Quantitative TDP-43 burden and distribution in old age: High and low probability of Alzheimer's disease and genetically confirmed FTLD-TDP-43.

Abstract

Transactive response DNA-binding protein of 43kDa (TDP-43) inclusions are found in the brains of patients with genetic frontotemporal lobar degeneration (gFTLD-TDP), patients with Alzheimer's disease (AD-TDP), as well as in older patients without any other advanced co-pathologies (pure-TDP). While phenotypic presentations of these three groups of patients might differ, it is unclear whether clinical presentations and TDP-43 burden and its distribution differ among these three groups in old patients. The brain bank at Mayo clinic, FL was queried for cases ≥75 years old at death and having TDP-43 in middle frontal cortex. Cases meeting criteria were split into the following three groups: 1) gFTLD-TDP (median age at death - 78; n=14) - 6 with progranulin (GRN) and 8 with C9ORF72 mutations; 2) AD-TDP (median age - 83; n=10) - cases with median Braak neurofibrillary tangle (NFT) stage VI and amyloid-beta Thal phase V and 3) pure-TDP (median age - 78; n=10) - cases with median Braak NFT stage I and Thal phase I. Demographic and clinical data were abstracted from medical records and TDP-43 burden was calculated using digital pathology for limbic regions (hippocampal dentate fascia, CA1 and subiculum), entorhinal, and middle frontal cortices. 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, particularly targeting CA1 and subiculum (Figure 1). Patients with gFTLD-TDP had higher TDP-43 burden in entorhinal cortex compared to those with AD-TDP (p=0.047). TDP-43 burden in middle frontal cortex did not differ between the three groups. Within gFTLD-TDP, C9ORF72 cases showed higher TDP-43 burden than GRN cases in the entorhinal cortex (p=0.045), but similar limbic-predominant pattern of distribution. In old age it is challenging to clinically and pathologically differentiate mutation associated FTLD-TDP from Alzheimer's associated and pure TDP-43 cases based on TDP-43 burden. Like AD-TDP, old age mutation-associated FTLD have a limbic predominant TDP-43 distribution. The fact that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP-43 directly and indirectly targets limbic regions.