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Acta Neuropathologica
Published in: Acta Neuropathologica 1/2017

01-07-2017 | Original Article

Reappraisal of TDP-43 pathology in FTLD-U subtypes

Authors: Ian R. Mackenzie, Manuela Neumann

Published in: Acta Neuropathologica | Issue 1/2017

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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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Metadata
Title
Reappraisal of TDP-43 pathology in FTLD-U subtypes
Authors
Ian R. Mackenzie
Manuela Neumann
Publication date
01-07-2017
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 1/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-017-1716-8

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