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Reappraisal of TDP-43 pathology in FTLD-U subtypes

Acta Neuropathologica volume 134, pages 79–96 (2017)Cite this article

Abstract

Frontotemporal lobar degeneration with tau-negative, ubiquitin-immunoreactive (-ir) pathology (FTLD-U) is subclassified based on the type and cortical laminar distribution of neuronal inclusions. Following the discovery of the transactive response DNA-binding protein Mr 43 kD (TDP-43) as the ubiquitinated protein in most FTLD-U, the same pathological criteria have been used to classify FTLD cases based on TDP-43-ir changes. However, the fact that immunohistochemistry (IHC) for ubiquitin and TDP-43 each recognizes slightly different pathological changes in these cases means that the original FTLD-U subtype criteria may not be directly applicable for use with TDP-43 IHC. We formally re-evaluated the TDP-43-ir pathological features that characterize the different FTLD-U subtypes to see if the current classification could be refined. In our series of 78 cases, 81% were classified as one of the common FTLD-U subtypes (29% A, 35% B, 17% C). With TDP-43 IHC, each subtype demonstrated consistent intra-group pathological features and clear inter-group differences. The TDP-43-ir changes that characterized type A and C cases were similar to those seen with ubiquitin IHC; specifically, compact neuronal cytoplasmic inclusions (NCI), short thick dystrophic neurites (DN), and lentiform neuronal intranuclear inclusions concentrated in cortical layer II in type A cases, and a predominance of long thick DN in type C. However, type B cases showed significant differences with TDP-43 compared with ubiquitin IHC; with many diffuse granular NCI and wispy thread and dots-like profiles in all cortical layers. The remaining 15 cases (12 with C9orf72 mutations) showed changes that were consistent with combined type A and type B pathology. These findings suggest that the pathological criteria for subtyping FTLD cases based on TDP-43 IHC might benefit from some refinement that recognizes differences in the morphologies of NCI and neurites. Furthermore, there is a significant subset of cases (most with the C9orf72 mutation) with the pathological features of multiple FTLD-TDP subtypes for which appropriate classification is difficult.

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Acknowledgements

We would like to thank Margaret Luk, Katrin Trautmann, and Manuel Gödan for their excellent technical assistance. This work was supported by the German Helmholtz Association (W2/W3-036, MN) and the Canadian Institutes of Health Research (74580, IRM).

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Authors and Affiliations

  1. Department of Pathology, Vancouver General Hospital, University of British Columbia, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada

    Ian R. Mackenzie

  2. Department of Neuropathology, DZNE, German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany

    Manuela Neumann

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Mackenzie, I.R., Neumann, M. Reappraisal of TDP-43 pathology in FTLD-U subtypes. Acta Neuropathol 134, 79–96 (2017). https://doi.org/10.1007/s00401-017-1716-8

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Keywords

  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • TDP-43
  • FTLD-U
  • FTLD-TDP