Premium
Old age genetically confirmed frontotemporal lobar degeneration with TDP‐43 has limbic predominant TDP‐43 deposition
Author(s) -
Buciuc Marina,
Whitwell Jennifer L.,
Baker Matthew C.,
Rademakers Rosa,
Dickson Dennis W.,
Josephs Keith A.
Publication year - 2021
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12727
Subject(s) - frontotemporal lobar degeneration , entorhinal cortex , frontotemporal dementia , c9orf72 , dementia , pathology , medicine , semantic dementia , hippocampus , neurofibrillary tangle , alzheimer's disease , psychology , disease , senile plaques
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.