Parsing the Heterogeneity of Brain Metabolic Disturbances in Autistic Spectrum Disorder

Abstract Background Despite rising prevalence of autistic spectrum disorder (ASD) its brain bases remain uncertain. Abnormal levels of N-acetyl-compounds (NAA), glutamate+glutamine (Glx), creatine+phosphocreatine (Cr), or choline-compounds (Cho) measured by proton magnetic resonance spectroscopy (MRS) suggest that neuron or glial density, mitochondrial energetic metabolism, and/or inflammation contribute to ASD neuropathology. The neuroanatomic distribution of these metabolites could help evaluate leading theories of ASD. But most prior MRS studies had small samples (all n Methods We acquired near-whole-brain MRS of NAA, Glx, Cr, and Cho in 78 ASD and 96 typically developing (TD) children and adults, rigorously evaluating effects of diagnosis and severity on metabolites, as moderated by age, sex, and IQ. Results Effects of ASD and its severity included reduced levels of multiple metabolites in white matter and perisylvian cortex and elevated levels in posterior cingulate, consistent with white-matter and social-brain theories of ASD. Regionally, both slower and faster decreases of metabolites with age were observed in ASD vs. TD. Male-female metabolite differences were widely smaller in ASD than TD. ASD-specific decreases in metabolites with decreasing IQ occurred in several brain areas. Conclusions Results support multifocal abnormal neuron or glial density, mitochondrial energetics, or neuroinflammation in ASD, alongside widespread starkly atypical moderating effects of age, sex, and IQ. These findings help parse the neurometabolic signature for ASD by phenotypic heterogeneity.