Biomarkers.

Area of Science:

• Neuroscience
• Biomarkers
• Neuroimaging

Background:

• Medial temporal lobe (MTL) atrophy on MRI is a sensitive but non-specific biomarker for Alzheimer's disease (AD)-linked neurodegeneration.
• Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a common co-pathology challenging to distinguish from AD using current biomarkers.
• Both AD and LATE involve hippocampal and entorhinal cortex atrophy, with potential differences in severity and spatial patterns.

Purpose of the Study:

• To investigate the relationship between MRI morphometric measures of atrophy in AD and LATE.
• To correlate MRI findings with direct postmortem measures of neurodegeneration, including neuron number, size, and density.

Main Methods:

• Utilized 9.4T postmortem MRI and thionin-stained histology from 24 brain donors (AD-LATE-, AD+LATE-, AD+LATE+).
• Employed deep learning (StarDist) and Gaussian mixture modeling for automated neuron and glia detection in hippocampus (CA1) and entorhinal cortex (ERC).
• Validated automated neuronal density estimates against stereology and compared neuronal measures with MTL volume and thickness from MRI.

Main Results:

• Automated neuronal density estimates showed good agreement with stereology (r=0.72).
• Higher neuron number and size in CA1 and ERC correlated with less atrophy, consistent with neuronal loss in advanced AD and LATE.
• Increased CA1 neuronal/glial density and ERC glial density in regions with greater atrophy suggest tighter packing and significant neuropil loss contributing to MRI atrophy measures.

Conclusions:

• Initial feasibility results support applying this pipeline to larger datasets for studying tau pathology and neuronal loss.
• The study aims to better differentiate atrophy linked to LATE and AD using paired postmortem MRI and histology.
• Findings encourage further research into refining MRI-based biomarkers for distinguishing AD and LATE pathologies.