Old age genetically confirmed frontotemporal lobar degeneration with TDP-43 has limbic predominant TDP-43 deposition

Aims: To assess the burden of transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions in a unique cohort of old-age patients with genetic frontotemporal lobar degeneration (gFTLD-TDP) and compare these patients with sporadic old-age individuals with TDP-43, either in the presence of Alzheimer's disease (AD-TDP) or in isolation (pure-TDP). Methods: The brain bank at Mayo Clinic-Jacksonville was searched for cases ≥75 years old at death with TDP-43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD-TDP (n = 15) with progranulin (GRN)/C9ORF72 mutations; (2) AD-TDP (n = 10)—cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure-TDP (n = 10)—cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP-43 burden was calculated using digital pathology. Results: Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP-43 burden in gFTLD-TDP and AD-TDP, but not pure-TDP, was limbic-predominant targeting CA1 and subiculum. Patients with gFTLD-TDP had higher burden in entorhinal cortex compared to AD-TDP. TDP-43 burden in middle frontal cortex did not differ between the three groups. Conclusions: In old age it is challenging to clinically and pathologically differentiate gFTLD-TDP from AD-TDP and pure-TDP-43 based on burden. Like AD-TDP, old age gFTLD-TDP have a limbic predominant TDP-43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP-43 directly and indirectly targets limbic regions.