Overlapping but distinct TDP‐43 and tau pathologic patterns in aged hippocampi

Abstract

Intracellular proteinaceous aggregates (inclusion bodies) are almost always detectable at autopsy in brains of elderly individuals. Inclusion bodies composed of TDP-43 and tau proteins often coexist in the same brain, and each of these pathologic biomarkers is associated independently with cognitive impairment. However, uncertainties remain about how the presence and neuroanatomical distribution of inclusion bodies correlate with underlying diseases including Alzheimer's disease (AD). To address this knowledge gap, we analyzed data from the University of Kentucky AD Center autopsy series (n = 247); none of the brains had frontotemporal lobar degeneration. A specific question for this study was whether neurofibrillary tangle (NFT) pathology outside of the Braak NFT staging scheme is characteristic of brains with TDP-43 pathology but lacking AD, that is those with cerebral age-related TDP-43 with sclerosis (CARTS). We also tested whether TDP-43 pathology is associated with comorbid AD pathology, and whether argyrophilic grains are relatively likely to be present in cases with, vs. without, TDP-43 pathology. Consistent with prior studies, hippocampal TDP-43 pathology was associated with advanced AD - Braak NFT stages V/VI. However, argyrophilic grain pathology was not more common in cases with TDP-43 pathology in this data set. In brains with CARTS (TDP-43[+]/AD[-] cases), there were more NFTs in dentate granule neurons than were seen in TDP-43[-]/AD[-] cases. These dentate granule cell NFTs could provide a proxy indicator of CARTS pathology in cases lacking substantial AD pathology. Immunofluorescent experiments in a subsample of cases found that, in both advanced AD and CARTS, approximately 1% of dentate granule neurons were PHF-1 immunopositive, whereas ∼25% of TDP-43 positive cells showed colocalized PHF-1 immunoreactivity. We conclude that NFTs in hippocampal dentate granule neurons are often present in CARTS, and TDP-43 pathology may be secondary to or occurring in parallel with tauopathy.

Possible concurrence of TDP‐43, tau and other proteins in amyotrophic lateral sclerosis/frontotemporal lobar degeneration

“…Arnold et al reported that 40% of elderly individuals with TDP‐43 pathology had argyrophilic grains (AG) pathology, while the prevalence of AG in elderly individuals without TDP‐43 pathology was limited to less than 20% . However, another study indicated no interaction between AG‐tau and TDP‐43 pathologies in elderly individuals …”

“…50 However, another study indicated no interaction between AG-tau and TDP-43 pathologies in elderly individuals. 51…”

Autopsied centenarian case of Alzheimer's disease combined with hippocampal sclerosis, TDP‐43, and α‐synuclein pathologies

“…TDP‐43 pathology has also been reported in HS cases, and HS‐aging is strongly associated with TDP‐43 pathology . Nelson et al recommend “cerebral age‐related TDP‐43 and sclerosis” (CARTS), as a more appropriate term for TDP‐43 pathology and HS‐recognized, but AD pathology‐negative, cases . They also emphasized that the dentate fascia granule‐cell NFTs could provide a proxy indicator of CARTS pathology in cases lacking substantial AD pathology .…”

“…4,13 Nelson et al recommend "cerebral age-related TDP-43 and sclerosis" (CARTS), as a more appropriate term for TDP-43 pathology and HS-recognized, but AD pathology-negative, cases. 15,18,19 They also emphasized that the dentate fascia granule-cell NFTs could provide a proxy indicator of CARTS pathology in cases lacking substantial AD pathology. 18 In contrast, if HS is observed in AD brains, comorbid TDP-43 pathology should be considered.…”

“…15,18,19 They also emphasized that the dentate fascia granule-cell NFTs could provide a proxy indicator of CARTS pathology in cases lacking substantial AD pathology. 18 In contrast, if HS is observed in AD brains, comorbid TDP-43 pathology should be considered. 4,5,13 Nag et al investigated the association of HS with TDP-43 and other common age-related pathologies in 646 community-dwelling older subjects.…”