Elevated Glutamatergic Compounds in Pregenual Anterior Cingulate in Pediatric Autism Spectrum Disorder Demonstrated by 1H MRS and 1H MRSI

PLOS ONE, Dec 2019

Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy (1H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging (1H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD.

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Elevated Glutamatergic Compounds in Pregenual Anterior Cingulate in Pediatric Autism Spectrum Disorder Demonstrated by 1H MRS and 1H MRSI

et al. (2012) Elevated Glutamatergic Compounds in Pregenual Anterior Cingulate in Pediatric Autism Spectrum Disorder Demonstrated by 1H MRS and 1H MRSI. PLoS ONE 7(7): e38786. doi:10.1371/journal.pone.0038786 Elevated Glutamatergic Compounds in Pregenual Anterior Cingulate in Pediatric Autism Spectrum 1 1 Disorder Demonstrated by H MRS and H MRSI Anthony Bejjani 0 Joseph O'Neill 0 John A. Kim 0 Andrew J. Frew 0 Victor W. Yee 0 Ronald Ly 0 Christina Kitchen 0 Noriko Salamon 0 James T. McCracken 0 Arthur W. Toga 0 Jeffry R. Alger 0 Jennifer G. Levitt 0 Grainne M. McAlonan, King's College London, United Kingdom 0 1 Division of Child and Adolescent Psychiatry, Semel Institute for Neurosciences, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 2 Laboratory of Neuroimaging, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 3 Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 4 Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 5 Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 6 Brain Research Institute, David Geffen School of Medicine at UCLA , Los Angeles, California , United States of America Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy (1H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p,0.05) and 21.2% (p,0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging (1H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p,0.05), Cr (6.7%, p,0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p,0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD. - Funding: This work was funded by award R01NS46018-01 (JGL) from the National Institute for Neurological Diseases and Stroke, by award KO8-MH01385 (JGL) from the National Institute of Mental Health, by NIH award P01 MH63357 (Strickland), and by the NIH Pediatric MRI Database (JGL/JMC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Proposed abnormal glutamate (Glu) metabolism in autism spectrum disorder (ASD) [17] is supported by several lines of evidence. Epilepsy is common in ASD [8] and epileptic seizures are propagated by excitatory Glu. Elevated Glu and other excitatory amino acids have been reported in blood serum, plasma, and platelets in ASD [913]. Post-mortem neuropathology in ASD has found elevated mRNA or protein levels of glutamatergic transporters and neurotransmitter receptors [14]. And finally, ASD has been associated with single-nucleotide polymorphisms (SNPs) in glutamatergic genes, including those coding for transporters [15], metabotropic and ionotropic receptors [3,16,17], the enzyme glutamate decarboxylase [18], and the mitochondrial aspartate/glutamate carrier [1926]. The last listed is also supported by neuropathology [27]. These various linkages give ample reason to ask if brain levels of Glu and related metabolites are disturbed in ASD and if such abnormalities have a bearing on clinical presentation. Neuroimaging assays of regional levels of these compounds may help evaluate glutamatergic theories of ASD and inform potential therapies targeting Glu in specific brain structures. Proton magnetic resonance spectroscopy (1H MRS) is a neuroimaging technique that measures in vivo brain Glu safely and non-invasively in children. Thereby, Glx, the combined signal for Glu and spectrally overlapping glutamine (Gln), is often more reliably assayed than Glu alone, especially at low field (,3 T). MRS investigations of autistic spectrum disorders have been numerous [2852], but few have reported Glu or Glx [28,31,32,35,47,53]. All of thes (...truncated)


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Anthony Bejjani, Joseph O'Neill, John A. Kim, Andrew J. Frew, Victor W. Yee, Ronald Ly, Christina Kitchen, Noriko Salamon, James T. McCracken, Arthur W. Toga, Jeffry R. Alger, Jennifer G. Levitt. Elevated Glutamatergic Compounds in Pregenual Anterior Cingulate in Pediatric Autism Spectrum Disorder Demonstrated by 1H MRS and 1H MRSI, PLOS ONE, 2012, Volume 7, Issue 7, DOI: 10.1371/journal.pone.0038786