Association Between Postmortem Pathologic Burden and the Rate of Clinical Progression in Patients With Frontotemporal...

Area of Science:

• Neuroscience
• Pathology
• Biomarker Development

Background:

• Histopathologic staging is crucial for validating Alzheimer disease imaging.
• Previous work established preliminary TDP-43 and tau progression phases.
• This study expands on prior research using digital pathology and clinical data.

Purpose of the Study:

• To model the relationship between clinical progression and postmortem frontotemporal lobar degeneration (FTLD) pathology.
• To comprehensively analyze TDP-43 and tau distribution and severity in FTLD.
• To investigate the association between pathologic metrics and clinical decline.

Main Methods:

• Retrospective cohort study of 101 FTLD patients (FTLD-Tau or FTLD-TDP).
• Quantification of primary pathology burden in up to 6 cortical regions.
• Construction of FTLD-TDP pathologic phase using published criteria.
• Association testing between pathology metrics and disease duration/clinical progression (CDR-SB, MMSE).

Main Results:

• Disease duration did not correlate with pathologic burden for either FTLD-TDP or FTLD-Tau.
• TDP-43 burden, but not FTLD-Tau burden, associated with worse CDR-SB and MMSE scores.
• TDP-43 phase also correlated with poorer clinical outcomes (CDR-SB, MMSE).
• TDP-43 burden, but not phase, associated with relative decline in bvFTD sensitivity analyses.

Conclusions:

• Increased TDP-43 burden is closely linked to antemortem clinical decline.
• Temporal dynamics of protein aggregation may differ between FTLD-Tau and FTLD-TDP.
• Findings have implications for interpreting FTLD-specific biomarkers.