White-matter microstructural alterations and cross-sectional thyroid hormone-cognition associations in hypothyroidism

Abstract Purpose Hypothyroidism is associated with cognitive and emotional dysfunction, which may be accompanied by alterations in white-matter (WM) microstructure. However, few studies have compared diffusion tensor imaging (DTI) measures and clinical correlates across overt hypothyroidism (OH), subclinical hypothyroidism (SCH), and healthy controls (HCs). We investigated DTI-derived WM microstructural measures and their associations with thyroid function and neuropsychiatric performance in adult-onset hypothyroidism. Methods We enrolled 44 patients with OH, 41 with SCH, and 53 HCs. Thyroid function, neuropsychiatric assessments, and DTI data were collected. Age, sex, and years of education were entered simultaneously as covariates in all inferential group-comparison models, exploratory two-sided partial Spearman correlations, and exploratory cross-sectional indirect-effect models, except when these covariates themselves were the descriptive variables compared. Results Both OH and SCH groups had lower Montreal Cognitive Assessment (MoCA) scores and higher depression scores than HCs. Compared with SCH and HCs, the OH group showed more extensive between-group differences in DTI-derived metrics; no SCH-HC differences survived family-wise error correction. Within the OH group, DTI measures showed nominal, covariate-adjusted exploratory associations with thyroid hormone concentrations and neuropsychiatric scores. Exploratory covariate-adjusted models identified indirect associations of total triiodothyronine (TT3) and total thyroxine (TT4) with MoCA through fractional anisotropy (FA) of the left posterior thalamic radiation (PTR). The corresponding total and direct associations were not statistically significant. Conclusions In this cohort, OH was associated with more extensive differences in DTI-derived WM measures than SCH. The exploratory indirect associations through left PTR FA do not establish a temporal or causal pathway.