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

Richard A. Armstrong, 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

Research output: Contribution to journalArticle

Abstract

Studies suggest that frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43kDa (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 (NCI), oligodendroglial inclusions (GI), neuronal intranuclear inclusions (NII), and dystrophic neurites (DN), surviving neurons, enlarged neurons (EN), 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.
Original languageEnglish
Pages (from-to)227-239
Number of pages13
JournalJournal of Neural Transmission
Volume117
Issue number2
DOIs
Publication statusPublished - 10 Dec 2009

Keywords

  • 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

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    Armstrong, R. A., Ellis, W., Hamilton, R. L., Mackenzie, I. R. A., Hedreen, J., Gearing, M., Montine, T., Vonsattel, J-P., Head, E., Lieberman, A. P., & Cairns, N. J. (2009). Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis. Journal of Neural Transmission, 117(2), 227-239. https://doi.org/10.1007/s00702-009-0350-6