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Characteristics of alpha-synucleinopathy in centenarians

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Abstract

To investigate the characteristics of alpha-synucleinopathy in the brains of centenarians, the autopsied brains and spinal cords from 23 cases were studied. Coronal slices were prepared from a section of the cerebral hemisphere, following the guidelines of the Consortium to Establish a Registry for Alzheimer’s Disease (AD) (CERAD) and the consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB). Spinal cord specimens were prepared at each segment from the third cervical to the third sacral segment. In all cases, we performed standard stainings of hematoxylin–eosin, Klüver–Barrera, and Gallyas–Braak combined with Luxol fast blue/cresyl violet, and alpha-synuclein (AS), phosphorylated tau (AT8) and beta-amyloid protein immunostainings. One-way ANOVA analysis, Chi-square or Fisher exact test were used for statistical analysis. Overall, AS-positive structures were found in 8 (34.8%) of our 23 centenarians, 6 (35.3%) of 17 demented patients, and four (40%) out of ten AD patients. The frequencies of AS lesions in the brains with senile plaque (SP) stage 0–A, B, and C were 27.7, 33, and 50%, respectively. No statistical differences were found among the frequencies of AS lesions in the subgroups of NFT stages I–II, III–IV, and V–VI (P=0.478). Most cases showed a widespread distribution of AS-positive structures except for one patient, in whose brain only the medulla was involved. The distribution pattern of AS-positive lesions was similar to that in Parkinson’s disease or DLB, but the pigmented neurons in substantia nigra were relatively well preserved. Our findings indicate that there is a high frequency of alpha-synucleinopathy in centenarians, SP-positive and AS-positive lesions may involve a synergistic interaction.

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References

  1. Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y (2001) Alpha-synuclein-positive structures in cases with sporadic Alzheimer’s disease: morphology and its relationship to tau aggregation. Brain Res 888:287–296

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  4. Brown DF, Dababo MA, Bigio EH, Risser RC, Eagan KP, Hladk CL, White CL 3rd (1998) Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson’s disease. J Neuropathol Exp Neurol 57:39–46

    Article  PubMed  CAS  Google Scholar 

  5. Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 4:1318–1320

    Article  PubMed  CAS  Google Scholar 

  6. Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H (2002) Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426

    PubMed  Google Scholar 

  7. Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  PubMed  CAS  Google Scholar 

  8. Giasson BI, Lee VM, Trojanowski JQ (2003) Interactions of amyloidogenic proteins. Neuromolecular Med 4:49–58

    Article  PubMed  CAS  Google Scholar 

  9. Gibb WR, Lee AJ (1988) The relevance of Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752

    Article  PubMed  CAS  Google Scholar 

  10. Hamilton RL (2000) Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using α-synuclein immunohistochemisty. Brain Pathol 10:378–394

    PubMed  CAS  Google Scholar 

  11. Hasegawa K, Inoue K, Moriya K (1974) An investigation of dementia rating scale for the elderly. Seishin Igaku 16:956–969

    Google Scholar 

  12. Hashimoto M, Rochenstein E, Crews L, Masliah E (2003) Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s disease. Neuromol Med 4:21–36

    Article  CAS  Google Scholar 

  13. Hladik CL, White CL (2003) Comparison of digestive enzyme and formic acid pretreatment for optimal immunohistochemical demonstration of alpha-synuclein-immunoreactive cerebral cortical Lewy neuritis. J Neuropathol Exp Neurol 4:49–58

    Google Scholar 

  14. Ince PG, Perry EK, Morris CM (1998) Dementia with Lewy bodies: a distinct non-Alzheimer dementia syndrome? Brain Pathol 8:299–324

    PubMed  CAS  Google Scholar 

  15. Jellinger KA (1998) Dementia with grains (argyrophilic grain disease). Brain Pathol 8:377–386

    PubMed  CAS  Google Scholar 

  16. Jellinger KA (2003) Alpha-synuclein pathology in Parkinson’s and Alzheimer’s disease brain: incidence and topographic distribution—a pilot study. Acta Neuropathol 106:191–201

    Article  PubMed  Google Scholar 

  17. Jellinger KA (2003) Age-associated prevalence and risk factors of Lewy body pathology in a general population. Acta Neuropathol 106:383–384

    Article  PubMed  Google Scholar 

  18. Jellinger KA (2004) Lewy body-related α-synucleinopathy in the aged human brain. J Neural Transm 111:1219–1235

    Article  PubMed  CAS  Google Scholar 

  19. Jellinger KA, Bancher C (1998) Senile dementia with tangles (tangle predominant form of senile dementia). Brain Pathol 8:367–376

    PubMed  CAS  Google Scholar 

  20. Kazee AM, Han LY (1995) Cortical Lewy bodies in Alzheimer’s disease. Arch Pathol Lab Med 119:448–453

    PubMed  CAS  Google Scholar 

  21. Kosaka K, Iseki E, Odawara T, Yamamoto T (1996) Cerebral type of Lewy body disease. Neuropathology 16:32–35

    Article  Google Scholar 

  22. Li WX, Lesuisse C, Xu YQ, Troncoso JC, Price DL, Lee MK (2004) Stabilization of α-synuclein protein with aging and familial Parkinson’s disease-linked A53T mutation. J Neurosci 24:7400–7409

    Article  PubMed  CAS  Google Scholar 

  23. Lippa CF, Fujiwara H, Mann DM, Giasson B, Baba M, Schmidt ML, Nee LE, O’Connell B, Pollen DA, St George-Hyslop P, Ghetti B, Nochlin D, Bird TD, Cairns NJ, Lee VM, Iwatsubo T, Trojanowski JQ (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 153:1365–1370

    PubMed  CAS  Google Scholar 

  24. 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 45:353–357

    Article  PubMed  CAS  Google Scholar 

  25. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L (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 98:12245–12250

    Article  PubMed  CAS  Google Scholar 

  26. Mattila PM, Rinne JO, Helenius H, Dickson DW, Roytta M (2000) Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson’s disease. Acta Neuropathol 100:285–290

    Article  PubMed  CAS  Google Scholar 

  27. McKeith IG, Galasko D, Kosaka K, Pery EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwarson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovetone S, Collerton D, Jansen ENH, Ballard C, de vos RAI, Wilcock GK, Jellinger KA, Perry RH (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 47:1113–1124

    PubMed  CAS  Google Scholar 

  28. Mikolaenko I, Pletnikova O, Kawas CH, O’Brien R, Resnick SM, Crain B, Troncoso JC (2005) Alpha-synuclein lesions in normal aging, Parkinson’s disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of Aging (BLSA). J Neuropathol Exp Neurol 68:156–162

    Google Scholar 

  29. Mirra SS, Heyman A, McKeel D, Sumi SM, Cain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The consortium to establish a registry for Alzheimer’s Disease (CERAD). Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  30. Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P, Louis JC, Wypych J, Biere AL, Citron AM (1999) Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J Biol Chem 274:9843–9846

    Article  PubMed  CAS  Google Scholar 

  31. Neuropathology Group of the Medical Research Council Cognitive Function, Aging Study (MRC CFAS) (2001) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet 357:169–175

    Article  Google Scholar 

  32. Parkinen L, Soininen H, Laakso M, Alafuzoff I (2001) Alpha-synuclein pathology is highly dependent on the case selection. Neuropathol Appl Neurobiol 27:314–325

    Article  Google Scholar 

  33. Parkkinen L, Soininen H, Alafuzoff I (2003) Regional distribution of α-synuclein pathology in unimpaired aging and Alzheimer disease. J Neuropathol Exp Neurol 62:363–367

    PubMed  CAS  Google Scholar 

  34. Rezaie P, Cairns NJ, Chadwick A, Lantos PL (1996) Lewy bodies are located preferentially in limbic areas in diffuse Lewy body disease. Neurosci Lett 212:111–114

    Article  PubMed  CAS  Google Scholar 

  35. Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated α-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654

    PubMed  CAS  Google Scholar 

  36. Saito Y, Ruberu NN, Sawabe M, Arai T, Kazawa H, Hosoi T, Yamanouchi H, Murayama S (2004) Lewy body-related α-synucleinopathy in aging. J Neuropthol Exp Neurol 63:742–749

    Google Scholar 

  37. The national institute on aging, Reagan institute working group on diagnostic criteria for the neuropathological assessment of Alzheimer’s disease (1997) Consensus recommendations for postmortem diagnosis of Alzheimer’s disease. Neurobiol Aging 18:S1–S2

    Article  Google Scholar 

  38. Togo T, Cookson N, Dickson DW (2002) Argyrophilic grain disease: Neuropathology, frequency in a dementia brain bank and lack of relationship with apolipoprotein E. Brain Pathol 12:45–52

    PubMed  Google Scholar 

  39. Vila M, Vukosavic S, Jackson-Lewis V, Neystat M, Jakowec M, Przedborski S (2000) α-Synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J Neurochem 74:721–729s

    Article  PubMed  CAS  Google Scholar 

  40. Wakisaka Y, Furuta A, Tanizaki Y, Kiyohala Y, Iida M, Iwaki T (2003) Age-associated prevalence and risk factors of Lewy body pathology in a general population: the Hisayama study. Acta Neuropathol 106:374–382

    Article  PubMed  Google Scholar 

  41. Yamada M (2003) Senile dementia of the neurofibrillary tangle type (tangle-only dementia): Neuropathological criteria and clinical guidelines for diagnosis. Neuropathology 23:311–317

    Article  PubMed  Google Scholar 

  42. Yamin G, Glaser CB, Uversky VN, Fink AL (2003) Certain metals trigger fibrillation of methionione-oxidized alpha-synuclein. J Biol Chem 278:27360–27365

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Mr. K. Kohtani, Mr. T. Mizuno, Mrs. C. Uno and Ms. T. Masuda for their skillful technical assistance.

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Authors and Affiliations

  1. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

    Zheng-Tong Ding & Yu-Ping Jiang

  2. Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China

    Yin Wang

  3. Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute-cho, Aichi-gun, 480-1195, Aichi, Japan

    Yoshio Hashizume, Mari Yoshida & Maya Mimuro

  4. Department of Neurology, Nagoyashi Kohseiin Geriatric Hospital, Nagoya, Japan

    Toshiaki Inagaki & Tamaki Iwase

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  1. Zheng-Tong Ding
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Correspondence to Yoshio Hashizume.

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Ding, ZT., Wang, Y., Jiang, YP. et al. Characteristics of alpha-synucleinopathy in centenarians. Acta Neuropathol 111, 450–458 (2006). https://doi.org/10.1007/s00401-005-0015-y

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  • DOI: https://doi.org/10.1007/s00401-005-0015-y

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