Alzheimer's Imaging Consortium | JoVE Visualize

Area of Science:

Neuroscience
Neuropathology
Radiology

Background:

Alzheimer's disease (AD) often co-occurs with Limbic-predominant Age-related TDP-43 Encephalopathy (LATE), characterized by TDP-43 inclusions.
Patients with comorbid AD and LATE exhibit greater hippocampal atrophy and cognitive decline than those with pure AD.
Differentiating the neurodegenerative contributions of tau and TDP-43 pathologies in the medial temporal lobe (MTL) is crucial for developing effective treatments but is challenging due to overlapping symptoms and lack of in-vivo TDP-43 biomarkers.

Purpose of the Study:

To investigate and differentiate the distinct contributions of tau and TDP-43 pathologies to the atrophy of specific MTL substructures in AD patients.
To determine the spatial distribution of TDP-43 and tau pathologies within the MTL using MRI.
To assess the longitudinal impact of these pathologies on brain volume changes.

Main Methods:

Cross-sectional and longitudinal MRI analyses were performed on 85 participants from the ADNI database with post-mortem neuropathological data.
Participants were categorized based on Braak tau stages (Low [0-III] vs. High [IV-VI]) and the presence or absence of TDP-43 in the MTL.
Statistical models, including correlations and linear mixed-effects models, were used to analyze the association between pathologies and MTL volumes, adjusting for relevant covariates.

Main Results:

TDP-43 pathology was significantly associated with hippocampal head volume reduction (R = -0.47, P < 0.01).
Neurofibrillary tangles (NFTs) were associated with reduced parahippocampal gyrus (PHG) thickness (R = -0.41, P < 0.01).
Longitudinal analysis revealed faster hippocampal head volume loss in the presence of TDP-43 (β = -6.71 mm³/year, P < 0.001) and faster PHG thinning with higher tau burden (β = -0.02 mm/year, P < 0.05).

Conclusions:

TDP-43 pathology primarily affects anterior MTL structures, particularly the hippocampal head, while tau pathology predominantly impacts posterior MTL regions like the PHG.
Hippocampal head atrophy serves as a potential imaging biomarker to distinguish AD patients with comorbid LATE.
Understanding the distinct regional effects of these pathologies is vital for targeted therapeutic strategies in neurodegenerative diseases.