Advertisement

Acta Neuropathologica

, Volume 120, Issue 6, pp 789–801 | Cite as

Effect of topographical distribution of α-synuclein pathology on TDP-43 accumulation in Lewy body disease

  • Osamu Yokota
  • Yvonne Davidson
  • Tetsuaki Arai
  • Masato Hasegawa
  • Haruhiko Akiyama
  • Hideki Ishizu
  • Seishi Terada
  • Stephen Sikkink
  • Stuart Pickering-Brown
  • David M. A. MannEmail author
Original Paper

Abstract

It has been reported that the development of TDP-43 pathology in cases of Lewy body disease (LBD) might be associated with the severity of tau pathology. However, the impact of α-synuclein pathology on TDP-43 accumulation in LBD remains unclear. To clarify whether α-synuclein pathology has an effect on TDP-43 accumulation, independent of tau pathology, we examined by immunohistochemistry 56 cases of LBD using a phosphorylation-dependent TDP-43 antibody. The frequency of TDP-43 pathology in all LBD cases was 18% (10/56). In 37 LBD cases with no or low tau burden (LBD-Ltau; Braak NFT stages 0-II), the frequency of TDP-43 pathology was 19% (7/37). The frequency of TDP-43 pathology in diffuse neocortical type LBD-Ltau cases was 36% (4/11), which was higher than those in limbic and brain stem-predominant types (11–14%). The amygdala and entorhinal cortex were the most frequently affected sites of TDP-43 pathology in LBD-Ltau cases. In LBD-Ltau cases, the proportion of diffuse neocortical type LBD was higher in the TDP-43-positive cases, than that in TDP-43-negative cases (57 vs. 23%). In all LBD cases, α-synuclein pathology in the temporal cortex was significantly more severe in TDP-43-positive cases, and significantly correlated with the severity of TDP-43 pathology in the amygdala. In a multivariate model, the presence of severe α-synuclein pathology was significantly associated with the development of TDP-43 pathology independent of age at death and tau pathology. In the amygdala, TDP-43 was often colocalized with α-synuclein or tau. Given these findings, we suggest that α-synuclein pathology is associated with TDP-43 accumulation in LBD cases.

Keywords

α-Synuclein DLB Lewy body disease Tau TDP-43 

Notes

Acknowledgments

We would like to thank Dr. F. Higaki (Department of Radiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences) for the statistical analysis, Ms. M. Onbe (Department of Neuropsychiatry. Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences) for their excellent technical assistance. We also acknowledge and thank the Parkinson’s Disease Society UK Brain Bank for making available tissue samples for this study. This study was supported in part by a research grant from the Uehara Memorial Foundation.

References

  1. 1.
    Amador-Ortiz C, Lin WL, Ahmed Z et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445CrossRefPubMedGoogle Scholar
  2. 2.
    Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136CrossRefPubMedGoogle Scholar
  3. 3.
    Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611CrossRefPubMedGoogle Scholar
  4. 4.
    Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404CrossRefPubMedGoogle Scholar
  5. 5.
    Cairns NJ, Neumann M, Bigio EH et al (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240CrossRefPubMedGoogle Scholar
  6. 6.
    Cairns NJ, Bigio EH, Mackenzie IR et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22CrossRefPubMedGoogle Scholar
  7. 7.
    Davidson Y, Kelley T, Mackenzie IR et al (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113:521–533CrossRefPubMedGoogle Scholar
  8. 8.
    Fujishiro H, Uchikado H, Arai T et al (2009) Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease. Acta Neuropathol 117:151–158CrossRefPubMedGoogle Scholar
  9. 9.
    Geser F, Winton MJ, Kwong LK et al (2008) Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115:133–145CrossRefPubMedGoogle Scholar
  10. 10.
    Geser F, Martinez-Lage M, Kwong LK et al (2009) Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J Neurol 256:1205–1214CrossRefPubMedGoogle Scholar
  11. 11.
    Hansen L, Salmon D, Galasko D et al (1990) The Lewy body variant of Alzheimer’s disease: a clinical and pathologic entity. Neurology 40:1–8PubMedGoogle Scholar
  12. 12.
    Hasegawa M, Arai T, Akiyama H et al (2007) TDP-43 is deposited in the Guam parkinsonism–dementia complex brains. Brain 130:1386–1394CrossRefPubMedGoogle Scholar
  13. 13.
    Hasegawa M, Arai T, Nonaka T et al (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64:60–70CrossRefPubMedGoogle Scholar
  14. 14.
    Higashi S, Iseki E, Yamamoto R et al (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294CrossRefPubMedGoogle Scholar
  15. 15.
    Hu WT, Josephs KA, Knopman DS et al (2008) Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 116:215–220CrossRefPubMedGoogle Scholar
  16. 16.
    Inukai Y, Nonaka T, Arai T et al (2008) Abnormal phosphorylation of Ser409/410 of TDP-43 in FTLD-U and ALS. FEBS Lett 582:2899–2904CrossRefPubMedGoogle Scholar
  17. 17.
    Jellinger KA (2010) The neuropathologic substrate of Parkinson disease dementia. Acta Neuropathol 119:151–153CrossRefPubMedGoogle Scholar
  18. 18.
    Josephs KA, Ahmed Z, Katsuse O et al (2007) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 66:142–151CrossRefPubMedGoogle Scholar
  19. 19.
    Josephs KA, Dickson DW (2007) Hippocampal sclerosis in tau-negative frontotemporal lobar degeneration. Neurobiol Aging 28:1718–1722CrossRefPubMedGoogle Scholar
  20. 20.
    Josephs KA, Whitwell JL, Knopman DS et al (2008) Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 70:1850–1857CrossRefPubMedGoogle Scholar
  21. 21.
    Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2008) Striatal beta-amyloid deposition in Parkinson disease with dementia. J Neuropathol Exp Neurol 67:155–161CrossRefPubMedGoogle Scholar
  22. 22.
    Kalaitzakis ME, Pearce RK (2009) The morbid anatomy of dementia in Parkinson’s disease. Acta Neuropathol 118:587–598CrossRefPubMedGoogle Scholar
  23. 23.
    Kosaka K (1990) Diffuse Lewy body disease in Japan. J Neurol 237:197–204CrossRefPubMedGoogle Scholar
  24. 24.
    Leverenz JB, Yu CE, Montine TJ (2007) A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. Brain 130:1360–1374CrossRefPubMedGoogle Scholar
  25. 25.
    Lin WL, Dickson DW (2008) Ultrastructural localization of TDP-43 in filamentous neuronal inclusions in various neurodegenerative diseases. Acta Neuropathol 116:205–213CrossRefPubMedGoogle Scholar
  26. 26.
    Markopoulou K, Dickson DW, McComb RD (2008) Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease. Variability in familial Parkinson’s disease. Acta Neuropathol 116:25–35CrossRefPubMedGoogle Scholar
  27. 27.
    McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872CrossRefPubMedGoogle Scholar
  28. 28.
    Nakashima-Yasuda H, Uryu K et al (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229CrossRefPubMedGoogle Scholar
  29. 29.
    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133CrossRefPubMedGoogle Scholar
  30. 30.
    Obi K, Akiyama H, Kondo H et al (2008) Relationship of phosphorylated alpha-synuclein and tau accumulation to Abeta deposition in the cerebral cortex of dementia with Lewy bodies. Exp Neurol 210:409–420CrossRefPubMedGoogle Scholar
  31. 31.
    The National Institute on Aging, and Reagan Institute Working Group (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer disease. The National Institute on Aging, and Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. Neurobiol Aging 18:S1–S2Google Scholar
  32. 32.
    Uryu K, Nakashima-Yasuda H, Forman MS et al (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564CrossRefPubMedGoogle Scholar
  33. 33.
    Yokota O, Tsuchiya K, Uchihara T et al (2007) Lewy body variant of Alzheimer’s disease or cerebral type Lewy body disease? Two autopsy cases of presenile onset with minimal involvement of the brainstem. Neuropathology 27:21–35CrossRefPubMedGoogle Scholar
  34. 34.
    Yokota O, Davidson Y, Bigio EH et al (2010) Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy. Acta Neuropathol 120:55–66CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Osamu Yokota
    • 1
    • 5
  • Yvonne Davidson
    • 1
  • Tetsuaki Arai
    • 3
  • Masato Hasegawa
    • 4
  • Haruhiko Akiyama
    • 3
  • Hideki Ishizu
    • 5
    • 6
  • Seishi Terada
    • 5
  • Stephen Sikkink
    • 2
  • Stuart Pickering-Brown
    • 2
  • David M. A. Mann
    • 1
    Email author
  1. 1.Neurodegeneration and Mental Health Research Group, Faculty of Medical and Human Sciences, School of Community Based Medicine, Greater Manchester Neurosciences Centre, Hope Hospital University of ManchesterSalfordUK
  2. 2.Neurodegeneration and Mental Health Research Group, Faculty of Medical and Human Sciences, School of Community Based Medicine, A V Hill BuildingUniversity of ManchesterManchesterUK
  3. 3.Department of PsychogeriatricsTokyo Institute of PsychiatryTokyoJapan
  4. 4.Department of Molecular NeurobiologyTokyo Institute of PsychiatryTokyoJapan
  5. 5.Department of NeuropsychiatryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  6. 6.Zikei Institute of PsychiatryOkayamaJapan

Personalised recommendations