Acta Neuropathologica

, Volume 114, Issue 1, pp 71–79 | Cite as

TDP-43 in differential diagnosis of motor neuron disorders

  • Dennis W. Dickson
  • Keith A. Josephs
  • Catalina Amador-Ortiz
Original Paper

Abstract

Motor neuron disorders are clinically and pathologically heterogeneous. They can be classified into those that affect primarily upper motor neurons, lower motor neurons or both. The most common disorder to affect both upper and lower motor neurons is amyotrophic lateral sclerosis (ALS). Some forms of motor neuron disease (MND) affect primarily motor neurons in the spinal cord or brainstem, while others affect motor neurons at all levels of the neuraxis. A number of genetic loci have been identified for the various motor neuron disorders. Several of the MND genes encode for proteins important for cytoskeletal stability and axoplasmic transport. Despite these genetic advances, the relationship of the various motor neuron disorders to each other is unclear. Except for rare familial forms of ALS associated with mutations in superoxide dismutase type 1 (SOD1), which are associated with neuronal inclusions that contain SOD1, specific molecular or cellular markers that differentiate ALS from other motor neuron disorders have not been available. Recently, the TAR DNA binding protein 43 (TDP-43) has been shown to be present in neuronal inclusions in ALS, and it has been suggested that TDP-43 may be a specific marker for ALS. This pilot study aimed to determine the value of TDP-43 in the differential diagnosis of MND. Immunohistochemistry for TDP-43 was used to detect neuronal inclusions in the medulla of disorders affecting upper motor neurons, lower motor neurons or both. Medullary motor neuron pathology also was assessed in frontotemporal lobar degeneration (FTLD) that had no evidence of MND. TDP-43 immunoreactivity was detected in the hypoglossal nucleus in all cases of ALS, all cases of FTLD-MND and some of cases of primary lateral sclerosis (PLS). It was not detected in FTLD-PLS. Surprisingly, sparse TDP-43 immunoreactivity was detected in motor neurons in about 10% of FTLD that did not have clinical or pathologic features of MND. The results suggest that TDP-43 immunoreactivity is useful in differentiating FTLD-MND and ALS from other disorders associated with upper or lower motor neuron pathology. It also reveals subclinical MND in a subset of cases of FTLD without clinical or pathologic evidence of MND.

Keywords

Amyotrophic lateral sclerosis (ALS) Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) Immunohistochemistry Motor neuron disease (MND) Primary lateral sclerosis TAR DNA binding protein 43 (TDP-43) 

Notes

Acknowledgments

Supported by NIH grants P50-AG25711, P50-AG16574, P50-NS40256, P01-AG17216 and P01-AG03949. KAJ is supported by the NIH Roadmap Multidisciplinary Clinical Research Career Development Award Grant (K12/NICHD)-HD49078. The histological support of Virginia Phillips, Linda Rousseau and Monica Casey-Castanedes is greatly appreciated. Genetic studies on some of the cases in this study were performed in the laboratory of Michael Hutton, including studies by Rosa Rademaker.

References

  1. 1.
    Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R, Graff-Radford NR, Hutton ML, Dickson DW (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445PubMedCrossRefGoogle Scholar
  2. 2.
    Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y 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 351:602–611PubMedCrossRefGoogle Scholar
  3. 3.
    Bergmann M, Kuchelmeister K, Schmid KW, Kretzschmar HA, Schroder R (1996) Different variants of frontotemporal dementia: a neuropathological and immunohistochemical study. Acta Neuropathol (Berl) 92:170–179CrossRefGoogle Scholar
  4. 4.
    Brugman F, Wokke JH, Vianney de Jong JM, Franssen H, Faber CG, Van den Berg LH (2005) Primary lateral sclerosis as a phenotypic manifestation of familial ALS. Neurology 64:1778–1779PubMedCrossRefGoogle Scholar
  5. 5.
    Bruijn LI, Miller TM, Cleveland DW (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 27:723–749PubMedCrossRefGoogle Scholar
  6. 6.
    Bruyn RP, Koelman JH, Troost D, de Jong JM (1995) Motor neuron disease (amyotrophic lateral sclerosis) arising from longstanding primary lateral sclerosis. J Neurol Neurosurg Psychiatry 58:742–744PubMedCrossRefGoogle Scholar
  7. 7.
    Carpenter S (1968) Proximal axonal enlargement in motor neuron disease. Neurology 18:841–851PubMedGoogle Scholar
  8. 8.
    Cooper PN, Jackson M, Lennox G, Lowe J, Mann DM (1995) Tau, ubiquitin, and alpha B-crystallin immunohistochemistry define the principal causes of degenerative frontotemporal dementia. Arch Neurol 52:1011–1015PubMedGoogle Scholar
  9. 9.
    Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DM (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol (Berl) 113:521–533CrossRefGoogle Scholar
  10. 10.
    Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R et al (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001PubMedCrossRefGoogle Scholar
  11. 11.
    Hirano A, Nakano I, Kurland LT, Mulder DW, Holley PW, Saccomanno G (1984) Fine structural study of neurofibrillary changes in a family with amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 43:471–480PubMedGoogle Scholar
  12. 12.
    Hudson AJ, Kiernan JA, Munoz DG, Pringle CE, Brown WF, Ebers GC (1993) Clinicopathological features of primary lateral sclerosis are different from amyotrophic lateral sclerosis. Brain Res Bull 30:359–364PubMedCrossRefGoogle Scholar
  13. 13.
    Ishizawa T, Ko LW, Cookson N, Davies P, Espinoza M, Dickson DW (2002) Selective neurofibrillary degeneration of the hippocampal CA2 sector is associated with four-repeat tauopathies. J Neuropathol Exp Neurol 61:1040–1047PubMedGoogle Scholar
  14. 14.
    Jackson M, Lowe J (1996) The new neuropathology of degenerative frontotemporal dementias. Acta Neuropathol (Berl) 91:127–134CrossRefGoogle Scholar
  15. 15.
    James PA, Talbot K (2006) The molecular genetics of non-ALS motor neuron diseases. Biochim Biophys Acta 1762:986–1000PubMedGoogle Scholar
  16. 16.
    Jellinger K, Jirasek A (1971) Neuroaxonal dystrophy in man: character and natural history. Acta Neuropathol (Berl) 5(Suppl 5):3–16Google Scholar
  17. 17.
    Josephs KA, Ahmed Z, Katsuse O, Parisi JF, Boeve BF, Knopman DS, Petersen RC, Davies P, Duara R, Graff-Radford NR et al (2007) Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 66:142–151PubMedGoogle Scholar
  18. 18.
    Josephs KA, Dickson DW (2007) Frontotemporal lobar degeneration with primary lateral sclerosis is a rare pathological entity. Neurology 68 (in press)Google Scholar
  19. 19.
    Josephs KA, Katsuse O, Beccano-Kelly DA, Lin WL, Uitti RJ, Fujino Y, Boeve BF, Hutton ML, Baker MC, Dickson DW (2006) Atypical progressive supranuclear palsy with corticospinal tract degeneration. J Neuropathol Exp Neurol 65:396–405PubMedGoogle Scholar
  20. 20.
    Josephs KA, Parisi JE, Knopman DS, Boeve BF, Petersen RC, Dickson DW (2006) Clinically undetected motor neuron disease in pathologically proven frontotemporal lobar degeneration with motor neuron disease. Arch Neurol 63:506–512PubMedCrossRefGoogle Scholar
  21. 21.
    Kato S, Shaw P, Wood-Allum C, Leigh PN, Shaw C (2003) Amyotrophic lateral sclerosis. In: Dickson DW (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 350–368Google Scholar
  22. 22.
    Katsuse O, Dickson DW (2005) Ubiquitin immunohistochemistry of frontotemporal lobar degeneration differentiates cases with and without motor neuron disease. Alzheimer Dis Assoc Disord 19(Suppl 1):S37–43PubMedCrossRefGoogle Scholar
  23. 23.
    Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59:1077–1079PubMedCrossRefGoogle Scholar
  24. 24.
    Lowe J, Rossor MN (2003) Frontotemporal lobar degeneration. In: Dickson DW (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 342–348Google Scholar
  25. 25.
    Mackenzie IR (2007) The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropathol (Berl)Google Scholar
  26. 26.
    Mackenzie IR, Baker M, West G, Woulfe J, Qadi N, Gass J, Cannon A, Adamson J, Feldman H, Lindholm C et al (2006) A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain 129:853–867PubMedCrossRefGoogle Scholar
  27. 27.
    Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H et al (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434PubMedCrossRefGoogle Scholar
  28. 28.
    Mackenzie IR, Feldman H (2004) Neuronal intranuclear inclusions distinguish familial FTD-MND type from sporadic cases. Dement Geriatr Cogn Disord 17:333–336PubMedCrossRefGoogle Scholar
  29. 29.
    McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ (2001) Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol 58:1803–1809PubMedCrossRefGoogle Scholar
  30. 30.
    Mott RT, Dickson DW, Trojanowski JQ, Zhukareva V, Lee VM, Forman M, Van Deerlin V, Ervin JF, Wang DS, Schmechel DE et al (2005) Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias. J Neuropathol Exp Neurol 64:420–428PubMedGoogle Scholar
  31. 31.
    Murphy JM, Henry RG, Langmore S, Kramer JH, Miller BL, Lomen-Hoerth C (2007) Continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol 64:530–534PubMedCrossRefGoogle Scholar
  32. 32.
    Neumann M, Kwong LK, Truax AC, Vanmassenhove B, Kretzschmar HA, Van Deerlin VM, Clark CM, Grossman M, Miller BL, Trojanowski JQ et al (2007) TDP-43-positive white matter pathology in frontotemporal lobar degeneration with ubiquitin-positive inclusions. J Neuropathol Exp Neurol 66:177–183PubMedGoogle Scholar
  33. 33.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRefGoogle Scholar
  34. 34.
    Okamoto K, Murakami N, Kusaka H, Yoshida M, Hashizume Y, Nakazato Y, Matsubara E, Hirai S (1992) Ubiquitin-positive intraneuronal inclusions in the extramotor cortices of presenile dementia patients with motor neuron disease. J Neurol 239:426–430PubMedCrossRefGoogle Scholar
  35. 35.
    Robertson J, Sanelli T, Xiao S, Yang W, Horne P, Hammond R, Pioro EP, Strong MJ (2007) Lack of TDP-43 abnormalities in mutant SOD1 transgenic mice shows disparity with ALS. Neurosci Lett (in press)Google Scholar
  36. 36.
    Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62PubMedCrossRefGoogle Scholar
  37. 37.
    Shibata N, Hirano A, Kobayashi M, Siddique T, Deng HX, Hung WY, Kato T, Asayama K (1996) Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement. J Neuropathol Exp Neurol 55:481–490PubMedGoogle Scholar
  38. 38.
    Swash M (2003) Primary lateral sclerosis. In: Dickson DW (ed) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 369–371Google Scholar
  39. 39.
    Talbot K, Ansorge O (2006) Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease. Hum Mol Genet 15(Spec No 2):R182–R187PubMedCrossRefGoogle Scholar
  40. 40.
    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
  41. 41.
    Tolnay M, Probst A (1995) Frontal lobe degeneration: novel ubiquitin-immunoreactive neurites within frontotemporal cortex. Neuropathol Appl Neurobiol 21:492–497PubMedGoogle Scholar
  42. 42.
    Tomonaga M (1980) Selective appearance of Bunina bodies in amyotrophic lateral sclerosis. A study of the distribution in midbrain and sacral cord. J Neurol 223:259–267PubMedCrossRefGoogle Scholar
  43. 43.
    Trojanowski JQ, Dickson D (2001) Update on the neuropathological diagnosis of frontotemporal dementias. J Neuropathol Exp Neurol 60:1123–1126PubMedGoogle Scholar
  44. 44.
    Uchikado H, Lin WL, DeLucia MW, Dickson DW (2006) Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65:685–697PubMedCrossRefGoogle Scholar
  45. 45.
    Watanabe M, Dykes-Hoberg M, Culotta VC, Price DL, Wong PC, Rothstein JD (2001) Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 8:933–941PubMedCrossRefGoogle Scholar
  46. 46.
    Whitwell JL, Jack CR Jr, Senjem ML, Josephs KA (2006) Patterns of atrophy in pathologically confirmed FTLD with and without motor neuron degeneration. Neurology 66:102–104PubMedCrossRefGoogle Scholar
  47. 47.
    Wightman G, Anderson VE, Martin J, Swash M, Anderton BH, Neary D, Mann D, Luthert P, Leigh PN (1992) Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia. Neurosci Lett 139:269–274PubMedCrossRefGoogle Scholar
  48. 48.
    Woulfe J, Kertesz A, Munoz DG (2001) Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions. Acta Neuropathol (Berl) 102:94–102Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Dennis W. Dickson
    • 1
  • Keith A. Josephs
    • 2
  • Catalina Amador-Ortiz
    • 1
  1. 1.Department of NeuroscienceMayo Clinic College of MedicineJacksonvilleUSA
  2. 2.Department of NeurologyMayo Clinic College of MedicineRochesterUSA

Personalised recommendations