Distinguishing the contribution of Tau and TDP-43 to MTL atrophy

The medial temporal lobe (MTL) is a crucial site for neuropathologies including tau, transactive response DNA-binding protein 43 (TDP-43), amyloid-β, and α-synuclein. Determining their specific impacts on MTL atrophy is essential for developing biomarkers to distinguish these pathologies. Specifically, the amygdalo-hippocampal complex can be divided into different substructures hypothesized to be differentially affected by neuropathologies. Our aim is to study their specific contribution to amygdalo-hippocampal complex atrophy. 63 patients with antemortem MRI and detailed neuropathology report were selected in the ADNI. MRIs were processed in FreeSurfer 7.2 to extract volumes of the hippocampus and subfields and the amygdala and subnuclei. Proteinopathies were assessed semi-quantitatively in CA1, dentate gyrus (DG), amygdala, entorhinal and parahippocampal cortices and aggregated into a composite score We analyzed the association between protein deposits and structure volumes, performing partial correlations to study independent contributions. Subjects were grouped based on tau and TDP levels, to study differences in volumes. All analyses were adjusted for intracranial volume, age, sex, apoE and MRI-death interval. Neocortical tau was the only predictor of global gray matter atrophy (R= -0.23, p=0.08). TDP-43 pathology was the only predictor of amygdala volume (R= -0.41, Fig.1A)), and all amygdala subnuclei but the medial and cortical nuclei. Tau pathology was associated with hippocampal atrophy (partial R= -0.38, Fig.1B), although TDP-43 was a stronger predictor (partial R=-0.50, p<0.001). Among hippocampal subfields, only the subiculum was still associated with tau pathology when the level of TDP43 pathology was adjusted for (partial R= -0.34, p=0.01). Despite no significant interaction, different effects on MTL substructures were observed, with DG, CA1, molecular layer, and the lateral and paralaminar nuclei atrophied only with TDP43 (Fig.2A) and central, cortical, and medial nuclei only with tau (Fig.2B). Accessory basal nucleus and CA4 were atrophied only when both proteins were present (Fig.2C), while subiculum and presubiculum were atrophied with both (Fig.2D). These results suggest that TDP43 is the major contributor of MTL atrophy, although tau is also involved. DG, CA1 and molecular layer seem to be specific for TDP43 whereas central, cortical, and medial nuclei seem to be specific for tau, echoing our previous results.

Affiliations

UCLouvainSSS/IONS/NEUR - Clinical Neuroscience

Citations

APA
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Salman, Y., Goloubeva, J., Hanseeuw, B., & et al. (2024). Distinguishing the contribution of Tau and TDP-43 to MTL atrophy. EUropean Meeting on Imaging of Neurodegenerative Diseases (EU-MIND 2024), Caen, France. https://hdl.handle.net/2078.5/242134