Linking Brain Morphometry to Psychometric Measures and Energy-Metabolic Biomarkers in Adults With Autism Spectrum...

Autism spectrum disorder (ASD) is associated with differences in neurodevelopment and altered metabolism, yet the interplay between brain morphometry, mitochondrial and energy metabolism biomarkers, and autistic traits in adults remains poorly understood. This study investigates the link between brain structure, psychometric measures, and both central and peripheral metabolic biomarkers in adults with ASD. We studied 145 adults, including 74 with ASD and 71 control participants (CON) using high-resolution 3-Tesla MRI to assess cortical thickness, subcortical and global brain volumes. Central energy metabolism was indexed by the posterior-cingulate lactate + threonine (Lac⁺) peak quantified with proton-MRS. We examined associations between biomarkers of mitochondrial function and energy metabolism (including lactate, pyruvate, creatine kinase, and multiple acylcarnitines). Psychometric evaluations included measures of ASD and attention-deficit/hyperactivity disorder (ADHD) symptom severity, as well as other psychiatric comorbidities. Between-group differences and correlations were assessed using robust statistics, controlling for age, sex, image quality, and total intracranial volume. Adults with ASD showed significantly larger bilateral caudate volumes compared to CON. Within the ASD group, higher ADHD symptom severity in childhood correlated with reduced cortical thickness in multiple frontal and temporal regions. Among metabolic markers, acylcarnitine C5:1 was positively associated with right insular cortex thickness, while C18:1-OH and C18:2 levels correlated positively with caudate volume. Caudate nucleus volume is associated not only with an ASD diagnosis but also with specific peripheral energy-metabolism blood markers, such as specific acylcarnitines. Alterations in cortical thickness were also correlated with acylcarnitine levels and, to a greater extent, with co-occurring ADHD symptoms. While alterations in cortical thickness and basal ganglia structure have been previously described in ASD and comorbid ADHD, the linkage between mitochondrial and energy metabolism biomarkers with neuroanatomical alterations in ASD is, to our knowledge, a novel observation that warrants further investigation.