Proton Magnetic Resonance Spectroscopy and MRI Reveal No Evidence for Brain Mitochondrial Dysfunction in Children with Autism Spectrum Disorder

Abstract

Brain mitochondrial dysfunction has been proposed as an etiologic factor in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopic imaging ((1)HMRS) and MRI were used to assess for evidence of brain mitochondrial dysfunction in longitudinal samples of children with ASD or developmental delay (DD), and cross-sectionally in typically developing (TD) children at 3-4, 6-7 and 9-10 years-of-age. A total of 239 studies from 130 unique participants (54ASD, 22DD, 54TD) were acquired. (1)HMRS and MRI revealed no evidence for brain mitochondrial dysfunction in the children with ASD. Findings do not support a substantive role for brain mitochondrial abnormalities in the etiology or symptom expression of ASD, nor the widespread use of hyperbaric oxygen treatment that has been advocated on the basis of this proposed relationship.

Substantial Problems with Measuring Brain Mitochondrial Dysfunction in Autism Spectrum Disorder Using Magnetic Resonance Spectroscopy

“…It should be noted that, although controversial, some investigators have reported that a low NAA is a marker of mitochondrial dysfunction and is consistent with inhibition of mitochondrial respiratory chain function (Bates et al 1996;Boumezbeur et al 2010;Clark 1998). For the present study (Corrigan et al 2011), the authors did not report if they measured any other metabolites besides lactate on MRS such as NAA. Based upon their previous studies, it would be unusual if they did not acquire NAA levels.…”

“…Since a lactate peak is a marker of mitochondrial dysfunction, the authors suggest that their study finds no evidence of mitochondrial dysfunction in children with ASD and suggest that this finding supports the idea that there is no association between mitochondrial dysfunction and ASD. While their findings are interesting and certainly add to the understanding of the complex biochemical abnormalities associated with ASD, we believe that the findings from Corrigan et al (Corrigan et al 2011) neither support nor refute an association between mitochondrial dysfunction and ASD for several reasons which we will outline below. We are particularly concerned that the results of this study will result in parents being told that mitochondrial disease has been ruled out (''No Evidence for Brain Mitochondrial Dysfunction'') based on a test that has very poor sensitivity.…”

“…It is unclear why the authors did not report NAA and other measured metabolites in this current study. Furthermore, it is unclear whether the participants in this study participated in either of their previous two studies (Friedman et al 2006;Friedman et al 2003) as the participant sample is the same size and age range in all 3 studies and data was apparently collected during the same time period as that during which the other studies were conducted (Corrigan et al 2011;Friedman et al 2006;Friedman et al 2003). To have a better idea concerning the evidence for or against brain mitochondrial dysfunction in the children with ASD from their present study, it would be helpful for the authors to publish any additional data available on these children or relate their findings to any already published data on the same children.…”

“…We read with interest the recent study by Corrigan et al (Corrigan et al 2011). The authors demonstrated that the prevalence of a lactate peak in the brain using magnetic resonance spectroscopy (MRS) measurements was no different between children with autism spectrum disorder (ASD) and typically developing control subjects.…”

“…Another MRS study in children with ASD and concomitant mitochondrial disease found elevated lactate in the brain on MRS in one child, but only in certain areas of the brain (Pons et al 2004). Since Corrigan et al (Corrigan et al 2011) only examined certain areas of the brain with MRS and not the whole brain, it is possible that isolated sections of brain mitochondrial dysfunction were missed. Furthermore, in a recent meta-analysis (Rossignol and Frye 2011), lactate was not elevated in several cases of children with proven mitochondria disease and ASD, including when measured in the cerebral spinal fluid (Ezugha et al 2010;Graf et al 2000), but rather other biomarkers of mitochondrial dysfunction were elevated.…”