Basic Science and Pathogenesis

Similarities between frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and limbic-predominant, age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), including some shared circuitry and similar inclusion morphologies by histology, have sparked debates about whether they represent a spectrum of the same disease. We reviewed cases from the UCSF Neurodegenerative Disease Brain Bank, which specializes in FTLD-TDP, and contrasted them with prior reports to examine whether Type A and LATE-NC inhabit a spectrum or are distinct diseases.

Patients were diagnosed with FTLD-TDP (N = 148) and classified into types A-D or deemed unclassifiable (usually due to mixed A and B features, or too sparse to classify); another 42 were classified as LATE-NC and staged (1-3). First, we compared the demographic, clinical, and genetic features of all FTLD-TDP subtypes to LATE-NC cases, including FTLD-TDP cases with intermediate-to-high AD neuropathological changes (ADNC). We then focused specifically on TDP-Type A and Type U cases, with or without coexisting AD pathology, and compared them to LATE-NC cases due to their similar morphological inclusion pattern. Next, because LATE-NC usually has ADNC, we contrasted TDP-Type A or U cases with intermediate or high ADNC to LATE-NC Stage 3. Lastly, four blinded raters assessed the middle frontal gyrus in all Type A and LATE-NC Stage 3 cases to evaluate whether routine diagnostic examination of this region-commonly analyzed for TDP-43 in most brain banks-can effectively differentiate Type A from LATE-NC Stage 3.

FTLD-TDP Type A has younger symptom onset, age at death, and shorter disease duration than LATE-NC, whereas FTLD-TDP+AD cases are in between. LATE-NC was diagnosed only in patients with sporadic disease, whereas Type A was often genetic. FTLD-TDP-A was associated with FTD syndromes, whereas LATE-NC often correlated with an AD-associated (amnestic) syndrome. Diagnosis using only middle frontal gyrus to assess TDP-43 proteinopathy generally was able to differentiate cases with finalized, blinded ratings and agreement analyses pending.

FTLD-TDP Type A and LATE-NC share some histological features, but they appear to be distinct entities in terms of clinical, genetic, and regional disease burden. Keeping separate diagnostic terms seems appropriate.