Acta Neuropathologica

, Volume 105, Issue 5, pp 484–488 | Cite as

Lewy body pathology is a frequent co-pathology in familial Alzheimer's disease

  • Yuri Trembath
  • Carolyn Rosenberg
  • John F. Ervin
  • Donald E. Schmechel
  • Perry Gaskell
  • Margaret Pericak-Vance
  • Jeffery Vance
  • Christine M. Hulette
Regular Paper

Abstract

Our institution is currently engaged in ongoing genetic studies of familial Alzheimer's disease (AD), which include clinical ascertainment and brain autopsy of both affected and non-affected family members. Here we describe the analysis of 22 AD families, each with at least one family member with a postmortem diagnosis of dementia with Lewy bodies (DLB). For this study, 47 brains were examined according to NINCDS-Reagan Institute criteria for the diagnosis of AD. Lewy body pathology was evaluated with α-synuclein immunohistochemistry. Four families, with either one or two autopsies showing Lewy body pathology, demonstrated linkage to 12p. Five families had two or more autopsies with Lewy body pathology, but their linkage status was unknown. The remaining 13 families had one autopsy demonstrating Lewy bodies. These findings suggest that at least one pathological form of DLB may be familial. In some families, the pathological phenotype is identical in all examined affected family members; but in others, there may be several pathologies that coexist. Careful neuropathological examination of affected family members may prove critical for future genetic analysis of AD and DLB.

Keywords

Alzheimer's disease Dementia with Lewy bodies Autopsy Genetics 

References

  1. 1.
    Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedGoogle Scholar
  2. 2.
    Dickson DW, Crystal H, Mattiace LA, et al (1989) Diffuse Lewy body disease: light and electron microscopic immunocytochemistry of senile plaques. Acta Neuropathol 78:572–584PubMedGoogle Scholar
  3. 3.
    Galasko D, Hansen LA, Katzman R, et al (1994) Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch Neurol 51:888–895PubMedGoogle Scholar
  4. 4.
    Hashimoto M, Hsu LJ, Rockenstein E, Takenouchi T, Mallory M, Masliah E (2002) α-Synuclein protects against oxidative stress via inactivation of the C-jun N-terminal kinase stress signaling pathway in neuronal cells. J Biol Chem 14:14Google Scholar
  5. 5.
    Hsu LJ, Sagara Y, Arroyo A, et al (2000) Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol 157:401–410PubMedGoogle Scholar
  6. 6.
    Hulette C, Mirra S, Wilkinson W, Heyman A, Fillenbaum G, Clark C (1995) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part IX. A prospective cliniconeuropathologic study of Parkinson's features in Alzheimer's disease. Neurology 45:1991–1995PubMedGoogle Scholar
  7. 7.
    Hulette CM, Welsh-Bohmer KA, Crain B, Szymanski MH, Sinclaire NO, Roses AD (1997) Rapid brain autopsy. The Joseph and Kathleen Bryan Alzheimer's Disease Research Center experience. Arch Pathol Lab Med 121:615–618PubMedGoogle Scholar
  8. 8.
    Hyman BT, Trojanowski JQ (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 56:1095–1097PubMedGoogle Scholar
  9. 9.
    Ishikawa A, Takahashi H, Tanaka H, Hayashi T, Tsuji S (1997) Clinical features of familial diffuse Lewy body disease. Eur Neurol 38:34–38PubMedGoogle Scholar
  10. 10.
    Kahle PJ, Neumann M, Ozmen L, et al (2000) Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha -synuclein in human and transgenic mouse brain. J Neurosci 20:6365–6373PubMedGoogle Scholar
  11. 11.
    Kanda S, Bishop JF, Eglitis MA, Yang Y, Mouradian MM (2000) Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. Neuroscience 97:279–284CrossRefPubMedGoogle Scholar
  12. 12.
    Kehoe P, Wavrant-De Vrieze F, Crook R, et al (1999) A full genome scan for late onset Alzheimer's disease. Hum Mol Genet 8:237–245Google Scholar
  13. 13.
    Lippa CF, Fujiwara H, Mann DM, et al (1998) Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes. Am J Pathol 153:1365–1370PubMedGoogle Scholar
  14. 14.
    Lippa CF, Schmidt ML, Lee VM, Trojanowski JQ (1999) Antibodies to alpha-synuclein detect Lewy bodies in many Down's syndrome brains with Alzheimer's disease. Ann Neurol 45:353–357PubMedGoogle Scholar
  15. 15.
    Masliah E, Rockenstein E, Veinbergs I, et al (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269CrossRefPubMedGoogle Scholar
  16. 16.
    Masliah E, Rockenstein E, Veinbergs I, et al (2001) Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci USA 98:12245–12250PubMedGoogle Scholar
  17. 17.
    McKeith IG, Galasko D, Kosaka K, et al (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124PubMedGoogle Scholar
  18. 18.
    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34:939–944PubMedGoogle Scholar
  19. 19.
    Mirra SS, Heyman A, McKeel D, et al (1991) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathological assessment of Alzheimer's disease. Neurology 41:479–486PubMedGoogle Scholar
  20. 20.
    Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B (2000) The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 20:6048–6054Google Scholar
  21. 21.
    Pericak-Vance, MA, Bass MP, Yamaoka LH, et al (1997) Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA 278:1237–1241PubMedGoogle Scholar
  22. 22.
    Rogaeva E, Premkumar S, Song Y, et al (1998) Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. JAMA 280:614–618PubMedGoogle Scholar
  23. 23.
    Rosenberg CK, Pericak-Vance MA, Saunders AM, Gilbert JR, Gaskell PC, Hulette CM (2000) Lewy body and Alzheimer pathology in a family with the amyloid-beta precursor protein APP717 gene mutation. Acta Neuropathol 100:145–152PubMedGoogle Scholar
  24. 24.
    Rosenberg CK, Cummings TJ, Saunders AM, Widico C, McIntyre LM, Hulette CM (2001) Dementia with Lewy bodies and Alzheimer's disease. Acta Neuropathol 102:621–626PubMedGoogle Scholar
  25. 25.
    Saha AR, Ninkina NN, Hanger DP, Anderton BH, Davies AM, Buchman VL (2000) Induction of neuronal death by alpha-synuclein. Eur J Neurosci 12:3073–3077CrossRefPubMedGoogle Scholar
  26. 26.
    Scott WK, Grubber JM, Abou-Donia SM, et al (1999) Further evidence linking late-onset Alzheimer disease with chromosome 12. JAMA 281:513–514PubMedGoogle Scholar
  27. 27.
    Scott WK, Grubber JM, Conneally PM, et al (2000) Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet 66:922–932Google Scholar
  28. 28.
    Stefanova N, Klimaschewski L, Poewe W, Wenning GK, Reindl M (2001) Glial cell death induced by overexpression of alpha-synuclein. J Neurosci Res 65:432–438CrossRefPubMedGoogle Scholar
  29. 29.
    Swanberg MM, Cummings JL (2002) Benefit-risk considerations in the treatment of dementia with Lewy bodies. Drug Saf 25:511–523PubMedGoogle Scholar
  30. 30.
    Uversky VN, Lie J, Fink AL (2001) Evidence for a partially folded intermediate in alpha-synuclein fibril formation. J Biol Chem 276:10737–10744PubMedGoogle Scholar
  31. 31.
    Wu WS, Holmans P, Wavrant-DeVrieze F, et al (1998) Genetic studies on chromosome 12 in late-onset Alzheimer disease. JAMA 280:619–622PubMedGoogle Scholar
  32. 32.
    Zhou W, Hurlbert MS, Schaack J, Prasad KN, Freed CR (2000) Overexpression of human alpha-synuclein causes dopamine neuron death in rat primary culture and immortalized mesencephalon-derived cells. Brain Res 866:33–43PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Yuri Trembath
    • 1
  • Carolyn Rosenberg
    • 1
  • John F. Ervin
    • 2
  • Donald E. Schmechel
    • 2
  • Perry Gaskell
    • 3
  • Margaret Pericak-Vance
    • 3
  • Jeffery Vance
    • 2
    • 3
  • Christine M. Hulette
    • 1
    • 3
  1. 1.Department of Pathology, Section of NeuropathologyDuke University Medical CenterDurhamUSA
  2. 2.Department of Medicine, Division of NeurologyDuke University Medical CenterUSA
  3. 3.Center for Human GeneticsBryan Alzheimer's Disease Research Center and Udall Parkinson Disease Center of ExcellenceDurhamUSA

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