Letters COMMENT & RESPONSE
Brain Lactate as a Potential Biomarker for Comorbid Anxiety Disorder in Autism Spectrum Disorder To the Editor Goh et al1 reported on magnetic resonance spectroscopic imaging detection of brain lactate in a community sample of individuals with autism spectrum disorder (ASD) that was strongly correlated with age. In this study, 8 of 41 adults but only 2 of 34 children exhibited lactate peaks as assessed by visual inspection.1 The authors suggested that the presence of brain lactate in their sample was pathological and evidence for mitochondrial dysfunction. Their argument would be stronger if there was evidence of magnetic resonance imaging structural changes secondary to an accumulative adverse bioenergetic impact, as seen in some mitochondrial diseases. It would also be stronger if there was complementary magnetic resonance spectroscopic imaging evidence of other metabolic alterations, such as elevated glutamate, which would be expected due to a shift in energy redox state.2 Moreover, although the authors took care to visually monitor for signs of anxiety or hyperventilation during scanning, they did not use an objective measure of respiratory status such as capnometry. This is an important point because altered respiration associated with acute anxiety is not always obvious and can increase brain lactate.3 Thus, we would advise caution in the authors’ conclusion that these findings reflect clinically relevant mitochondrial dysfunction. If elevated brain lactate reflected etiological factors underlying the development of ASD, one would expect to observe it early on during childhood because accumulating evidence points to symptom emergence and brain alterations during infancy in ASD. The observation of increased brain lactate at later ages could instead reflect a relationship with comorbid conditions associated with ASD and aging. For example, detection of brain lactate might represent a marker for comorbid anxiety disorders. Although comorbid anxiety disorders in adults with ASD are increasingly recognized as a serious clinical concern, this can be difficult to identify using conventional behavioral measures of emotional cognition. Given the well-characterized relationship between abnormal brain lactate elevations and anxiety disorders, particularly panic disorder,3,4 results from this study1 could alternatively have distinguished a neurobiological subgroup of ASD having comorbid anxiety disorders. If mitochondrial function does worsen in ASD with advancing age, a further consideration would be the putative age relationship between progressive mitochondrial dysfunction and dementia.5 We are not aware of any literature reports of a higher incidence of dementia in older individuals with ASD; however, in the context of these results, this could prove an interesting area for future investigation. 190
Overall, findings from this study1 speak to the need for further studies of ASD and associated conditions across the life span. Stephen R. Dager, MD Neva M. Corrigan, PhD Dennis W. W. Shaw, MD Author Affiliations: Department of Radiology, University of Washington, Seattle (Dager, Corrigan, Shaw); Department of Bioengineering, University of Washington, Seattle (Dager); Seattle Children’s Hospital, Seattle, Washington (Shaw). Corresponding Author: Stephen R. Dager, MD, University of Washington School of Medicine, 1701 Columbia Rd, SB 202-206, Seattle, WA 98195 (srd@u .washington.edu). Conflict of Interest Disclosures: None reported. Additional Contributions: We thank Annette Estes, PhD (director, UW Autism Center, University of Washington), for helpful comments and suggestions. She did not receive compensation for her contribution. 1. Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS. Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: evidence from brain imaging. JAMA Psychiatry. 2014;71(6):665-671. 2. Dager SR, Friedman SD, Parow A, et al. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry. 2004;61 (5):450-458. 3. Dager SR. The vexing role of baseline: implications for neuroimaging studies of panic disorder. Int J Psychophysiol. 2010;78(1):20-26. 4. Maddock RJ, Buonocore MH, Miller AR, Yoon JH, Soosman SK, Unruh AM. Abnormal activity-dependent brain lactate and glutamate+glutamine responses in panic disorder. Biol Psychiatry. 2013;73(11):1111-1119. 5. Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA. Mitochondrial involvement in Alzheimer’s disease. Biochim Biophys Acta. 1999;1410(2):171-182.
In Reply In their letter, Dager et al suggest several ways in which the findings of our study1 could be strengthened. First, they posit that magnetic resonance imaging (MRI) structural changes would support the interpretation that elevated brain lactate is secondary to mitochondrial dysfunction. However, a review on this topic concluded that “neither normal brain MRI nor normal [magnetic resonance spectroscopy] can exclude the diagnosis of respiratory chain deficiency.” 2 It has long been known that MRI structural changes may or may not be present in mitochondrial diseases, and their absence does not exclude the presence of mitochondrial disease. Moreover, in a sample of autistic individuals who were not preselected on the basis of having classic mitochondrial disease, as in the sample we studied, it seems likely that structural brain MRI changes would be even less common. (It is worth noting that we did acquire structural data in this sample but the anatomical findings have yet to be reported.) Finally, the lactate elevations seem to have been uniquely localized in specific brain regions of these participants, suggesting that anatomical abnormalities, even if present, would have been highly localized and different across participants, making their detection difficult.
JAMA Psychiatry February 2015 Volume 72, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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Letters
Second, Dager et al suggest that comorbid panic disorder in the participants with ASD would be a more plausible explanation than mitochondrial dysfunction for elevated brain lactate. Indeed, some studies have reported more rapid rises in brain lactate in individuals with panic disorder following infusion of sodium lactate to precipitate a panic episode. However, it would be difficult to generalize this finding to the present study, which did not infuse sodium lactate and in which participants showed no signs and reported no symptoms of a panic episode. Such an extrapolation would require speculation that events occurred in the study which, in fact, did not occur. In addition, a previous publication by Dager et al3 reported that “[d]espite substantial baseline anxiety, we also do not typically observe elevated baseline lactate levels in patients with panic disorder about to undergo a lactate infusion designed to induce panic.” An additional argument against anxiety disorder as the etiology for elevated brain lactate is that, in those with panic disorder, brain lactate changes in response to lactate infusion have been found to be diffusely distributed throughout the brain rather than regionally localized,4 as was the case in our study.1 Dager et al suggest that the absence of capnometry is a weakness of the study; however, there is no evidence to support the idea that capnometry would detect physiological changes that would lead to regional increases in brain lactate and would not otherwise be detectable by direct behavioral observation. In addition, the higher frequency of brain lactate that we detected in adults with ASD is unlikely to reflect an association with comorbid conditions, such as anxiety disorder, because there is no evidence that anxiety is more common in adults than in children with ASD. Indeed, the hypersensitivity to sensory stimuli, which is a major contribution to anxiety in this population, is most prominent in children with ASD, and anxiety during MRI scans is generally more common in children than in adults. On the other hand, the research evidence for high rates of mitochondrial dysfunction in ASD is compelling and has been confirmed in numerous studies that have assessed peripheral markers of mitochondrial dysfunction in ASD. Dager et al make no mention of this literature, although it informs in an important way the research study in question and subsequent commentary on that study.
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Third, Dager et al posit that if elevated brain lactate reflects etiological factors underlying the development of ASD, then it should be observable during childhood. There are several cogent explanations for why this, in fact, would not be the case, and these are provided in our article1: “A key finding from this study is the higher rate of elevated brain lactate in adults with ASD. This finding has at least 2 possible explanations. First, ascertainment bias could have contributed to these age-specific findings. Some children with ASD no longer meet diagnostic criteria as adults, and mitochondrial dysfunction may be more frequent in those who meet diagnostic criteria into adulthood. Therefore, recruitment of clinically identified adults could preferentially recruit those who have mitochondrial dysfunction. Second, the specific findings could represent a worsening of mitochondrial function with aging.” Bradley S. Peterson, MD Suzanne Goh, MD Zhengchao Dong, PhD Author Affiliations: Institute for the Developing Mind, Children’s Hospital Los Angeles, Los Angeles, California (Peterson); Keck School of Medicine, University of Southern California, Los Angeles (Peterson); Division of Child Neurology, Rady Children’s Hospital of San Diego, San Diego, California (Goh); Department of Psychiatry, Columbia University Medical Center, New York, New York (Dong); New York State Psychiatric Institute, New York (Dong). Corresponding Author: Bradley S. Peterson, MD, Children’s Hospital Los Angeles, Institute for the Developing Mind, 4650 Sunset Blvd, MS 135, Los Angeles, CA 90027 ([email protected]). Conflict of Interest Disclosures: Dr Goh is chief medical officer of MitoMedical LLC. No other disclosures were reported. 1. Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS. Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: evidence from brain imaging. JAMA Psychiatry. 2014;71(6):665-671. 2. Bricout M, Grévent D, Lebre AS, et al. Brain imaging in mitochondrial respiratory chain deficiency: combination of brain MRI features as a useful tool for genotype/phenotype correlations. J Med Genet. 2014;51(7):429-435. 3. Dager SR, Friedman SD, Parow A, et al. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry. 2004;61 (5):450-458. 4. Dager SR. The vexing role of baseline: implications for neuroimaging studies of panic disorder. Int J Psychophysiol. 2010;78(1):20-26.
(Reprinted) JAMA Psychiatry February 2015 Volume 72, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Georgia User on 06/04/2015
191
Brain Lactate as a Potential Biomarker for Comorbid Anxiety Disorder in Autism Spectrum Disorder To the Editor Goh et al1 reported on magnetic resonance spectroscopic imaging detection of brain lactate in a community sample of individuals with autism spectrum disorder (ASD) that was strongly correlated with age. In this study, 8 of 41 adults but only 2 of 34 children exhibited lactate peaks as assessed by visual inspection.1 The authors suggested that the presence of brain lactate in their sample was pathological and evidence for mitochondrial dysfunction. Their argument would be stronger if there was evidence of magnetic resonance imaging structural changes secondary to an accumulative adverse bioenergetic impact, as seen in some mitochondrial diseases. It would also be stronger if there was complementary magnetic resonance spectroscopic imaging evidence of other metabolic alterations, such as elevated glutamate, which would be expected due to a shift in energy redox state.2 Moreover, although the authors took care to visually monitor for signs of anxiety or hyperventilation during scanning, they did not use an objective measure of respiratory status such as capnometry. This is an important point because altered respiration associated with acute anxiety is not always obvious and can increase brain lactate.3 Thus, we would advise caution in the authors’ conclusion that these findings reflect clinically relevant mitochondrial dysfunction. If elevated brain lactate reflected etiological factors underlying the development of ASD, one would expect to observe it early on during childhood because accumulating evidence points to symptom emergence and brain alterations during infancy in ASD. The observation of increased brain lactate at later ages could instead reflect a relationship with comorbid conditions associated with ASD and aging. For example, detection of brain lactate might represent a marker for comorbid anxiety disorders. Although comorbid anxiety disorders in adults with ASD are increasingly recognized as a serious clinical concern, this can be difficult to identify using conventional behavioral measures of emotional cognition. Given the well-characterized relationship between abnormal brain lactate elevations and anxiety disorders, particularly panic disorder,3,4 results from this study1 could alternatively have distinguished a neurobiological subgroup of ASD having comorbid anxiety disorders. If mitochondrial function does worsen in ASD with advancing age, a further consideration would be the putative age relationship between progressive mitochondrial dysfunction and dementia.5 We are not aware of any literature reports of a higher incidence of dementia in older individuals with ASD; however, in the context of these results, this could prove an interesting area for future investigation. 190
Overall, findings from this study1 speak to the need for further studies of ASD and associated conditions across the life span. Stephen R. Dager, MD Neva M. Corrigan, PhD Dennis W. W. Shaw, MD Author Affiliations: Department of Radiology, University of Washington, Seattle (Dager, Corrigan, Shaw); Department of Bioengineering, University of Washington, Seattle (Dager); Seattle Children’s Hospital, Seattle, Washington (Shaw). Corresponding Author: Stephen R. Dager, MD, University of Washington School of Medicine, 1701 Columbia Rd, SB 202-206, Seattle, WA 98195 (srd@u .washington.edu). Conflict of Interest Disclosures: None reported. Additional Contributions: We thank Annette Estes, PhD (director, UW Autism Center, University of Washington), for helpful comments and suggestions. She did not receive compensation for her contribution. 1. Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS. Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: evidence from brain imaging. JAMA Psychiatry. 2014;71(6):665-671. 2. Dager SR, Friedman SD, Parow A, et al. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry. 2004;61 (5):450-458. 3. Dager SR. The vexing role of baseline: implications for neuroimaging studies of panic disorder. Int J Psychophysiol. 2010;78(1):20-26. 4. Maddock RJ, Buonocore MH, Miller AR, Yoon JH, Soosman SK, Unruh AM. Abnormal activity-dependent brain lactate and glutamate+glutamine responses in panic disorder. Biol Psychiatry. 2013;73(11):1111-1119. 5. Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA. Mitochondrial involvement in Alzheimer’s disease. Biochim Biophys Acta. 1999;1410(2):171-182.
In Reply In their letter, Dager et al suggest several ways in which the findings of our study1 could be strengthened. First, they posit that magnetic resonance imaging (MRI) structural changes would support the interpretation that elevated brain lactate is secondary to mitochondrial dysfunction. However, a review on this topic concluded that “neither normal brain MRI nor normal [magnetic resonance spectroscopy] can exclude the diagnosis of respiratory chain deficiency.” 2 It has long been known that MRI structural changes may or may not be present in mitochondrial diseases, and their absence does not exclude the presence of mitochondrial disease. Moreover, in a sample of autistic individuals who were not preselected on the basis of having classic mitochondrial disease, as in the sample we studied, it seems likely that structural brain MRI changes would be even less common. (It is worth noting that we did acquire structural data in this sample but the anatomical findings have yet to be reported.) Finally, the lactate elevations seem to have been uniquely localized in specific brain regions of these participants, suggesting that anatomical abnormalities, even if present, would have been highly localized and different across participants, making their detection difficult.
JAMA Psychiatry February 2015 Volume 72, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Georgia User on 06/04/2015
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Letters
Second, Dager et al suggest that comorbid panic disorder in the participants with ASD would be a more plausible explanation than mitochondrial dysfunction for elevated brain lactate. Indeed, some studies have reported more rapid rises in brain lactate in individuals with panic disorder following infusion of sodium lactate to precipitate a panic episode. However, it would be difficult to generalize this finding to the present study, which did not infuse sodium lactate and in which participants showed no signs and reported no symptoms of a panic episode. Such an extrapolation would require speculation that events occurred in the study which, in fact, did not occur. In addition, a previous publication by Dager et al3 reported that “[d]espite substantial baseline anxiety, we also do not typically observe elevated baseline lactate levels in patients with panic disorder about to undergo a lactate infusion designed to induce panic.” An additional argument against anxiety disorder as the etiology for elevated brain lactate is that, in those with panic disorder, brain lactate changes in response to lactate infusion have been found to be diffusely distributed throughout the brain rather than regionally localized,4 as was the case in our study.1 Dager et al suggest that the absence of capnometry is a weakness of the study; however, there is no evidence to support the idea that capnometry would detect physiological changes that would lead to regional increases in brain lactate and would not otherwise be detectable by direct behavioral observation. In addition, the higher frequency of brain lactate that we detected in adults with ASD is unlikely to reflect an association with comorbid conditions, such as anxiety disorder, because there is no evidence that anxiety is more common in adults than in children with ASD. Indeed, the hypersensitivity to sensory stimuli, which is a major contribution to anxiety in this population, is most prominent in children with ASD, and anxiety during MRI scans is generally more common in children than in adults. On the other hand, the research evidence for high rates of mitochondrial dysfunction in ASD is compelling and has been confirmed in numerous studies that have assessed peripheral markers of mitochondrial dysfunction in ASD. Dager et al make no mention of this literature, although it informs in an important way the research study in question and subsequent commentary on that study.
jamapsychiatry.com
Third, Dager et al posit that if elevated brain lactate reflects etiological factors underlying the development of ASD, then it should be observable during childhood. There are several cogent explanations for why this, in fact, would not be the case, and these are provided in our article1: “A key finding from this study is the higher rate of elevated brain lactate in adults with ASD. This finding has at least 2 possible explanations. First, ascertainment bias could have contributed to these age-specific findings. Some children with ASD no longer meet diagnostic criteria as adults, and mitochondrial dysfunction may be more frequent in those who meet diagnostic criteria into adulthood. Therefore, recruitment of clinically identified adults could preferentially recruit those who have mitochondrial dysfunction. Second, the specific findings could represent a worsening of mitochondrial function with aging.” Bradley S. Peterson, MD Suzanne Goh, MD Zhengchao Dong, PhD Author Affiliations: Institute for the Developing Mind, Children’s Hospital Los Angeles, Los Angeles, California (Peterson); Keck School of Medicine, University of Southern California, Los Angeles (Peterson); Division of Child Neurology, Rady Children’s Hospital of San Diego, San Diego, California (Goh); Department of Psychiatry, Columbia University Medical Center, New York, New York (Dong); New York State Psychiatric Institute, New York (Dong). Corresponding Author: Bradley S. Peterson, MD, Children’s Hospital Los Angeles, Institute for the Developing Mind, 4650 Sunset Blvd, MS 135, Los Angeles, CA 90027 ([email protected]). Conflict of Interest Disclosures: Dr Goh is chief medical officer of MitoMedical LLC. No other disclosures were reported. 1. Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS. Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: evidence from brain imaging. JAMA Psychiatry. 2014;71(6):665-671. 2. Bricout M, Grévent D, Lebre AS, et al. Brain imaging in mitochondrial respiratory chain deficiency: combination of brain MRI features as a useful tool for genotype/phenotype correlations. J Med Genet. 2014;51(7):429-435. 3. Dager SR, Friedman SD, Parow A, et al. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry. 2004;61 (5):450-458. 4. Dager SR. The vexing role of baseline: implications for neuroimaging studies of panic disorder. Int J Psychophysiol. 2010;78(1):20-26.
(Reprinted) JAMA Psychiatry February 2015 Volume 72, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a University of Georgia User on 06/04/2015
191
