Abstract
Abnormal trajectory of brain development has been suggested by previous structural magnetic resonance imaging and head circumference findings in autism spectrum disorders (ASDs); however, the neurochemical backgrounds remain unclear. To elucidate neurochemical processes underlying aberrant brain growth in ASD, we conducted a comprehensive literature search and a meta-analysis of 1H-magnetic resonance spectroscopy (1H-MRS) studies in ASD. From the 22 articles identified as satisfying the criteria, means and s.d. of measure of N-acetylaspartate (NAA), creatine, choline-containing compounds, myo-Inositol and glutamate+glutamine in frontal, temporal, parietal, amygdala-hippocampus complex, thalamus and cerebellum were extracted. Random effect model analyses showed significantly lower NAA levels in all the examined brain regions but cerebellum in ASD children compared with typically developed children (n=1295 at the maximum in frontal, P<0.05 Bonferroni-corrected), although there was no significant difference in metabolite levels in adulthood. Meta-regression analysis further revealed that the effect size of lower frontal NAA levels linearly declined with older mean age in ASD (n=844, P<0.05 Bonferroni-corrected). The significance of all frontal NAA findings was preserved after considering between-study heterogeneities (P<0.05 Bonferroni-corrected). This first meta-analysis of 1H-MRS studies in ASD demonstrated robust developmental changes in the degree of abnormality in NAA levels, especially in frontal lobes of ASD. Previously reported larger-than-normal brain size in ASD children and the coincident lower-than-normal NAA levels suggest that early transient brain expansion in ASD is mainly caused by an increase in non-neuron tissues, such as glial cell proliferation.
Highlights
Autism spectrum disorder (ASD) is a representative neurodevelopmental disorder that is behaviorally defined by deficits in social reciprocity, impaired verbal communication, and restrictive and repetitive behavior.[1,2] In the background of such atypical behavioral development, previous studies have suggested the existence of atypical brain development in ASD that overall brain size was slightly reduced at birth, dramatically increased within the first year of life, but gradually plateaued into adulthood.[3,4,5] brain size studies cannot provide tissue neurochemical information
Previous studies have used 1H-magnetic resonance spectroscopy (1H-MRS) to quantify glutamine/glutamate; N-acetylaspartate (NAA), a marker of neuronal density and activity;[9] choline-containing compounds (Cho), a measure primarily reflecting the constituents of cell membranes;[10] creatine and phosphocreatine (Cre), a measure of cellular energy metabolism;[10] and myo-Inositol, a major osmolite, precursor for phosphoinositides involved in the second messenger system.[11]
As brain structural studies show an aberrant trajectory of neurodevelopment, it was reasonable to predict that the degree of neurochemical abnormalities indexed by 1H-MRS may change according to developmental stages in ASD
Summary
Autism spectrum disorder (ASD) is a representative neurodevelopmental disorder that is behaviorally defined by deficits in social reciprocity, impaired verbal communication, and restrictive and repetitive behavior.[1,2] In the background of such atypical behavioral development, previous studies have suggested the existence of atypical brain development in ASD that overall brain size was slightly reduced at birth, dramatically increased within the first year of life, but gradually plateaued into adulthood.[3,4,5] brain size studies cannot provide tissue neurochemical information. Post-mortem studies demonstrated cytoarchitectonic abnormalities, aberrant minicolumnar organizations and microglial activations in brains of autistic individuals,[6] post-mortem studies lack information about the trajectory of brain development. 1H-magnetic resonance spectroscopy (1H-MRS) is a noninvasive neuroimaging technique that estimates specific chemical metabolite measures in vivo.[8] Previous studies have used 1H-MRS to quantify glutamine/glutamate (referred to collectively as ‘Glx’); N-acetylaspartate (NAA), a marker of neuronal density and activity;[9] choline-containing compounds (Cho), a measure primarily reflecting the constituents of cell membranes;[10] creatine and phosphocreatine (Cre), a measure of cellular energy metabolism;[10] and myo-Inositol (mI), a major osmolite, precursor for phosphoinositides involved in the second messenger system.[11] Previous 1H-MRS findings have yielded some inconsistency such as decreased[12,13,14] or no difference or increased NAA measure in ASD people compared with typically developed (TD) individuals.[15,16,17,18] The statistical power of each single previous 1H-MRS study is relatively small, and previous studies have not corrected for multiple comparisons. Performing a meta-analysis is one possible solution to realize sufficient statistical power for making conclusion about the neurochemical abnormality of autistic brain and is currently the only way to examine age-related change of 1H-MRS abnormality of autistic brain
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