Lipid dysregulation is associated with anxiety symptoms and left frontopolar cortical network alterations in overt hypothyroidism.

PURPOSE: Neuropsychiatric symptoms persist in overt hypothyroidism (OH) despite hormone replacement. This study examined whether cortical morphometric similarity network alterations are associated with lipid dysregulation and neuropsychiatric symptoms in OH.

METHODS

We enrolled 87 treatment-naïve OH patients and 87 matched healthy controls. Cortical morphometric similarity networks were constructed from T1-weighted magnetic resonance imaging (MRI) using Morphometric Inverse Divergence (MIND) across 360 regions. Mediation, spatial transcriptomic, and neurotransmitter mapping analyses were performed.

RESULTS

OH patients exhibited reduced MIND strength in five cortical regions (false discovery rate [FDR]-corrected P < 0.05), most notably the left frontopolar area (L-10 pp; Cohen's d = -0.40), with connectivity disruptions across all seven canonical networks. Bootstrap mediation analyses (5000 resamples) identified L-10 pp as a significant indirect link between lipid markers and mood symptoms: four of five models showed robust indirect effects (95% confidence intervals [CIs] excluding zero), including triglycerides (TG) → L-10 pp → 24-item Hamilton Depression Rating Scale (HAMD-24) (0.086, [0.010, 0.148]) and high-density lipoprotein cholesterol (HDL-C) → L-10 pp → Hamilton Anxiety Rating Scale (HAMA) (-0.081, [-0.148, -0.005]). MIND alterations spatially correlated with serotonergic/monoaminergic systems (spin-test FDR-corrected P < 0.05) and were enriched in endothelial cell (normalized enrichment score [NES] = 2.097, P = 0.001), oligodendrocyte (NES = 1.806, P = 0.003), and microglia (NES = 1.575, P = 0.048) gene expression (all FDR-corrected).

CONCLUSIONS

In OH, lipid dysregulation is associated with mood symptoms, and mediation analysis identifies reduced structural integrity of L-10 pp as a plausible indirect link. The spatial pattern of MIND alterations corresponds to transcriptional profiles enriched in oligodendrocyte and endothelial cell genes.