Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium

J Neural Transm (Vienna). 2015 Jul;122(7):957-72. doi: 10.1007/s00702-014-1304-1. Epub 2014 Sep 20.

Abstract

The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Brain / metabolism*
  • Brain / pathology
  • DNA-Binding Proteins / metabolism*
  • Europe
  • Female
  • Frontotemporal Lobar Degeneration / metabolism
  • Frontotemporal Lobar Degeneration / pathology*
  • Humans
  • Inclusion Bodies / metabolism*
  • Male
  • Neurites / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphorylation
  • Retrospective Studies
  • Sequestosome-1 Protein
  • Tissue Array Analysis
  • Ubiquitin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • TARDBP protein, human
  • Ubiquitin