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Unexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy

An autopsy study

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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.

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References

  1. Ariesen MJ, Claus SP, Rinkel GJ, Algra A (2003) Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke 34:2060–2065

    Article  PubMed  CAS  Google Scholar 

  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 2:305–312

    Article  PubMed  Google Scholar 

  3. Attems J, Jellinger KA, Lintner F (2005) Alzheimer’s disease pathology influences severity and topographical distribution of cerebral amyloid angiopathy. Acta Neuropathol (Berl) 110:222–231

    Article  PubMed  Google Scholar 

  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, 2007

  5. 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 257:49–55

    Article  PubMed  Google Scholar 

  6. 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) 94:403–409

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. 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 60:342–349

    PubMed  CAS  Google Scholar 

  9. 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 42:473–480

    PubMed  CAS  Google Scholar 

  10. Cardonnier C, Al-Shahi Salman R, Wardlaw J (2007) Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 130:1988–2003

    Article  Google Scholar 

  11. Duyckaerts C (2007) Neuropathological diagnostic criteria for Alzheimer’s disease (Abstr. ). Neuropathol Appl Neurobiol 33:250–251

    Google Scholar 

  12. 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 46:1592–1596

    PubMed  CAS  Google Scholar 

  13. Gilbert JJ, Vinters HV (1983) Cerebral amyloid angiopathy: incidence and complications in the aging brain. I Cerebral hemorrhage. Stroke 14:915–923

    PubMed  CAS  Google Scholar 

  14. 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 38:254–259

    Article  PubMed  CAS  Google Scholar 

  15. 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 27:1333–1337

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  17. 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 693–705

  18. Hanyu H, Tanaka Y, Shimizu S, Takasaki M, Abe K (2003) Cerebral microbleeds in Alzheimer’s disease. J Neurol 250:1496–1497

    Article  PubMed  Google Scholar 

  19. Hill MD, Silver FL, Austin PC, Tu JV (2000) Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke 31:123–127

    PubMed  CAS  Google Scholar 

  20. Hyman BT (1998) New neuropathological criteria for Alzheimer disease. Arch Neurol 55:1174–1176

    Article  PubMed  CAS  Google Scholar 

  21. Ishii N, Nishihara Y, Horie A (1984) Amyloid angiopathy and lobar cerebral haemorrhage. J Neurol Neurosurg Psychiatry 47:1203–1210

    Article  PubMed  CAS  Google Scholar 

  22. 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 116:135–141

    Article  PubMed  CAS  Google Scholar 

  23. 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 64:160–164

    Article  PubMed  Google Scholar 

  24. Jellinger K (1977) Cerebrovascular amyloidosis with cerebral hemorrhage. J Neurol 214:195–206

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. Jellinger KA (2006) Spatial distribution of hemorrhages in cerebral amyloid angiopathy. Ann Neurol 59:215

    Article  PubMed  Google Scholar 

  27. Jellinger KA, Attems J (2006) Prevalence and impact of cerebrovascular pathology in Alzheimer’s disease and parkinsonism. Acta Neurol Scand 114:38–46

    Article  PubMed  CAS  Google Scholar 

  28. Jellinger KA, Attems J (2007) Neuropathological evaluation of mixed dementia. J Neurol Sci available online 26 Feb. 2007:doi:10. 1016/ j. jns2007. 1001. 1045

  29. Jellinger KA, Lauda F, Attems J (2007) Sporadic cerebral amyloid angiopathy is not a frequent cause of spontaneous brain hemorrhage. Eur J Neurol 14:923–928

    Article  PubMed  CAS  Google Scholar 

  30. Kalaria RN, Ballard C (1999) Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord 13 (Suppl. 3):S115–S123

    Article  PubMed  Google Scholar 

  31. Knudsen KA, Rosand J, Karluk D, Greenberg SM (2001) Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology 56:537–539

    PubMed  CAS  Google Scholar 

  32. Koennecke HC (2006) Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications. Neurology 66:165–171

    Article  PubMed  Google Scholar 

  33. Lee SH, Bae HJ, Kwon SJ, Kim H, Kim YH, Yoon BW, Roh JK (2004) Cerebral microbleeds are regionally associated with intracerebral hemorrhage. Neurology 62:72–76

    PubMed  CAS  Google Scholar 

  34. 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 258:111–114

    Article  PubMed  Google Scholar 

  35. Lipton RB, Berger AR, Lesser ML, Lantos G, Portenoy RK (1987) Lobar vs thalamic and basal ganglion hemorrhage: clinical and radiographic features. J Neurol 234:86–90

    Article  PubMed  CAS  Google Scholar 

  36. Maurino J, Saposnik G, Lepera S, Rey RC, Sica RE (2001) Multiple simultaneous intracerebral hemorrhages: clinical features and outcome. Arch Neurol 58:629–632

    Article  PubMed  CAS  Google Scholar 

  37. 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 30:1643–1646

    PubMed  CAS  Google Scholar 

  38. 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 58:711–718

    PubMed  CAS  Google Scholar 

  39. McCarron MO, Nicoll JA (2000) Apolipoprotein E genotype and cerebral amyloid angiopathy-related hemorrhage. Ann N Y Acad Sci 903:176–179

    Article  PubMed  CAS  Google Scholar 

  40. 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 65:1863–1872

    Article  PubMed  CAS  Google Scholar 

  41. 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 41:479–486

    PubMed  CAS  Google Scholar 

  42. Mughal M, Allen S (2002) Cerebral amyloid angiopathy as a cause of recurrent intracerebral hemorrhage. Conn Med 66:67–70

    PubMed  Google Scholar 

  43. 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 22:8–14

    Article  PubMed  Google Scholar 

  44. 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 39:682–683

    Article  PubMed  CAS  Google Scholar 

  45. 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 41:716–721

    Article  PubMed  CAS  Google Scholar 

  46. Nicoll JA, McCarron MO (2001) APOE gene polymorphism as a risk factor for cerebral amyloid angiopathy-related hemorrhage. Amyloid 8 (Suppl 1):51–55

    PubMed  CAS  Google Scholar 

  47. 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 342:240–245

    Article  Google Scholar 

  48. 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 

  49. 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 64:1233–1237

    PubMed  CAS  Google Scholar 

  50. 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 21:266–270

    Article  PubMed  CAS  Google Scholar 

  51. 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 28:491–499

    PubMed  CAS  Google Scholar 

  52. 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 31:589–599

    Article  PubMed  CAS  Google Scholar 

  53. Thanvi B, Robinson T (2006) Sporadic cerebral amyloid angiopathy – an important cause of cerebral haemorrhage in older people. Age Ageing 35:565–571

    Article  PubMed  Google Scholar 

  54. 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 31:1223–1229

    PubMed  CAS  Google Scholar 

  55. Tian J, Shi J, Mann DM (2004) Cerebral amyloid angiopathy and dementia. Panminerva Med 46:253–264

    PubMed  CAS  Google Scholar 

  56. 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) 113:23–31

    Article  PubMed  CAS  Google Scholar 

  57. 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 

  58. Vinters HV, Duckwiler GR (1992) Intracranial hemorrhage in normotensive elderly patients. Neuroimaging Clin North Am 2:153–169

    Google Scholar 

  59. 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 

  60. 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

    Article  PubMed  CAS  Google Scholar 

  61. Wagle WA, Smith TW, Weiner M (1984) Intracerebral hemorrhage caused by cerebral amyloid angiopathy: radiographic- pathologic correlation. AJNR Am J Neuroradiol 5:171–176

    PubMed  CAS  Google Scholar 

  62. Xu D, Yang CH, Wang LN (2003) [Prevalence and characteristics of cerebral amyloid angiopathy in the elderly]. Zhonghua Nei Ke Za Zhi 42:541–544

    PubMed  Google Scholar 

  63. 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 5:1262–1269

    Article  PubMed  Google Scholar 

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  1. Institute of Pathology, Otto Wagner Hospital, Baumgartner Hoehe 1, 1145, Vienna, Austria

    J. Attems & F. Lauda

  2. Institute of Clinical Neurobiology, Kenyongasse 18, 1070, Vienna, Austria

    K. A. Jellinger MD

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  1. J. Attems
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Attems, J., Lauda, F. & Jellinger, K.A. Unexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy. J Neurol 255, 70–76 (2008). https://doi.org/10.1007/s00415-008-0674-4

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