Biomarkers.

Area of Science:

• Neurodegenerative diseases
• Neuroimaging
• Neuropathology

Background:

• Alzheimer's disease (AD) often co-occurs with Limbic-predominant Age-related TDP-43 Encephalopathy (LATE).
• Both pathologies affect the medial temporal lobe (MTL), causing similar symptoms and atrophy.
• Differentiating their specific contributions to neurodegeneration is crucial for effective treatment.

Purpose of the Study:

• To investigate the distinct roles of tau and TDP-43 pathologies in MTL substructure atrophy in AD patients.
• To disentangle the neuropathological contributions to neurodegeneration in the medial temporal lobe.

Main Methods:

• Cross-sectional and longitudinal MRI analyses were performed on 85 participants from the ADNI database.
• Participants were categorized by Braak tau stage (Low [0-III] vs. High [IV-VI]) and presence of TDP-43 in the MTL.
• Statistical models adjusted for MRI-death interval, age, sex, and intracranial volume to predict volume changes.

Main Results:

• TDP-43 pathology correlated with hippocampal head volume reduction, while tau NFTs correlated with parahippocampal gyrus thickness reduction.
• TDP-43 was associated with atrophy in anterior MTL structures (except PHC) in low-tau individuals.
• High tau levels were linked to atrophy in posterior MTL structures (hippocampal body, entorhinal cortex, PHC) in TDP-43-negative individuals.

Conclusions:

• TDP-43 pathology predominantly affects anterior MTL volumes, whereas tau pathology affects posterior MTL volumes.
• Hippocampal head atrophy may serve as a biomarker to differentiate AD patients with and without comorbid LATE.
• Understanding these distinct pathological effects is key for targeted therapeutic strategies.