Response to: Clinical Imaging Features of Sporadic and Genetic Frontotemporal Lobar Degeneration TDP-43 A and B

We read with great interest the article “Clinical Imaging Features of Sporadic and Genetic Frontotemporal Lobar Degeneration TDP-43 A and B” by Coulborn et al. [1]. The notion that some sporadic forms of frontotemporal lobar degeneration (FTLD) are the counterpart to genetic forms of FTLD is critically important. In recent years, research cohorts of genetic FTD, such as the Genetic Frontotemporal Initiative (GENFI) and the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD), have contributed to the expansion of our knowledge of the phenotypes of genetic FTLD. This knowledge could be further extended to sporadic cases if genetic and sporadic cases of FTLD that share the same molecular subtype also share the same clinical and neuroimaging phenotype. For example, we know that FTLD-TDP subtype A cases due to GRN mutations lead to a specific phenotype characterized by asymmetric fronto-temporo-parietal atrophy [2]. Could cases with the same pattern of atrophy, but lacking GRN mutations, indicate the presence of FTLD-TDP subtype A?

The authors conclude that clinical and neuroimaging phenotypes are influenced not only by neuropathological subtype but also, to some extent, by genotype. However, we observed that, particularly for FTLD-TDP A cases, this conclusion seems to be driven mainly by the inclusion of C9orf72 cases within that group. When considering only sporadic and GRN cases, these subtypes appear to share many clinical and neuroimaging similarities. This discrepancy may result from the classification methodology used in the study [3], rather than the more recent classification proposed by Mackenzie and Neumann [4]. In their work, it is highlighted that certain C9orf72 cases might exhibit neuropathological features consistent with both TDP-43 subtype A and B. This mixed classification of the neuropathology of C9orf72 expansion carriers is problematic and not desirable. For this reason, they proposed some additional neuropathological features that, in our expertise, lead to the reclassification of most of the C9orf72 carriers as FTLD-TDP subtype B pathology. This leads us to consider that, when C9orf72 carriers are excluded from the equation, the similarities between sporadic and genetic FTLD-TDP A cases are considerable. Of note, these similarities have also been found at the transcriptomic level [5].

In conclusion, we consider that sporadic and genetic FTLD-TDP cases indeed share relevant phenotypic features. From our point of view, the work of Coulborn et al. [1] also points in that direction, but the inclusion of cases with C9orf72 as TDP43 subtype A might blur the message.

Sergi Borrego-Écija: conceptualization, writing – original draft, writing – review and editing. Cèlia Cruz-Escalera: writing – review and editing, validation. Agnes Perez-Millán: writing – review and editing, validation, supervision. Jordi Juncà-Parellà: writing – review and editing, validation, supervision.

The authors declare no conflicts of interest.