Article ; Online: TDP-43 and tau concurrence in the entorhinal subfields in primary age-related tauopathy and preclinical Alzheimer's disease.
Brain pathology (Zurich, Switzerland)
2023 Volume 33, Issue 4, Page(s) e13159
Abstract: Phosphorylated tau (p-tau) pathology correlates strongly with cognitive decline and is a pathological hallmark of Alzheimer's Disease (AD). In recent years, phosphorylated transactive response DNA-binding protein (pTDP-43) has emerged as a common ... ...
| Abstract | Phosphorylated tau (p-tau) pathology correlates strongly with cognitive decline and is a pathological hallmark of Alzheimer's Disease (AD). In recent years, phosphorylated transactive response DNA-binding protein (pTDP-43) has emerged as a common comorbidity, found in up to 70% of all AD cases (Josephs et al., Acta Neuropathol, 131(4), 571-585; Josephs, Whitwell, et al., Acta Neuropathol, 127(6), 811-824). Current staging schemes for pTDP-43 in AD and primary age-related tauopathy (PART) track its progression throughout the brain, but the distribution of pTDP-43 within the entorhinal cortex (EC) at the earliest stages has not been studied. Moreover, the exact nature of p-tau and pTDP-43 co-localization is debated. We investigated the selective vulnerability of the entorhinal subfields to phosphorylated pTDP-43 pathology in preclinical AD and PART postmortem tissue. Within the EC, posterior-lateral subfields showed the highest semi-quantitative pTDP-43 density scores, while the anterior-medial subfields had the lowest. On the rostrocaudal axis, pTDP-43 scores were higher posteriorly than anteriorly (p < 0.010), peaking at the posterior-most level (p < 0.050). Further, we showed the relationship between pTDP-43 and p-tau in these regions at pathology-positive but clinically silent stages. P-tau and pTDP-43 presented a similar pattern of affected subregions (p < 0.0001) but differed in density magnitude (p < 0.0001). P-tau burden was consistently higher than pTDP-43 at every anterior-posterior level and in most EC subfields. These findings highlight pTDP-43 burden heterogeneity within the EC and the posterior-lateral subfields as the most vulnerable regions within stage II of the current pTDP-43 staging schemes for AD and PART. The EC is a point of convergence for p-tau and pTDP-43 and identifying its most vulnerable neuronal populations will prove key for early diagnosis and disease intervention. |
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| MeSH term(s) | Humans ; Alzheimer Disease/pathology ; Tauopathies/pathology ; tau Proteins/metabolism ; DNA-Binding Proteins/metabolism ; Entorhinal Cortex/metabolism ; Brain/pathology |
| Chemical Substances | tau Proteins ; DNA-Binding Proteins |
| Language | English |
| Publishing date | 2023-04-10 |
| Publishing country | Switzerland |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 1051484-3 |
| ISSN | 1750-3639 ; 1015-6305 |
| ISSN (online) | 1750-3639 |
| ISSN | 1015-6305 |
| DOI | 10.1111/bpa.13159 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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