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Symmetric Bihemispheric Postmortem Brain Cutting to Study Healthy and Pathological Brain Conditions in Humans
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Locus coeruleus TDP-43 pathology in a community-based cohort: Clinical and pathological correlates
Allison M Neltner1, Ryan K Shahidehpour1, Megan E Hall1,2
1Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States.
Journal of Neuropathology and Experimental Neurology
|April 20, 2026
Summary
Phosphorylated TDP-43 (pTDP-43) pathology in the locus coeruleus (LC) is common in aging brains and linked to limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). This LC pTDP-43 was associated with depressive symptoms.
Area of Science:
- Neuroscience
- Neuropathology
- Aging Research
Background:
- The locus coeruleus (LC) is a key brain region for norepinephrine production.
- LC dysfunction is implicated in cognitive impairment and dementia-related symptoms.
- Phosphorylated TDP-43 (pTDP-43) pathology in the LC remains understudied, especially concerning aging and LATE-NC.
Purpose of the Study:
- To investigate the prevalence and characteristics of pTDP-43 and pTau pathologies in the LC.
- To examine the association of LC pTDP-43 with aging, LATE-NC, and clinical symptoms.
Main Methods:
- Analysis of post-mortem brain samples (n=134) from the University of Kentucky ADRC cohort.
- Assessment of locus coeruleus pTDP-43 and pTau pathologies.
- Correlation with neuropathologic changes (LATE-NC, ADNC, PART) and clinical data (cognition, BPSD, depression).
Main Results:
- LC pTDP-43 pathology was present in 20.9% of brains, often sparse and granular.
- LC pTDP-43 increased with aging and showed an imperfect correlation with LATE-NC staging.
- LC pTDP-43 was associated with depressive symptoms but not global cognition or other BPSDs.
- LC pTau pathology correlated with cortical pTau severity and LATE-NC stages.
Conclusions:
- LC pTDP-43 pathology is a frequent finding in brain aging.
- LC pTDP-43 is associated with LATE-NC, suggesting a role in this neurodegenerative process.
- The findings highlight the clinical relevance of LC pTDP-43, particularly concerning mood symptoms.
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