Polypathologic Associations with Gray Matter Atrophy in Neurodegenerative Disease

Area of Science:

• Neuroscience
• Neuropathology
• Radiology

Background:

• Mixed pathologies are common in neurodegenerative diseases.
• Antemortem imaging often fails to capture co-pathologic effects on brain atrophy due to a lack of validated biomarkers for non-Alzheimer's pathologies.

Purpose of the Study:

• To assess polypathologic associations with brain atrophy using antemortem MRI and postmortem histopathology.
• To develop and validate a model that accounts for multiple proteinopathies in predicting brain atrophy.

Main Methods:

• Utilized a dataset of 125 dementia patients with T1-weighted MRI and postmortem histopathology.
• Employed linear mixed-effects models to relate regional volumes to ratings of amyloid, tau, TDP-43, and alpha-synuclein.
• Contrasted a polypathologic model with primary diagnosis and protein-agnostic models, evaluating fits with log-likelihood and correlation analyses.

Main Results:

• The polypathologic model demonstrated superior fits in both training and testing datasets.
• Tau, TDP-43, and alpha-synuclein burden were inversely associated with regional brain volumes, while amyloid was not.
• Gliosis and neuronal loss explained residual variance and mediated the effects of tau, TDP-43, and alpha-synuclein on atrophy.

Conclusions:

• Regional brain atrophy reflects primary molecular pathology and co-occurring proteinopathies.
• Inflammatory responses, such as gliosis, may independently contribute to neurodegeneration.
• Antemortem biomarkers are essential for detecting mixed pathologies in neurodegenerative diseases.