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The neuronal RNA‐binding protein HuD is involved in synaptic plasticity and learning and memory mechanisms. These effects are thought to be due to HuD‐mediated stabilization and translation of target mRNAs associated with plasticity. To investigate the potential role of HuD in drug addiction, we first used bioinformatics prediction algorithms together with microarray analyses to search for specific genes and functional networks upregulated within the forebrain of HuD overexpressing mice (HuDOE). When this set was further limited to genes in the knowledgebase of addiction‐related genes database (KARG) that contains predicted HuD‐binding sites in their 3′ untranslated regions (3′UTRs), we found that HuD regulates networks that have been associated with addiction‐like behavior. These genes included Bdnf and Camk2a, 2 previously validated HuD targets. Since addiction is hypothesized to be a disorder stemming from altered gene expression causing aberrant plasticity, we sought to test the role of HuD in cocaine conditioned placed preference (CPP), a model of addiction‐related behaviors. HuD mRNA and protein were upregulated by CPP within the nucleus accumbens of wild‐type C57BL/6J mice. These changes were associated with increased expression of Bdnf and Camk2a mRNA and protein. To test this further, we trained HuDOE and wild‐type mice in CPP and found that HuDOE mice showed increased cocaine CPP compared with controls. This was also associated with elevated expression of HuD target mRNAs and proteins, CaMKIIα and BDNF. These findings suggest HuD involvement in addiction‐related behaviors such as cocaine conditioning and seeking, through increased plasticity‐related gene expression. [ABSTRACT FROM AUTHOR]

Autism Spectrum Disorder (ASD) is associated with persistent impairments in adaptive abilities across multiple domains. These social, personal, and communicative impairments become increasingly pronounced with development, and are present regardless of IQ. The Vineland Adaptive Behavior Scales, Second Edition (Vineland‐II) is the most commonly used instrument for quantifying these impairments, but minimal clinically important differences (MCIDs) on Vineland‐II scores have not been rigorously established in ASD. We pooled data from several consortia/registries (EU‐AIMS LEAP study, ABIDE‐I, ABIDE‐II, INFOR, Simons Simplex Collection and Autism Treatment Network [ATN]) and clinical investigations and trials (Stanford, Yale, Roche) resulting in a data set of over 9,000 individuals with ASD. Two approaches were used to estimate MCIDs: distribution‐based methods and anchor‐based methods. Distribution‐based MCID [d‐MCID] estimates included the standard error of the measurement, as well as one‐fifth and one‐half of the covariate‐adjusted standard deviation (both cross‐sectionally and longitudinally). Anchor‐based MCID [a‐MCID] estimates include the slope of linear regression of clinician ratings of severity on the Vineland‐II score, the slope of linear regression of clinician ratings of longitudinal improvement category on Vineland‐II change, the Vineland‐II change score maximally differentiating clinical impressions of minimal versus no improvement, and equipercentile equating. Across strata, the Vineland‐II Adaptive Behavior Composite standardized score MCID estimates range from 2.01 to 3.2 for distribution‐based methods, and from 2.42 to 3.75 for sample‐size‐weighted anchor‐based methods. Lower Vineland‐II standardized score MCID estimates were observed for younger and more cognitively impaired populations. These MCID estimates enable users of Vineland‐II to assess both the statistical and clinical significance of any observed change. Autism Res2018, 11: 270–283. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary: The Vineland Adaptive Behavior Scales (2nd edition; Vineland‐II) is the most widely used scale for assessing day‐to‐day “adaptive” skills. Yet, it is unknown how much Vineland‐II scores must change for those changes to be regarded as clinically significant. We pooled data from over 9,000 individuals with ASD to show that changes of 2–3.75 points on the Vineland‐II Composite score represent the “minimal clinically‐important difference.” These estimates will help evaluate the benefits of potential new treatments for ASD. [ABSTRACT FROM AUTHOR]

Objective: This paper reviews the current status of gene therapy in the neuroendocrine system and discusses the interventive potential of this methodology for neuroendocrine pathologies associated with aging.Background and Results: A brief description is first presented of the viral-vector-based gene delivery systems being currently used in the neuroendocrine system, namely the adenoviral and herpetic (HSV1) vector systems. Next, an account of the neuroendocrine pathologies for which gene therapy approaches in animal models are being implemented is provided. This includes the treatment of experimental pituitary tumors by adenoviral-vector-mediated transfer of the suicide gene for the HSV-1 thymidine kinase. At the hypothalamic level, an adenovirus harboring the cDNA for arginine vasopressin has been used in Brattleboro rats to correct their diabetes insipidus. Next, the interventive potential of gene therapy for correcting age-associated neurodegenerative processes at neuroendocrine level is outlined. Finally, the role that emerging technologies may play in the development of future genetic therapies for aging is considered.Conclusion: Although effective implementation of gene therapy strategies still faces significant technical obstacles, these are likely to be progressively overcome as gene delivery systems are refined. [ABSTRACT FROM AUTHOR]

The dynamics of prolactin (PRL) and luteinizing hormone (LH) secretion in the anoestrous bitch is poorly known. Therefore, the objective of this study was to characterize the 24 h profiles of serum PRL and LH in crossbred anoestrous bitches and to assess whether a relationship exists between the secretory patterns of these two hormones. Serum PRL and LH concentrations were measured in 10 healthy anoestrous crossbred bitches at 145 min intervals for 24 h. During the experiment the animals received continuous artificial illumination and remained undisturbed except at the time of blood sampling. Serum PRL was measured by a homologous enzyme-linked immunosorbent assay, whereas LH and progesterone (P4) were determined by radioimmunoassay. The anoestrous state of the bitches was assessed by vaginal cytology, vaginoscopy and physical examination. Two groups of animals were identified according to their PRL levels: a high PRL group (n=3, mean ± SEM 12.3 ± 2.7 ng/ml) and a low PRL group (n=7, mean ± SEM: 2.5 ± 0.9 ng/ml). In the low PRL group, the PRL profiles were flat and did not show any significant circadian pattern. Nevertheless, occasional single-point peaks were detected in some of the bitches. In the high PRL group the individual PRL profiles were variable. To detect the presence of a circadian change of PRL concentrations, two different sets of time windows (TW) of sampling were studied. The first set was: day [TW1A, samples 1–5 (0900–1840 h)] and night [TW1B, samples 6–10 (2105–0645 h)]. The second set was chosen after visual inspection of the average PRL profiles for both (high and low) groups: [TW2A, samples 3–7 (1350–2330 h) and TW2B, samples 1–2 and 8–10 (0155–1125 h)]. PRL concentrations were not significantly different between day and night. In the high PRL group, but not in the low PRL group, average serum PRL was significantly (p < 0.01) higher in TW2A than TW2B. In both groups serum LH levels were more homogeneous than PRL levels. Neither TW showed circadian changes in LH patterns of secretion (TW1A versus TW1B, p < 0.69; TW2A versus TW2B, p < 0.88). On the other hand, bitches in the high PRL group showed significantly (p < 0.01) lower serum LH levels than those in the low PRL group of animals. Serum PRL concentrations presented a significant inverse correlation with LH concentrations (r=-0.21, p < 0.03) and a significant positive correlation with P4 concentrations across the study (0.92, p < 0.01). It is concluded that in anoestrous crossbred bitches serum PRL is highly variable and inversely related to LH. No circadian rhythm of PRL secretion appears to exist in most anoestrous bitches. [ABSTRACT FROM AUTHOR]

The thymic-pituitary axis constitutes a bidirectional circuit where the ascending feedback loop is effected by thymic factors of epithelial origin. The aim of the present article is, first, to introduce the idea of an immune-neuroendocrine homeostatic network in higher animals. Next, the relevance of the thymus in this network and the possible role of this gland in the neuroendocrine imbalances associated with aging are discussed. A number of studies are next reviewed which show that the endocrine thymus produces several bioactive molecules, generally called thymic hormones, which in addition to possessing immunoregulatory properties are also active on nervous and endocrine circuits. In particular, the reported activities of thymosin fraction five, thymosin alpha 1 and thymosin beta 4 on beta-endorphin, adrenocorticotropic hormone, glucocorticoids, luteinizing hormone-releasing hormone and luteinizing hormone secretion in different animal and cell models are reviewed. The known hypophysiotropic actions of other thymic hormones like thymulin, homeostatic thymus hormone and thymus factor are also summarized, and the impact of aging on pituitary responsiveness to thymic hormones is discussed. As a conclusion, it is proposed that in addition to its central role in the regulation of the immune function, the thymus gland may extend its influence to nonimmunologic components of the body, including the neuroendocrine system. The early onset of thymus involution might, therefore, act as a triggering event which would initiate the gradual decline in homeostatic potential that characterizes the aging process. [ABSTRACT FROM AUTHOR]

The long-term consequences of adenovirus-mediated conditional cytotoxic gene therapy for gliomas remain uncharacterized. We report here detection of active brain inflammation 3 months after successful inhibition of syngeneic glioma growth. The inflammatory infiltrate consisted of activated macrophages/microglia and astrocytes, and T lymphocytes positive for leucosyalin, CD3 and CD8, and included secondary demyelination. We detected strong widespread herpes simplex virus I thymidine kinase immunoreactivity and vector genomes throughout large areas of the brain. Thus, patient evaluation and the design of clinical trials in ongoing and future gene therapy for brain glioblastoma must address not only tumor-killing efficiency, but also long-term active brain inflammation, loss of myelin fibers and persistent transgene expression. [ABSTRACT FROM AUTHOR]

Background: Apraglutide is a novel long-acting GLP-2 analog in development for short bowel syndrome with intestinal failure (SBS-IF). This multicenter, open-label, phase 2 study in SBS-IF and colon-in-continuity (CiC) investigates the safety and efficacy of apraglutide., Methods: This was a 52-week phase 2 metabolic balance study (MBS) in 9 adult patients with SBS-IF-CiC receiving once-weekly subcutaneous apraglutide injections. Safety was the primary endpoint. Secondary endpoints included changes in absorption parameters (MBS at baseline, after 4 weeks with stable parenteral support (PS), and 48 weeks), PS needs (48-week PS adjustment period based on monthly 48-h fluid balances) and intestinal morphology and motility (static and cine MRI at baseline and 4, 24 and 48 weeks)., Results: PS volume decreased by -4702 mL/week (-52 %; p < 0.001) at week 52. Seven patients (78 %) achieved ≥1 day off PS at week 52. At 4 weeks, fecal output was reduced by 253 g/day (p = 0.013). At 48 weeks, increases in wet weight absorption by 316 g/day (p = 0.039), energy absorption by 1134 kJ/day (p = 0.041) and carbohydrate absorption by 56.1 g/day (p = 0.024) were observed. Moreover, small bowel length increased from 29.7 to 40.7 cm (p = 0.012), duodenal wall thickness increased by 0.8 mm (p = 0.02) and motility in the proximal colon was reduced (p = 0.031). A total of 127 adverse events was reported, which were mostly mild to moderate., Conclusion: Apraglutide had an acceptable safety profile and was associated with significant reductions in PS needs and days off PS, improvements in intestinal absorption, and structural and functional intestinal changes in patients with SBS-IF-CiC., Clinicaltrials: gov, Number NCT04964986., Competing Interests: Declaration of competing interest Astrid Verbiest: nothing to declare. Mark Krogh Hvistendahl: full time employee at Zealand Pharma A/S as per 01/Jun2024. Federico Bolognani: FB was an employee of VectivBio, now part of Ironwood Pharmaceuticals, Inc., at the time of the conduct of the study. Carrie Li: CL was an employee of VectivBio, now part of Ironwood Pharmaceuticals, Inc., at the time of the conduct of the study and data analysis. Nader N. Youssef: NNY was an employee of VectivBio, now part of Ironwood Pharmaceuticals, Inc., at the time of the conduct of the study. Susanna Huh: Employee of Ironwood Pharmaceuticals. Alex Menys: CEO of Motilent. Gauraang Bhatnagar: Clinical Imaging Lead at Motilent. Ragna Vanslembrouck: nothing to declare. Ronald Peeters: nothing to declare. Ricardo Sartoris: nothing to declare. Pieter Vermeersch: nothing to declare. Lucas Wauters: nothing to declare. Kristin Verbeke: nothing to declare. Palle Bekker Jeppesen: Albumedix A/S, ArTara Therapeutics, Bainan Biotech, Baxter, Coloplast A/S, Ferring Pharmaceuticals, Fresenius Kabi, GlyPharma Therapeutic, Hanmi Pharmaceuticals, Ironwood, Naia Pharmaceuticals, NPS Pharmaceuticals, Protara Therapeutics, Shire, Takeda, The Novo Nordisk Foundation, Therachon, VectiveBio AG, Zealand Pharma A/S Francisca Joly: has received grants/research support/honoraria or consultation fees from Agomab, Baxter, Fresenius Kabi, Nestlé Health Sciences, BBraun, Theradial, Mayoli, Biocodex, mobile3e Consulting, Carembouche, NPS Pharmaceuticals, NorthSea Therapeutics, Shire, Takeda, Therachon, VectivBio and Zealand Pharma. Tim Vanuytsel: has served as a speaker for Baxter, Fresenius Kabi, Ironwood, VectivBio, Zealand Pharma and consultant for Agomab, Baxter, Hanmi Pharmaceuticals, Ironwood, NorthSea Therapeutics, VectivBio, Zealand Pharma., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Renal impairment is a common complication in patients with short bowel syndrome with intestinal failure (SBS-IF). Glucagon-like peptide-2 analogs, such as apraglutide, have been developed as a treatment option for SBS-IF. This study assessed the potential for apraglutide overexposure in individuals with severely impaired renal function versus healthy volunteers with normal renal function. In this phase 1, open-label, multicenter, nonrandomized, parallel-group study, a single dose of apraglutide 5 mg was administered subcutaneously to individuals with severely impaired renal function (<30 mL/min/1.73 m 2 ) and healthy volunteers with normal renal function (≥90 mL/min/1.73 m 2 ). Primary pharmacokinetic endpoints were maximum observed concentration (C max ) and exposure to apraglutide (area under the curve [AUC] from time 0 to infinity [AUC inf ], and AUC from time 0 to the last quantifiable concentration [AUC last ]). Each group comprised 8 individuals. Results show that patients with severe renal impairment do not have increased apraglutide exposure. Apraglutide achieved a lower C max and AUC inf in individuals with severe renal impairment versus those with normal renal function (C max = 36.9 vs 59.5 ng/L; AUC inf = 3100 vs 4470 h · ng/mL, respectively). The respective geometric mean ratios were 0.620 and 0.693 for C max and AUC inf , and the upper bound of their 90% confidence intervals were <2, indicating patients with severe renal impairment were not overexposed to apraglutide versus those with normal renal function. Adverse events were mild or moderate in severity. Apraglutide does not require dose reduction for any degree of renal impairment and could be used in a broader patient population of renally impaired patients without dose adjustment., (© 2024 VectivBio AG. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Apraglutide (FE 203799) is a glucagon-like peptide-2 (GLP-2) analog under development for the treatment of intestinal failure associated with short bowel syndrome (SBS-IF) and graft-versus-host disease (GvHD). Compared with native GLP-2, apraglutide has slower absorption, reduced clearance, and higher protein binding, enabling once-weekly dosing. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of apraglutide in healthy adults. Healthy volunteers were randomized to receive 6 weekly subcutaneous administrations of 1, 5, or 10 mg apraglutide or placebo. PK and citrulline (an enterocyte mass PD marker) samples were collected at multiple time points. Kinetic parameters of apraglutide and citrulline were calculated using noncompartmental analysis; repeated PD measures were analyzed with a mixed model of covariance. A population PK/PD model was developed that also included data from a previous phase 1 study in healthy volunteers. Twenty-four subjects were randomized; 23 received all study drug administrations. Mean estimated apraglutide clearance was 16.5-20.7 l/day, and mean volume of distribution was 55.4-105.0 liters. A dose-dependent increase in citrulline plasma concentration was observed, with 5-mg and 10-mg doses inducing higher citrulline levels than 1-mg doses and placebo. PK/PD analysis showed that weekly 5-mg apraglutide induced the maximal citrulline response. Increased plasma citrulline levels were sustained for 10-17 days after the final apraglutide administration. Apraglutide displays predictable dose-dependent PK and PD profiles, with a 5-mg dose showing significant PD effects. Results suggest that apraglutide has early and enduring effects on enterocyte mass and supports the continued development of weekly subcutaneous apraglutide for SBS-IF and GvHD patient populations. SIGNIFICANCE STATEMENT: Once-weekly subcutaneous apraglutide results in dose-dependent elevations of plasma citrulline (an enterocyte mass pharmacodynamic marker) with parameters suggesting that apraglutide has lasting effects on enterocyte mass and the potential to provide therapeutic benefits. This is the first report of a model relating glucagon-like peptide-2 (GLP-2) agonism and its effects in intestinal mucosa, affording not only the ability to predict pharmacologic effects of GLP-2 analogs but also the exploration of optimal dosing regimens for this drug class across populations with different body weights., (Copyright © 2023 by The Author(s).)

Background: Apraglutide is a novel long-acting glucagon-like peptide-2 (GLP-2) analog designed for once-weekly subcutaneous dosing, with the potential to increase fluid and nutrient absorption by the remnant intestine of patients who have short bowel syndrome (SBS) with intestinal insufficiency (SBS-II) or intestinal failure (SBS-IF). This trial investigated the safety and effects on intestinal absorption of apraglutide in patients with SBS-II and SBS-IF., Methods: In this open-label, phase 1 and 2 trial, adult patients with SBS-II (n = 4) or SBS-IF (n = 4) and a fecal output of ≥1500 g/day received once-weekly subcutaneous 5 mg apraglutide for 4 weeks. Safety was the primary end point. Secondary end points included change from baseline in intestinal absorption of wet weight (indicative of fluid absorption), electrolytes, and energy (by bomb calorimetry) measured by inpatient metabolic balance studies., Results: Common treatment-related adverse events were decreased gastrointestinal (GI) stoma output (n = 6), stoma complications (n = 6), GI stoma complications (n = 5), nausea (n = 5), flatulence (n = 4), abnormal GI stoma output (n = 4), polyuria (n = 3), and abdominal pain (n = 3). The only treatment-related serious adverse event (experienced in one patient) was abdominal pain. Apraglutide significantly increased wet weight and energy absorption by an adjusted mean of 741 g/day (95% CI, 194 to 1287; P = 0.015) and 1095 kJ/day (95% CI, 196 to 1994; P = 0.024), respectively. Sodium and potassium absorption significantly increased by an adjusted mean of 38 mmol/day (95% CI, 3 to 74; P = 0.039) and 18 mmol/day (95% CI, 4 to 32; P = 0.020), respectively., Conclusion: Once-weekly 5 mg apraglutide was well tolerated in patients with SBS-II and SBS-IF and significantly improved the absorption of fluids, electrolytes, and energy., (© 2022 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Background: Treatment with glucagon-like peptide-2 (GLP-2) analogs improve intestinal adaptation in patients with short bowel syndrome-associated intestinal failure (SBS-IF) and may reduce parenteral support requirements. Apraglutide is a novel, long-acting GLP-2 analog designed for once-weekly dosing. This trial investigated the safety and efficacy of apraglutide in patients with SBS-IF., Methods: In this placebo-controlled, double-blind, randomized, crossover phase 2 trial, eight adults with SBS-IF were treated with once-weekly 5-mg apraglutide doses and placebo for 4 weeks, followed by once-weekly 10-mg apraglutide doses for 4 weeks, with a washout period of 6-10 weeks between treatments. Safety was the primary end point. Secondary end points included changes from baseline in urine volume output compared with placebo, collected for 48 h before and after each treatment period., Results: Common treatment-related adverse events (AEs) were mild to moderate and included polyuria, decreased stoma output, stoma complications, decreased thirst, and edema. No serious AEs were considered to be related to apraglutide treatment. The safety profile was comparable for the lower and higher doses. Treatment with once-weekly 5- and 10-mg apraglutide doses significantly increased urine volume output by an adjusted mean of 714 ml/day (95% CI, 490-939; P < .05) and 795 ml/day (95% CI, 195-1394; P < .05), respectively, compared with placebo, with no significant differences between doses., Conclusions: Once-weekly apraglutide was well tolerated at both tested doses and significantly increased urine volume output, providing evidence for increased intestinal fluid absorption. A phase 3 trial is underway in adults with SBS-IF., (© 2021 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Rigidity contributes to severity and functional impairment in autism spectrum disorder (ASD). There is an unmet need for a valid, reliable, and sensitive outcome measure to assess rigidity in ASD., Objective: To develop and validate the Montefiore-Einstein Rigidity Scale-Revised (MERS-R) to assess the Behavioral Rigidity Domain (BRD), Cognitive Rigidity Domain (CRD), and Protest Domain (PD)., Materials and Methods: The MERS-R was administered to 93 individuals with ASD (children and adults, high and low IQ) at baseline, Week 2, and Week 12. Internal consistency was assessed for domain scores, Total Rigidity Composite (TRC = BRD + CRD), and Total Composite (TC = BRD + CRD + PD) with Cronbach's α. Intraclass correlation coefficients (ICCs) assessed test-retest reliability from baseline to weeks 2 and 12. Pearson's correlations assessed the relationship between the MERS-R and age, sex, and IQ. Convergent validity assessed the correlation of MERS-R scores to the Children's Yale-Brown Obsessive-Compulsive Scale-ASD (CY-BOCS-ASD)., Results: Good internal consistency was demonstrated for the BRD, PD, TRC and TC (Cronbach's α = 0.83, 0.88, 0.82, and 0.89, respectively) and adequate internal consistency for the CRD (α = .72). Good or excellent test-test reliability was demonstrated over two weeks (ICC: 0.66─.79), and fair or good reliability over 12 weeks (ICC: 0.56-66). MERS-R scores did not differ by age, sex, or IQ (p: 0.16─.99) with the exception that higher PD scores were associated with younger age (correlation = -0.25, p = 0.01). Significant convergent validity was demonstrated between all MERS-R scores and the CY-BOCS-ASD (p < 0.0001)., Discussion: The MERS-R demonstrated internal consistency, test-retest reliability, convergent validity and applicability to autistic children and adults of different sexes and IQ levels. It is a valid, sensitive, and reliable instrument to measure behavioral and cognitive rigidity in ASD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

There are no approved pharmacological therapies to address the core symptoms of autism spectrum disorder (ASD), namely, persistent deficits in social communication and social interaction and the presence of restricted, repetitive patterns of behaviors, interests, or activities. The neuropeptide vasopressin has been implicated in the regulation of social behaviors, and its modulation has emerged as a therapeutic target for ASD. The phase 2 VANILLA clinical trial reported here evaluated balovaptan, an orally administered selective vasopressin V1a receptor antagonist, in 223 men with ASD and intelligence quotient ≥70. The drug was administered daily for 12 weeks and was compared with placebo. Participants were randomized to placebo ( n = 75) or one of three balovaptan dose arms (1.5 mg, n = 32; 4 mg, n = 77; 10 mg, n = 39). Balovaptan treatment was not associated with a change from baseline compared with placebo at 12 weeks in the primary efficacy endpoint (Social Responsiveness Scale, 2nd Edition). However, dose-dependent and clinically meaningful improvements on the Vineland-II Adaptive Behavior Scales composite score were observed for participants treated with balovaptan 4 or 10 mg compared with placebo. This was driven principally by improvements in the Vineland-II socialization and communication scores. Balovaptan was well tolerated across all doses, and no drug-related safety concerns were identified. These results support further study of balovaptan as a potential treatment for the socialization and communication deficits in ASD., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Autism spectrum disorder (ASD) is a developmental disorder underdiagnosed in adults. To date, no consistent evidence of alterations in brain structure has been reported in adults with ASD and few studies were conducted at that age. We analyzed structural magnetic resonance imaging data from 167 high functioning adults with ASD and 195 controls. We ran our analyses on a discovery (n = 301) and a replication sample (n = 61). The right caudal anterior cingulate cortical thickness was significantly thinner in adults with ASD compared to controls in both the discovery and the replication sample. Our work underlines the relevance of studying the brain anatomy of an adult ASD population.

Despite the high clinical burden, little is known about pathophysiology underlying autism spectrum disorder (ASD). Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have found atypical synchronization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance of these alterations. Here, we addressed these questions in four large ASD cohorts. Using rs-fMRI, we identified functional connectivity alterations associated with ASD. We tested for associations of these imaging phenotypes with clinical and demographic factors such as age, sex, medication status, and clinical symptom severity. Our results showed reproducible patterns of ASD-associated functional hyper- and hypoconnectivity. Hypoconnectivity was primarily restricted to sensory-motor regions, whereas hyperconnectivity hubs were predominately located in prefrontal and parietal cortices. Shifts in cortico-cortical between-network connectivity from outside to within the identified regions were shown to be a key driver of these abnormalities. This reproducible pathophysiological phenotype was partially associated with core ASD symptoms related to communication and daily living skills and was not affected by age, sex, or medication status. Although the large effect sizes in standardized cohorts are encouraging with respect to potential application as a treatment and for patient stratification, the moderate link to clinical symptoms and the large overlap with healthy controls currently limit the usability of identified alterations as diagnostic or efficacy readout., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Attention Deficit and Hyperactive Disorder (ADHD) and Autism Spectrum Disorders (ASD) are frequent comorbid neurodevelopmental conditions and the overlap between both disorders remains to be delineated. A more complete understanding of the shared genetic and environmental factors is needed. Using a family-based method, we evaluated the risk of ADHD in a group of relatives with an ASD proband (ASD-) and a group of relatives with an ASD and ADHD proband (ASD+). We enrolled 1245 individuals in the study: 499 probands, their 746 first-degree relatives and 140 controls. We used a multivariate generalized estimating equation (GEE) model, in which the dependent variable was the ADHD diagnosis in the relatives and the independent variable the ASD+ or ASD- in probands. We adjusted for sociodemographic factors (age, sex, IQ) and for the nature of the familial relationship with the affected proband (parent or sibling). Among the probands, there were 287 ASD- and 212 ASD+ individuals. ADHD was more frequent in relatives (19%) than in the control group (7%) (p = 0.001). The risk of ADHD was higher in the ASD+ relatives group than in the ASD- relatives group (GEE model OR 1.58 [95% CI 1.04-2.38], p = 0.032). This result was found in parents (OR 1.96 [95% CI  1.14-3.36], but not in siblings (OR 1.28 [95% CI 0.84-1.94], p = 0.434). Our study provides a representative estimate of the family distribution of ADHD in relatives of ASD probands but supports the modest effect of shared genetic and environmental factors between both disorders.

The current theory implying local, short-range overconnectivity in autism spectrum disorder, contrasting with long-range underconnectivity, is based on heterogeneous results, on limited data involving functional connectivity studies, on heterogeneous paediatric populations and non-specific methodologies. In this work, we studied short-distance structural connectivity in a homogeneous population of males with high-functioning autism spectrum disorder and used a novel methodology specifically suited for assessing U-shaped short-distance tracts, including a recently developed tractography-based atlas of the superficial white matter fibres. We acquired diffusion-weighted MRI for 58 males (27 subjects with high-functioning autism spectrum disorder and 31 control subjects) and extracted the mean generalized fractional anisotropy of 63 short-distance tracts. Neuropsychological evaluation included Wechsler Adult Intelligence Scale IV (WAIS-IV), Communication Checklist-Adult, Empathy Quotient, Social Responsiveness Scale and Behaviour Rating Inventory of Executive Function-Adult (BRIEF-A). In contradiction with the models of short-range over-connectivity in autism spectrum disorder, we found that patients with autism spectrum disorder had a significantly decreased anatomical connectivity in a component comprising 13 short tracts compared to controls. Specific short-tract atypicalities in temporal lobe and insula were significantly associated with clinical manifestations of autism spectrum disorder such as social awareness, language structure, pragmatic skills and empathy, emphasizing their importance in social dysfunction. Short-range decreased anatomical connectivity may thus be an important substrate of social deficits in autism spectrum disorder, in contrast with current models.

Psychiatric comorbidities and use of psychotropic medications are common among patients with autism spectrum disorder (ASD). However, most previous research used data from the United States (US) and few studies have compared medication use in ASD to control groups, making contextualization of results difficult. In the United Kingdom (UK), general practitioners play a key role in the management of ASD. We conducted a retrospective, cross-sectional study over calendar year 2015, using primary care data from the UK. We identified a prevalent cohort of ASD cases (n = 10,856) and matched control groups of (a) general population (n = 21,712) and (b) attention deficit hyperactivity disorder (ADHD; n = 7,058) on age, sex and region. We described psychiatric comorbidities, psychotropic medications, and healthcare utilization in all three cohorts. Within the ASD cohort, we used multivariable logistic regression models to explore associations between patient characteristics and the outcomes of: any psychotropic medication, polypharmacy, and number of primary care visits. We used conditional logistic regression to compare the ASD and control groups. Psychiatric comorbidities were recorded for 41.5% of ASD patients; 32.3% received psychotropic medication and 9.8% received polypharmacy. Increased age and all psychiatric comorbidities (except conduct disorder) were associated with treatment use. Males were less likely to receive a treatment than females [Odds ratio (OR) 0.74 (0.66-0.83)]. ASD patients were more likely to take psychotropic medications than the general population [OR 4.91 (4.46-5.40)], but less likely compared to ADHD patients [OR 0.40 (0.37-0.44)]. Overall, rates of medication use in the UK were lower than those previously reported in the US. Autism Research 2018, 11: 1690-1700. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We used electronic medical records from the UK, to describe the amount of psychiatric comorbidities, psychotropic medication use and healthcare resource use in ASD. Around one in three people with ASD were prescribed a psychotropic medication, which was more than the general population, but less than for those with ADHD. Increased age, psychiatric comorbidities and female gender were all independently associated with psychotropic medication use. Rates of medication use in the UK were lower than those previously reported in the US., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

The aim of this study was to generate a patient-centered conceptual model of the impact of living with autism spectrum disorder, which can be used to support the selection of outcome measures for clinical trials. Following an initial literature review to identify preliminary concepts and inform an interview guide, in-depth face-to-face interviews were conducted with adolescents and adults with autism spectrum disorder (IQ ⩾ 70) (n = 10), as well as parents of children, adolescents, and adults with autism spectrum disorder (IQ ⩾ 70) (n = 26). Data were analyzed using established qualitative research methods. The resultant conceptual model contains three interrelated domains reflecting core symptoms of autism spectrum disorder (communication deficits, socialization deficits, and restrictive, repetitive patterns of behavior), three domains reflecting associated symptoms of autism spectrum disorder (physical, cognitive, and emotional/behavioral), and three domains representing the impacts of living with autism spectrum disorder (impacts on activities of daily living, school/work, and social life). Interview respondents also cited social communication deficits as priority targets for new treatments. The conceptual model provides a patient-centered perspective of relevant concepts of autism spectrum disorder from the perspectives of people with autism spectrum disorder and their parents and offers a valuable tool for identifying valid patient-centered outcome measures for future clinical trials.

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression and are implicated in the etiology of several neuropsychiatric disorders, including substance use disorders (SUDs). Using in silico genome-wide sequence analyses, we identified miR-495 as a miRNA whose predicted targets are significantly enriched in the Knowledgebase for Addiction Related Genes (ARG) database (KARG; http://karg.cbi.pku.edu.cn). This small non-coding RNA is also highly expressed within the nucleus accumbens (NAc), a pivotal brain region underlying reward and motivation. Using luciferase reporter assays, we found that miR-495 directly targeted the 3'UTRs of Bdnf, Camk2a and Arc. Furthermore, we measured miR-495 expression in response to acute cocaine in mice and found that it is downregulated rapidly and selectively in the NAc, along with concomitant increases in ARG expression. Lentiviral-mediated miR-495 overexpression in the NAc shell (NAcsh) not only reversed these cocaine-induced effects but also downregulated multiple ARG mRNAs in specific SUD-related biological pathways, including those that regulate synaptic plasticity. miR-495 expression was also downregulated in the NAcsh of rats following cocaine self-administration. Most importantly, we found that NAcsh miR-495 overexpression suppressed the motivation to self-administer and seek cocaine across progressive ratio, extinction and reinstatement testing, but had no effect on food reinforcement, suggesting that miR-495 selectively affects addiction-related behaviors. Overall, our in silico search for post-transcriptional regulators identified miR-495 as a novel regulator of multiple ARGs that have a role in modulating motivation for cocaine.

This study investigated psychotropic medication usage in two large, cohorts of people with autism spectrum disorder (ASD) throughout the calendar year 2014. The cohorts referred to individuals with commercial (employer-sponsored) and Medicaid insurance in the United States. We aimed to understand prescribing patterns of such medications across a wide age-range and in the presence/absence of other clinical and non-clinical characteristics, including psychiatric comorbidities. We described the prevalence and length of prescriptions by age, psychiatric comorbidity and overall. We also fitted multivariable logistic regression models to describe the relationship between treatments and subject characteristics simultaneously. Eighty percent of the identified population was male, although gender did not impact the odds of receiving medication. Medication use was strongly associated with age, increasing most rapidly before adulthood; generally plateauing thereafter. All psychiatric comorbidities studied also individually increased the chances of medication use, with epilepsy and ADHD having the highest associations in both the commercial (OR > 7) and Medicaid (OR around 12) cohorts. Those in non-capitated insurance plans, in foster care and white individuals also had increased odds of prescriptions. Overall, slightly more Medicaid enrollees received any psychotropic treatment (commercial: 64%, Medicaid: 69%). Nonetheless in both cohorts, a large proportion of individuals received treatment even without a diagnosis of any other psychiatric comorbidity (commercial: 31%, Medicaid: 33%). In summary, this report sheds new light on the latest patterns of psychiatric comorbidity profile and psycho-pharmacological treatment patterns in ASD Autism Res 2017, 10: 2037-2047. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: this study identified a large number of children and adults in the US with autism spectrum disorder (autism) from employer-sponsored and government funded (Medicaid) health insurance data. Psychotropic medications were used by over two thirds of people, and four in ten people received two medications at the same time. The chances of receiving medication increased for individuals with other psychiatric conditions (e.g., ADHD), and also increased with age., (© 2017 International Society for Autism Research, Wiley Periodicals, Inc.)

The cerebellum is implicated in social cognition and is likely to be involved in the pathophysiology of autism spectrum disorder (ASD). The goal of our study was to explore cerebellar morphology in adults with ASD and its relationship to eye contact, as measured by fixation time allocated on the eye region using an eye-tracking device. Two-hundred ninety-four subjects with ASD and controls were included in our study and underwent a structural magnetic resonance imaging scan. Global segmentation and cortical parcellation of the cerebellum were performed. A sub-sample of 59 subjects underwent an eye tracking protocol in order to measure the fixation time allocated to the eye region. We did not observe any difference in global cerebellar volumes between ASD patients and controls; however, regional analyses found a decrease of the volume of the right anterior cerebellum in subjects with ASD compared to controls. There were significant correlations between fixation time on eyes and the volumes of the vermis and Crus I. Our results suggest that cerebellar morphology may be related to eye avoidance and reduced social attention. Eye tracking may be a promising neuro-anatomically based stratifying biomarker of ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by dysfunctions in social interactions resulting from a complex interplay between immunogenetic and environmental risk factors. Autoimmunity has been proposed as a major etiological component of ASD. Whether specific autoantibodies directed against brain targets are involved in ASD remains an open question. Here, we identified within a cohort an ASD patient with multiple circulating autoantibodies, including the well-characterized one against glutamate NMDA receptor (NMDAR-Ab). The patient exhibited alexithymia and previously suffered from two major depressive episodes without psychotic symptoms. Using a single molecule-based imaging approach, we demonstrate that neither NMDAR-Ab type G immunoglobulin purified from the ASD patient serum, nor that from a seropositive healthy subject, disorganize membrane NMDAR complexes at synapses. These findings suggest that the autistic patient NMDAR-Abs do not play a direct role in the etiology of ASD and that other autoantibodies directed against neuronal targets should be investigated.

The KH-type splicing regulatory protein (KSRP) promotes the decay of AU-rich element (ARE)-containing mRNAs. Although KSRP is expressed in the nervous system, very little is known about its role in neurons. In this study, we examined whether KSRP regulates the stability of the ARE-containing GAP-43 mRNA. We found that KSRP destabilizes this mRNA by binding to its ARE, a process that requires the presence of its fourth KH domain (KH4). Furthermore, KSRP competed with the stabilizing factor HuD for binding to these sequences. We also examined the functional consequences of KSRP overexpression and knockdown on the differentiation of primary hippocampal neurons in culture. Overexpression of full length KSRP or KSRP without its nuclear localization signal hindered axonal outgrowth in these cultures, while overexpression of a mutant protein without the KH4 domain that has less affinity for binding to GAP-43's ARE had no effect. In contrast, depletion of KSRP led to a rise in GAP-43 mRNA levels and a dramatic increase in axonal length, both in KSRP shRNA transfected cells and neurons cultured from Ksrp(+/-) and Ksrp(-/-) embryos. Finally we found that overexpression of GAP-43 rescued the axonal outgrowth deficits seen with KSRP overexpression, but only when cells were transfected with GAP-43 constructs containing 3' UTR sequences targeting the transport of this mRNA to axons. Together, our results suggest that KSRP is an important regulator of mRNA stability and axonal length that works in direct opposition to HuD to regulate the levels of GAP-43 and other ARE-containing neuronal mRNAs.