Locus coeruleus TDP-43 pathology in a community-based cohort: Clinical and pathological correlates

The locus coeruleus (LC) is the source of norepinephrinergic innervation in the human brain. Locus coeruleus pathology has been linked to clinical conditions such as cognitive impairment and behavioral and psychiatric symptoms of dementia (BPSD). However, phosphorylated TDP-43 (pTDP-43) pathology in the LC has been understudied, particularly in the contexts of aging and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Here, a convenience sample (n = 134) of autopsied participants from the University of Kentucky Alzheimer's Disease Research Center community-based cohort was analyzed for LC pTDP-43 and phosphorylated tau (pTau) pathologies. Locus coeruleus pTDP-43 pathology was found in 28/134 (20.9%) brains and was generally sparse when present. Locus coeruleus pTDP-43 lesions typically appeared as round granular structures that measured ∼3-12 µm in diameter. Locus coeruleus pTDP-43 pathology was increased with aging and was imperfectly correlated with LATE-NC staging; it showed no correlation with cortical pTau pathology in ADNC or PART. In terms of clinical-pathological correlations, LC pTDP-43 pathology was associated with depressive symptoms but not with global cognition or with other BPSDs. Locus coeruleus pTau pathology was positively correlated with cortical pTau pathologic severity and with LATE-NC stages. In conclusion, LC pTDP-43 pathology is a common feature of brain aging, associated with LATE-NC.