Acta Neuropathologica

, Volume 115, Issue 1, pp 133–145 | Cite as

Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam

  • Felix Geser
  • Matthew J. Winton
  • Linda K. Kwong
  • Yan Xu
  • Sharon X. Xie
  • Lionel M. Igaz
  • Ralph M. Garruto
  • Daniel P. Perl
  • Douglas Galasko
  • Virginia M.-Y. Lee
  • John Q. Trojanowski
Original Paper


Pathological TDP-43 is the major disease protein in frontotemporal lobar degeneration characterized by ubiquitin inclusions (FTLD-U) with/without motor neuron disease (MND) and in amyotrophic lateral sclerosis (ALS). As Guamanian parkinsonism–dementia complex (PDC) or Guamanian ALS (G-PDC or G-ALS) of the Chamorro population may present clinically similar to FTLD-U and ALS, TDP-43 pathology may be present in the G-PDC and G-ALS. Thus, we examined cortical or spinal cord samples from 54 Guamanian subjects for evidence of TDP-43 pathology. In addition to cortical neurofibrillary and glial tau pathology, G-PDC was associated with cortical TDP-43 positive dystrophic neurites and neuronal and glial inclusions in gray and/or white matter. Biochemical analyses showed the presence of FTLD-U-like insoluble TDP-43 in G-PDC, but not in Guam controls (G-C). Spinal cord pathology of G-PDC or G-ALS was characterized by tau positive tangles as well as TDP-43 positive inclusions in lower motor neurons and glial cells. G-C had variable tau and negligible TDP-43 pathology. These results indicate that G-PDC and G-ALS are associated with pathological TDP-43 similar to FTLD-U with/without MND as well as ALS, and that neocortical or hippocampal TDP-43 pathology distinguishes controls from disease subjects better than tau pathology. Finally, we conclude that the spectrum of TDP-43 proteinopathies should be expanded to include neurodegenerative cognitive and motor diseases, affecting the Chamorro population of Guam.


Parkinsonism–dementia complex Amyotrophic lateral sclerosis Guam TDP-43 



The authors would like to thank T. Schuck, A. Truax, M. Getahun, J. Robinson, J. McBride, and N. Camacho for their expert technical assistance. Further, they thank their patients and families and the dedicated efforts of the research team at the University of Guam who made this research possible. This work was funded by the National Institutes of Health (AG10124, AG17586, AG14382).

Supplementary material


  1. 1.
    Anderson FH, Richardson EP Jr, Okazaki H, Brody JA (1979) Neurofibrillary degeneration on Guam: frequency in Chamorros and non Chamorros with no known neurological disease. Brain 102:65–77PubMedCrossRefGoogle Scholar
  2. 2.
    Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611PubMedCrossRefGoogle Scholar
  3. 3.
    Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL, III, Schneider JA, Kretzschmar HA, Carter D, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VM-Y, Mackenzie IRA (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240Google Scholar
  4. 4.
    Chen L (1981) Neurofibrillary change on Guam. Arch Neurol 38:16–18PubMedGoogle Scholar
  5. 5.
    Croisier E, Graeber MB (2006) Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration. Acta Neuropathol (Berl) 112:517–530CrossRefGoogle Scholar
  6. 6.
    Elizan TS, Hirano A, Abrams BM, Need RL, Van Nuis C, Kurland LT (1966) Amyotrophic lateral sclerosis and parkinsonism–dementia complex of Guam: neurological reevaluation. Arch Neurol 14:356–368PubMedGoogle Scholar
  7. 7.
    Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van D, V, Lee VM-Y, Miller BL, Trojanowski JQ, Grossman M (2006) Frontotemporal dementia: clinicopathological correlations. Ann Neurol 59:952–962PubMedCrossRefGoogle Scholar
  8. 8.
    Forman MS, Schmidt ML, Kasturi S, Perl DP, Lee VM-Y, Trojanowski JQ (2002) Tau and alpha-synuclein pathology in amygdala of Parkinsonism–dementia complex patients of Guam. Am J Pathol 160:1725–1731PubMedGoogle Scholar
  9. 9.
    Forman MS, Trojanowski JQ, Lee VM-Y (2004) Hereditary tauopathies and idiopathic frontotemporal dementias. In: Esiri MM, Lee VM-Y, Trojanowski JQ (eds) The neuropathology of dementia. Cambridge University Press, Cambridge, pp 257–288Google Scholar
  10. 10.
    Galasko D, Salmon D, Craig UK, Wiederholt W (2000) The clinical spectrum of Guam ALS and Parkinson–dementia complex: 1997–1999. Ann N Y Acad Sci 920:120–125PubMedCrossRefGoogle Scholar
  11. 11.
    Geser F, Lee VM-Y, Trojanowski JQ (2007) Frontotemporal dementias. In: Rosenberg RN, DiMauro S, Paulson H, Ptacek L, Nestler E (eds) The molecular and genetic basis of neurological and psychiatric disease. Lippincott Williams & Wilkins, Philadelphia (in press)Google Scholar
  12. 12.
    Greenberg SG, Davies P (1990) A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci USA 87:5827–5831PubMedCrossRefGoogle Scholar
  13. 13.
    Hasegawa M, Arai T, Akiyama H, Nonaka T, Mori H, Hashimoto T, Yamazaki M, Oyanagi K (2007) TDP-43 is deposited in the Guam parkinsonism–dementia complex brains. Brain 130:1386–1394PubMedCrossRefGoogle Scholar
  14. 14.
    Hirano A, Malamud N, Kurland LT (1961) Parkinsonism–dementia complex, an endemic disease on the island of Guam: II. Pathological features. Brain 84:662–679PubMedCrossRefGoogle Scholar
  15. 15.
    Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A, Morris JC, Wilhelmsen KC, Schellenberg GD, Trojanowski JQ, Lee VM-Y (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282:1914–1917PubMedCrossRefGoogle Scholar
  16. 16.
    Ikemoto A, Hirano A, Akiguchi I, Kimura J (1997) Comparative study of ubiquitin immunoreactivity of hippocampal granular cells in amyotrophic lateral sclerosis with dementia, Guamanian amyotrophic lateral sclerosis and Guamanian parkinsonism–dementia complex. Acta Neuropathol (Berl) 93:265–270CrossRefGoogle Scholar
  17. 17.
    Kosik KS, Orecchio LD, Binder L, Trojanowski JQ, Lee VM-Y, Lee G (1988) Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1:817–825PubMedCrossRefGoogle Scholar
  18. 18.
    Kuzuhara S (2007) TDP-43 accumulation in ALS/parkinsonism-dementia complex (ALS/PDC) of the Kii peninsula of Japan. Neuropathology 27:161Google Scholar
  19. 19.
    Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H, Eisen A, McClusky L, Kretzschmar HA, Monoranu CM, Highley JR, Kirby J, Siddique T, Shaw PJ, Lee VM-Y, Trojanowski JQ (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434PubMedCrossRefGoogle Scholar
  20. 20.
    Mackenzie IR, Feldman HH (2005) Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum. J Neuropathol Exp Neurol 64:730–739PubMedCrossRefGoogle Scholar
  21. 21.
    Mimuro M, Kokubo Y, Kuzuhara S (2007) Similar topographical distribution of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonism–dementia complex in people living in the Kii peninsula of Japan suggests a single tauopathy. Acta Neuropathol (Berl) 113:653–658CrossRefGoogle Scholar
  22. 22.
    Neumann M, Kwong LK, Truax AC, Vanmassenhove B, Kretzschmar HA, Van Deerlin VM, Clark CM, Grossman M, Miller BL, Trojanowski JQ, Lee VM-Y (2007) TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions. J Neuropathol Exp Neurol 66:177–183PubMedGoogle Scholar
  23. 23.
    Neumann M, Mackenzie IR, Cairns NJ, Boyer PJ, Markesbery WR, Smith CD, Taylor JP, Kretzschmar HA, Kimonis VE, Forman MS (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66:152–157PubMedGoogle Scholar
  24. 24.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM-Y (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  25. 25.
    Oyanagi K (2005) The nature of the parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam and magnesium deficiency. Parkinsonism Relat Disord 11(Suppl 1):S17–S23PubMedCrossRefGoogle Scholar
  26. 26.
    Oyanagi K, Makifuchi T, Ohtoh T, Chen KM, van der ST, Gajdusek DC, Chase TN, Ikuta F (1994) Amyotrophic lateral sclerosis of Guam: the nature of the neuropathological findings. Acta Neuropathol (Berl) 88:405–412CrossRefGoogle Scholar
  27. 27.
    Oyanagi K, Makifuchi T, Ohtoh T, Ikuta F, Chen KM, Chase TN, Gajdusek DC (1994) Topographic investigation of brain atrophy in parkinsonism–dementia complex of Guam: a comparison with Alzheimer’s disease and progressive supranuclear palsy. Neurodegeneration 3:301–304PubMedGoogle Scholar
  28. 28.
    Oyanagi K, Wada M (1999) Neuropathology of parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam: an update. J Neurol 246(Suppl 2):II19–II27PubMedCrossRefGoogle Scholar
  29. 29.
    Perl DP, Hof PR, Purohit DP, Loerzel A, Belli D (1995) Changes in the outbreak of ALS/parkinsonism–dementia complex: neuropathologic studies of asympomatic Chamorros. J Neuropathol Exp Neurol 54:416Google Scholar
  30. 30.
    Perl DP, Hof PR, Purohit DP, Loerzel AJ, Kakulas BA (2003) Hippocampal and entorhinal cortex neurofibrillary tangle formation in Guamanian Chamorros free of overt neurologic dysfunction. J Neuropathol Exp Neurol 62:381–388PubMedGoogle Scholar
  31. 31.
    Persaud R (1994) Correlation, regression, and repeated data. BMJ 308:1510PubMedGoogle Scholar
  32. 32.
    Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A, Bruce J, Grossman M, Trojanowski JQ, Lee VM-Y (2006) Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 169:1343–1352PubMedCrossRefGoogle Scholar
  33. 33.
    Schmidt ML, Garruto R, Chen J, Lee VM-Y, Trojanowski JQ (2000) Tau epitopes in spinal cord neurofibrillary lesions in Chamorros of Guam. Neuroreport 11:3427–3430PubMedCrossRefGoogle Scholar
  34. 34.
    Schmidt ML, Zhukareva V, Perl DP, Sheridan SK, Schuck T, Lee VM-Y, Trojanowski JQ (2001) Spinal cord neurofibrillary pathology in Alzheimer disease and Guam Parkinsonism–dementia complex. J Neuropathol Exp Neurol 60:1075–1086PubMedGoogle Scholar
  35. 35.
    Schwab C, Steele JC, McGeer PL (1997) Dystrophic neurites are associated with early stage extracellular neurofibrillary tangles in the parkinsonism–dementia complex of Guam. Acta Neuropathol (Berl) 94:486–492CrossRefGoogle Scholar
  36. 36.
    Tan CF, Eguchi H, Tagawa A, Onodera O, Iwasaki T, Tsujino A, Nishizawa M, Kakita A, Takahashi H (2007) TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol (Berl) 113:535–542CrossRefGoogle Scholar
  37. 37.
    Trojanowski JQ, Ishihara T, Higuchi M, Yoshiyama Y, Hong M, Zhang B, Forman MS, Zhukareva V, Lee VM-Y (2002) Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam. Exp Neurol 176:1–11PubMedCrossRefGoogle Scholar
  38. 38.
    Winton MJ, Joyce S, Zhukareva V, Practico D, Perl DP, Galasko D, Craig U, Trojanowski JQ, Lee VM-Y (2006) Characterization of tau pathologies in gray and white matter of Guam parkinsonism-dementia complex. Acta Neuropathol (Berl) 111:401–412CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Felix Geser
    • 1
  • Matthew J. Winton
    • 1
  • Linda K. Kwong
    • 1
  • Yan Xu
    • 1
  • Sharon X. Xie
    • 2
  • Lionel M. Igaz
    • 1
  • Ralph M. Garruto
    • 3
  • Daniel P. Perl
    • 4
  • Douglas Galasko
    • 5
  • Virginia M.-Y. Lee
    • 1
  • John Q. Trojanowski
    • 1
  1. 1.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer’s Disease Core Center, Institute on AgingUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of Biostatistics and EpidemiologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Department of Anthropology and Biological SciencesState University of New York at BinghamtonBinghamtonUSA
  4. 4.Department of PathologyMt. Sinai School of MedicineNew YorkUSA
  5. 5.Department of NeurologyUniversity of California at San DiegoSan DiegoUSA

Personalised recommendations