Hideo Nakatani

Two genetic variants of CD38 in subjects with autism spectrum disorder and controls.

The neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons. In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p<0.040) and rs3796863 (p<0.005) showed significant associations with a subset of ASD (IQ>70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD.

High prevalence of bipolar disorder comorbidity in adolescents and young adults with high-functioning autism spectrum disorder: A preliminary study of 44 outpatients

BACKGROUND Psychiatric comorbidity of autism spectrum disorder (ASD) has not been well examined. METHODS Mood disorders in 44 consecutive outpatients with high-functioning ASD were examined at a university hospital according to DSM-IV. Inclusion criteria were an IQ of 70 or higher on the Wechsler Intelligence Scale and age of 12 years or over. RESULTS Sixteen patients (36.4%) were diagnosed with mood disorder. Of these 16 patients, four were diagnosed as having major depressive disorder, two patients as bipolar I disorder, six patients as bipolar II disorder, and four patients as bipolar disorder not otherwise specified. Bipolar disorder accounted for 75% of cases. Twelve patients had Asperger disorder and four patients had pervasive developmental disorder not otherwise specified. None of the patients had autistic disorder. LIMITATIONS The sample size was small. We could not use Autism Diagnostic Interview - Revised. Referral bias could not be avoided in this study. CONCLUSIONS The major comorbid mood disorder in patients with high-functioning ASD is bipolar disorder and not major depressive disorder. The autistic spectrum may share common vulnerability genes with the bipolar spectrum.

Altered brain connectivity in 3-to 7-year-old children with autism spectrum disorder.

Autism spectrum disorder (ASD) is often described as a disorder of aberrant neural connectivity and/or aberrant hemispheric lateralization. Although it is important to study the pathophysiology of the developing ASD cortex, the physiological connectivity of the brain in young children with ASD under conscious conditions has not yet been described. Magnetoencephalography (MEG) is a noninvasive brain imaging technique that is practical for use in young children. MEG produces a reference-free signal and is, therefore, an ideal tool for computing the coherence between two distant cortical rhythms. Using a custom child-sized MEG, we recently reported that 5- to 7-year-old children with ASD (n = 26) have inherently different neural pathways than typically developing (TD) children that contribute to their relatively preserved performance of visual tasks. In this study, we performed non-invasive measurements of the brain activity of 70 young children (3–7 years old, of which 18 were aged 3-4 years), a sample consisting of 35 ASD children and 35 TD children. Physiological connectivity and the laterality of physiological connectivity were assessed using intrahemispheric coherence for 9 frequency bands. As a result, significant rightward connectivity between the parietotemporal areas, via gamma band oscillations, was found in the ASD group. As we obtained the non-invasive measurements using a custom child-sized MEG, this is the first study to demonstrate a rightward-lateralized neurophysiological network in conscious young children (including children aged 3–4 years) with ASD.

Oxytocin for Male Subjects with Autism Spectrum Disorder and Comorbid Intellectual Disabilities: A Randomized Pilot Study.

Approximately half of autism spectrum disorder (ASD) individuals suffer from comorbid intellectual disabilities (IDs). Oxytocin (OXT) receptors are highly expressed in temporal lobe structures and are likely to play a modulatory role in excitatory/inhibitory balance, at least based on animal model findings. Thus, it is feasible that in the highly representative group of Kanner-type ASD subjects, OXT could have a beneficial effect on social communication and social interaction. The aim of this pilot study is to investigate the feasibility and adverse events, such as epilepsy, of the long-term administration of intranasal OXT for adolescent and adult ASD subjects with ID because such patients frequently have seizures. We also addressed the question on how to scale the OXT effects to the core symptoms of social deficits because of the relative difficulty in obtaining objective measurements. Twenty-nine males (aged 15–40 years old) participated in a randomized, double-blind, and placebo-controlled crossover study (each for 8 weeks) with OXT (16 IU/day). Except for seizures experienced by one participant, other serious adverse events did not occur. The primary and secondary outcomes measured using the Childhood Autism Rating Scale and several standard scales, respectively, revealed no difference between the OXT and placebo groups. Instead, in an exploratory analysis, the social interactions observed in the play sessions or in daily life were significantly more frequent in the initial half period in the OXT-first arm of the crossover trial. There were also significant correlations between the plasma OXT concentration and subscale scores for irritability on the Aberrant Behavior Checklist. In conclusion, this pilot study demonstrates that long-term administration of intranasal OXT is tolerable in a representative cohort of ASD individuals with ID and suggests that future multicenter trials of OXT are warranted and should include measurements of reciprocal social interactions based on daily life under closer surveillance for epilepsy. Trial registration: UMIN000007250.

Broader autism phenotype in mothers predicts social responsiveness in young children with autism spectrum disorders.

The aim of this study was to identify phenotypes in mothers and fathers that are specifically associated with disturbances in reciprocal social interactions and communication in their young children with autism spectrum disorder (ASD) in a Japanese sample.

The Contribution of Increased Gamma Band Connectivity to Visual Non-Verbal Reasoning in Autistic Children: A MEG Study

Some individuals with autism spectrum (AS) perform better on visual reasoning tasks than would be predicted by their general cognitive performance. In individuals with AS, mechanisms in the brain’s visual area that underlie visual processing play a more prominent role in visual reasoning tasks than they do in normal individuals. In addition, increased connectivity with the visual area is thought to be one of the neural bases of autistic visual cognitive abilities. However, the contribution of such brain connectivity to visual cognitive abilities is not well understood, particularly in children. In this study, we investigated how functional connectivity between the visual areas and higher-order regions, which is reflected by alpha, beta and gamma band oscillations, contributes to the performance of visual reasoning tasks in typically developing (TD) (n = 18) children and AS children (n = 18). Brain activity was measured using a custom child-sized magneto-encephalograph. Imaginary coherence analysis was used as a proxy to estimate the functional connectivity between the occipital and other areas of the brain. Stronger connectivity from the occipital area, as evidenced by higher imaginary coherence in the gamma band, was associated with higher performance in the AS children only. We observed no significant correlation between the alpha or beta bands imaginary coherence and performance in the both groups. Alpha and beta bands reflect top-down pathways, while gamma band oscillations reflect a bottom-up influence. Therefore, our results suggest that visual reasoning in AS children is at least partially based on an enhanced reliance on visual perception and increased bottom-up connectivity from the visual areas.

A Study of Single Nucleotide Polymorphisms of the SLC19A1/RFC1 Gene in Subjects with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate–methionine cycle may play a key role in the etiology of ASD. SLC19A1, also referred to as reduced folate carrier 1 (RFC1), is a member of the solute carrier group of transporters and is one of the key enzymes in the folate metabolism pathway. Findings from multiple genomic screens suggest the presence of an autism susceptibility locus on chromosome 21q22.3, which includes SLC19A1. Therefore, we performed a case-control study in a Japanese population. In this study, DNA samples obtained from 147 ASD patients at the Kanazawa University Hospital in Japan and 150 unrelated healthy Japanese volunteers were examined by the sequence-specific primer-polymerase chain reaction method pooled with fluorescence correlation spectroscopy. p < 0.05 was considered to represent a statistically significant outcome. Of 13 single nucleotide polymorphisms (SNPs) examined, a significant p-value was obtained for AA genotype of one SNP (rs1023159, OR = 0.39, 95% CI = 0.16–0.91, p = 0.0394; Fisher’s exact test). Despite some conflicting results, our findings supported a role for the polymorphism rs1023159 of the SLC19A1 gene, alone or in combination, as a risk factor for ASD. However, the findings were not consistent after multiple testing corrections. In conclusion, although our results supported a role of the SLC19A1 gene in the etiology of ASD, it was not a significant risk factor for the ASD samples analyzed in this study.

Ammonium acid urate urolithiasis in anorexia nervosa: a case report and literature review.

Ammonium acid urate urolithiasis is a quite rare condition. Our literature review of ammonium acid urate urolithiasis suggests that ammonium acid urate urolithiasis should be regarded as a general medical complication related to anorexia nervosa, and purging by laxative abuse might be a crucially important risk.

Prefrontal oxygenation during verbal fluency and cognitive function in adolescents with bipolar disorder type II

Evaluation of depressive states in children can be challenging. Most of the studies that have investigated cognitive function and cerebral blood volume changes using functional MRI (fMRI) in bipolar disorder (BD) have been confined to BDI or heterogeneous cohorts with attention-deficit/hyperactivity disorder (ADHD). This study investigated cognitive functions in adolescents with BDII and without ADHD using near-infrared spectroscopy (NIRS) and a Das-Naglieri Cognitive Assessment System (DN-CAS). Ten patients with BDII and without ADHD symptoms and 10 age- and gender-matched healthy controls were enrolled in the present study. NIRS was used to detect hemoglobin concentration changes during a verbal fluency test (VFT). In addition, the DN-CAS was used to evaluate cognitive function in four domains: planning, attention, simultaneous, and successive processing. Significant differences between the BDII and control groups in [oxy-Hb] changes during the early phase of VFT were observed in the lower prefrontal cortex but not in cognitive functioning. Furthermore, there was a significant correlation between planning and attention scores in BD subjects.

Is Intranasal Administration of Oxytocin Effective for Social Impairments in Autism Spectrum Disorder

© 2012 Munesue et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Is Intranasal Administration of Oxytocin Effective for Social Impairments in Autism Spectrum Disorder?