Locus Coeruleus TDP-43 Pathology in Aging Cohort

Key Takeaways

• LC pTDP-43 appeared in about one-fifth of brains and was generally sparse when detected.
• Prevalence increased with age and higher LATE-NC stage, but alignment was incomplete and did not mirror cortical pTau burden in ADNC or PART.
• Lesion counts were linked to depressive symptoms, whereas global cognition and other BPSD were not, and the findings were not viewed as a strong staging signal.

When present, lesions most often appeared as small round granular structures measuring about 3 to 12 µm. Prevalence rose with advancing age and tended to accompany higher LATE-NC stages in older brains. That distribution only partly matched established aging-related TDP-43 staging across the cohort.

Investigators analyzed a community-based convenience sample of 134 autopsied participants from the University of Kentucky Alzheimer’s Disease Research Center cohort, drawn from 145 sampled autopsies and preferentially including some LATE-NC stage 3 and CERAD neuritic plaque score "none" cases. Participants entered the study after age 60 and underwent annual follow-up until death over a mean 10.1 years. The average age at death was 86.1 years, the last visit-to-autopsy interval averaged 1.7 years, and 10 individuals were excluded for limited LC tissue, with 1 additional LATE-NC stage 3 case excluded for insufficient metadata. The analysis compared LC pTDP-43 with age, LATE-NC, tau-related pathology, and clinical measures overall.

LC pTDP-43 burden was low overall, with round granular lesions predominating among detectable pathologic forms. Of the 28 positive cases, 17 showed only round-granular pathology on routine microscopic review. Other morphologies included neuronal cytoplasmic inclusions and dystrophic neurites, and manual counting with neuropathologist review was used because sparsity and neuromelanin complicated automation. A subset of higher-burden cases also underwent immunofluorescence for pTDP-43, DAPI, and GFAP, supporting a limited rather than diffuse lesion pattern.

In LC pTDP-43 clinicopathologic analyses, age at death was associated with pathology presence, with an odds ratio of 1.1 and a 95% CI of 1.0 to 1.2. That association reached P=.025. LATE-NC stage greater than 1 showed a stronger association, with an odds ratio of 8.5, a 95% CI of 3.0 to 24.3, and P<.001. The relationship with LATE-NC was imperfect, however, and pathology did not significantly track sex, Braak NFT stage greater than 4, or cortical pTau in ADNC or PART. By comparison, LC pTau followed cortical pTau severity more closely in ADNC and was positively correlated with LATE-NC stages in this cohort.

Among the 124 participants with replete behavioral data, LC pTDP-43 lesion count was positively associated with depressive symptoms, with a relative risk of 2.4. The 95% CI was 1.1 to 5.1, and that association reached P=.028. LC pTDP-43 was not associated with global cognition, and presence alone was not associated with other behavioral and psychiatric symptoms of dementia. The authors said the findings did not provide compelling evidence for incorporating LC pTDP-43 into neuropathology-based staging or classification for aging-related TDP-43 proteinopathy or LATE-NC.