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Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity

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Abstract

Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.

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References

  1. Arai T, Ikeda K, Akiyama H et al (2001) Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick’s disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol 101:167–173

    CAS  PubMed  Google Scholar 

  2. Arai T, Ikeda K, Akiyama H et al (2004) Identification of amino-terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration. Ann Neurol 55:72–79

    Article  CAS  PubMed  Google Scholar 

  3. Bigio EH, Lipton AM, Yen S-H et al (2001) Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia. J Neuropathol Exp Neurol 60:328–341

    CAS  PubMed  Google Scholar 

  4. Boeve BF, Lang AE, Litvan I (2003) Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 54(Suppl 5):S15–S19

    Article  PubMed  Google Scholar 

  5. Boeve BF, Maraganore DM, Parisi JE et al (1999) Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 53:795–800

    CAS  PubMed  Google Scholar 

  6. Buée L, Delacourte A (1999) Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick’s disease. Brain Pathol 9:681–693

    PubMed  Google Scholar 

  7. Cairns NJ, Bigio EH, Mackenzie IRA et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the consortium for frontotemporal lobar degeneration. Acta Neuropathol 114:5–22

    Article  PubMed  Google Scholar 

  8. de Silva R, Lashley T, Gibb G et al (2003) Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies. Neuropathol Appl Neurobiol 29:288–302

    Article  PubMed  Google Scholar 

  9. Dickson DW (1999) Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol 246(Suppl 2):II6–II15

    Google Scholar 

  10. Dickson DW, Bergeron C, Chin SS et al (2002) Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935–946

    CAS  PubMed  Google Scholar 

  11. Dickson D, Litvan I (2003) Corticobasal degeneration. In: Dickson DW (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 115–123

    Google Scholar 

  12. Dickson DW, Rademarkers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol 17:74–82

    Article  CAS  PubMed  Google Scholar 

  13. Ferrer I, Hernández I, Boada M et al (2003) Primary progressive aphasia as the initial manifestation of corticobasal degeneration and unusual tauopathies. Acta Neuropathol 106:419–435

    Article  CAS  PubMed  Google Scholar 

  14. Ghetti B, Hutton ML, Wszolek ZK (2003) Frontotemporal dementia and Parkinsonism linked to chromosome 17 associated with tau gene mutation (FTDP-17T). In: Dickson DW (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 86–102

    Google Scholar 

  15. Hauw J-J, Agid Y (2003) Progressive supranuclear palsy (PSP) or Steele-Richardson-Olszewski disease. In: Dickson DW (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 103–114

    Google Scholar 

  16. Josephs KA, Katsuse O, Beccano-Kelly DA et al (2006) Atypical progressive supranuclear palsy with corticospinal tract degeneration. J Neuropathol Exp Neurol 65:396–405

    Article  PubMed  Google Scholar 

  17. Katsuse O, Iseki E, Arai T et al (2003) 4-Repeat tauopathy sharing pathological and biochemical features of corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol 106:251–260

    Article  PubMed  Google Scholar 

  18. Komori T, Arai N, Oda M, Nakayama H et al (1998) Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol 96:401–408

    Article  CAS  PubMed  Google Scholar 

  19. Kovacs GG, Majtenyi K, Spina S et al (2008) White matter tauopathy with globular glial inclusions: a distinct sporadic frontotemporal lobar degeneration. J Neuropathol Exp Neurol 67:963–975

    Article  PubMed  Google Scholar 

  20. Kuroda S, Otsuki S, Tateishi J, Hirano A (1979) Neurofibrillary degeneration in a case of quadriplegia and myoclonic movement. Acta Neuropathol 45:105–109

    Article  CAS  PubMed  Google Scholar 

  21. Litvan I, Agid Y, Calne D et al (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47:1–9

    CAS  PubMed  Google Scholar 

  22. Litvan I, Grimes DA, Lang AE (2000) Phenotypes and prognosis: clinicopathologic studies of corticobasal degeneration. Adv Neurol 82:183–196

    CAS  PubMed  Google Scholar 

  23. Mackenzie IRA, Neumann M, Bigio EH et al (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18

    Article  PubMed  Google Scholar 

  24. Mackenzie IRA, Neumann M, Bigio EH et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4

    Article  PubMed  Google Scholar 

  25. Martinaud O, Laquerrière A, Guyant-Maréchal L et al (2005) Frontotemporal dementia, motor neuron disease and tauopathy: clinical and neuropathological study in a family. Acta Neuropathol 110:84–92

    Article  CAS  PubMed  Google Scholar 

  26. Munoz DG, Neumann M, Kusaka H, Yokota O, Ishihara K, Terada S, Kuroda S, Mackenzie IR (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627

    Article  CAS  PubMed  Google Scholar 

  27. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IRA (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931

    Article  PubMed  Google Scholar 

  28. Nishihira Y, Tan CF, Onodera O et al (2008) Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. Acta Neuropathol 116:169–182

    Article  CAS  PubMed  Google Scholar 

  29. Okazaki K, Fu Y-J, Nishihira Y et al (2009) Alzheimer’s disease: report of tow autopsy cases with a clinical diagnosis of corticobasal degeneration. Neuropathology doi:10.1111/j.1440-1789.2009.01062.x

  30. Piao Y-S, Tan C-F, Iwanaga K et al (2005) Sporadic four-repeat tauopathy with frontotemporal degeneration, Parkinsonism and motor neuron disease. Acta Neuropathol 110:600–609

    Article  PubMed  Google Scholar 

  31. Piao Y-S, Wakabayashi K, Kakita A et al (2003) Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000. Brain Pathol 12:10–22

    Google Scholar 

  32. Powers JM, Bryne NP, Ito M et al (2003) A novel leukoencephalopathy associated with tau deposits primarily in white matter glia. Acta Neuropathol 106:181–187

    Article  CAS  PubMed  Google Scholar 

  33. Rizzu P, Van Swieten JC, Joosse M et al (1999) High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet 64:414–421

    Article  CAS  PubMed  Google Scholar 

  34. Sakai K, Piao Y-S, Kikugawa K et al (2006) Corticobasal degeneration with focal, massive tau accumulation in the subcortical white matter astrocytes. Acta Neuropathol 112:341–348

    Article  PubMed  Google Scholar 

  35. Spillantini MG, Bird TD, Ghetti B (1998) Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 8:387–402

    Article  CAS  PubMed  Google Scholar 

  36. Tan C-F, Kakita A, Piao Y-S et al (2003) Primary lateral sclerosis: a rare upper-motor-predominant form of amyotrophic lateral sclerosis often accompanied by frontotemporal lobar degeneration with ubiquitinated neuronal inclusions? Report of an autopsy case and a review of the literature. Acta Neuropathol 105:615–620

    PubMed  Google Scholar 

  37. Tan C-F, Piao Y-S, Kakita A et al (2005) Frontotemporal dementia with co-occurrence of astrocytic plaques and tufted astrocytes, and severe degeneration of the cerebral white matter: a variant of corticobasal degeneration? Acta Neuropathol 109:329–338

    Article  PubMed  Google Scholar 

  38. Uchihara T (2007) Silver diagnosis in neuropathology: principles, practice and revised interpretation. Acta Neuropathol 113:483–499

    Article  PubMed  Google Scholar 

  39. Uchihara T, Ikeda K, Tsuchiya K (2003) Pick body disease and Pick syndrome. Neuropathology 23:318–326

    Article  PubMed  Google Scholar 

  40. van Swieten J, Spillantini MG (2007) Hereditary frontotemporal dementia caused by tau gene mutations. Brain Pathol 17:63–73

    Article  PubMed  CAS  Google Scholar 

  41. Yokota O, Tsuchiya K, Oda T et al (2006) Amyotrophic lateral sclerosis with dementia: an autopsy case showing many Bunina bodies, tau-positive neuronal and astrocytic plaque-like pathologies, and pallido-nigral degeneration. Acta Neuropathol 112:633–645

    Article  PubMed  Google Scholar 

  42. Zarranz JJ, Ferrer I, Lezcano E et al (2005) A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease. Neurology 64:1578–1585

    Article  CAS  PubMed  Google Scholar 

  43. Zhukareva V, Mann D, Pickering-Brown S et al (2002) Sporadic Pick’s disease: a tauopathy characterized by a spectrum of pathological τ isoforms in gray and white matter. Ann Neurol 51:730–739

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank C. Tanda, J. Takasaki, H. Saito, T. Fujita and S. Egawa for their technical assistance. This work was supported by a grant from the Research Committee for CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare, Japan (H. T.), Grants-in-Aid 20240037 (to H. T.) and 21200041 (to T. I.) for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and a Project Research Promotion Grant from the University of Niigata (to H. T.).

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Authors and Affiliations

  1. Department of Pathology, Brain Research Institute, University of Niigata, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan

    Yong-Juan Fu, Yasushi Nishihira, Yasuko Toyoshima, Yue-Shan Piao, Chun-Feng Tan & Hitoshi Takahashi

  2. Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan

    Shigetoshi Kuroda

  3. Department of Neurology, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Tomohiko Ishihara, Makoto Shinozaki & Masatoyo Nishizawa

  4. Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Akinori Miyashita & Ryozo Kuwano

  5. Department of Neurology, Nishi-Niigata Chuo National Hospital, Niigata, 950-2085, Japan

    Takashi Tani & Ryoko Koike

  6. Section of Neurology, Nagasaki Kita Hospital, Nagasaki, 852-8061, Japan

    Keisuke Iwanaga & Mitsuhiro Tsujihata

  7. Department of Molecular Neuroscience, Center for Bioresources, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Osamu Onodera & Takeshi Ikeuchi

  8. Department of Pathological Neuroscience, Center for Bioresources, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan

    Akiyoshi Kakita

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  1. Yong-Juan Fu
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Correspondence to Hitoshi Takahashi.

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Fu, YJ., Nishihira, Y., Kuroda, S. et al. Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity. Acta Neuropathol 120, 21–32 (2010). https://doi.org/10.1007/s00401-010-0649-2

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  • DOI: https://doi.org/10.1007/s00401-010-0649-2

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