRefGoogle Scholar
  40. 40.
    Fisher, M. (1994) Clinical Atlas of Cerebrovascular Disorders, Mosby Wolfe, London.Google Scholar
  41. 41.
    Yong, W.H., Robert, M.E., Secor, D.L., Kleikamp, T.J., & Vinters, H.V. (1992) Cerebral hemorrhage with biopsy-proved amyloid angiopathy, Arch. Neurol. 49, 51–58.PubMedCrossRefGoogle Scholar
  42. 42.
    Vinters, H.V., Secor, D.L., Read, S.L., Frazee, J.G., Tomiyasu, U., Stanley, T.M., Ferreiro, J.A., & Akers, M-A. Microvasculature in brain biopsy specimens from patients with Alzheimer’s disease: An immunohistochemical and ultrastructural study, Ultrastruct. Pathol. 18, 333–348.Google Scholar
  43. 43.
    Wang, Z.Z., Jensson, O, Thorsteinsson, L., & Vinters, H.V. (1997) Microvascular degeneration in hereditary cystatin C amyloid angiopathy of the brain, APMIS 105, 41–47.PubMedCrossRefGoogle Scholar
  44. 44.
    Scholz, W. (1938) Studien zur Pathologie der Himgefässe II. Die drusige Entartung der Hirnarterien und -capillaren. (Eine From seniler Gefässerkrankung), Zeitschrift fir die gesamte Neurologie und Psychiatrie (Berlin) 162, 694–715.CrossRefGoogle Scholar
  45. 45.
    Luyendijk, W., Bots, G.T.A.M., Vegter-van der Vlis, M., Went, L.N., & Frangione, B. (1988) Hereditary cerebral hemorrhage caused by cortical amyloid angiopathy, JNeurol Sci 85, 267–280.Google Scholar
  46. 46.
    Neumann, M.A. (1960) Combined amyloid vascular changes and argyrophilic plaques in the central nervous system, J. Neuropathol. Exp. Neurol. 19, 370–382.PubMedCrossRefGoogle Scholar
  47. 47.
    Ojemann, R.G., & Heros, R.C. (1983) Spontaneous brain hemorrhage, Stroke 14, 468–475.PubMedCrossRefGoogle Scholar
  48. 48.
    Cosgrove, G.R., Leblanc, R., Meagher-Villemure, K., & Ethier, R. (1985) Cerebral amyloid angiopathy, Neurology 35, 625–631.Google Scholar
  49. 49.
    Ulrich, G., Taghavy, A., & Schmidt, H. (1973) Zur Nosologie und Ätiologie der kongophilen Angiopathie (Gefässform der cerebralen Amyloidosis), Zeitschrift fair die gesamte Neurologie und Psychiatrie (Berlin) 206, 39–59.Google Scholar
  50. 50.
    Greene, G.M., Godersky, J.C., Biller, J., Hart, M.N., & Adams, H.P. Jr. (1990) Surgical experience with cerebral amyloid angiopathy, Stroke 21, 1545–1549.PubMedCrossRefGoogle Scholar
  51. 51.
    Regli, F., Vonsattel, J.P., Perentes, E., & Assal, G. (1981) L’angiopathie amyloïde cérébrale. Une maladie cérébro-vasculaire peu connue. Etude d’une observation anatomoclinique, Revue Neurologique 137, 181–194.PubMedGoogle Scholar
  52. 52.
    Brandenburg, W., & Hallervorden, J. (1954) Dementia pugilistica mit anatomischem Befund, Virchows Archiv fir Pathologische Anatomie und Physiologie und fur Klinische Medizin 325, 680–709.Google Scholar
  53. 53.
    Murphy, M.N., & Sima, A.A.F. (1985) Cerebral amyloid angiopathy associated with giant cell arteritis: a case report, Stroke 16, 514–517.PubMedCrossRefGoogle Scholar
  54. 54.
    Probst, A., & Ulrich, J. (1985) Amyloid angiopathy combined with granulomatous angiitis of the central nervous system: report on two patients, Clin. Neuropathol. 4, 250–259.PubMedGoogle Scholar
  55. 55.
    Le Coz, P., Mikol, J., Ferrand, J., Woimant, F., Masters, C., Beyreuther, K., Haguenau, M., Cophignon, J., & Pepin, B. (1991) Granulomatous angiitis and cerebral amyloid angiopathy presenting as a mass lesion, Neuropathol. Appl. Neurobiol. 17, 149–155.PubMedCrossRefGoogle Scholar
  56. 56.
    Shintaku, M., Osawa, K., Toki, J., Maeda, R., & Nishiyama, T. (1986) A case of granulomatous angiitis of the central nervous system associated with amyloid angiopathy, Acta Neuropathol. 70, 340–342.PubMedCrossRefGoogle Scholar
  57. 57.
    Fountain, N.B., & Lopes, B.S. (1999) Control of primary angiitis of the CNS associated with cerebral amyloid angiopathy by cyclophosphamide alone, Neurology 52, 660–662.PubMedCrossRefGoogle Scholar
  58. 58.
    Ferreiro, J.A., Ansbacher, L.E., & Vinters, H.V. (1989) Stroke related to cerebral amyloid angiopathy: the significance of systemic vascular disease, J. Neurol. 236, 267–272.PubMedCrossRefGoogle Scholar
  59. 59.
    Natté, R., Vinters, H.V., Maat-Schieman, M.L.C., Bomebroek, M., Haan, J., Roos, R.A.C., & van Duinen, S.G. (1998) Microvasculopathy is associated with the number of cerebrovascular lesions in hereditary cerebral hemorrhage with amyloidosis, Dutch type, Stroke 29, 1588–1594.PubMedCrossRefGoogle Scholar
  60. 60.
    Bruni, J., Bilbao, J.M., & Pritzker, K.P.H. (1977) Vascular amyloid in the aging central nervous system. Clinico-pathological study and literature review, Can. J Neurol. Sci. 4, 239–244.PubMedGoogle Scholar
  61. 61.
    Masuda, J., Tanaka, K., Ueda, K., & Omae, T. (1988) Autopsy study of incidence and distribution of cerebral amyloid angiopathy in Hisayama, Japan, Stroke 19, 205–210.PubMedCrossRefGoogle Scholar
  62. 62.
    Mandybur, T.I., & Bates, S.R.D. (1978) Fatal massive intracerebral hemorrhage complicating cerebral amyloid angiopathy, Arch. Neurol. 35, 246–248.PubMedCrossRefGoogle Scholar
  63. 63.
    Mandybur, T.I. (1986) Cerebral amyloid angiopathy: the vascular pathology and complications, J. Neuropathol. Exp. Neurol. 45, 79–90.PubMedCrossRefGoogle Scholar
  64. 64.
    Rengachary, S.S., Racela, L.S., Watanabe, I., & Abdou, N. (1980) Neurosurgical and immunological implications of primary cerebral amyloid (Congophilic) angiopathy, Neurosurgery 7, 1–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Corsellis, J.A.N., & Brierley, J.B. (1954) An unusual type of pre-senile dementia (atypical Alzheimer’s disease with amyloid vascular changes), Brain 77, 571–586.PubMedCrossRefGoogle Scholar
  66. 66.
    Dahme, E., & Schröder, B. (1979) Kongophile Angiopathie, cerebrovasculäre Mikroaneurysmen und cerebrale Blutungen beim alten Hund, Zentralbi. Veterinar. Med. [A] 26, 601–613.CrossRefGoogle Scholar
  67. 67.
    Dubas, F., Gray, F., Roullet, E., & Escourolle, R. (1985) Leucoencéphalopathies artériopathiques (17 cas anatomo-cliniques), Revue Neurologique 141, 93–108.PubMedGoogle Scholar
  68. 68.
    DeWitt, L.D., Davis, K.R., Hedley-Whyte, E.T., Fenton, M.L., McGrail, K., & Louis, D.N. (1991) Case Records of the Massachusetts General Hospital. Case 27–1991. A 75year-old man with dementia, myoclonic jerks, and tonic-clonic seizures, N. Engl. J. Med. 325, 42–54.CrossRefGoogle Scholar
  69. 69.
    Ellison, D., Love, S., Chimelli, L., Harding, B., Lowe, J., Roberts, G.W., & Vinters, H.V. (1998) Neuropathology. A Reference Text of CNS Pathology, Mosby, London, pp. 10. 110. 25.Google Scholar
  70. 70.
    Vinters, H.V., Farrell, M.A., Mischel, P.S., & Anders, K.H. (1998) Diagnostic Neuropathology, Marcel Dekker, New York, pp. 110–146.Google Scholar
  71. 71.
    Anders, K.H., Wang, Z.Z., Kornfeld, M., Fray, F., Soontornniyomkij, V., Reed, L.A., Hart, M.N., Menchine, M., Secor, D.L., & Vinters, H.V. (1997) Giant cell arteritis in association with cerebral amyloid angiopathy: Immunohistochemical and molecular studies, Hum. Pathol. 28, 1237–1246.PubMedCrossRefGoogle Scholar
  72. 72.
    Mackenzie, I.R.A. (1997) Cerebral amyloid angiopathy with extensive mineralization, Clin. Neuropathol. 16, 209–213.PubMedGoogle Scholar
  73. 73.
    Vinters, H.V., Natté, R., Maat-Schieman, M.L.C., van Duinen S.G., Hegeman-Kleinn, I., Welling-Graafland, C., Haan, J., & Roos, R.A.C. (1998) Secondary microvascular degeneration in amyloid angiopathy of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), Acta Neuropathol. 95, 235–244.PubMedCrossRefGoogle Scholar
  74. 74.
    Gray, F., Vinters, H.V., Le Noan, H., Salama, J., Delaporte, P., & Poirier, J. (1990) Cerebral amyloid angiopathy and granulomatous angiitis: Immunohistochemical study using antibodies to the Alzheimer A4 peptide, Hum. Pathol. 21, 1290–1293.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2000

Authors and Affiliations

  • Harry V. Vinters
    • 1
  • Jean-Paul G. Vonsattel
    • 2
  1. 1.Department of Pathology & Laboratory Medicine, Brain Research Institute & Neuropsychiatric InstituteUCLA Medical CenterLos AngelesUSA
  2. 2.Department of Pathology and Neuroscience CenterMassachusetts General Hospital and Harvard Medical SchoolCharlestownUSA

Personalised recommendations