Skip to main content


Log in

Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript


Recently, TDP-43, a 43 kDa nuclear TAR DNA-binding protein, was identified as the major disease protein in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), FTLD-U with motor neuron disease (FTLD–MND), and amyotrophic lateral sclerosis. To date, TDP-43 pathology in sporadic FTLD–MND has been reported only in select central nervous system areas. However, this distribution of lesions is insufficient to explain all clinical signs of FTLD–MND and the extent of TDP-43 pathology, throughout the brain, remains unknown. Therefore, as a pilot study, we performed an immunohistochemical whole brain scan of two cases diagnosed clinically as FTLD–MND and two control subjects. We found evidence of both neuronal and glial TDP-43 pathology in multiple brain areas including the nigro-striatal system, neo- and allocortical brain areas, with varying frequency, morphology, and degree, and nowhere in control tissue. The finding of a distinct cytopathological profile consisting of a cell nucleus devoid of endogenous TDP-43 staining coupled with diffuse/granular cytoplasmic staining (“pre-inclusion”) was prominent in a couple of brain areas. These pre-inclusions were not or only weakly ubiquitin-immunoreactive. While the findings of severe involvement of extracortical or extrapyramidal areas are strongly suggestive for FTLD–MND being a TDP-43 multisystem proteinopathy rather than a disease predominantly affecting the cortex and spinal cord, more detailed clinicopathological studies of larger cohorts are needed to fully elucidate the distribution and severity of pathological TDP-43 in this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others


  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 61:435–445

    Article  PubMed  CAS  Google Scholar 

  2. Buratti E, Baralle FE (2001) Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J Biol Chem 276:36337–36343

    Article  PubMed  CAS  Google Scholar 

  3. Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM-Y, Hatanpaa KJ, White CL III, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM (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 

  4. Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL III, Schneider JA, Kretzschmar HA, Carter D, Taylor-Reinwald L, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VM, Mackenzie IR (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240

    Article  PubMed  CAS  Google Scholar 

  5. Croisier E, Graeber MB (2006) Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration. Acta Neuropathol 112:517–530

    Article  PubMed  Google Scholar 

  6. Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du PD, Neary D, Snowden JS, Mann DM (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113:521–533

    Article  PubMed  CAS  Google Scholar 

  7. Deymeer F, Smith TW, DeGirolami U, Drachman DA (1989) Thalamic dementia and motor neuron disease. Neurology 39:58–61

    PubMed  CAS  Google Scholar 

  8. Dickson DW, Josephs KA, Amador-Ortiz C (2007) TDP-43 in differential diagnosis of motor neuron disorders. Acta Neuropathol 114:71–79

    Article  PubMed  CAS  Google Scholar 

  9. Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van Deerlin V, Lee VM-Y, Miller BL, Trojanowski JQ, Grossman M (2006) Frontotemporal dementia: clinicopathological correlations. Ann Neurol 59:952–962

    Article  PubMed  Google Scholar 

  10. 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, pp 330–338

    Google Scholar 

  11. Geser F, Winton MJ, Kwong LK, Xu Y, Xie SX, Igaz LM, Garruto RM, Perl DP, Galasko D, Lee VM-Y, Trojanowski JQ (2007) Pathological TDP-43 in parkinsonism–dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol. 10.1007/s00401-007-0257-y

  12. Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, Fujisawa K, Togo T, Katsuse O, Uchikado H, Furukawa Y, Kosaka K, Arai H (2007) Appearance pattern of TDP-43 in Japanese frontotemporal lobar degeneration with ubiquitin-positive inclusions. Neurosci Lett 419:213–218

    Article  PubMed  CAS  Google Scholar 

  13. Kim JS (2002) Post-stroke emotional incontinence after small lenticulocapsular stroke: correlation with lesion location. J Neurol 249:805–810

    Article  PubMed  Google Scholar 

  14. Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ (2007) TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. Acta Neuropathol 114:63–70

    Article  PubMed  CAS  Google Scholar 

  15. Leverenz JB, Yu CE, Montine TJ, Steinbart E, Bekris LM, Zabetian C, Kwong LK, Lee VM, Schellenberg GD, Bird TD (2007) A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. Brain 130:1360–1374

    Article  PubMed  CAS  Google Scholar 

  16. 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 61:427–434

    Article  PubMed  CAS  Google Scholar 

  17. 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 64:730–739

    PubMed  Google Scholar 

  18. Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, Arnold SE, Siderowf A, Grossman M, Leverenz JB, Woltjer R, Lopez OL, Hamilton R, Tsuang DW, Galasko D, Masliah E, Kaye J, Clark CM, Montine TJ, Lee VM, Trojanowski JQ (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229

    Article  PubMed  CAS  Google Scholar 

  19. 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 66:177–183

    PubMed  CAS  Google Scholar 

  20. 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 66:152–157

    Article  PubMed  Google Scholar 

  21. 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 314:130–133

    Article  PubMed  CAS  Google Scholar 

  22. Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69:3584–3596

    PubMed  CAS  Google Scholar 

  23. 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 169:1343–1352

    Article  PubMed  CAS  Google Scholar 

  24. Schiffer R, Pope LE (2005) Review of pseudobulbar affect including a novel and potential therapy. J Neuropsychiatry Clin Neurosci 17:447–454

    PubMed  CAS  Google Scholar 

  25. Seelaar H, Jurgen SH, Azmani A, Kusters B, Rosso S, Majoor-Krakauer D, de Rijik MC, Rizzu P, Brummelhuis MT, van Doorn PA, Kamphorst W, Willemsen R, van Swieten JC (2007) TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations. Brain 130:1375–1385

    Article  PubMed  Google Scholar 

  26. Snowden J, Neary D, Mann D (2007) Frontotemporal lobar degeneration: clinical and pathological relationships. Acta Neuropathol 114:31–38

    Article  PubMed  Google Scholar 

  27. 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 113:535–542

    Article  PubMed  CAS  Google Scholar 

  28. Wang HY, Wang IF, Bose J, Shen CK (2004) Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83:130–139

    Article  PubMed  CAS  Google Scholar 

  29. Zhang H, Tan CF, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K (2007) TDP-43-immunoreactive neuronal and glial inclusions in the neostriatum in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol. 10.1007/s00401-007-0285-7

Download references


The authors would like to thank T. Schuck, J. Robinson, and M. Getahun for their expert technical assistance and M. Martinez-Lage for critical comments on the discussion. Further, they thank their patients and families who made this research possible. This work was funded by the National Institutes of Health (AG10124, AG17586, and HL071483).

Author information

Authors and Affiliations


Corresponding author

Correspondence to John Q. Trojanowski.

Additional information

Nicholas J. Brandmeir and Felix Geser contributed equally to this manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brandmeir, N.J., Geser, F., Kwong, L.K. et al. Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease. Acta Neuropathol 115, 123–131 (2008).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: