Lipid dysregulation is associated with anxiety symptoms and left frontopolar cortical network alterations in overt
Jiancang Cao1, Quan Zou2, Xingqi Liu2
1Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, China; Department of Radiology, Gansu Provincial Hospital, Lanzhou, Gansu 730000, China.
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.
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