Acta Neuropathologica

, Volume 106, Issue 4, pp 367–373 | Cite as

Cerebral amyloid angiopathy in the elderly: vessel walls changes and relationship with dementia

  • Dina Zekry
  • Charles Duyckaerts
  • Joël Belmin
  • Caroline Geoffre
  • Robert Moulias
  • Jean-Jacques Hauw
Regular Paper


Aβ peptide deposits are observed in brain cortical and leptomeningeal microvessels in a few families, in patients with Alzheimer's disease and in cognitively normal elderly subjects. These deposits, which cause Aβ amyloid angiopathy, are usually associated with other lesions induced by Aβ peptide and tau pathologies. To investigate the consequences of cerebral amyloid angiopathy on arterial morphology and search for correlations with the degree of cognitive impairment, we carried out a prospective clinicopathological and morphometric study in 29 institutionalized elderly patients cognitively normal or affected with sporadic dementia associated with Alzheimer-type lesions, cerebral infarcts or both. We measured the external and internal diameters of arteries 40–120 μm wide, containing moderate or severe Aβ deposits, and of unaffected arteries in the temporal and frontal lobes. We found no differences in the mean external diameters. In contrast, the mean internal diameters of vessels with moderate Aβ deposits were smaller than those of unaffected vessels. Conversely, the internal diameters of severely affected vessels were larger than those of unaffected vessels. This suggests that arterial walls become thicker during the early stages of amyloid angiopathy, and the diameter of the lumen decreases, whereas during advanced stages, the walls become thinner and the lumen becomes larger. In addition, we assessed the overall severity of amyloid angiopathy. This showed that thinner arterial walls and the severity of amyloid angiopathy were correlated to dementia. In a multivariate model that integrates the other macroscopic and microscopic lesions that may be implied in the mechanism of cognitive impairment, the severity of amyloid angiopathy per se explained 10% of the variability in the cognitive impairment.


Cerebral amyloid angiopathy Aβ peptide Alzheimer's disease Vascular dementia Morphometry 


  1. 1.
    Alonzo NC, Hyman BT, Rebeck GW, Greenberg SM (1998) Progression of cerebral amyloid angiopathy: accumulation of amyloid-beta40 in affected vessels. J Neuropathol Exp Neurol 57:353–359PubMedGoogle Scholar
  2. 2.
    American Psychiatric Association (1980) Diagnostic and statistical manual of mental disorders, 3rd edn. American Psychiatric Association, WashingtonGoogle Scholar
  3. 3.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedGoogle Scholar
  4. 4.
    Brodmann K (1909) Vergleichende Lokalisationlehre der Grosshirnrinde in ihren Prinzipen dargestellt auf Grund des Zellenbaues. J A Barth, LeipzigGoogle Scholar
  5. 5.
    Davis DG, Schmitt FA, Wekstein DR, Markesbery WR (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58:376–388PubMedGoogle Scholar
  6. 6.
    Esiri MM, Wilcock GK (1986) Cerebral amyloid angiopathy in dementia and old age. J Neurol Neurosurg Psychiatry 49:1221–1226PubMedGoogle Scholar
  7. 7.
    Folstein MF, Folstein SE, Mac Hugh PR (1975) Mini Mental State: a practical method for grading the cognitive state of patients for the clinician. J Pychiatr Res 12:189–198Google Scholar
  8. 8.
    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 120:885–890PubMedGoogle Scholar
  9. 9.
    Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM (2001) Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 49:697–705CrossRefPubMedGoogle Scholar
  10. 10.
    Hardy JA, Mann DMA, Wester P, Winblad B (1986) An integrative hypothesis concerning the pathogenesis and progression of Alzheimer's disease. Neurobiol Aging 7:489–502CrossRefPubMedGoogle Scholar
  11. 11.
    Hauw JJ, Vignolo P, Duyckaerts C, Beck H, Forette F, Henry JF, Laurent M, Piette F, Sachet A, Berthaux P (1986) Neuropathological study of 12 centenarians: the incidence of Alzheimer type senile dementia is not particularly increased in this group of very old patients. Rev Neurol (Paris)142:107–115Google Scholar
  12. 12.
    Hauw J-J, Seilhean D, Duyckaerts (1998) Cerebral amyloid angiopathy. In: Ginsberg MD, Bogousslavsky J (eds) Cerebrovascular disease: pathophysiology, diagnosis and management. Blackwell Science, Massachusetts, pp 1772–1794Google Scholar
  13. 13.
    Imaoka K, Kobayashi S, Fujihara S, Shimode K, Nagasaki M (1999) Leukoencephalopathy with cerebral amyloid angiopathy: a semiquantitative and morphometric study. J Neurol 246:661–666PubMedGoogle Scholar
  14. 14.
    Itoh Y, Yamada M, Suematsu N, Matsushita M, Otomo E (1998) An immunohistochemical study of centenarian brains: a comparison. J Neurol Sci 157:73–81PubMedGoogle Scholar
  15. 15.
    Jellinger KA, Attems J (2003) Incidence of cerebrovascular lesions in Alzheimer's disease: a postmortem study. Acta Neuropathol 105:14–17PubMedGoogle Scholar
  16. 16.
    Joachim CL, Morris JH, Selkoe DJ (1987) Amyloid angiopathy in 100 cases of Alzheimer's disease. Neurology 37 (Suppl 1):225Google Scholar
  17. 17.
    Kalaria RN (1996) Cerebral vessels in ageing and Alzheimer's disease. Pharmacol Ther 72:193–214CrossRefPubMedGoogle Scholar
  18. 18.
    Kawai M, Kalaria RN, Cras P, Siedlak SL, Velasco ME, Shelton ER, Chan HW, Greenberg BD, Perry G (1993) Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease. Brain Res 623:142–146PubMedGoogle Scholar
  19. 19.
    Maeda A, Yamada M, Itoh Y, Otomo E, Hayakawa M, Miyatake T (1993) Computer-assisted three-dimensional image analysis of cerebral amyloid angiopathy. Stroke 21:397–403Google Scholar
  20. 20.
    Mancardi GL, Perdelli F, Rivano C, Leonardi A, Bugiani O (1980) Thickening of the basement membrane of cortical capillaries in Alzheimer's disease. Acta Neuropathol (Berl) 49:79–83Google Scholar
  21. 21.
    Mandybur TI (1986) Cerebral amyloid angiopathy: the vascular pathology and complications. J Neuropathol Exp Neurol 45:79–90PubMedGoogle Scholar
  22. 22.
    Maruyama K, Ikeda S, Ishihara T, Allsop D, Yanagisawa N (1990) Immunohistochemical characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to β protein and cystatin C. Stroke 21:397–403PubMedGoogle Scholar
  23. 23.
    Masuda J, Tanaka K, Ueda K, Omae T (1988) Autopsy study of incidence and distribution of cerebral amyloid angiopathy in Hisayama, Japan. Stroke 19:205–210PubMedGoogle Scholar
  24. 24.
    Mesulam MM (1985) Pattern in behavioral neuroanatomy: association areas, the limbic system, and hemispheric specialization. In: Mesulam MM (ed) Principles of behavioral neurology. FA Davis Company, Philadelphia, pp 1–58Google Scholar
  25. 25.
    Mirra SS, A Heyman, D McKeel, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, Belle G van, Berg L, and participating CERAD neuropathologists (1991) The Consortium to Establish a Registry for Alzheimer's disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 41:479–486PubMedGoogle Scholar
  26. 26.
    Morel F (1950) Petite contribution à l'étude d'une angiopathie apparemment dyshorique et topistique. Monatsschr Psychiatr Neurol 120:352–357Google Scholar
  27. 27.
    Natté R, Vinters HV, Maat-Schieman MLC, Bornebroek M, Haan J, Roos RA, Duinen SG van (1998) Microvasculopathy is associated with the number of cerebrovascular lesions in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Stroke 29:1588–1594PubMedGoogle Scholar
  28. 28.
    Natté R, Boer WI de, Maat-Schieman ML, Baelde HJ, Vinters HV, Roos RA, Duinen SG van (1999) Amyloid beta precursor protein-mRNA is expressed throughout cerebral vessel walls. Brain Res 828:179–183CrossRefPubMedGoogle Scholar
  29. 29.
    Okazaki H, Reagan TJ, Campbell RJ (1979) Clinicopathologic studies of primary cerebral amyloid angiopathy. Mayo Clinic Proc 54:22–31Google Scholar
  30. 30.
    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 57:869–874CrossRefPubMedGoogle Scholar
  31. 31.
    Pantelakis S (1954) Un type particulier d'angiopathie sénile du système nerveux central: l'angiopathie congophile. Topographie et fréquence. Monatsschr Psychiatr Neurol 128:219–256Google Scholar
  32. 32.
    Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ (2002) Cerebral amyloid angiopathy and cognitive function. Neurology 58:1629–1634PubMedGoogle Scholar
  33. 33.
    Reisberg B, Ferris SH, De Leon MJ, Crook KT (1988) Global deterioration scale. Psychopharmacol Bull 24:661–663PubMedGoogle Scholar
  34. 34.
    Roman G, Erkinjuntti T, Wallin A, Pantoni L, Chui HC (2002) Subcortical ischaemic vascular dementia. Lancet Neurol 1:426–436CrossRefPubMedGoogle Scholar
  35. 35.
    Scheibel AB, Duong T, Tomiyasu U (1987) Denervation microangiopathy in senile dementia, Alzheimer type. Alzheimer Dis Assoc Disord 1:19–37PubMedGoogle Scholar
  36. 36.
    Vinters HV (1987) Cerebral amyloid angiopathy–a critical review. Stroke 18:311–324PubMedGoogle Scholar
  37. 37.
    Vinters HV (1998) Cerebral amyloid angiopathy. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM (eds) Stroke. Pathophysiology, diagnosis and management, 3rd edn. Churchill Livingstone, New York, pp 945–962Google Scholar
  38. 38.
    Vinters HV (2001) Cerebral amyloid angiopathy: a microvascular link between parenchymal and vascular dementia? Ann Neurol 49:691–693Google Scholar
  39. 39.
    Vinters HV, Gilbert JJ (1983) Cerebral amyloid protein: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14:924–928PubMedGoogle Scholar
  40. 40.
    Vinters HV, Secor DL, Read SL, Frazee JG, Tomiyasu U, Stanley TM, Ferreiro JA, Akers MA (1994) Microvasculature in brain biopsy specimens from patients with Alzheimer's disease: an immunohistochemical and ultrastructural study. Ultrastruct Pathol 18:333–348PubMedGoogle Scholar
  41. 41.
    Vinters HV, Ellis WG, Zarow C, Zaias BW, Jagust WJ, Mack WJ, Chui HC (2000) Neuropathologic substrates of ischemic vascular dementia. J Neuropathol Exp Neurol 59:931–945PubMedGoogle Scholar
  42. 42.
    Weibel ER (1980) Stereological methods: practical methods for biological morphometry. Academic Press, New YorkGoogle Scholar
  43. 43.
    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 183:120–123CrossRefPubMedGoogle Scholar
  44. 44.
    Xuereb JH, Brayne C, Dufouil C, Gertz H, Wischik C, Harrington C, Mukaetova-Ladinska E, McGee MA, O'Sullivan A, O'Connor D, Paykel ES, Huppert FA (2000) Neuropathological findings in the very old. Results from the first 101 brains of a population-based longitudinal study of dementing disorders. Ann N Y Acad Sci 903:490–496PubMedGoogle Scholar
  45. 45.
    Yamada M, Tsukagoshi H, Otomo E, Hayakawa M (1987) Cerebral amyloid angiopathy in the aged. J Neurol 234:371–376PubMedGoogle Scholar
  46. 46.
    Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F, Hauw JJ (2002) Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly. Acta Neuropathol 103:481–487PubMedGoogle Scholar
  47. 47.
    Zekry D, Duyckaerts C, Belmin J, Geoffre C, Moulias R, Hauw JJ (2002) Alzheimer's disease and brain infarcts in the elderly. Agreement with neuropathology. J Neurol 249:1529–1534PubMedGoogle Scholar
  48. 48.
    Zekry D, Duyckaerts C, Belmin J, Geoffre C, Herrmann F, Moulias R, Hauw JJ (2003) The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy. Neurobiol Aging 24:213–219CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Dina Zekry
    • 1
  • Charles Duyckaerts
    • 1
  • Joël Belmin
    • 2
  • Caroline Geoffre
    • 2
  • Robert Moulias
    • 2
  • Jean-Jacques Hauw
    • 1
  1. 1.Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, INSERM U 106 and 360, Association Claude BernardPierre et Marie Curie UniversityParisFrance
  2. 2.Hôpital Charles FoixIvry-sur-SeineFrance

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