Mean apparent propagator MRI of distributed brain microstructure in anxiety-related heterogeneity among children with autism spectrum disorder: associations with thyroid hormones and trace elements

Abstract

Anxiety-related symptoms contribute substantially to clinical variability in autism spectrum disorder (ASD), but the extent to which peripheral endocrine and trace-element measures map onto brain microstructure remains insufficiently defined. We investigated whether thyroid-related indices and trace elements correspond to mean apparent propagator (MAP)-MRI features that distinguish children with ASD who have elevated anxiety symptoms. We included 460 children: 140 with ASD and elevated anxiety symptoms, 160 with ASD without elevated anxiety symptoms, and 160 typically developing controls. Serum triiodothyronine (FT3), total thyroxine (TT4), thyroid-stimulating hormone (TSH), iron, blood lead, and magnesium were assayed, and eight MAP-MRI metrics were summarized across 68 brain regions. Analyses included group comparisons, prespecified multiplicity corrected Pearson correlations, and exploratory cross-sectional statistical association decomposition models. Relative to children with ASD without elevated anxiety symptoms and to typically developing controls, the ASD-ANX subgroup had higher FT3, TT4, and blood lead levels, lower serum iron, and distributed MAP-MRI differences, with the largest and most consistent non-Gaussian diffusion effects in the amygdala, hippocampus, insula, rostral anterior cingulate cortex, putamen, and globus pallidus. Within ASD-ANX, iron was positively associated with MAP-MRI metrics, whereas blood lead and thyroid hormones showed inverse associations, most prominently in the amygdala and hippocampus. Cross-sectional models decomposed these observed associations into direct and FT3-related indirect components. An independent, small exploratory BTBR component showed reduced amygdala fibre area and disrupted fibre organization in mice with anxiety-like behavior. Children with ASD and elevated anxiety symptoms show an association profile involving peripheral thyroid measures, trace elements, and distributed MAP-MRI abnormalities with prominent limbic and striatal involvement. These cross-sectional findings characterize anxiety-related heterogeneity within ASD but do not establish temporal or causal relations among the biochemical and imaging measures.