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Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study

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Abstract

Data on the relationship between cerebral amyloid angiopathy (CAA) (“congophilic angiopathy”) and Alzheimer’s disease (AD) pathology are conflicting. In the present study, CAA and capillary CAA (CapCAA) (“dyshoric angiopathy”) were examined in the frontal cortex of 100 human brains obtained at autopsy from both male and female, demented and non-demented patients (mean age ± SD 84.3±9.3 years); 50 brains with high (mean 5.0) and 50 with low (mean 2.4) Braak stages. CAA was assessed according to the method of Olichney et al. [25]; CapCAA was grouped into four grades by counting the affected capillaries in 10 high power fields. General CAA was present in 61% (87.5% demented, 55.6% non-demented; 70% with high and 52% low Braak stages). CAA did not correlate with either clinical diagnosis of dementia or high-grade AD pathology; CapCAA showed a low correlation with dementia and a medium positive correlation with high Braak stages. The severity of both lesions did not correlate with clinical dementia; whereas that of CAA showed low correlation with CERAD, Braak, and NIA-Reagan-Institute criteria, the severity of CapCAA correlated significantly with all three AD criteria. The presence and severity of CAA and CapCAA showed only low correlation, suggesting a different pathogenesis of these types of lesion. Since CapCAA represents insoluble amyloid peptide (Aβ) deposits in and around capillaries, its correlation with neuritic AD pathology supports the concept of neuronal origin of Aβ via drainage from interstitial fluid from the central nervous system to capillary walls. Studies to answer the question whether CapCAA represents an epiphenomenon or an indicator of a pathogenic association between tau cytopathology and Aβ deposition in capillaries are in progress.

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References

  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 57:353–359

    CAS  PubMed  Google Scholar 

  2. Bergeron C, Ranalli PJ, Miceli PN (1987) Amyloid angiopathy in Alzheimer’s disease. Can J Neurol Sci 14:564–569

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Cadavid D, Mena H, Koeller K, Frommelt RA (2000) Cerebral beta amyloid angiopathy is a risk factor for cerebral ischemic infarction. A case control study in human brain biopsies. J Neuropathol Exp Neurol 59:768–773

    PubMed  Google Scholar 

  5. 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 USA 96:14088–14093

    Article  CAS  PubMed  Google Scholar 

  6. Davis DG, Schmitt FA, Wekstein DR, Markesbery WR (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58:376–388

    CAS  PubMed  Google Scholar 

  7. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295:2264–2267

    Article  PubMed  Google Scholar 

  8. Dermaut B, Kumar-Singh S, De Jonghe C, Cruts M, Lofgren A, Lubke U, Cras P, Dom R, De Deyn PP, Martin JJ, Van Broeckhoven C (2001) Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer’s disease due to a novel presenilin 1 mutation. Brain 124:2383–2392

    Article  PubMed  Google Scholar 

  9. 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

    CAS  PubMed  Google Scholar 

  10. Holton JL, Ghiso J, Lashley T, Rostagno A, Guerin CJ, Gibb G, Houlden H, Ayling H, Martinian L, Anderton BH, Wood NW, Vidal R, Plant G, Frangione B, Revesz T (2001) Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia. Am J Pathol 158:515–526

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Jellinger KA, Attems J (2003) Incidence of cerebrovascular lesions in Alzheimer’s disease: a postmortem study. Acta Neuropathol 105:14–17

    PubMed  Google Scholar 

  14. Jellinger KA, Mitter-Ferstl E (2003) The impact of cerebrovascular lesions in Alzheimer disease. A comparative autopsy study. J Neurol 252:1050–1055

    Article  Google Scholar 

  15. Kuo YM, Crawford F, Mullan M, Kokjohn TA, Emmerling MR, Weller RO, Roher AE (2000) Elevated A beta and apolipoprotein E in A betaPP transgenic mice and its relationship to amyloid accumulation in Alzheimer’s disease. Mol Med 6:430–439

    PubMed  Google Scholar 

  16. Mackic JB, Weiss MH, Miao W, Kirkman E, Ghiso J, Calero M, Bading J, Frangione B, Zlokovic BV (1998) Cerebrovascular accumulation and increased blood-brain barrier permeability to circulating Alzheimer’s amyloid beta peptide in aged squirrel monkey with cerebral amyloid angiopathy. J Neurochem 70:210–215

    PubMed  Google Scholar 

  17. 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  Google Scholar 

  18. Maruyama K, Ikeda S, Ishihara T, Allsop D, Yanagisawa N (1990) Immunohistochemical characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to beta protein and cystatin C. Stroke 21:397–403

    CAS  PubMed  Google Scholar 

  19. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, Belle G van, 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

    CAS  PubMed  Google Scholar 

  20. Morel F, Wildi E (1957) Contribution à la connaissance des différentes altérations cerebrales des grande áge. Schweiz Arch Neurol Psychiat 76:174–223

    PubMed  Google Scholar 

  21. Natte 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 828:179–183

    Article  PubMed  Google Scholar 

  22. Natte R, Yamaguchi H, Maat-Schieman ML, Prins FA, Neeskens P, Roos RA, Duinen SG van (1999) Ultrastructural evidence of early non-fibrillar Abeta42 in the capillary basement membrane of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type. Acta Neuropathol 98:577–582

    Article  PubMed  Google Scholar 

  23. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–452

    Article  PubMed  Google Scholar 

  24. 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  Google Scholar 

  25. Olichney JM, Ellis RJ, Katzman R, Sabbagh MN, Hansen L (1997) Types of cerebrovascular lesions associated with severe cerebral amyloid angiopathy in Alzheimer’s disease. Ann N Y Acad Sci 826:493–497

    CAS  PubMed  Google Scholar 

  26. Pantelakis S (1954) Un type particulier d’angiopathie sémile du systême nerveux central: l’angiopathie congophile. Topographie et fréquence. Mschr Psychiat Neurol 128:219

    Article  PubMed  Google Scholar 

  27. Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ (2002) Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology 58:1629–1634

    CAS  PubMed  Google Scholar 

  28. Preston SD, Steart PV, Wilkinson A, Nicoll JA, Weller RO (2003) Capillary and arterial cerebral amyloid angiopathy in Alzheimer’s disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol 29:106–117

    PubMed  Google Scholar 

  29. Revesz T, Holton JL, Lashley T, Plant G, Rostagno A, Ghiso J, Frangione B (2002) Sporadic and familial cerebral amyloid angiopathies. Brain Pathol 12:343–357

    PubMed  Google Scholar 

  30. 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  Google Scholar 

  31. Revesz T, Ghiso J, Plant G, Holton JL, Frangione B (2003) Inherited amyloidosis and neurodegenerations in familial British and Danish dementia. In: Dickson DW (ed) Neurodegeneration. The molecular pathology of dementia and movement disorders. ISN Neuropath Press Basel, pp 380–385

  32. Roher AE, Kuo YM, Esh C, Knebel C, Weiss N, Kalback W, Luehrs DC, Childress JL, Beach TG, Weller RO, Kokjohn TA (2003) Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Mol Med 9:112–122

    PubMed  Google Scholar 

  33. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV (2000) Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106:1489–1499

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  35. Thal DR, Dhebremedhin E, Orantes M, Wiestler OD (2003) Small vessel lesions related to cerebral amyloid angiopathy (CAA) and arteriosclerosis/lipohylinosis (AS/LH) are associated with Alzheimer disease. Brain Pathol 13 (Suppl 1):S7–S8

    Google Scholar 

  36. Tian J, Shi J, Bailey K, Mann DMA (2003) Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimers’s disease. Neurosci Lett 354:137–140

    PubMed  Google Scholar 

  37. Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18:311–324

    CAS  PubMed  Google Scholar 

  38. Vinters HV, Secor DL, Pardridge WM, Gray F (1990) Immunohistochemical study of cerebral amyloid angiopathy. III. Widespread Alzheimer A4 peptide in cerebral microvessel walls colocalizes with gamma trace in patients with leukoencephalopathy. Ann Neurol 28:34–42

    PubMed  Google Scholar 

  39. 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 18:333–348

    CAS  PubMed  Google Scholar 

  40. 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  Google Scholar 

  41. 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

    Google Scholar 

  42. Weller RO, Massey A, Kuo YM, Roher AE (2000) Cerebral amyloid angiopathy: accumulation of A beta in interstitial fluid drainage pathways in Alzheimer’s disease. Ann N Y Acad Sci 903:110–117

    CAS  PubMed  Google Scholar 

  43. Weller RO, Nicoll JAR (2003) Cerebral amyloid angiopathy: pathogenesis and effects on the ageing and Alzheimer brain. Neurol Res 25:611–616

    Google Scholar 

  44. Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L (2001) TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 7:612–618

    Article  CAS  PubMed  Google Scholar 

  45. Xu D, Yang C, Wang L (2003) Cerebral amyloid angiopathy in aged Chinese: a clinico-neuropathological study. Acta Neuropathol 106:89–91

    PubMed  Google Scholar 

  46. Yamada M, Tsukagoshi H, Otomo E, Hayakawa M (1987) Cerebral amyloid angiopathy in the aged. J Neurol 234:371–376

    CAS  PubMed  Google Scholar 

  47. Zekry D, Duyckaerts C, Belmin J, Geoffre C, Moulias R, Hauw JJ (2003) Cerebral amyloid angiopathy in the elderly: vessel walls changes and relationship with dementia. Acta Neuropathol 106:367–373

    Article  PubMed  Google Scholar 

  48. Zlokovic BV, Ghiso J, Mackic JB, McComb JG, Weiss MH, Frangione B (1993) Blood-brain barrier transport of circulating Alzheimer’s amyloid beta. Biochem Biophys Res Commun 197:1034–1040

    Article  PubMed  Google Scholar 

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Acknowledgement

The authors thank Mrs. Veronika Rappelsberger and Mrs. Barbara Weidinger for excellent laboratory work, and Erich Mitter-Ferstl, PhD, for secretarial and computer work. Part of the study was supported by the Society for the Support of Research in the Field of Experimental Neurology, Vienna, Austria.

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Correspondence to Kurt A. Jellinger.

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Attems, J., Jellinger, K.A. Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study. Acta Neuropathol 107, 83–90 (2004). https://doi.org/10.1007/s00401-003-0796-9

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  • DOI: https://doi.org/10.1007/s00401-003-0796-9

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