Frontotemporal lobar degeneration (FTLD) concept and classification update

FTLD is a neuroanatomical disease concept defined only by the presence of degeneration of the frontal and temporal lobes regardless of the underlying histopathological features, and therefore inevitably includes heterogeneous diseases that affect those cerebral regions. The ambiguous idea of Pick disease, the prototype of FTLD, constantly caused great nosological confusion as to FTLD. Progress in molecular neuropathology aimed at clarification of the protein constituents of the inclusion bodies seen in conditions causing FTLD, however, has resolved this problem by providing FTLD with a new concise nomenclature and classification based on the inclusion body proteins. The substances in inclusions in FTLD with ubiquitin-only inclusions (FTLD-U) have been discovered one after another; TDP-43 was the first, being found in inclusions in ALS and ALS with dementia (ALSD) too, and soon FUS/TLS was identified in some TDP-43-negative FTLD-U groups. Thus, FTLD has been divided into three main subgroups; 1) FTLD-tau, which includes Pick disease, PSP, CBD, etc., 2) FTLD-TDP, which is further divided to types A-D, ALSD belonging to type B, and 3) FTLD-FUS, which includes aFTLD-U, NIFID, and BIBD. Further deciphering of yet-unidentified proteins of some FTLD-U subsets will add more subclasses.