Parsing the Heterogeneity of Brain Metabolic Disturbances in Autistic Spectrum Disorder

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 < 60, most n < 20), interrogated only a small fraction of brain, and avoided assessing effects of age, sex, and IQ. 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. the heterogeneity of ASD (in symptoms, age, sex, IQ,…) To address this heterogeneity, the present study examined a large, well-characterized sample of ASD and typically developing (TD) children and adults that permitted assessment of between-group differences and modifying effects of age, sex, IQ, and ASD symptoms on MRS metabolites using state-of-the-art acquisition and analysis with multiplanar chemical shift imaging (MPCSI). Unlike single-voxel MRS, MPCSI does not readily permit use of short echo-time (TE) and water-referenced quantitation, but it does enable simultaneous wide sampling of brain regions implicated in ASD at high spatial-resolution (~1 cc) in tolerable scantimes. samples using a model that age. the higher incidence of ASD in males than females, we compared metabolites between the ASD and TD groups using male participants only and a model that included age. Effects of FSIQ on metabolites were assessed in the combined sample using a model that included age, sex, diagnosis, and a FSIQ-by-diagnosis interaction. The interaction identified where in the brain group differences varied with FSIQ. In follow-up, we assessed effects of FSIQ on metabolites in ASD alone and TD alone using a model that included age and sex. Moreover, current use of any psychotropic medication (binary yes/no) was added to the model for all analyses that included ASD participants. All such analyses were repeated excluding ASD participants taking medication (for findings, see Supplemental Results). Findings are reported only for cases that were significant both when covarying for medication and when excluding medicated participants.