Reappraisal of TDP-43 pathology in FTLD-U subtypes

Acta Neuropathol. 2017 Jul;134(1):79-96. doi: 10.1007/s00401-017-1716-8. Epub 2017 May 2.


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.

Keywords: FTLD-TDP; FTLD-U; Frontotemporal dementia; Frontotemporal lobar degeneration; TDP-43.

MeSH terms

  • Aged
  • Aged, 80 and over
  • C9orf72 Protein / genetics
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • DNA-Binding Proteins / metabolism*
  • Female
  • Frontotemporal Dementia / classification*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology*
  • Humans
  • Immunohistochemistry
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Male
  • Middle Aged
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphorylation
  • Ubiquitins / metabolism


  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • TARDBP protein, human
  • Ubiquitins

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