Obsessive-Compulsive Disorder and Autism Spectrum Disorders: Longitudinal and Offspring Risk

Background

Despite substantial similarities and overlaps in the pathophysiology of obsessive-compulsive disorders (OCD) and autism spectrum disorders, little is known about the clinical and etiologic cohesion of these two disorders. We therefore aimed to determine the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders.

Methods

In a prospective study design we explored the effect of a prior diagnosis of OCD in patients and parents on the susceptibility to autism spectrum disorders and vice versa. Analyses were adjusted for sex, age, calendar year, parental age and place at residence at time of birth. As measures of relative risk incidence rate ratios (IRR) and accompanying 95% confidence intervals (CIs) were employed.

Results

The risk of a comorbid diagnosis of OCD in individuals with autism spectrum disorder and aggregation of autism spectrum disorders in offspring of parents with OCD were increased. Individuals first diagnosed with autism spectrum disorders had a 2-fold higher risk of a later diagnosis of OCD (IRR = 2.18, 95% CI = 1.91–2.48), whereas individuals diagnosed with OCD displayed a nearly 4-fold higher risk to be diagnosed with autism spectrum disorders (IRR = 3.91, 95% CI = 3.46–4.40) later in life. The observed associations were somewhat stronger for less severe types of autism spectrum disorders without a comorbid diagnosis of mental disabilities.

Conclusions

The high comorbidity, sequential risk, and shared familial risks between OCD and autism spectrum disorders are suggestive of partially shared etiological mechanisms. The results have implications for current gene-searching efforts and for clinical practice.     

妊娠期高血压疾病发病危险因素及对妊娠结局的影响

目的:探讨妊娠期高血压疾病(HDCP)发病的危险因素及其对妊娠结局的影响,以期为HDCP的诊断和早期预防提供一定的临床依据。方法:选择2011年11月到2014年11月在我院接受治疗的120例HDCP患者,设为实验组,同期选择120例正常孕产妇作为对照组。自制调查问卷调查受试者的临床资料以及妊娠结局,分析HDCP的危险因素,对比观察两组妊娠结局的差异。结果:(1)单因素分析显示,HDCP发病的危险因素可能有:年龄、体质指数(BMI)、月收入、高血压家族史、孕期并发症、负面情绪、文化程度(均P0.05)。(2)进一步行多因素非条件Logistic回归分析显示,HDCP发病的危险因素有:BMI、高血压家族史、负面情绪及文化程度。(3)实验组患者胎儿窘迫、低体重儿、新生儿窒息、围产儿死亡及胎儿畸形的发生率均明显高于对照组,具有显著性差异(P0.05)。结论:导致HDCP发病的危险因素较多,主要有BMI、高血压家族史、负面情绪及文化程度等,这些因素极易导致不良妊娠结局。     

HERVs Expression in Autism Spectrum Disorders

Background

Autistic Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder, resulting from complex interactions among genetic, genomic and environmental factors. Here we have studied the expression of Human Endogenous Retroviruses (HERVs), non-coding DNA elements with potential regulatory functions, and have tested their possible implication in autism.

Methods

The presence of retroviral mRNAs from four HERV families (E, H, K and W), widely implicated in complex diseases, was evaluated in peripheral blood mononuclear cells (PBMCs) from ASD patients and healthy controls (HCs) by qualitative RT-PCR. We also analyzed the expression of the env sequence from HERV-H, HERV-W and HERV-K families in PBMCs at the time of sampling and after stimulation in culture, in both ASD and HC groups, by quantitative Real-time PCR. Differences between groups were evaluated using statistical methods.

Results

The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.

Conclusions

Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.     

LPS Exposure Increases Maternal Corticosterone Levels,Causes Placental Injury and Increases IL-1Β Levels in Adult Rat Offspring: Relevance to Autism

Maternal immune activation can induce neuropsychiatric disorders, such as autism and schizophrenia. Previous investigations by our group have shown that prenatal treatment of rats on gestation day 9.5 with lipopolysaccharide (LPS; 100 μg/kg, intraperitoneally), which mimics infections by gram-negative bacteria, induced autism-like behavior in male rats, including impaired communication and socialization and induced repetitive/restricted behavior. However, the behavior of female rats was unchanged. Little is known about how LPS-induced changes in the pregnant dam subsequently affect the developing fetus and the fetal immune system. The present study evaluated the hypothalamic-pituitary-adrenal (HPA) axis activity, the placental tissue and the reproductive performance of pregnant Wistar rats exposed to LPS. In the adult offspring, we evaluated the HPA axis and pro-inflammatory cytokine levels with or without a LPS challenge. LPS exposure increased maternal serum corticosterone levels, injured placental tissue and led to higher post-implantation loss, resulting in fewer live fetuses. The HPA axis was not affected in adult offspring. However, prenatal LPS exposure increased IL-1β serum levels, revealing that prenatal LPS exposure modified the immune response to a LPS challenge in adulthood. Increased IL-1β levels have been reported in several autistic patients. Together with our previous studies, our model induced autistic-like behavioral and immune disturbances in childhood and adulthood, indicating that it is a robust rat model of autism.     

Interactive Social Neuroscience to Study Autism Spectrum Disorder

Individuals with autism spectrum disorder (ASD) demonstrate difficulty with social interactions and relationships, but the neural mechanisms underlying these difficulties remain largely unknown. While social difficulties in ASD are most apparent in the context of interactions with other people, most neuroscience research investigating ASD have provided limited insight into the complex dynamics of these interactions. The development of novel, innovative “interactive social neuroscience” methods to study the brain in contexts with two interacting humans is a necessary advance for ASD research. Studies applying an interactive neuroscience approach to study two brains engaging with one another have revealed significant differences in neural processes during interaction compared to observation in brain regions that are implicated in the neuropathology of ASD. Interactive social neuroscience methods are crucial in clarifying the mechanisms underlying the social and communication deficits that characterize ASD.     

The Cost of Autism Spectrum Disorders

Objective

A diagnosis of an autism spectrum disorders is usually associated with substantial lifetime costs to an individual, their family and the community. However, there remains an elusive factor in any cost-benefit analysis of ASD diagnosis, namely the cost of not obtaining a diagnosis. Given the infeasibility of estimating the costs of a population that, by its nature, is inaccessible, the current study compares expenses between families whose children received a formal ASD diagnosis immediately upon suspecting developmental atypicality and seeking advice, with families that experienced a delay between first suspicion and formal diagnosis.

Design

A register based questionnaire study covering all families with a child with ASD in Western Australia.

Participants

Families with one or more children diagnosed with an ASD, totalling 521 children diagnosed with an ASD; 317 records were able to be included in the final analysis.

Results

The median family cost of ASD was estimated to be AUD $34,900 per annum with almost 90% of the sum ($29,200) due to loss of income from employment. For each additional symptom reported, approximately $1,400 cost for the family per annum was added. While there was little direct influence on costs associated with a delay in the diagnosis, the delay was associated with a modest increase in the number of ASD symptoms, indirectly impacting the cost of ASD.

Conclusions

A delay in diagnosis was associated with an indirect increased financial burden to families. Early and appropriate access to early intervention is known to improve a child''s long-term outcomes and reduce lifetime costs to the individual, family and society. Consequently, a per symptom dollar value may assist in allocation of individualised funding amounts for interventions rather than a nominal amount allocated to all children below a certain age, regardless of symptom presentation, as is the case in Western Australia.     

The Contribution of Mosaic Variants to Autism Spectrum Disorder

De novo mutation is highly implicated in autism spectrum disorder (ASD). However, the contribution of post-zygotic mutation to ASD is poorly characterized. We performed both exome sequencing of paired samples and analysis of de novo variants from whole-exome sequencing of 2,388 families. While we find little evidence for tissue-specific mosaic mutation, multi-tissue post-zygotic mutation (i.e. mosaicism) is frequent, with detectable mosaic variation comprising 5.4% of all de novo mutations. We identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in ASD (KMT2C, NCKAP1, and MYH10) in probands but none in siblings. We find a strong ascertainment bias for mosaic mutations in probands relative to their unaffected siblings (p = 0.003). We build a model of de novo variation incorporating mosaic variants and errors in classification of mosaic status and from this model we estimate that 33% of mosaic mutations in probands contribute to 5.1% of simplex ASD diagnoses (95% credible interval 1.3% to 8.9%). Our results indicate a contributory role for multi-tissue mosaic mutation in some individuals with an ASD diagnosis.     

Lipopolysaccharide Exposure during Pregnancy Leads to Aortic Dysfunction in Offspring Rats

Background

Prenatal exposure to Lipopolysaccharide (LPS) produces hypertension in adult offspring rats. The present study was to explore the effects of prenatal inflammation on morphological and functional changes in the aorta from offspring rats and to further assess its susceptibility to cardiovascular diseases.

Methods and Results

Pregnant rats were treated intraperitoneally on gestation Days 8, 10 and 12 with saline, LPS (0.79 mg/kg), or pyrrolidine dithiocarbamate (PDTC, 100 mg/kg)+LPS, respectively. Aortic ring reactivity and histopathological alteration were analyzed in offspring at the age of 12 weeks. The detections of connexin (Cx) 37, Cx40, Cx43, and Cx45, including immunofluorescent patterns, protein levels and mRNA expression in the aorta, were performed as well. Furthermore, the expressions of Nuclear factor (NF)-κB (p65), IκBα, phospho-IκBα and IκBβ were determined. The results showed that prenatal LPS exposure leads to morphological abnormalities and impaired aortic reactivity in offspring. Prenatal LPS exposure also decreased the protein and mRNA expression of Cx37 in the aorta from offspring rats. NF-κB and phospho-IκBα levels were both increased, IκBα level, however, was decreased in the aorta of offspring from the maternal LPS exposure compared to the controls. Simultaneously, PDTC treatment markedly reversed the action of LPS.

Conclusions

Decreased expression of Cx37 contributed to the aortic dysfunction of prenatal LPS exposure offspring, which should be associated with NF-κB activation.     

Vocal Identity Recognition in Autism Spectrum Disorder

Voices can convey information about a speaker. When forming an abstract representation of a speaker, it is important to extract relevant features from acoustic signals that are invariant to the modulation of these signals. This study investigated the way in which individuals with autism spectrum disorder (ASD) recognize and memorize vocal identity. The ASD group and control group performed similarly in a task when asked to choose the name of the newly-learned speaker based on his or her voice, and the ASD group outperformed the control group in a subsequent familiarity test when asked to discriminate the previously trained voices and untrained voices. These findings suggest that individuals with ASD recognized and memorized voices as well as the neurotypical individuals did, but they categorized voices in a different way: individuals with ASD categorized voices quantitatively based on the exact acoustic features, while neurotypical individuals categorized voices qualitatively based on the acoustic patterns correlated to the speakers'' physical and mental properties.     

The Use of Stem Cells to Study Autism Spectrum Disorder

Autism spectrum disorder (ASD) affects as many as 1 in 68 children and is said to be the fastest-growing serious developmental disability in the United States. There is currently no medical cure or diagnostic test for ASD. Furthermore, the U.S. Food and Drug Administration has yet to approve a single drug for the treatment of autism’s core symptoms. Despite numerous genome studies and the identification of hundreds of genes that may cause or predispose children to ASD, the pathways underlying the pathogenesis of idiopathic ASD still remain elusive. Post-mortem brain samples, apart from being difficult to obtain, offer little insight into a disorder that arises through the course of development. Furthermore, ASD is a disorder of highly complex, human-specific behaviors, making it difficult to model in animals. Stem cell models of ASD can be generated by performing skin biopsies of ASD patients and then dedifferentiating these fibroblasts into human-induced pluripotent stem cells (hiPSCs). iPSCs closely resemble embryonic stem cells and retain the unique genetic signature of the ASD patient from whom they were originally derived. Differentiation of these iPSCs into neurons essentially recapitulates the ASD patient’s neuronal development in a dish, allowing for a patient-specific model of ASD. Here we review our current understanding of the underlying neurobiology of ASD and how the use of stem cells can advance this understanding, possibly leading to new therapeutic avenues.     

Anticipatory Smooth Eye Movements in Autism Spectrum Disorder

Smooth pursuit eye movements are important for vision because they maintain the line of sight on targets that move smoothly within the visual field. Smooth pursuit is driven by neural representations of motion, including a surprisingly strong influence of high-level signals representing expected motion. We studied anticipatory smooth eye movements (defined as smooth eye movements in the direction of expected future motion) produced by salient visual cues in a group of high-functioning observers with Autism Spectrum Disorder (ASD), a condition that has been associated with difficulties in either generating predictions, or translating predictions into effective motor commands. Eye movements were recorded while participants pursued the motion of a disc that moved within an outline drawing of an inverted Y-shaped tube. The cue to the motion path was a visual barrier that blocked the untraveled branch (right or left) of the tube. ASD participants showed strong anticipatory smooth eye movements whose velocity was the same as that of a group of neurotypical participants. Anticipatory smooth eye movements appeared on the very first cued trial, indicating that trial-by-trial learning was not responsible for the responses. These results are significant because they show that anticipatory capacities are intact in high-functioning ASD in cases where the cue to the motion path is highly salient and unambiguous. Once the ability to generate anticipatory pursuit is demonstrated, the study of the anticipatory responses with a variety of types of cues provides a window into the perceptual or cognitive processes that underlie the interpretation of events in natural environments or social situations.     

Future Prospects for Epigenetics in Autism Spectrum Disorder

Molecular Diagnosis & Therapy - Despite decades of investigation into the genetics of autism spectrum disorder (ASD), a current consensus in the field persists that ASD risk is too...     

神经元增殖与孤独症谱系障碍大脑过度生长

在患儿发育早期,某一亚类孤独症谱系障碍（autism spectrum disorders, ASDs）大脑呈过度生长趋势。研究发现,部分伴随有大脑过度增生的患者局部脑区神经元数目异常增多。进一步研究表明,神经元的增殖紊乱与局部脑区神经元数目异常增多密切相关。本综述从ASDs相关信号分子对神经元增殖的调控入手,归纳总结近年来基于神经元增殖调控异常的ASDs大脑过度增生的分子机制研究,为探究ASDs的发病机制提供一个重要的突破口。     

Impaired Perception of Facial Motion in Autism Spectrum Disorder

Facial motion is a special type of biological motion that transmits cues for socio-emotional communication and enables the discrimination of properties such as gender and identity. We used animated average faces to examine the ability of adults with autism spectrum disorders (ASD) to perceive facial motion. Participants completed increasingly difficult tasks involving the discrimination of (1) sequences of facial motion, (2) the identity of individuals based on their facial motion and (3) the gender of individuals. Stimuli were presented in both upright and upside-down orientations to test for the difference in inversion effects often found when comparing ASD with controls in face perception. The ASD group’s performance was impaired relative to the control group in all three tasks and unlike the control group, the individuals with ASD failed to show an inversion effect. These results point to a deficit in facial biological motion processing in people with autism, which we suggest is linked to deficits in lower level motion processing we have previously reported.     

Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder according to the Diagnostic and Statistical Manual of Disorders, Fifth Edition and is defined as a congenital impairment of the central nervous system. ASD may be caused by a chromosomal abnormality or gene mutation. However, these etiologies are insufficient to account for the pathogenesis of ASD. Therefore, we propose that the etiology and pathogenesis of ASD are related to the stress of the endoplasmic reticulum (ER). ER stress, induced by valproic acid, increased in ASD mouse model, characterized by an unfolded protein response that is activated by this stress. The inhibition of neurite outgrowth and expression of synaptic factors are observed in ASD. Similarly, ER stress suppresses the neurite outgrowth and expression of synaptic factors. Additionally, hyperplasia of the brain is observed in patients with ASD. ER stress also enhances neuronal differentiation. Synaptic factors, such as cell adhesion molecule and shank, play important roles in the formation of neural circuits. Thus, ER stress is associated with the abnormalities of neuronal differentiation, neurite outgrowth, and synaptic protein expression. ER stress elevates the expression of the ubiquitin-protein ligase HRD1 for the degradation of unfolded proteins. HRD1 expression significantly increased in the middle frontal cortex in the postmortem of patients with ASD. Moreover, HRD1 silencing improved the abnormalities induced by ER stress. Because other ubiquitin ligases are related with neurite outgrowth, ER stress may be related to the pathogenesis of neuronal developmental diseases via abnormalities of neuronal differentiation or maturation.     

谷氨酸-谷氨酰胺循环异常与孤独症谱系障碍研究进展

孤独症谱系障碍（autism spectrum disorder,ASD）是一种多病因神经发育性疾病,人群患病率高,病因复杂多样,包括炎症、自身免疫、基因异常等,但具体发病机制尚不清楚。在哺乳动物中枢神经系统（central nervous system,CNS）中,谷氨酸是最主要的兴奋性神经递质,也是一种潜在的神经毒素,其引起的兴奋毒性可能导致神经细胞的死亡。而星形胶质细胞和神经元之间谷氨酸-谷氨酰胺的代谢偶联,防止了过量的谷氨酸扩散到周围神经元上,进而避免了神经元的过度兴奋,对神经元起到保护作用。有研究表明,谷氨酸-谷氨酰胺循环异常可能为ASD发生的核心机制。因此,对炎症、自身免疫、基因异常等孤独症谱系障碍经典病因与谷氨酸-谷氨酰胺循环之间的联系进行综述,以期为孤独症谱系障碍分型和治疗提供一种新思路。     

蛋白质组学在妊娠期高血压疾病中的研究进展

蛋白质组学的兴起能快速筛选并鉴定疾病的特异性生物标志物,有助于研究妊娠期高血压疾病的病因、发生机制,通过特异性生物标志物进行早期诊断,从而改善母儿结局,降低母儿严重发病率和死亡率。本文综述近年来与妊娠期高血压疾病相关的蛋白质研究及其在妊娠期高血压疾病患者血液、脑脊液、尿液、羊水、滋养细胞中差异蛋白质谱的分析,为进一步研究提供思路。     

Reduced Personal Space in Individuals with Autism Spectrum Disorder

Maintaining an appropriate distance from others is important for establishing effective communication and good interpersonal relations. Autism spectrum disorder (ASD) is a developmental disorder associated with social difficulties, and it is thus worth examining whether individuals with ASD maintain typical or atypical degrees of social distance. Any atypicality of social distancing may impact daily social interactions. We measured the preferred distances when individuals with ASD and typically developing (TD) individuals approached other people (a male experimenter) and objects (a coat rack with clothes) or when other people approached them. Individuals with ASD showed reduced interpersonal distances compared to TD individuals. The same tendency was found when participants judged their preferred distance from objects. In addition, when being approached by other people, both individuals with ASD and TD individuals maintained larger interpersonal distances when there was eye contact, compared to no eye contact. These results suggest that individuals with ASD have a relatively small personal space, and that this atypicality exists not only for persons but also for objects.     

Auditory Processing in High-Functioning Adolescents with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder including abnormalities in perceptual processing. We measure perception in a battery of tests across speech (filtering, phoneme categorization, multisensory integration) and music (pitch memory, meter categorization, harmonic priming). We found that compared to controls, the ASD group showed poorer filtering, less audio-visual integration, less specialization for native phonemic and metrical categories, and a higher instance of absolute pitch. No group differences were found in harmonic priming. Our results are discussed in a developmental framework where culture-specific knowledge acquired early compared to late in development is most impaired, perhaps because of early-accelerated brain growth in ASD. These results suggest that early auditory remediation is needed for good communication and social functioning.     

Toward Innovative,Cost-Effective,and Systemic Solutions to Improve Outcomes and Well-Being of Military Families Affected by Autism Spectrum Disorder

The burdens faced by military families who have a child with autism are unique. The usual challenges of securing diagnostic, treatment, and educational services are compounded by life circumstances that include the anxieties of war, frequent relocation and separation, and a demand structure that emphasizes mission readiness and service. Recently established military autism-specific health care benefits set the stage for community-viable and cost-effective solutions that can achieve better outcomes for children and greater well-being for families. Here we argue for implementation of evidence-based solutions focused on reducing age of diagnosis and improving access to early intervention, as well as establishment of a tiered menu of services, individualized to the child and family, that fit with the military ethos and system of health care. Absence of this new model of care could compromise the utility and sustainability of the autism-specific benefit.