Parsing the Heterogeneity of Brain Metabolic Disturbances in Autism Spectrum Disorder

Joseph O'Neill; Ravi Bansal; Suzanne Goh; Martina Rodie; Siddhant Sawardekar; Bradley S Peterson

doi:10.1016/j.biopsych.2019.06.010

Parsing the Heterogeneity of Brain Metabolic Disturbances in Autism Spectrum Disorder

Biol Psychiatry. 2020 Jan 15;87(2):174-184. doi: 10.1016/j.biopsych.2019.06.010. Epub 2019 Jun 21.

Authors

Joseph O'Neill¹, Ravi Bansal², Suzanne Goh³, Martina Rodie⁴, Siddhant Sawardekar², Bradley S Peterson⁵

Affiliations

¹ Division of Child and Adolescent Psychiatry, Jane and Terry Semel Institute for Neuroscience, University of California, Los Angeles, California. Electronic address: joneill@mednet.ucla.edu.
² Institute for the Developing Mind, the Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California.
³ Division of Child Neurology, Rady Children's Hospital, University of California, San Diego, San Diego, California.
⁴ School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, United Kingdom.
⁵ Institute for the Developing Mind, the Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address: bpeterson@chla.usc.edu.

Abstract

Background: Despite rising prevalence of autism spectrum disorder (ASD), its brain bases remain uncertain. Abnormal levels of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, or choline compounds measured by proton magnetic resonance spectroscopy 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. However, most prior magnetic resonance spectroscopy studies had small samples (all <60, most <20), interrogated only a small fraction of the brain, and avoided assessing effects of age, sex, and IQ.

Methods: We acquired near-whole-brain magnetic resonance spectroscopy of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, and choline compounds in 78 children and adults with ASD and 96 typically developing 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 the perisylvian cortex and elevated levels in the 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 versus TD. Male-female metabolite differences were widely smaller in ASD than typically developing children and adults. 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.

Keywords: Age; Autism; Intelligence; Magnetic resonance spectroscopy; Sex; Symptom domains.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Autism Spectrum Disorder*
Brain / diagnostic imaging
Child
Choline
Female
Humans
Magnetic Resonance Imaging
Magnetic Resonance Spectroscopy
Male

Substances

Choline

Grants and funding

R01 MH089582/MH/NIMH NIH HHS/United States