Kaori Matsumoto

Microglial activation in young adults with autism spectrum disorder.

CONTEXT A growing body of evidence suggests that aberrant immunologic systems underlie the pathophysiologic characteristics of autism spectrum disorder (ASD). However, to our knowledge, no information is available on the patterns of distribution of microglial activation in the brain in ASD. OBJECTIVES To identify brain regions associated with excessively activated microglia in the whole brain, and to examine similarities in the pattern of distribution of activated microglia in subjects with ASD and control subjects. DESIGN Case-control study using positron emission tomography and a radiotracer for microglia--[11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide) ([11C](R)-PK11195). SETTING Subjects recruited from the community. PARTICIPANTS Twenty men with ASD (age range, 18-31 years; mean [SD] IQ, 95.9 [16.7]) and 20 age- and IQ-matched healthy men as controls. Diagnosis of ASD was made in accordance with the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised. MAIN OUTCOME MEASURES Regional brain [11C](R)-PK11195 binding potential as a representative measure of microglial activation. RESULTS The [11C](R)-PK11195 binding potential values were significantly higher in multiple brain regions in young adults with ASD compared with those of controls (P < .05, corrected). Brain regions with increased binding potentials included the cerebellum, midbrain, pons, fusiform gyri, and the anterior cingulate and orbitofrontal cortices. The most prominent increase was observed in the cerebellum. The pattern of distribution of [11C](R)-PK11195 binding potential values in these brain regions of ASD and control subjects was similar, whereas the magnitude of the [11C](R)-PK11195 binding potential in the ASD group was greater than that of controls in all regions. CONCLUSIONS Our results indicate excessive microglial activation in multiple brain regions in young adult subjects with ASD. The similar distribution pattern of regional microglial activity in the ASD and control groups may indicate augmented but not altered microglial activation in the brain in the subjects with ASD.

Plasma Cytokine Profiles in Subjects with High-Functioning Autism Spectrum Disorders

Background Accumulating evidence suggests that dysregulation of the immune system is involved in the pathophysiology of autism spectrum disorders (ASD). The aim of the study was to explore immunological markers in peripheral plasma samples from non-medicated subjects with high-functioning ASD. Methodology/Principal Findings A multiplex assay for cytokines and chemokines was applied to plasma samples from male subjects with high-functioning ASD (n = 28) and matched controls (n = 28). Among a total of 48 analytes examined, the plasma concentrations of IL-1β, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were significantly higher in subjects with ASD compared with the corresponding values of matched controls after correction for multiple comparisons. Conclusion/Significance The results suggest that abnormal immune responses as assessed by multiplex analysis of cytokines may serve as one of the biological trait markers for ASD.

Alteration of plasma glutamate and glutamine levels in children with high-functioning autism

Background It has recently been hypothesized that hyperglutamatergia in the brain is involved in the pathophysiology of autism. However, there is no conclusive evidence of the validity of this hypothesis. As peripheral glutamate/glutamine levels have been reported to be correlated with those of the central nervous system, the authors examined whether the levels of 25 amino acids, including glutamate and glutamine, in the platelet-poor plasma of drug-naïve, male children with high-functioning autism (HFA) would be altered compared with those of normal controls. Methodology/Principal Findings Plasma levels of 25 amino acids in male children (N = 23) with HFA and normally developed healthy male controls (N = 22) were determined using high-performance liquid chromatography. Multiple testing was allowed for in the analyses. Compared with the normal control group, the HFA group had higher levels of plasma glutamate and lower levels of plasma glutamine. No significant group difference was found in the remaining 23 amino acids. The effect size (Cohens d) for glutamate and glutamine was large: 1.13 and 1.36, respectively. Using discriminant analysis with logistic regression, the two values of plasma glutamate and glutamine were shown to well-differentiate the HFA group from the control group; the rate of correct classification was 91%. Conclusions/Significance The present study suggests that plasma glutamate and glutamine levels can serve as a diagnostic tool for the early detection of autism, especially normal IQ autism. These findings indicate that glutamatergic abnormalities in the brain may be associated with the pathobiology of autism.

Brain region-specific altered expression and association of mitochondria-related genes in autism

BackgroundMitochondrial dysfunction (MtD) has been observed in approximately five percent of children with autism spectrum disorders (ASD). MtD could impair highly energy-dependent processes such as neurodevelopment, thereby contributing to autism. Most of the previous studies of MtD in autism have been restricted to the biomarkers of energy metabolism, while most of the genetic studies have been based on mutations in the mitochondrial DNA (mtDNA). Despite the mtDNA, most of the proteins essential for mitochondrial replication and function are encoded by the genomic DNA; so far, there have been very few studies of those genes. Therefore, we carried out a detailed study involving gene expression and genetic association studies of genes related to diverse mitochondrial functions.MethodsFor gene expression analysis, postmortem brain tissues (anterior cingulate gyrus (ACG), motor cortex (MC) and thalamus (THL)) from autism patients (n=8) and controls (n=10) were obtained from the Autism Tissue Program (Princeton, NJ, USA). Quantitative real-time PCR arrays were used to quantify the expression of 84 genes related to diverse functions of mitochondria, including biogenesis, transport, translocation and apoptosis. We used the delta delta Ct (∆∆Ct) method for quantification of gene expression. DNA samples from 841 Caucasian and 188 Japanese families were used in the association study of genes selected from the gene expression analysis. FBAT was used to examine genetic association with autism.ResultsSeveral genes showed brain region-specific expression alterations in autism patients compared to controls. Metaxin 2 (MTX2), neurofilament, light polypeptide (NEFL) and solute carrier family 25, member 27 (SLC25A27) showed consistently reduced expression in the ACG, MC and THL of autism patients. NEFL (P = 0.038; Z-score 2.066) and SLC25A27 (P = 0.046; Z-score 1.990) showed genetic association with autism in Caucasian and Japanese samples, respectively. The expression of DNAJC19, DNM1L, LRPPRC, SLC25A12, SLC25A14, SLC25A24 and TOMM20 were reduced in at least two of the brain regions of autism patients.ConclusionsOur study, though preliminary, brings to light some new genes associated with MtD in autism. If MtD is detected in early stages, treatment strategies aimed at reducing its impact may be adopted.

Paternal age at birth and high-functioning autistic-spectrum disorder in offspring.

BACKGROUND Previous studies have reported the association between advanced paternal age at birth and the risk of autistic-spectrum disorder in offspring, including offspring with intellectual disability. AIMS To test whether an association between advanced paternal age at birth is found in offspring with high-functioning autistic-spectrum disorder (i.e. offspring without intellectual disability). METHOD A case-control study was conducted in Japan. The participants consisted of individuals with full-scale IQ>or=70, with a DSM-IV autistic disorder or related diagnosis. Unrelated healthy volunteers were recruited as controls. Parental ages were divided into tertiles (i.e. three age classes). Odds ratios and 95% confidence intervals were estimated using logistic regression analyses, with an adjustment for age, gender and birth order. RESULTS Eighty-four individuals with autistic-spectrum disorder but without intellectual disability and 208 healthy controls were enrolled. Increased paternal, but not maternal, age was associated with an elevated risk of high-functioning autistic-spectrum disorder. A one-level advance in paternal age class corresponded to a 1.8-fold increase in risk, after adjustment for covariates. CONCLUSIONS Advanced paternal age is associated with an increased risk for high-functioning autistic-spectrum disorder.

Psychosocial risk factors for postpartum depression and their relation to timing of onset: The Hamamatsu Birth Cohort (HBC) Study

BACKGROUND The time frame for postpartum depression (PPD) defined in the literature differs among studies - either 4 weeks or 3 months after childbirth. To address potential difference in PPD in relation to onset of the illness, we investigated risk factors for early- and late-onset PPD using a representative birth cohort in Japan. METHODS We evaluated 675 women who completed the Edinburgh Postnatal Depression Scale (EPDS) for two to three times within 3 months after childbirth. Mothers with an onset of PPD (≥ 9 points on EPDS) within 4 weeks after childbirth were classified as having early-onset PPD, and those with PPD that occurred during the period of the 5th to 12th week after childbirth were classified as having late-onset PPD. We adopted multinomial logistic regression to investigate risk factors associated with each of early- and late-onset PPD, whilst simultaneously allowing for all risk factors a priori selected in the model. RESULTS The period prevalence of early- and late-onset PPD was 11% and 4%, respectively. Primiparity was associated only with early-onset PPD (OR=2.6, 95%CI 1.5-4.4). Younger (<25 years: OR=3.6, 95%CI 1.2-11.2) and advanced age (≥ 35 years: OR=2.5, 95%CI 1.1-5.8) of the participating women was significantly associated only with late-onset PPD. Lack of emotional support and a history of depression/anxiety appeared to increase risk both for early- and late-onset PPD. LIMITATIONS Moderate sample size and diagnosis of PPD without use of structured interviews may limit generalisability of the findings. CONCLUSION The finding that risk sets for early- and late-onset PPD differ suggests that these two types may have different aetiology.

Age-specific 3-month cumulative incidence of postpartum depression: The Hamamatsu Birth Cohort (HBC) Study

BACKGROUND The prevalence of postpartum depression (PPD) in the general population has been reported to be 10% to 15% worldwide. However, the relevance of age of the parturients to the emergence of PPD has not been well documented. To address this, we estimated the age-specific 3-month cumulative incidence of PPD using the Hamamatsu Birth Cohort for Mothers and Children (HBC). METHODS Women with PPD were defined as those scoring 9 points or higher using the Edinburgh Postnatal Depression Scale 3 months after childbirth. RESULTS Among 675 participating parturients, 100 women were found to have PPD; the cumulative incidence of PPD over the 3 months after childbirth was 14.8%. The age-specific estimates were 20.8% for <25 years, 14.2% for 25 to 29 years, 11.5% for 30 to 34 years, and 17.9% for ≥ 35 years. In the logistic regression analysis, the increased OR for having PPD among parturients aged ≥ 35 years was 1.7, which remained significant after controlling for age of partner, parity, and household income. LIMITATIONS Although the sample was representative, the sample size was modest. CONCLUSION The cumulative incidence of PPD was significantly different across age groups, with the highest estimates in the advanced age band. The heightened estimate was not accounted for by the age of the partner, parity, or annual household income.

Reduced Acetylcholinesterase Activity in the Fusiform Gyrus in Adults With Autism Spectrum Disorders

CONTEXT Both neuropsychological and functional magnetic resonance imaging studies have shown deficiencies in face perception in subjects with autism spectrum disorders (ASD). The fusiform gyrus has been regarded as the key structure in face perception. The cholinergic system is known to regulate the function of the visual pathway, including the fusiform gyrus. OBJECTIVES To determine whether central acetylcholinesterase activity, a marker for the cholinergic system, is altered in ASD and whether the alteration in acetylcholinesterase activity, if any, is correlated with their social functioning. DESIGN Using positron emission tomography and a radiotracer, N-[(11)C]methyl-4-piperidyl acetate ([(11)C]MP4A), regional cerebrocortical acetylcholinesterase activities were estimated by reference tissue-based linear least-squares analysis and expressed in terms of the rate constant k(3). Current and childhood autism symptoms in the adult subjects with ASD were assessed by the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised, respectively. Voxel-based analyses as well as region of interest-based methods were used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. SETTING Participants recruited from the community. PARTICIPANTS Twenty adult subjects with ASD (14 male and 6 female; age range, 18-33 years; mean [SD] intelligence quotient, 91.6 [4.3]) and 20 age-, sex-, and intelligence quotient-matched healthy controls. RESULTS Both voxel- and region of interest-based analyses revealed significantly lower [(11)C]MP4A k(3) values in the bilateral fusiform gyri of subjects with ASD than in those of controls (P < .05, corrected). The fusiform k(3) values in subjects with ASD were negatively correlated with their social disabilities as assessed by Autism Diagnostic Observation Schedule as well as Autism Diagnostic Interview-Revised. CONCLUSIONS The results suggest that a deficit in cholinergic innervations of the fusiform gyrus, which can be observed in adults with ASD, may be related to not only current but also childhood impairment of social functioning.

Metabolite alterations in the hippocampus of high-functioning adult subjects with autism

The aim of the present study was to investigate metabolite alterations in the hippocampal formation as they relate to aggression in high-functioning adults with autism. We measured concentrations of N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine plus phosphocreatine (Cr+PCr) in the hippocampal formation by proton magnetic resonance spectroscopy in 12 non-medicated male subjects with autism and 12 age- and sex-matched controls. Aggression was scored in the autistic subjects using the Buss-Perry Aggression Questionnaire. The concentrations of Cho and Cr+PCr in the hippocampal formation in autistic subjects were significantly higher than the corresponding values in control subjects, and a significant positive correlation was observed between the concentrations of these metabolites in the hippocampal formation and scores on the Buss-Perry Aggression Questionnaire in autistic subjects. Results suggest that high-functioning adult subjects with autism have abnormal metabolite concentrations in the hippocampal formation, which may in part account for their aggression.

Serum levels of platelet-derived growth factor BB homodimers are increased in male children with autism.

BACKGROUND The neurobiological basis of autism remains poorly understood. To examine the role played by serum cytokines in brain development, we hypothesized that Platelet-Derived Growth Factor (PDGF) and Vascular Endothelial Growth Factor (VEGF) may be associated with pathophysiology of autism. In this study, we screened serum levels of these growth factors in young male subjects with autism. METHODS We measured serum levels of PDGF subtypes and VEGF in the 31 male children with autism (6-19 years old) and 31 healthy age- and gender-matched subjects. RESULTS The serum levels of PDGF-BB in male children with autism (N=31, 5624.5+/-1651.8 pg/mL [mean+/-SD]) were significantly higher (two-tailed Students t-test: p=0.0188) than those of normal control subjects (N=31, 4758.2+/-1521.5 pg/mL [mean+/-SD]). There was a significant and positive correlation (Pearsons r=0.5320, p=0.0010) between the serum levels of PDGF-BB and the Autism Diagnostic Interview-Revised (ADI-R) domain C scores, which represent stereotyped patterns of behavior in the children with autism. However, there were no marked or significant correlations between serum PDGF-BB levels and clinical variables, including the other ADI-R scores and Intellectual Quotient (IQ) scores by WAIS-R. There were no significant change and correlations with clinical variables in serum PDGF-AA, PDGF-AB, and VEGF levels in the children with autism. CONCLUSIONS Increased levels of serum PDGF-BB homodimers might be implicated in the pathophysiology of autism.