Journal of Neurology

, Volume 255, Issue 1, pp 70–76

Unexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy

An autopsy study
ORIGINAL COMMUNICATION

Abstract

In a retrospective study of a consecutive autopsy series of 2060 elderly subjects (mean age 78.5 ± 6.8 SD years), sporadic cerebral amyloid angiopathy (CAA) of various degrees was detected in 73.2% and in 98.5% of autopsy-confirmed cases of typical (plaque and tangle) Alzheimer disease (AD). Spontaneous (non-traumatic) intracerebral hemorrhages (ICH) (excluding microbleeds) were seen in 5.6% of the total cohort and in 7.2% of definite AD cases; CAA was found in 49% of brains without and in 48.7% with ICH which was not significantly different. The latter groups showed a significantly higher frequency of severe degrees of CAA than those without ICH (80.4 vs 30.9%, p < 0.001). Patients with CAA were older than those without CAA, showing a higher frequency of clinical dementia and pathologically confirmed AD, but signs of hypertension (history and/or autopsy) were seen in 41 and 33.6% of these cases, respectively, compared to 70–75% in patients with non-CAA related ICHs. CAA-related ICH much more frequently involved cerebral lobes or hemispheres, while non-CAA related lesions were more often located in basal ganglia and brainstem. The data of a lower prevalence of CAA in cases without than with ICH, but a similar prevalence of ICH with and without CAA do not support the concept that CAA represents the most evident risk factor for ICH in the aged. While severe degrees of CAA were indeed associated with ICH, the general prevalence of large ICH in this autopsy cohort was much higher in cases without CAA, probably due to other risk factors including hypertension, which was documented in around 40% of cases with CAA-related ICH. APOE ε3/4 and ε4/4 were significantly more frequent in AD (n = 163) than in age-matched controls (n = 47) and were associated with more severe degrees of CAA, but no general genotyping in ICHs with and without CAA was performed. Hence, the role of APOE in the pathogenesis of ICH with and without CAA needs further elucidation.

Key words

cerebral amyloid angiopathy spontaneous intracerebral hemorrhage Alzheimer disease prevalence of cerebral amyloid angiopathy in brains with and without intracerebral hematomas lobar and deep hemorrhages hypertension 

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References

  1. 1.
    Ariesen MJ, Claus SP, Rinkel GJ, Algra A (2003) Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke 34:2060–2065PubMedCrossRefGoogle Scholar
  2. 2.
    Atri A, Locascio JJ, Lin JM, Yap L, Dickerson BC, Grodstein F, Irizarry MC, Growdon JH, Greenberg SM (2005) Prevalence and effects of lobar microhemorrhages in early-stage dementia. Neurodegener Dis 2:305–312PubMedCrossRefGoogle Scholar
  3. 3.
    Attems J, Jellinger KA, Lintner F (2005) Alzheimer’s disease pathology influences severity and topographical distribution of cerebral amyloid angiopathy. Acta Neuropathol (Berl) 110:222–231PubMedCrossRefGoogle Scholar
  4. 4.
    Attems J, Lauda F, Lintner F, Jellinger KA (2007) Intracerebral haemorrhages are not associated to cerebral amyloid angiopathy in an autopsy study on 394 cases (Abstract). Conference on "Cerebral Amyloid Angiopathy: emerging concepts" Reykjavík, Iceland: Aug. 8–11, 2007Google Scholar
  5. 4a.
    Attems J, Quass M, Jellinger KA, Lintner F (2007) Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology. J Neurol Sci 257:49–55PubMedCrossRefGoogle Scholar
  6. 5.
    Bancher C, Egensperger R, Kosel S, Jellinger K, Graeber MB (1997) Low prevalence of apolipoprotein E epsilon 4 allele in the neurofibrillary tangle predominant form of senile dementia. Acta Neuropathol (Berl) 94:403–409PubMedCrossRefGoogle Scholar
  7. 6.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239–259PubMedCrossRefGoogle Scholar
  8. 7.
    Cho HS, Hyman BT, Greenberg SM, Rebeck GW (2001) Quantitation of ApoE domains in Alzheimer disease brain suggests a role for apoE in A beta aggregation. J Neuropathol Exp Neurol 60:342–349PubMedGoogle Scholar
  9. 8.
    Chui HC, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R (1992) Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology 42:473–480PubMedGoogle Scholar
  10. 8a.
    Cardonnier C, Al-Shahi Salman R, Wardlaw J (2007) Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 130:1988–2003CrossRefGoogle Scholar
  11. 9.
    Duyckaerts C (2007) Neuropathological diagnostic criteria for Alzheimer’s disease (Abstr. ). Neuropathol Appl Neurobiol 33:250–251Google Scholar
  12. 10.
    Ellis RJ, Olichney JM, Thal LJ, Mirra SS, Morris JC, Beekly D, Heyman A (1996) Cerebral amyloid angiopathy in the brains of patients with Alzheimer’s disease: the CERAD experience, Part XV. Neurology 46:1592–1596PubMedGoogle Scholar
  13. 11.
    Gilbert JJ, Vinters HV (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. I Cerebral hemorrhage. Stroke 14:915–923PubMedGoogle Scholar
  14. 12.
    Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT (1995) Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol 38:254–259PubMedCrossRefGoogle Scholar
  15. 13.
    Greenberg SM, Briggs ME, Hyman BT, Kokoris GJ, Takis C, Kanter DS, Kase CS, Pessin MS (1996) Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke 27:1333–1337PubMedGoogle Scholar
  16. 14.
    Greenberg SM, Vonsattel JP (1997) Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke 28:1418–1422PubMedGoogle Scholar
  17. 15.
    Greenberg SM (2004) Cerebral amyloid angiopathy. In:Mohr JP, Choi DW, Grotta JC, Weir B, Wolf PA (eds) Stroke – Pathophysiology, Diagnosis, and Management. 4th Edition. Churchill Livingstone Philadelphia, pp 693–705Google Scholar
  18. 16.
    Hanyu H, Tanaka Y, Shimizu S, Takasaki M, Abe K (2003) Cerebral microbleeds in Alzheimer’s disease. J Neurol 250:1496–1497PubMedCrossRefGoogle Scholar
  19. 17.
    Hill MD, Silver FL, Austin PC, Tu JV (2000) Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke 31:123–127PubMedGoogle Scholar
  20. 18.
    Hyman BT (1998) New neuropathological criteria for Alzheimer disease. Arch Neurol 55:1174–1176PubMedCrossRefGoogle Scholar
  21. 19.
    Ishii N, Nishihara Y, Horie A (1984) Amyloid angiopathy and lobar cerebral haemorrhage. J Neurol Neurosurg Psychiatry 47:1203–1210PubMedCrossRefGoogle Scholar
  22. 20.
    Itoh Y, Yamada M, Hayakawa M, Otomo E, Miyatake T (1993) Cerebral amyloid angiopathy: a significant cause of cerebellar as well as lobar cerebral hemorrhage in the elderly. J Neurol Sci 116:135–141PubMedCrossRefGoogle Scholar
  23. 21.
    Izumihara A, Suzuki M, Ishihara T (2005) Recurrence and extension of lobar hemorrhage related to cerebral amyloid angiopathy: multivariate analysis of clinical risk factors. Surg Neurol 64:160–164PubMedCrossRefGoogle Scholar
  24. 22.
    Jellinger K (1977) Cerebrovascular amyloidosis with cerebral hemorrhage. J Neurol 214:195–206PubMedCrossRefGoogle Scholar
  25. 23.
    Jellinger KA (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109:813–836PubMedCrossRefGoogle Scholar
  26. 24.
    Jellinger KA (2006) Spatial distribution of hemorrhages in cerebral amyloid angiopathy. Ann Neurol 59:215PubMedCrossRefGoogle Scholar
  27. 25.
    Jellinger KA, Attems J (2006) Prevalence and impact of cerebrovascular pathology in Alzheimer’s disease and parkinsonism. Acta Neurol Scand 114:38–46PubMedCrossRefGoogle Scholar
  28. 26.
    Jellinger KA, Attems J (2007) Neuropathological evaluation of mixed dementia. J Neurol Sci available online 26 Feb. 2007:doi:10. 1016/ j. jns2007. 1001. 1045Google Scholar
  29. 26a.
    Jellinger KA, Lauda F, Attems J (2007) Sporadic cerebral amyloid angiopathy is not a frequent cause of spontaneous brain hemorrhage. Eur J Neurol 14:923–928PubMedCrossRefGoogle Scholar
  30. 27.
    Kalaria RN, Ballard C (1999) Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord 13 (Suppl. 3):S115–S123PubMedCrossRefGoogle Scholar
  31. 28.
    Knudsen KA, Rosand J, Karluk D, Greenberg SM (2001) Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 56:537–539PubMedGoogle Scholar
  32. 29.
    Koennecke HC (2006) Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications. Neurology 66:165–171PubMedCrossRefGoogle Scholar
  33. 30.
    Lee SH, Bae HJ, Kwon SJ, Kim H, Kim YH, Yoon BW, Roh JK (2004) Cerebral microbleeds are regionally associated with intracerebral hemorrhage. Neurology 62:72–76PubMedGoogle Scholar
  34. 30a.
    Lee SH, Kim SM, Kim N, Yoon BW, Roth JK (2007) Cortico-subcortical distribution of microbleeds is different between hypertension and cerebral amyloid angiopathy. J Neurol Sci 258:111–114PubMedCrossRefGoogle Scholar
  35. 31.
    Lipton RB, Berger AR, Lesser ML, Lantos G, Portenoy RK (1987) Lobar vs thalamic and basal ganglion hemorrhage: clinical and radiographic features. J Neurol 234:86–90PubMedCrossRefGoogle Scholar
  36. 32.
    Maurino J, Saposnik G, Lepera S, Rey RC, Sica RE (2001) Multiple simultaneous intracerebral hemorrhages: clinical features and outcome. Arch Neurol 58:629–632PubMedCrossRefGoogle Scholar
  37. 33.
    McCarron MO, Nicoll JA, Ironside JW, Love S, Alberts MJ, Bone I (1999) Cerebral amyloid angiopathy-related hemorrhage. Interaction of APOE epsilon2 with putative clinical risk factors. Stroke 30:1643–1646PubMedGoogle Scholar
  38. 34.
    McCarron MO, Nicoll JA, Stewart J, Ironside JW, Mann DM, Love S, Graham DI, Dewar D (1999) The apolipoprotein E epsilon2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage. J Neuropathol Exp Neurol 58:711–718PubMedGoogle Scholar
  39. 35.
    McCarron MO, Nicoll JA (2000) Apolipoprotein E genotype and cerebral amyloid angiopathy-related hemorrhage. Ann N Y Acad Sci 903:176–179PubMedCrossRefGoogle Scholar
  40. 36.
    McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova- Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872PubMedCrossRefGoogle Scholar
  41. 37.
    Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (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
  42. 38.
    Mughal M, Allen S (2002) Cerebral amyloid angiopathy as a cause of recurrent intracerebral hemorrhage. Conn Med 66:67–70PubMedGoogle Scholar
  43. 39.
    Nakata-Kudo Y, Mizuno T, Yamada K, Shiga K, Yoshikawa K, Mori S, Nishimura T, Nakajima K, Nakagawa M (2006) Microbleeds in Alzheimer disease are more related to cerebral amyloid angiopathy than cerebrovascular disease. Dement Geriatr Cogn Disord 22:8–14PubMedCrossRefGoogle Scholar
  44. 40.
    Nicoll JA, Burnett C, Love S, Graham DI, Ironside JW, Vinters HV (1996) High frequency of apolipoprotein E epsilon 2 in patients with cerebral hemorrhage due to cerebral amyloid angiopathy. Ann Neurol 39:682–683PubMedCrossRefGoogle Scholar
  45. 41.
    Nicoll JA, Burnett C, Love S, Graham DI, Dewar D, Ironside JW, Stewart J, Vinters HV (1997) High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol 41:716–721PubMedCrossRefGoogle Scholar
  46. 42.
    Nicoll JA, McCarron MO (2001) APOE gene polymorphism as a risk factor for cerebral amyloid angiopathy-related hemorrhage. Amyloid 8 (Suppl 1):51–55PubMedGoogle Scholar
  47. 43.
    O’Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, Ikeda D, Greenberg SM (2000) Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med 342:240–245CrossRefGoogle Scholar
  48. 44.
    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 52:702–708PubMedGoogle Scholar
  49. 45.
    Ritter MA, Droste DW, Hegedus K, Szepesi R, Nabavi DG, Csiba L, Ringelstein EB (2005) Role of cerebral amyloid angiopathy in intracerebral hemorrhage in hypertensive patients. Neurology 64:1233–1237PubMedGoogle Scholar
  50. 46.
    Seifert T, Lechner A, Flooh E, Schmidt H, Schmidt R, Fazekas F (2006) Lack of association of lobar intracerebral hemorrhage with apolipoprotein E genotype in an unselected population. Cerebrovasc Dis 21:266–270PubMedCrossRefGoogle Scholar
  51. 47.
    Sudlow CL, Warlow CP (1997) Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke 28:491–499PubMedGoogle Scholar
  52. 48.
    Tanskanen M, Lindsberg PJ, Tienari PJ, Polvikoski T, Sulkava R, Verkkoniemi A, Rastas S, Paetau A, Kiuru-Enari S (2005) Cerebral amyloid angiopathy in a 95+ cohort: complement activation and apolipoprotein E (ApoE) genotype. Neuropathol Appl Neurobiol 31:589–599PubMedCrossRefGoogle Scholar
  53. 49.
    Thanvi B, Robinson T (2006) Sporadic cerebral amyloid angiopathy – an important cause of cerebral haemorrhage in older people. Age Ageing 35:565–571PubMedCrossRefGoogle Scholar
  54. 50.
    Thrift AG, McNeil JJ, Forbes A, Donnan GA (1998) Three important subgroups of hypertensive persons at greater risk of intracerebral hemorrhage. Melbourne Risk Factor Study Group. Hypertension 31:1223–1229PubMedGoogle Scholar
  55. 51.
    Tian J, Shi J, Mann DM (2004) Cerebral amyloid angiopathy and dementia. Panminerva Med 46:253–264PubMedGoogle Scholar
  56. 52.
    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 (Berl) 113:23–31PubMedCrossRefGoogle Scholar
  57. 53.
    Vinters HV, Gilbert JJ (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke 14:924–928PubMedGoogle Scholar
  58. 54.
    Vinters HV, Duckwiler GR (1992) Intracranial hemorrhage in normotensive elderly patients. Neuroimaging Clin North Am 2:153–169Google Scholar
  59. 55.
    Vinters HV, Wang ZZ, Secor DL (1996) Brain parenchymal and microvascular amyloid in Alzheimer’s disease. Brain Pathol 6:179–195PubMedGoogle Scholar
  60. 56.
    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 30:637–649PubMedCrossRefGoogle Scholar
  61. 57.
    Wagle WA, Smith TW, Weiner M (1984) Intracerebral hemorrhage caused by cerebral amyloid angiopathy: radiographic- pathologic correlation. AJNR Am J Neuroradiol 5:171–176PubMedGoogle Scholar
  62. 58.
    Xu D, Yang CH, Wang LN (2003) [Prevalence and characteristics of cerebral amyloid angiopathy in the elderly]. Zhonghua Nei Ke Za Zhi 42:541–544PubMedGoogle Scholar
  63. 59.
    Zhan RY, Tong Y, Shen JF, Lang E, Preul C, Hempelmann RG, Hugo HH, Buhl R, Barth H, Klinge H, Mehdorn HM (2004) Study of clinical features of amyloid angiopathy hemorrhage and hypertensive intracerebral hemorrhage. J Zhejiang Univ Sci 5:1262–1269PubMedCrossRefGoogle Scholar

Copyright information

© Steinkopff-Verlag 2008

Authors and Affiliations

  1. 1.Institute of PathologyOtto Wagner HospitalViennaAustria
  2. 2.Institute of Clinical NeurobiologyViennaAustria

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