The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer’s disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43409/410, but also for pTDP-43 phosphorylated at serines 403/404 (pTDP-43403/404) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as ADTDP + FL because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409/410 (pTDP-43409, pTDP-43409/410). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as ADTDP + CTF. Ten AD cases did not contain any TDP-43 pathology and were referred to as ADTDP-. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of ADTDP + CTF cases, 63,6% of ADTDP + FL and 100% of the ADTDP- cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of ADTDP + FL, in 16,6% of the ADTDP + CTF, and in none of the ADTDP- cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from ADTDP- to ADTDP + CTF and ADTDP + FL with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in ADTDP + FL cases.
An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.
Alzheimer's disease (AD) is the leading cause of dementia in elderly people and is characterized by two major neuropathological hallmarks: amyloid β-protein (Aβ)-containing senile plaques and neurofibrillary tangles (NFTs) consisting of abnormal phosphorylated τ protein (p-τ). Besides these proteins, transactive response DNA-binding protein 43 (TDP-43) was also discovered to accumulate in the limbic regions of AD brains, by forming cytoplasmic inclusions [1, 2, 10]. Studies have shown that in AD, TDP-43 is associated with smaller hippocampal volumes and more severe cognitive impairment [7]. Accordingly, patients with abnormal TDP-43 immunoreactivity were shown to have a clinically more severe degree of dementia, compared to those without TDP-43 inclusions [6, 8]. Some studies have shown the co-localization of TDP-43 and p-τ pathology in the AD brain, as well as the presence of TDP-43 in NFTs [3, 12, 13]. Moreover, TDP-43 spreading pattern in the brain reminisces that of p-τ [5]. However, whether these two proteins interact and how they are associated during AD pathogenesis was not yet addressed.Here, we report the association and interaction of TDP-43 with p-τ in human symptomatic and nonsymptomatic AD cases using histochemical and biochemical approaches. We have analyzed 13 nondiseased controls and 10 pathologically-defined pre-clinical AD cases (p-preAD) with TDP-43 pathology, which exhibited AD-related neuropathological changes but lacked AD symptoms during their lifetime. We also included 25 symptomatic AD cases (sympAD) with TDP-43 pathology and used 9 FTLD-TDP cases as positive controls for TDP-43 pathology (Suppl. Tab. 1, online-resource).To investigate the co-occurrence of pTDP-43 and p-τ in the different morphological TDP-43 lesions, we first performed double-label immunofluorescence with anti-phosphorylated TDP-43 (pTDP-43) and anti-p-τ antibodies (Suppl. Tab. 2, online-resource). We observed that sympAD cases displayed dystrophic neurites positive for both proteins (Fig. 1a). As for neuronal cytoplasmic inclusions (NCIs), we observed some inclusions positive for pTDP-43, but negative for p-τ (Fig. 1a). Further, we observed neurofibrillary tangle-like structures positive for pTDP-43 and p-τ (Fig. 1a).We then quantified the severity of pTDP-43 lesions (DNs, NCIs or NFT-like material), as well as p-τ pathology (p-τ-positive NFTs) in our cohort. The severity of pTDP-43 pathology was significantly increased in sympAD and FTLD-TDP cases, when compared to non-AD cases (Fig. 1b, Suppl. Tab. 3, online-resource). Additionally, NFT severity was also significantly increased in sympAD cases compared to non-AD and FTLD-TDP cases (Fig. 1c). p-preAD cases showed a trend towards an increased severity compared to non-AD and FTLD-TDP cases (Suppl. Tab. 4, online-resource).To address whether neurons that present NFTs still contain physiological nuclear TDP-43, we performed co-staining with antibodies against non-phosphorylated N-(N-t, 1-50aa.) or C-terminal (C-t, 260-414aa.) epitopes of TDP-43 and p-τ (Suppl. Tab. 2, onli...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.