Atypical Developmental Patterns of Brain Chemistry in Children With Autism Spectrum Disorder

Abstract

IMPORTANCE Autism spectrum disorder (ASD) is a neurodevelopmental disorder with symptoms emerging during early childhood. The pathophysiology underlying the disorder remains incompletely understood. OBJECTIVE To examine cross-sectional and longitudinal patterns of brain chemical concentrations in children with ASD or idiopathic developmental delay (DD) from 3 different age points, beginning early in the clinical course. DESIGN Proton magnetic resonance spectroscopic imaging data were acquired longitudinally for children with ASD or DD, and primarily cross-sectionally for children with typical development (TD), at 3 to 4, 6 to 7, and 9 to 10 years of age. SETTING Recruitment, diagnostic assessments, and magnetic resonance imaging were performed at the University of Washington in Seattle. PARTICIPANTS Seventy-three children (45 with ASD, 14 with DD, and 14 with TD) at 3 to 4 years of age; 69 children (35 with ASD, 14 with DD, and 20 with TD) at 6 to 7 years of age; and 77 children (29 with ASD, 15 with DD, and 33 with TD) at 9 to 10 years of age. MAIN OUTCOMES AND MEASURES Concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), and glutamine plus glutamate (Glx) in cerebral gray matter (GM) and white matter (WM) at 3 to 4, 6 to 7, and 9 to 10 years of age, and calculation of rates of change of these chemicals between 3 and 10 years of age. RESULTS At 3 to 4 years of age, the ASD group exhibited lower NAA, Cho, and Cr concentrations than did the TD group in both GM and WM, alterations that largely were not observed at 9 to 10 years of age. The DD group exhibited reduced GM and WM NAA concentrations at 3 to 4 years of age; GM NAA concentrations remained reduced at 9 to 10 years of age compared with the TD group. There were distinct differences between the ASD and DD groups in the rates of GM NAA, Cho, and Cr changes between 3 and 10 years of age. CONCLUSIONS AND RELEVANCE The GM chemical changes between 3 and 10 years of age differentiated the children with ASD from those with DD. Most notably, a dynamic reversal of GM NAA reductions was observed in the children with ASD. By contrast, persistent GM NAA reductions in the children with DD suggest a different, more static, underlying developmental process.

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations

“…Rojas, 2013); and the cerebellum; striatum and frontal lobe (Hassan et al, 2013). However, other studies have found decreased glutamate/Glx in ASD in regions including the ACC (Bernardi et al, 2011;van Elst, Maier, Fangmeier, & Endres, 2014) the basal ganglia (Horder et al, 2013); frontal and occipital cortex, the cerebellum (Devito et al, 2007) and white matter (Corrigan et al, 2013). Yet other studies have found no significant differences in glutamate / Glx levels between individuals with and without ASD in several different brain regions including parietal lobes (Horder et al, 2013;Page et al, 2006), frontal lobes (Horder et al, 2013) temporal lobes (Devito et al, 2007), and occipital lobes (Robertson, Ratai, & Kanwisher, 2015); the thalamus (Bernardi et al, 2011;Doyle-Thomas et al, 2014;Hardan et al, 2008); hippocampus (Joshi et al, 2012);and cerebellum (van Elst et al, 2014).…”

Basic Principles and Clinical Applications of Magnetic Resonance Spectroscopy in Neuroradiology

“…48 Following up on children with idiopathic developmental delay, NAA remained reduced at the age of 9 to 10 years. 49 In children with congenital heart disease, NAA increased significantly slower during further development within the third trimester compared with controls. 50 There is further discordance in the literature with regard to autism.…”

“…Compared with controls, lower levels of NAA, Cr, and Cho were found. 51,52 In later childhood (at 9-10 years old 49 ) and in adulthood, 53 this was no longer apparent. Other studies found increased values of mI and Cho but no significant differences in NAA compared with controls 54 or even no evidence for brain mitochondrial dysfunction in children with autism 55 ; thus, caution should be exercised in interpreting data concerning agedependent fluctuations in metabolite levels.…”

Creatine as Biomarker

“…Some authors have described reductions of Cr in gray matter, insula, corpus callosum, body of caudate, occipital cortex, and frontal and parietal white matter from subjects of less than 13 years of age (Baruth et al 2013). Another study reported by Corrigan et al (2013) also showed significant Cr decrease in gray as well as in white matter from children with ASDs. Recently, some authors have analyzed the metabolic profile in urine from children with ASDs using two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) and showed a decreased Cr concentration (Mavel et al 2013).…”