Journal of Neural Transmission

, Volume 117, Issue 2, pp 227–239 | Cite as

Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis

  • Richard A. ArmstrongEmail author
  • William Ellis
  • Ronald L. Hamilton
  • Ian R. A. Mackenzie
  • John Hedreen
  • Marla Gearing
  • Thomas Montine
  • Jean-Paul Vonsattel
  • Elizabeth Head
  • Andrew P. Lieberman
  • Nigel J. Cairns
Dementias - Original Article


Studies suggest that frontotemporal lobar degeneration with transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity and the validity of the subtypes, we studied neuropathological variation within the frontal and temporal lobes of 94 cases of FTLD-TDP using quantitative estimates of density and principal components analysis (PCA). A PCA based on the density of TDP-43 immunoreactive neuronal cytoplasmic inclusions, oligodendroglial inclusions, neuronal intranuclear inclusions, and dystrophic neurites, surviving neurons, enlarged neurons, and vacuolation suggested that cases were not segregated into distinct subtypes. Variation in the density of the vacuoles was the greatest source of variation between cases. A PCA based on TDP-43 pathology alone suggested that cases of FTLD-TDP with progranulin (GRN) mutation segregated to some degree. The pathological phenotype of all four subtypes overlapped but subtypes 1 and 4 were the most distinctive. Cases with coexisting motor neuron disease (MND) or hippocampal sclerosis (HS) also appeared to segregate to some extent. We suggest: (1) pathological variation in FTLD-TDP is best described as a ‘continuum’ without clearly distinct subtypes, (2) vacuolation was the single greatest source of variation and reflects the ‘stage’ of the disease, and (3) within the FTLD-TDP ‘continuum’ cases with GRN mutation and with coexisting MND or HS may have a more distinctive pathology.


Frontotemporal lobar degeneration with TDP-43 proteinopathy FTLD with ubiquitin-positive inclusions TAR DNA-binding protein of 43 kDa Neuronal cytoplasmic inclusions Neuropathologic heterogeneity Principal components analysis 



We thank clinical, genetic, pathology, and technical staff of the participating centres and especially C. Kaminski, Centre for Neurodegenerative Disease Research, University of Pennsylvania for making information and tissue samples available for this study and we thank the families of patients whose generosity made this research possible. Support for this work was provided by grants from the NIH (National Institute on Aging): P50-AG05681, P01-AG03991, U01-AG16976, P30-AG13854, and P30-NS057105 to N.J. Cairns, P50-AG16573 and P50-AG000658 to E. Head, P50-AG05133 to Pittsburgh, Alzheimer’s Disease Research Center, and P50AG008671 to A.P. Lieberman, the Hope Center for Neurological Disorders to N.J. Cairns, and the Charles Knight Fund to N.J. Cairns.

Conflict of interest statement



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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Richard A. Armstrong
    • 1
    Email author
  • William Ellis
    • 2
  • Ronald L. Hamilton
    • 3
  • Ian R. A. Mackenzie
    • 4
  • John Hedreen
    • 5
  • Marla Gearing
    • 6
  • Thomas Montine
    • 7
  • Jean-Paul Vonsattel
    • 8
  • Elizabeth Head
    • 9
  • Andrew P. Lieberman
    • 10
  • Nigel J. Cairns
    • 11
  1. 1.Vision SciencesAston UniversityBirminghamUK
  2. 2.Department of PathologyUniversity of California, DavisSacramentoUSA
  3. 3.Department of PathologyUniversity of PittsburghPittsburghUSA
  4. 4.Department of PathologyVancouver General HospitalVancouverCanada
  5. 5.McLean Hospital and Harvard Brain Tissue Resource CenterBelmontUSA
  6. 6.Center for Neurodegenerative DiseaseEmory UniversityAtlantaUSA
  7. 7.Department of PathologyUniversity of WashingtonSeattleUSA
  8. 8.New York Brain Bank at Columbia UniversityNew YorkUSA
  9. 9.Institute for Brain Aging and DementiaUniversity of CaliforniaIrvineUSA
  10. 10.Department of PathologyUniversity of MichiganAnn ArborUSA
  11. 11.Departments of Neurology and Pathology and ImmunologyWashington University School of MedicineSt LouisUSA

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