Disease Pathology

The FTD spectrum of disorders characteristically show progressive and dramatic brain shrinkage, mainly in the frontal and temporal cortical lobes of the brain. The term frontotemporal lobar degeneration (FTLD) is now used in reference to the disease neuropathology, although initially FTD disorders were named using the term FTLD. While diagnostic criteria have been expanded and improved and new research has added considerably to our understanding of the genetics of FTD, a ‘definite’ diagnosis of frontotemporal degeneration is still based on confirming neuropathology obtained postmortem.

Complex pathology

The FTD disorders have a complex pathology; they all have in common the abnormal aggregation of proteins in nerve cells (a proteinopathy); but the type of proteinopathy can vary even within one syndrome. For example, TDP-43 proteinopathy or tauopathy can occur in behavioral variant FTD. And while PSP and CBD are tauopathies, the aggregates are from the 4R form of tau rather than the 3R form found in bvFTD.  FTD-ALS is a TDP-43 proteinopathy.

The PPA disorders are just as complex. The semantic variant PPA is a TDP-43 proteinopathy, but the nonfluent agrammatic variant PPA is predominantly a tauopathy but TDP-43 proteinopathy or even an Alzheimer’s like neuropathology can occur. In contrast, the logopenic variant PPA shows an Alzheimer’s disease neuropathology more than a TDP-43 or tauopathy.