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AlzheimersDementia-2025-Salman-SpecificatrophypatternsdistinguishtauandTDP43pathologyalongitudinalMRI.pdf
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Abstract
Background Alzheimer's disease (AD) cases often present with TDP-43 inclusions at autopsy, suggesting comorbid Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). These patients show smaller hippocampal volume and more severe cognitive decline than ‘pure’ AD patients. Distinguishing the contributions of both pathologies to neurodegeneration is crucial for treatment development; but is challenging as both pathologies affect the medial temporal lobe (MTL), share similar clinical symptoms and there is no in-vivo biomarker for TDP-43. We aimed to disentangle the relative contribution of tau and TDP-43 pathologies to the atrophy of MTL substructures in AD patients. Methods We conduced antemortem cross-sectional and longitudinal MRI analyses in participants with neuropathological data obtained at post-mortem. Participants were selected from the ADNI database (N = 85) and grouped according to Braak stages (Low tau [0-III] or High Tau [IV-VI]) and the presence of TDP-43 in the MTL. Statistical analyses included cross-sectional correlations, group analyses, and liner-mixed models predicting volume changes before death. All models were adjusted for MRI-death-interval, age, sex and intracranial-volume. Results TDP-43 was mostly associated with the volume of the hippocampal head (R = -0.47; P < 0.01, Figure 1) while NFTs were associated with the thickness of the parahippocampal gryrus (PHG; R = -0.41; P < 0.01, Figure 1). Consistently, among individuals with low levels of tau, TDP-43-positivity was associated with atrophy in all MTL structures except the parahippocampal cortex (PHC, Figure 2). In contrast, in TDP-43-negative individuals, high tau was associated with atrophy in the hippocampal body (β = -137mm3, P < 0.05), entorhinal cortex (β = -0.49mm, P < 0.01) and PHC (β = -0.28mm, P < 0.01, Figure 2). Longitudinal analysis showed that the hippocampal head volume reduction over time was faster in the presence of TDP-43 in the MTL (β = -6.71mm3/year, P < 0.001, Figure 3) while the PHG thickness reduction over time was faster with higher Braak stages (β = -0.02mm/year, P < 0.05, Figure 3). Conclusion We observed an anterior-posterior effect of TDP-43 and tau on the MTL with TDP-43 affecting anterior MTL volumes and tau posterior MTL volumes. Hippocampal head atrophy could help distinguish between AD patients with/without comorbid LATE.
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Salman, Y., Goloubeva, J., Huyghe, L., Quenon, L., Tomé, S. O., & Hanseeuw, B. (2025). Specific atrophy patterns distinguish tau and TDP‐43 pathology: a longitudinal MRI ante‐mortem study. Alzheimer’s & Dementia, 21(S2), 1-5. https://doi.org/10.1002/alz70856_098328 (Original work published 2025)