Response inhibition and serotonin in autism:a functional MRI study using acute tryptophan depletion

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Autism spectrum disorder in adults:diagnosis, management, and health services development

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by pervasive difficulties since early childhood across reciprocal social communication and restricted, repetitive interests and behaviors. Although early ASD research focused primarily on children, there is increasing recognition that ASD is a lifelong neurodevelopmental disorder. However, although health and education services for children with ASD are relatively well established, service provision for adults with ASD is in its infancy. There is a lack of health services research for adults with ASD, including identification of comorbid health difficulties, rigorous treatment trials (pharmacological and psychological), development of new pharmacotherapies, investigation of transition and aging across the lifespan, and consideration of sex differences and the views of people with ASD. This article reviews available evidence regarding the etiology, legislation, diagnosis, management, and service provision for adults with ASD and considers what is needed to support adults with ASD as they age. We conclude that health services research for adults with ASD is urgently warranted. In particular, research is required to better understand the needs of adults with ASD, including health, aging, service development, transition, treatment options across the lifespan, sex, and the views of people with ASD. Additionally, the outcomes of recent international legislative efforts to raise awareness of ASD and service provision for adults with ASD are to be determined. Future research is required to identify high-quality, evidence-based, and cost-effective models of care. Furthermore, future health services research is also required at the beginning and end of adulthood, including improved transition from youth to adult health care and increased understanding of aging and health in older adults with ASD

The neuroprotective effects of estrogen on the aging brain

The population of the western world is ageing. This increase in the elderly population will inevitably mean a rise in the prevalence of age-related cognitive decline and late-onset neuropsychiatric disorder, such as Alzheimer’s disease (AD). There are sex differences in the incidence and age of onset of these disorders. Sex steroids and sex chromosomes are therefore implicated in their pathophysiology. We have identified relevant past and current literature using a Medline search and from the references of relevant papers. These were then reviewed and relevant articles have been summarized and included in the review. Evidence is presented for the wide-ranging actions of estrogen in the brain at the cellular, metabolic and neurotransmitter levels as well as from the cognitive, AD, depression and cerebrovascular perspectives. The authors conclude that it is unlikely that estrogen will become a stand-alone treatment for any of these disorders, although there may still be a role as an adjunctive treatment and as a prophylactic measure

Cortical and subcortical glutathione levels in adults with autism spectrum disorder

The causes of autism spectrum disorder (ASD) are uncertain and there are no pharmacological treatments for core symptoms of this condition. However, new evidence suggests that the brain cells in people with ASD may be poorly defended against harmful by-products, called ‘reactive oxygen species’ or ROS. The anti-oxidant Glutathione (GSH) produced by our cells helps protect against the damage caused by ROS. Some studies have shown that the amount of GSH in blood is lower in people with ASD. However, it is not clear whether this is also true inside the brain. Here we compared GSH levels in the brain of adult men with and without ASD using a safe and painless scanning technique called magnetic resonance spectroscopy (MRS). We found no differences in GSH between the people with ASD and those without; nor were GSH levels related to symptom severity in ASD. These findings suggest that brain antioxidant defences are not, in fact, weakened in this particular group of adult men with ASD