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Acta Neuropathologica

, Volume 120, Issue 1, pp 55–66 | Cite as

Phosphorylated TDP-43 pathology and hippocampal sclerosis in progressive supranuclear palsy

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

Abstract

TDP-43 is characteristically accumulated in TDP-43 proteinopathies such as frontotemporal lobar degeneration and motor neurone disease, but is also present in some tauopathies, including Alzheimer’s disease, argyrophilic grain disease, and corticobasal degeneration (CBD). However, several studies have suggested that cases of progressive supranuclear palsy (PSP) lack TDP-43 pathology. We have therefore examined limbic regions of the brain in 19 PSP cases, as well as in 12 CBD cases, using phosphorylation-dependent anti-TDP-43 antibodies. We observed TDP-43-positive inclusions in five PSP cases (26%), as well as in two CBD cases (17%). The amygdala and hippocampal dentate gyrus were most frequently affected in PSP. Regional tau burden tended to be higher in TDP-43-positive PSP cases, and a significant correlation between tau and TDP-43 burden was noted in the occipitotemporal gyrus. Hippocampal sclerosis (HS) was found in 3/5 TDP-43-positive PSP cases, but HS was significantly more frequent in TDP-43-positive than TDP-43 negative PSP cases. Dementia was present in 13/19 (58%) of the PSP cases, in 4/5 TDP-43-positive cases, in all 3 TDP-43-positive cases with HS, in 1/2 TDP-43-positive cases without HS, and 7/14 cases lacking both. TDP-43 and tau were frequently colocalized in the amygdala, but not in the hippocampal dentate gyrus. Immunoblotting demonstrated the characteristic (for TDP-43 proteinopathies) 45 and 25 kDa bands and high molecular weight smear in the TDP-43-positive PSP case. These findings suggest that (1) although PSP is nominally a tauopathy, pathological TDP-43 can accumulate in the limbic system in some cases, and (2) TDP-43 pathology may be concurrent with HS.

Keywords

Argyrophilic grains Hippocampal sclerosis Progressive supranuclear palsy Tau TDP-43 

Notes

Acknowledgments

This study was supported in part by a research grant from the Uehara Memorial Foundation and Grant No. AG13854 from the National Institutes of Health. We thank Ms. M. Onbe (Department of Neuropsychiatry. Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences) for their excellent technical assistance, and the Parkinson’s Disease Society Brain Bank for making available tissue samples for this study. A part of this study was presented at the 111th annual meeting of the British Neuropathological Society in January 2010.

References

  1. 1.
    Ala TA, Beh GO, Frey WH 2nd (2000) Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer’s disease. Neurology 54:843–848PubMedGoogle Scholar
  2. 2.
    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
  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.
    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
  5. 5.
    Beach TG, Sue L, Scott S et al (2003) Hippocampal sclerosis dementia with tauopathy. Brain Pathol 13:263–278PubMedGoogle Scholar
  6. 6.
    Bigio EH, Brown DF, White CL 3rd (1999) Progressive supranuclear palsy with dementia: cortical pathology. J Neuropathol Exp Neurol 58:359–364CrossRefPubMedGoogle Scholar
  7. 7.
    Bigio EH, Mishra M, Hatanpaa KJ et al (2010) TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease. Acta Neuropathol (in press). doi: 10.1007/s00401-010-0681-2
  8. 8.
    Braak H, Braak E (1990) Neurofibrillary changes confined to the entorhinal region and an abundance of cortical amyloid in cases of presenile and senile dementia. Acta Neuropathol 80:479–486CrossRefPubMedGoogle Scholar
  9. 9.
    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
  10. 10.
    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
  11. 11.
    Cordato NJ, Duggins AJ, Halliday GM, Morris JG, Pantelis C (2005) Clinical deficits correlate with regional cerebral atrophy in progressive supranuclear palsy. Brain 128:1259–1266CrossRefPubMedGoogle Scholar
  12. 12.
    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
  13. 13.
    Dickson DW, Davies P, Bevona C et al (1994) Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans. Acta Neuropathol 88:212–221CrossRefPubMedGoogle Scholar
  14. 14.
    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
  15. 15.
    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
  16. 16.
    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
  17. 17.
    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
  18. 18.
    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
  19. 19.
    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
  20. 20.
    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
  21. 21.
    Jellinger KA (2000) Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer’s disease. Neurology 55:739–740PubMedGoogle Scholar
  22. 22.
    Jellinger KA (2008) Different tau pathology pattern in two clinical phenotypes of progressive supranuclear palsy. Neurodegener Dis 5:339–346CrossRefPubMedGoogle Scholar
  23. 23.
    Josephs KA, Dickson DW (2007) Hippocampal sclerosis in tau-negative frontotemporal lobar degeneration. Neurobiol Aging 28:1718–1722CrossRefPubMedGoogle Scholar
  24. 24.
    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
  25. 25.
    Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574CrossRefPubMedGoogle Scholar
  26. 26.
    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
  27. 27.
    Miklossy J, Steele JC, Yu S et al (2008) Enduring involvement of tau, β-amyloid, α-synuclein, ubiquitin and TDP-43 pathology in the amyotrophic lateral sclerosis/parkinsonism–dementia complex of Guam (ALS/PDC). Acta Neuropathol 116:625–637CrossRefPubMedGoogle Scholar
  28. 28.
    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 neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486PubMedGoogle Scholar
  29. 29.
    Nakano I (1993) Temporal lobe lesions in amyotrophic lateral sclerosis with or without dementia—a neuropathological study. Neuropathology 13:215–227CrossRefGoogle Scholar
  30. 30.
    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
  31. 31.
    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
  32. 32.
    Neumann M, Mackenzie IR, Cairns NJ et al (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66:152–157CrossRefPubMedGoogle Scholar
  33. 33.
    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
  34. 34.
    Probst A, Taylor KI, Tolnay M (2007) Hippocampal sclerosis dementia: a reappraisal. Acta Neuropathol 114:335–345CrossRefPubMedGoogle Scholar
  35. 35.
    Saito Y, Ruberu NN, Sawabe M et al (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63:911–918PubMedGoogle Scholar
  36. 36.
    Schneider JA, Watts RL, Gearing M et al (1997) Corticobasal degeneration: neuropathologic and clinical heterogeneity. Neurology 48:959–969PubMedGoogle Scholar
  37. 37.
    Schwab C, Arai T, Hasegawa M, Yu S, McGeer PL (2008) Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J Neuropathol Exp Neurol 67:1159–1165CrossRefPubMedGoogle Scholar
  38. 38.
    Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672CrossRefPubMedGoogle Scholar
  39. 39.
    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–S2CrossRefGoogle Scholar
  40. 40.
    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
  41. 41.
    Van Deerlin VM, Leverenz JB, Bekris LM et al (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7:409–416CrossRefPubMedGoogle Scholar
  42. 42.
    Williams DR, Lees AJ (2009) Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 8:270–279CrossRefPubMedGoogle Scholar
  43. 43.
    Williams DR, Holton JL, Strand C et al (2007) Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson’s syndrome. Brain 130:1566–1576CrossRefPubMedGoogle Scholar
  44. 44.
    Yokoseki A, Shiga A, Tan CF et al (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63:538–542CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Osamu Yokota
    • 1
    • 4
  • Yvonne Davidson
    • 1
  • Eileen H. Bigio
    • 3
  • Hideki Ishizu
    • 4
    • 5
  • Seishi Terada
    • 4
  • Tetsuaki Arai
    • 6
  • Masato Hasegawa
    • 7
  • Haruhiko Akiyama
    • 6
  • 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 HospitalUniversity 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 PathologyNorthwestern University Feinberg School of MedicineChicagoUSA
  4. 4.Department of NeuropsychiatryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  5. 5.Zikei Institute of PsychiatryOkayamaJapan
  6. 6.Department of PsychogeriatricsTokyo Institute of PsychiatryTokyoJapan
  7. 7.Department of Molecular NeurobiologyTokyo Institute of PsychiatryTokyoJapan

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