Neuroimaging biomarkers in school‐aged children with autism: MRI ‐measured lipid content in the limbic system

Background Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Alterations in brain lipids may elucidate ASD's neurophysiological mechanisms, but evidence remains limited. This study aims to assess whether the MRI‐measured lipid content in limbic brain regions could serve as novel biomarkers for neurophysiological changes in school‐aged children with ASD. Methods This prospective study included 98 school‐aged (7–16 years) children with ASD and 94 age‐ and gender‐matched typically developing (TD) children, an age window selected based on established milestones of structural brain maturation. Lipid content in limbic regions was quantified via MRI‐based proton density fat fraction (PDFF). Between‐group differences, blood lipid correlations, and clinical scale associations were analyzed. In vitro validation and histopathology in ASD mice confirmed lipid quantification accuracy and deposits. Receiver operating characteristic (ROC) analyses evaluated diagnostic utility. Results Children with ASD exhibited significantly elevated MRI‐measured lipid content in the bilateral fusiform gyrus (FUS) ( p fdr < .01), with positive correlations observed between lipid content and total cholesterol (left hemisphere: r = .38, p < .01; right hemisphere r = .46, p < .01). Histopathological examination of BTBR mice brain sections stained with ammonium ferric sulfate revealed significant cholesterol deposits. Additionally, reduced lipid content in the bilateral caudal anterior cingulate cortex (cACC) (left hemisphere: p fdr < .01, right hemisphere: p fdr < .01) was found in children with ASD, and the lipid content of the right cACC was negatively correlated with impairments in social communication ( r = −.32, p fdr = .04). Results of ROC analyses demonstrated that multimodal integration of bilateral FUS and cACC lipid contents yielded the highest AUC (0.89, 95% CI: 0.84–0.94). Conclusions Alterations in the FUS and cACC underscore their roles in ASD neuropathology. These findings suggest that MRI‐measured lipid levels of specific regions from the brain limbic system could serve as a biomarker for neurophysiological changes in school‐aged children with ASD.