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Metabolite alterations in autistic children: a 1H MR spectroscopy study
Vol. 57(1) · 2012 · pp 152-156 · DOI: 10.2478/v10039-012-0014-x · Advances in Medical Sciences© ·Medical University of Bialystok, Poland
Metabolite alterations in autistic children: a 1H MR spectroscopy study Kubas B1*, Kułak W2, Sobaniec W3, Tarasow E1, Łebkowska U1, Walecki J4 1 Radiology Department, Medical University of Bialystok, Bialystok, Poland 2 Department of Pediatric Rehabilitation, Medical University of Bialystok, Bialystok, Poland 3 Department of Pediatric Neurology, Medical University of Bialystok, Bialystok, Poland 4 Polish Academy of Sciences Medical Research Center, Warsaw, Bialystok, Poland
* CORRESPONDING AUTHOR: Department of Radiology, Medical University of Bialystok, 24A M. Sklodowskiej-Curie, 15-274 Bialystok, Poland Tel: +48 85 7468403; Fax: +48 85 7468478 e-mail address: [email protected] (Bożena Kubas)
Received 04.04.2011 Accepted 16.02.2012 Advances in Medical Sciences Vol. 57(1) · 2012 · pp 152-156 DOI: 10.2478/v10039-012-0014-x © Medical University of Bialystok, Poland
ABSTRACT Purpose: The purpose of this study was to assess the role of proton magnetic resonance spectroscopy (1H MRS) in the detection of changes in cerebral metabolite levels in autistic children. Material and methods: Study group consisted of 12 children, aged 8-15 years, who were under the care of Pediatric Neurology Department and Pediatric Rehabilitation Department of Medical University of Bialystok. The diagnosis of autism was established by neurologist, psychiatrist and psychologist in every case. All patients matched the clinical criteria of the disease according to International Statistical Classification of Diseases and Related Health Problems (ICD-10). The control group included 16 healthy children aged 7-17. ¹H MRS was performed with a single-voxel method (TE-36, TR-1500, NEX-192). The volume of interest (VOI) was located in the frontal lobe regions, separately on each side. Results: We showed lower N-acetylaspartate/creatine (NAA/Cr), γ-aminobutyric acid /creatine (GABA/Cr) and glutamate/ creatine (Glx/Cr) in the frontal lobes in the study group comparing with healthy controls. The ratio of myoinositol/creatine (mI/Cr) was increased in autistic children. No differences in choline/creatine (Cho/Cr) ratio in study group and controls were found. There was a correlation between age and NAA/Cr in autistic children (R=0.593 p=0.041). No significant differences in metabolite ratios between right and left hemisphere in ASD and controls were found. Conclusions: ¹H MRS can provide important information regarding abnormal brain metabolism. Differences in NAA/Cr, GABA/Cr, Glx/Cr and mI/Cr may contribute to the pathogenesis of autism. Key words: autism, magnetic resonance imaging, spectroscopy
INTRODUCTION Autism (sometimes called “classical autism”) is the most common condition in a group of developmental disorders known as the autism spectrum disorders (ASDs). Autism is characterized by impaired social interaction, problems with verbal and nonverbal communication, and unusual, repetitive, or severely limited activities and interests. Other ASDs include Asperger syndrome, Rett syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (usually referred to as PDD-NOS). Some brain imaging studies have reported neurobiological abnormalities in autism, but the nature and distribution of the underlying
neurochemical irregularities are still unknown. Glutamate is the major excitatory neurotransmitter and is of crucial importance to brain development, leading some to propose that autistic spectrum disorders are caused by abnormalities in glutamate transmission [1]. 1H-MRS can be used to quantify a range of brain metabolites, including glutamine/glutamate (Glx); N-acetylaspartate (NAA), a marker of neuronal density and/or mitochondrial function; choline-containing compounds (Cho), a measure of membrane synthesis/turnover; creatine and phosphocreatine (Cr+PCr), a measure of cellular energy metabolism; and myoinositol, a major osmolite and precursor to several brain metabolites.
153
Kubas B et al.
H MRS studies, which provide in vivo measure of neuronal health, are beginning to identify neurochemical abnormalities in ASD. Reduced levels of NAA, a neuronal marker which can serve as an index of neuron density and viability [2], in bilateral cingulated, left body of the caudate, right thalamus, left temporal lobe, right parietal white matter and the cerebellum [2-4] in ASD were found. However, inconsistent results have been reported. In contrast other studies [5,6] did not find abnormally reduced levels of NAA in the frontal grey matter; temporal lobes, bilateral thalamus and the amygdala– hippocampal and parietal regions in ASD. These findings are difficult to interpret because studies differ widely in age range and level of functioning of their participants and technical methodology. The purpose of this study was to assess the role of 1H MRS in the detection of changes in cerebral metabolite levels in autistic children. We hypothesized that these children would exhibit neurochemical differences compared with healthy children of parents without a psychiatric disorder. 1
Figure 1. Localization of voxels (ROI) in frontal lobes.
MATERIAL AND METHODS Subjects Study group consisted of 12 children, aged 8-15 (mean age 10.55±4.90 years), who were under the care of Pediatric Neurology Department and Pediatric Rehabilitation Department of Medical University of Bialystok. The diagnosis of autism was established by neurologist, psychiatrist and psychologist in every case. All patients matched the clinical criteria of the disease according to International Statistical Classification of Diseases and Related Health Problems (ICD-10), the clinical observation was not shorter than two years. The control group included 16 patients aged 7-17 (mean age 11.35±4.20 years) with no clinical symptoms of the disorder and no lesions in the brain on MR studies. There was no statistical difference between the study group and control group.
MRI and ¹H MRS MRI and ¹H MRS examination was performed on 1.5T Eclipse (Marconi Medical Systems, USA) scanner. Morphological MRI examination of the brain was carried out in transverse planes, parallel to longitudinal axis of temporal lobe in spin echo (SE), fast spin echo (FSE) and fluid attenuation inversion recovery (FLAIR) sequences, in T1- and T2-weighted images and in frontal plane, perpendicular to longitudinal axis of temporal lobe in T1-weighted images. Sagittal plane was performed perpendicular to the line connecting the lowest parts of temporal lobes. Morphological examination enabled us to exclude other pathologies, such as congenital abnormalities, lesions in cerebral palsy, tumors and hydrocephalus, which might have similar clinical symptoms and can alter metabolite concentrations. ¹H MRS was performed with a single-voxel method. The volume of interest (VOI) was located in the frontal lobe regions,
separately on each side (Fig. 1). ¹H MRS examination was carried out with a single-voxel method using point-resolved selective spectroscopy (PRESS) sequence. Routine 3-impulse sequences of 90, 180, 180 degrees and double crusher impulse were used. The examination was preceded with an automated standardization of the field in the entire encephalon/brain (total shimming) and in the examined sample (local shimming). For water suppression, the multiply optimized insensitive suppression train (MOIST) technique was used. Spectra were recorded within the following parameters: echo time (TE)=35ms, repetition time (TR)=1500ms, thickness=15mm, signal averages=192. Assignment of resonance lines of particular metabolites was based on NAA signal with the chemical shift set to 2.0 p.p.m. The spectra were analyzed using the manufacturer-supplied software package for the MRS (Marconi). In some cases, it was necessary to correct the phase manually in order to obtain a maximum of symmetrical signal of residual water and to maintain a proper base line. Relative concentration ratios of particular metabolites, i.e. NAA, Cho, mI, GABA, Glx were analyzed in reference to the signal of creatine considering its level as an inner standard of the examination. In the statistical analysis, Wilcoxon test and Pearson’s correlation coefficient were used. Statistical significance was defined as p˂0.05.
RESULTS Out of 12 patients in 4, we observed arachnoideal cyst in the posterior fossa, in two children, there were widened Robin-Virchow spaces in centrum semiovale. In others, no
154
Metabolite alterations in autistic children: a 1H MR spectroscopy study
Table 1. Clinical data of children with autism spectrum disorders (ASD) and controls. Data
ASD (N=12)
Controls (N=16)
Age, mean (SD) years
10.55 ± 4.90
11.35 ± 4.20
Sex Males Females
7 5
9 7
Duration of disease
Longer than 2 years in all cases
Normal development
MRI abnormalities
Arachnoideal cyst in posterior fossa in 4 patients Widened Robin-Virchow spaces in centrum semiovale in 2 children
No
Figure 2. Mean NAA/Cr ratio in frontal lobes in autistic children and control group. (X ± Standard Deviation), Wilcoxon’s test, N-acetylaspartate (NAA), creatine (Cr).
Figure 3. Mean GABA/Cr ratio in frontal lobes in autistic children and control group. (X ± Standard Deviation), Wilcoxon’s test, γ-aminobutyric acid (GABA), creatine (Cr).
Figure 4. Mean Glx/Cr ratio in frontal lobes in autistic children and control group. (X ± Standard Deviation), Wilcoxon’s test, creatine (Cr), glutamate/glutamine (Glx).
Figure 5. Mean mI/Cr ratio in frontal lobes in autistic children and control group. (X ± Standard Deviation), Wilcoxon’s test, myoinositol (mI), creatine (Cr).
abnormalities were detected in MRI examinations (Tab. 1). In 1HMRS study, we found no differences in metabolite ratios between right and left hemisphere in ASD and controls. We showed lower NAA/Cr (Fig. 2). GABA/Cr and Glx/Cr ratios in the frontal lobes in the study group comparing with healthy controls (Fig. 3, Fig. 4). The ratio of mI/Cr was increased in
ASD children (Fig. 5). We showed no differences in Cho/ Cr ratios in study group and controls. There was correlation between age and NAA/Cr in autistic children (R=0.593; p=0.041) (Fig. 6, Tab. 2).
155
Kubas B et al.
Table 2. Metabolite ratios (mean [SD]) in left and right basal ganglia of children with autism spectrum disorders (ASD and controls. NAA/Cr
mI/Cr
GABA/Cr
Glx/Cr
Mean
1.068969 *
3.714108
1.675894^
2.57884 #
Min
0.53257
0.99560
1.064574
1.501110
Max.
2.61212
1.11.9754
1.934235
3.819237
SD
0.743738
4.028340
0.266652
0.754308
Mean
1.874564
1.837453
1.990513
3.381674
Min
1.440842
0.992456
1.563623
1.456456
Max.
2.51155
4.87134
2.948945
5.565000
SD
0.24493
0.73802
0.276658
0.753053
ASD (N=12)
Controls (N=16)
*p=0.0005 vs controls; ^ p=0.004 vs controls; #p=0.009 vs controls; Wilcoxon singed ranks two-tailed test Figure 6. Correlation between NAA/Cr ratio in frontal lobes and age of the patients. Spearman’s test. (R=0.593 p=0.041).
DISCUSSION In the present 1H MRS study, we found no differences in metabolite ratios between right and left hemisphere in ASD group and controls. Our findings are in accordance with reports by Chugani and Page [5,6]. NAA and lactate levels in the frontal lobe, temporal lobe and the cerebellum of nine ASD were compared to five sibling controls using MRS. Lower levels of NAA cerebellum in autistic children were found. Lactate was detected in the frontal lobe in one ASD boy, but was not detected any of the other ASD or siblings [4]. We also noted lower NAA, GABA and GLx ratios compared to controls. In contrast, Fatemi et al. [7] found in patients with ASD a significantly higher concentration of glutamine (Glu), glutamate (Gln) and Cr in amygdala-hippocampal complex than comparison subjects. At 1.5-Tesla MRI, it is not possible to examine which compound (i.e., Glu or Gln) is contributing most to the elevation in Glx. However, glutamate is the most abundant central neurotransmitter and is crucial for many neurodevelopmental processes, including synapse induction, cell migration, and synapse elimination. It has been suggested that neurodevelopmental differences in ASD may be partially
explained by differences in the glutamatergic system [6]. This proposal is supported by recent postmortem reports of glutamatergic abnormalities in cerebellum of patients with ASD [7]. In the present study, we found an increase in mI/Cr in frontal lobes in autistic children compared with controls. Similar findings were reported by Vasconcelos et al. [8]. They detected significant increase in mI and Cho peak areas in anterior cingulate and in mI/Cr ratio in anterior cingulate and left striatum [8]. Interesting findings were reported in an MRS study performed on 14 patients with Asperger syndrome and 18 controls which showed that patients with Asperger syndrome had higher NAA concentrations in the prefrontal lobe than controls and that these concentrations correlated to obsessive behavior [9]. It was hypothesized that the excess of NAA concentration could reflect increased mitochondrial metabolism, which might correlate with hyperactivity. These findings imply that the increases in metabolite ratios would fail to down-regulate in childhood and late teenage years [10]. Endo in 1H MRS study measured brain metabolites in the right medial temporal lobe, medial prefrontal cortex, and cerebellar vermis in children with autism, Asperger’s Disorder, and pervasive developmental. They found significantly lower NAA/Cr ratio in the autism group compared with the pervasive developmental disorder and controls [11].
CONCLUSIONS Magnetic resonance spectroscopy can provide important information regarding abnormal brain metabolism. Differences in NAA/Cr, GABA/Cr, Glx/Cr and mI/Cr may contribute to the pathogenesis of autism.
REFERENCES 1. Polleux F, Lauder JM. Toward a developmental neurobiology of autism. Ment Retard Dev Disabil Res Rev. 2004;10(4):303-17. 2.
Levitt JG, O’Neill J, Blanton RE, Smalley
156
Metabolite alterations in autistic children: a 1H MR spectroscopy study
S, Fadale D, McCracken JT, Guthrie D, Toga AW, Alger JR. Proton magnetic resonance spectroscopic imaging of the brain in childhood autism. Biol Psychiatry. 2003 Dec 15;54(12):1355-66. 3. Friedman SD, Shaw DW, Artru AA, Richards TL, Gardner J, Dawson G, Posse S, Dager SR. Regional brain chemical alterations in young children with autism spectrum disorder. Neurology. 2003 Jan 14;60(1):100-7. 4. Otsuka H, Harada M, Mori K, Hisaoka S, Nishitani H. Brain metabolites in the hippocampus-amygdala region and cerebellum in autism: an 1H-MR spectroscopy study. Neuroradiology. 1999 Jul;41(7):517-9. 5. Chugani DC, Sundram BS, Behen M, Lee ML, Moore GJ. Evidence of altered energy metabolism in autistic children. Prog Neuropsychopharmacol Biol Psychiatry. 1999 May;23(4):635-41. 6. Page LA, Daly E, Schmitz N, Simmons A, Toal F, Deeley Q, Ambery F, McAlonan GM, Murphy KC, Murphy DG. In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. Am J Psychiatry. 2006 Dec;163(12):2189-92. 7. Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz
SC, Realmuto GR. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry. 2002 Oct 15;52(8):805-10. 8. Vasconcelos MM, Brito AR, Domingues RC, da Cruz LC Jr, Gasparetto EL, Werner J Jr, Gonçalves JP. Proton magnetic resonance spectroscopy in school-aged autistic children. J Neuroimaging. 2008 Jul;18(3):288-95. 9. Murphy DG, Critchley HD, Schmitz N, McAlonan G, Van Amelsvoort T, Robertson D, Daly E, Rowe A, Russell A, Simmons A, Murphy KC, Howlin P. Asperger syndrome: a proton magnetic resonance spectroscopy study of brain. Arch Gen Psychiatry. 2002 Oct;59(10):885-91. 10. Fayed N, Modrego PJ. Comparative study of cerebral white matter in autism and attention-deficit/hyperactivity disorder by means of magnetic resonance spectroscopy. Acad Radiol. 2005 May;12(5):566-9. 11. Endo T, Shioiri T, Kitamura H, Kimura T, Endo S, Masuzawa N, Someya T. Altered chemical metabolites in the amygdala-hippocampus region contribute to autistic symptoms of autism spectrum disorders. Biol Psychiatry. 2007 Nov 1;62(9):1030-7.
Metabolite alterations in autistic children: a 1H MR spectroscopy study Kubas B1*, Kułak W2, Sobaniec W3, Tarasow E1, Łebkowska U1, Walecki J4 1 Radiology Department, Medical University of Bialystok, Bialystok, Poland 2 Department of Pediatric Rehabilitation, Medical University of Bialystok, Bialystok, Poland 3 Department of Pediatric Neurology, Medical University of Bialystok, Bialystok, Poland 4 Polish Academy of Sciences Medical Research Center, Warsaw, Bialystok, Poland
* CORRESPONDING AUTHOR: Department of Radiology, Medical University of Bialystok, 24A M. Sklodowskiej-Curie, 15-274 Bialystok, Poland Tel: +48 85 7468403; Fax: +48 85 7468478 e-mail address: [email protected] (Bożena Kubas)
Received 04.04.2011 Accepted 16.02.2012 Advances in Medical Sciences Vol. 57(1) · 2012 · pp 152-156 DOI: 10.2478/v10039-012-0014-x © Medical University of Bialystok, Poland
ABSTRACT Purpose: The purpose of this study was to assess the role of proton magnetic resonance spectroscopy (1H MRS) in the detection of changes in cerebral metabolite levels in autistic children. Material and methods: Study group consisted of 12 children, aged 8-15 years, who were under the care of Pediatric Neurology Department and Pediatric Rehabilitation Department of Medical University of Bialystok. The diagnosis of autism was established by neurologist, psychiatrist and psychologist in every case. All patients matched the clinical criteria of the disease according to International Statistical Classification of Diseases and Related Health Problems (ICD-10). The control group included 16 healthy children aged 7-17. ¹H MRS was performed with a single-voxel method (TE-36, TR-1500, NEX-192). The volume of interest (VOI) was located in the frontal lobe regions, separately on each side. Results: We showed lower N-acetylaspartate/creatine (NAA/Cr), γ-aminobutyric acid /creatine (GABA/Cr) and glutamate/ creatine (Glx/Cr) in the frontal lobes in the study group comparing with healthy controls. The ratio of myoinositol/creatine (mI/Cr) was increased in autistic children. No differences in choline/creatine (Cho/Cr) ratio in study group and controls were found. There was a correlation between age and NAA/Cr in autistic children (R=0.593 p=0.041). No significant differences in metabolite ratios between right and left hemisphere in ASD and controls were found. Conclusions: ¹H MRS can provide important information regarding abnormal brain metabolism. Differences in NAA/Cr, GABA/Cr, Glx/Cr and mI/Cr may contribute to the pathogenesis of autism. Key words: autism, magnetic resonance imaging, spectroscopy
INTRODUCTION Autism (sometimes called “classical autism”) is the most common condition in a group of developmental disorders known as the autism spectrum disorders (ASDs). Autism is characterized by impaired social interaction, problems with verbal and nonverbal communication, and unusual, repetitive, or severely limited activities and interests. Other ASDs include Asperger syndrome, Rett syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (usually referred to as PDD-NOS). Some brain imaging studies have reported neurobiological abnormalities in autism, but the nature and distribution of the underlying
neurochemical irregularities are still unknown. Glutamate is the major excitatory neurotransmitter and is of crucial importance to brain development, leading some to propose that autistic spectrum disorders are caused by abnormalities in glutamate transmission [1]. 1H-MRS can be used to quantify a range of brain metabolites, including glutamine/glutamate (Glx); N-acetylaspartate (NAA), a marker of neuronal density and/or mitochondrial function; choline-containing compounds (Cho), a measure of membrane synthesis/turnover; creatine and phosphocreatine (Cr+PCr), a measure of cellular energy metabolism; and myoinositol, a major osmolite and precursor to several brain metabolites.
153
Kubas B et al.
H MRS studies, which provide in vivo measure of neuronal health, are beginning to identify neurochemical abnormalities in ASD. Reduced levels of NAA, a neuronal marker which can serve as an index of neuron density and viability [2], in bilateral cingulated, left body of the caudate, right thalamus, left temporal lobe, right parietal white matter and the cerebellum [2-4] in ASD were found. However, inconsistent results have been reported. In contrast other studies [5,6] did not find abnormally reduced levels of NAA in the frontal grey matter; temporal lobes, bilateral thalamus and the amygdala– hippocampal and parietal regions in ASD. These findings are difficult to interpret because studies differ widely in age range and level of functioning of their participants and technical methodology. The purpose of this study was to assess the role of 1H MRS in the detection of changes in cerebral metabolite levels in autistic children. We hypothesized that these children would exhibit neurochemical differences compared with healthy children of parents without a psychiatric disorder. 1
Figure 1. Localization of voxels (ROI) in frontal lobes.
MATERIAL AND METHODS Subjects Study group consisted of 12 children, aged 8-15 (mean age 10.55±4.90 years), who were under the care of Pediatric Neurology Department and Pediatric Rehabilitation Department of Medical University of Bialystok. The diagnosis of autism was established by neurologist, psychiatrist and psychologist in every case. All patients matched the clinical criteria of the disease according to International Statistical Classification of Diseases and Related Health Problems (ICD-10), the clinical observation was not shorter than two years. The control group included 16 patients aged 7-17 (mean age 11.35±4.20 years) with no clinical symptoms of the disorder and no lesions in the brain on MR studies. There was no statistical difference between the study group and control group.
MRI and ¹H MRS MRI and ¹H MRS examination was performed on 1.5T Eclipse (Marconi Medical Systems, USA) scanner. Morphological MRI examination of the brain was carried out in transverse planes, parallel to longitudinal axis of temporal lobe in spin echo (SE), fast spin echo (FSE) and fluid attenuation inversion recovery (FLAIR) sequences, in T1- and T2-weighted images and in frontal plane, perpendicular to longitudinal axis of temporal lobe in T1-weighted images. Sagittal plane was performed perpendicular to the line connecting the lowest parts of temporal lobes. Morphological examination enabled us to exclude other pathologies, such as congenital abnormalities, lesions in cerebral palsy, tumors and hydrocephalus, which might have similar clinical symptoms and can alter metabolite concentrations. ¹H MRS was performed with a single-voxel method. The volume of interest (VOI) was located in the frontal lobe regions,
separately on each side (Fig. 1). ¹H MRS examination was carried out with a single-voxel method using point-resolved selective spectroscopy (PRESS) sequence. Routine 3-impulse sequences of 90, 180, 180 degrees and double crusher impulse were used. The examination was preceded with an automated standardization of the field in the entire encephalon/brain (total shimming) and in the examined sample (local shimming). For water suppression, the multiply optimized insensitive suppression train (MOIST) technique was used. Spectra were recorded within the following parameters: echo time (TE)=35ms, repetition time (TR)=1500ms, thickness=15mm, signal averages=192. Assignment of resonance lines of particular metabolites was based on NAA signal with the chemical shift set to 2.0 p.p.m. The spectra were analyzed using the manufacturer-supplied software package for the MRS (Marconi). In some cases, it was necessary to correct the phase manually in order to obtain a maximum of symmetrical signal of residual water and to maintain a proper base line. Relative concentration ratios of particular metabolites, i.e. NAA, Cho, mI, GABA, Glx were analyzed in reference to the signal of creatine considering its level as an inner standard of the examination. In the statistical analysis, Wilcoxon test and Pearson’s correlation coefficient were used. Statistical significance was defined as p˂0.05.
RESULTS Out of 12 patients in 4, we observed arachnoideal cyst in the posterior fossa, in two children, there were widened Robin-Virchow spaces in centrum semiovale. In others, no
154
Metabolite alterations in autistic children: a 1H MR spectroscopy study
Table 1. Clinical data of children with autism spectrum disorders (ASD) and controls. Data
ASD (N=12)
Controls (N=16)
Age, mean (SD) years
10.55 ± 4.90
11.35 ± 4.20
Sex Males Females
7 5
9 7
Duration of disease
Longer than 2 years in all cases
Normal development
MRI abnormalities
Arachnoideal cyst in posterior fossa in 4 patients Widened Robin-Virchow spaces in centrum semiovale in 2 children
No
Figure 2. Mean NAA/Cr ratio in frontal lobes in autistic children and control group. (X ± Standard Deviation), Wilcoxon’s test, N-acetylaspartate (NAA), creatine (Cr).
Figure 3. Mean GABA/Cr ratio in frontal lobes in autistic children and control group. (X ± Standard Deviation), Wilcoxon’s test, γ-aminobutyric acid (GABA), creatine (Cr).
Figure 4. Mean Glx/Cr ratio in frontal lobes in autistic children and control group. (X ± Standard Deviation), Wilcoxon’s test, creatine (Cr), glutamate/glutamine (Glx).
Figure 5. Mean mI/Cr ratio in frontal lobes in autistic children and control group. (X ± Standard Deviation), Wilcoxon’s test, myoinositol (mI), creatine (Cr).
abnormalities were detected in MRI examinations (Tab. 1). In 1HMRS study, we found no differences in metabolite ratios between right and left hemisphere in ASD and controls. We showed lower NAA/Cr (Fig. 2). GABA/Cr and Glx/Cr ratios in the frontal lobes in the study group comparing with healthy controls (Fig. 3, Fig. 4). The ratio of mI/Cr was increased in
ASD children (Fig. 5). We showed no differences in Cho/ Cr ratios in study group and controls. There was correlation between age and NAA/Cr in autistic children (R=0.593; p=0.041) (Fig. 6, Tab. 2).
155
Kubas B et al.
Table 2. Metabolite ratios (mean [SD]) in left and right basal ganglia of children with autism spectrum disorders (ASD and controls. NAA/Cr
mI/Cr
GABA/Cr
Glx/Cr
Mean
1.068969 *
3.714108
1.675894^
2.57884 #
Min
0.53257
0.99560
1.064574
1.501110
Max.
2.61212
1.11.9754
1.934235
3.819237
SD
0.743738
4.028340
0.266652
0.754308
Mean
1.874564
1.837453
1.990513
3.381674
Min
1.440842
0.992456
1.563623
1.456456
Max.
2.51155
4.87134
2.948945
5.565000
SD
0.24493
0.73802
0.276658
0.753053
ASD (N=12)
Controls (N=16)
*p=0.0005 vs controls; ^ p=0.004 vs controls; #p=0.009 vs controls; Wilcoxon singed ranks two-tailed test Figure 6. Correlation between NAA/Cr ratio in frontal lobes and age of the patients. Spearman’s test. (R=0.593 p=0.041).
DISCUSSION In the present 1H MRS study, we found no differences in metabolite ratios between right and left hemisphere in ASD group and controls. Our findings are in accordance with reports by Chugani and Page [5,6]. NAA and lactate levels in the frontal lobe, temporal lobe and the cerebellum of nine ASD were compared to five sibling controls using MRS. Lower levels of NAA cerebellum in autistic children were found. Lactate was detected in the frontal lobe in one ASD boy, but was not detected any of the other ASD or siblings [4]. We also noted lower NAA, GABA and GLx ratios compared to controls. In contrast, Fatemi et al. [7] found in patients with ASD a significantly higher concentration of glutamine (Glu), glutamate (Gln) and Cr in amygdala-hippocampal complex than comparison subjects. At 1.5-Tesla MRI, it is not possible to examine which compound (i.e., Glu or Gln) is contributing most to the elevation in Glx. However, glutamate is the most abundant central neurotransmitter and is crucial for many neurodevelopmental processes, including synapse induction, cell migration, and synapse elimination. It has been suggested that neurodevelopmental differences in ASD may be partially
explained by differences in the glutamatergic system [6]. This proposal is supported by recent postmortem reports of glutamatergic abnormalities in cerebellum of patients with ASD [7]. In the present study, we found an increase in mI/Cr in frontal lobes in autistic children compared with controls. Similar findings were reported by Vasconcelos et al. [8]. They detected significant increase in mI and Cho peak areas in anterior cingulate and in mI/Cr ratio in anterior cingulate and left striatum [8]. Interesting findings were reported in an MRS study performed on 14 patients with Asperger syndrome and 18 controls which showed that patients with Asperger syndrome had higher NAA concentrations in the prefrontal lobe than controls and that these concentrations correlated to obsessive behavior [9]. It was hypothesized that the excess of NAA concentration could reflect increased mitochondrial metabolism, which might correlate with hyperactivity. These findings imply that the increases in metabolite ratios would fail to down-regulate in childhood and late teenage years [10]. Endo in 1H MRS study measured brain metabolites in the right medial temporal lobe, medial prefrontal cortex, and cerebellar vermis in children with autism, Asperger’s Disorder, and pervasive developmental. They found significantly lower NAA/Cr ratio in the autism group compared with the pervasive developmental disorder and controls [11].
CONCLUSIONS Magnetic resonance spectroscopy can provide important information regarding abnormal brain metabolism. Differences in NAA/Cr, GABA/Cr, Glx/Cr and mI/Cr may contribute to the pathogenesis of autism.
REFERENCES 1. Polleux F, Lauder JM. Toward a developmental neurobiology of autism. Ment Retard Dev Disabil Res Rev. 2004;10(4):303-17. 2.
Levitt JG, O’Neill J, Blanton RE, Smalley
156
Metabolite alterations in autistic children: a 1H MR spectroscopy study
S, Fadale D, McCracken JT, Guthrie D, Toga AW, Alger JR. Proton magnetic resonance spectroscopic imaging of the brain in childhood autism. Biol Psychiatry. 2003 Dec 15;54(12):1355-66. 3. Friedman SD, Shaw DW, Artru AA, Richards TL, Gardner J, Dawson G, Posse S, Dager SR. Regional brain chemical alterations in young children with autism spectrum disorder. Neurology. 2003 Jan 14;60(1):100-7. 4. Otsuka H, Harada M, Mori K, Hisaoka S, Nishitani H. Brain metabolites in the hippocampus-amygdala region and cerebellum in autism: an 1H-MR spectroscopy study. Neuroradiology. 1999 Jul;41(7):517-9. 5. Chugani DC, Sundram BS, Behen M, Lee ML, Moore GJ. Evidence of altered energy metabolism in autistic children. Prog Neuropsychopharmacol Biol Psychiatry. 1999 May;23(4):635-41. 6. Page LA, Daly E, Schmitz N, Simmons A, Toal F, Deeley Q, Ambery F, McAlonan GM, Murphy KC, Murphy DG. In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. Am J Psychiatry. 2006 Dec;163(12):2189-92. 7. Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz
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