Locus Coeruleus Microstructure and Connectivity as Novel Markers of Depression and Cognitive Dysfunction in Older Adults

Biol Psychiatry Cogn Neurosci Neuroimaging. 2025 Oct 17:S2451-9022(25)00308-8. doi: 10.1016/j.bpsc.2025.10.007. Online ahead of print.

ABSTRACT

BACKGROUND: Late-life depression (LLD) is a risk factor for age-related cognitive decline. Postmortem studies highlight pathological changes in the locus coeruleus (LC) and its projections as potential early cognitive vulnerability markers. Here, we use a novel individualized multimodal magnetic resonance imaging (MRI) approach to characterize the cognitive correlates of LC microstructure and connectivity in participants with LLD and age-matched never-depressed (ND) controls.

METHODS: Diffusion-weighted and LC-sensitive MRI were acquired in 52 participants (LLD: n=26, 19 females, age 67.8+/-5.48; ND: n=26, 12 females, age 69.8+/-7.62). Using LC-sensitive MRI to localize the LC in each participant’s native space, we computed diffusion metrics (fractional anisotropy, FA; mean diffusivity, MD) for the LC and its projections to the hippocampus (Hp), reconstructed with constrained spherical deconvolution tractography. Associations of FA and MD with diagnosis and cognitive performance were evaluated with analyses of covariance and Pearson correlations, respectively, adjusted for demographic/disease covariates and multiple testing (p-Bonferroni<0.05).

RESULTS: Higher MD (F=10.07, p=0.003) was observed in the LC of individuals with LLD relative to ND. Conversely, no group differences emerged in the LC-Hp pathway. Across the combined LLD-ND sample, accounting for LLD diagnosis, lower FA in the LC and its hippocampal projections were associated with worse processing speed (LC: r_Word-Reading=-0.47; LC-MTL: r_Word-Reading=-0.46, r_Color-Naming=-0.49; all p≤0.0007) and executive functions (LC-MTL: r_Inhibition=-0.50, r_{Inhibition/Switching}=-0.45, r_{Number/Letter-Sequencing}=-0.40; all p≤0.0033).

CONCLUSIONS: Neuronal injury of the LC may be a marker of LLD. Alternatively, the microstructural status of LC-Hp projections might be a biomarker more specific to age-related cognitive deterioration, irrespective of depression diagnosis.

PMID:41110552 | DOI:10.1016/j.bpsc.2025.10.007