Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions

Area of Science:

• Neuroscience
• Neuropathology
• Radiology

Background:

• The medial temporal lobe (MTL) is crucial for memory and frequently affected by neurodegenerative diseases.
• Studying polypathology within the MTL is vital for understanding complex neurodegeneration.
• High-resolution post-mortem MRI offers a unique window into MTL subregional changes.

Purpose of the Study:

• To investigate the associations between key neurodegenerative pathologies (tau, TDP-43, amyloid-β, α-synuclein) and the thickness of MTL subregions.
• To determine if specific proteinopathies correlate with atrophy in distinct MTL areas.
• To explore the role of tau pathology in early-stage neurodegeneration, particularly in the absence of other pathologies.

Main Methods:

• Utilized high-resolution post-mortem MRI scans of excised MTL specimens from 58 individuals.
• Quantified thickness of MTL subregions including the entorhinal cortex (ERC), hippocampus, and related areas.
• Assessed the severity of tau, TDP-43, amyloid-β, and α-synuclein pathologies using a standardized scale (0-3).
• Employed Spearman's rank correlations, correcting for age, sex, and hemisphere, to analyze associations between pathologies and thickness.

Main Results:

• Found significant negative correlations between TAR DNA-binding protein 43 (TDP-43) pathology and thickness across all measured MTL subregions.
• Identified significant associations between tau pathology and the thickness of Brodmann Area 35 (BA35) and stratum radiatum lacunosum moleculare (SRLM).
• In cases negative for amyloid-β and TDP-43, tau pathology showed strong negative associations with thickness in the ERC, BA35, subiculum, and cornu ammonis (CA)1.

Conclusions:

• TDP-43 pathology is linked to widespread atrophy in the medial temporal lobe.
• Tau pathology is associated with atrophy in regions typically affected early in Braak staging.
• The strong link between tau and thickness in early Braak regions, independent of amyloid-β, highlights the potential role of Primary Age-Related Tauopathy in neurodegeneration.