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Autism symptom severity change was evaluated during early childhood in 125 children diagnosed with autism spectrum disorder (ASD). Children were assessed at approximately 3 and 6 years of age for autism symptom severity, IQ and adaptive functioning. Each child was assigned a change score, representing the difference between ADOS Calibrated Severity Scores (CSS) at the two ages. A Decreased Severity Group (28.8%) decreased by 2 or more points; a Stable Severity Group (54.4%) changed by 1 point or less; and an Increased Severity Group (16.8%) increased by 2 or more points. Girls tended to decrease in severity more than boys and increase in severity less than boys. There was no clear relationship between intervention history and membership in the groups.

Many autistic children experience changes in core symptom severity across middle childhood, when co-occurring mental health conditions emerge. We evaluated this relationship in 75 autistic children from 6 to 11 years old. Autism symptom severity change was evaluated for total autism symptoms using the autism diagnostic observation schedule calibrated severity score, as well as social-communication symptoms calibrated severity score, and restricted/repetitive behaviors calibrated severity score. Children were grouped based on their symptom severity change patterns. Mental health symptoms (attention-deficit hyperactivity disorder, anxiety, disruptive behavior problems) were assessed via parental interview and questionnaire and compared across the groups. Co-occurring mental health symptoms were more strongly associated with change in social-communication symptom or restricted/repetitive behavior severity than with total autism symptom severity. Two relevant groups were identified. The social-communication symptom-increasing-severity-group (21.3%) had elevated and increasing levels of anxiety, attention-deficit hyperactivity disorder, and disruptive behavior problems compared with children with stable social-communication symptom severity. The restricted/repetitive behavior-decreasing-severity-group (22.7%) had elevated and increasing levels of anxiety; 94% of these children met criteria for an anxiety disorder. Autism symptom severity change during middle childhood is associated with co-occurring mental health symptoms. Children that increase in social-communication symptom severity are also likely to demonstrate greater psychopathology, while decreases in restricted/repetitive behavior severity are associated with higher levels of anxiety. For many autistic children, the severity of their autism symptoms changes during middle childhood. We studied whether these changes are associated with the emergence of other mental health challenges such as anxiety and attention-deficit hyperactivity disorder. Children who had increased social-communication challenges had more anxiety and attention-deficit hyperactivity disorder symptoms and disruptive behavior problems than other children. Children who decreased their restricted and repetitive behaviors, on the contrary, had more anxiety. We discuss why these changes in autism symptoms may lead to increases in other mental health concerns. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a progressive neurodegenerative brain disorder associated with uncontrolled body movements, cognitive decline, and reduced circulating melatonin levels. Melatonin is a potent antioxidant and exogenous melatonin treatment is neuroprotective in experimental HD models. In neurons, melatonin is exclusively synthesized in the mitochondrial matrix. Thus, we investigated the integrity of melatonin biosynthesis pathways in pineal and extrapineal brain areas in human HD brain samples, in the R6/2 mouse model of HD and in full‐length mutant huntingtin knock‐in cells. Aralkylamine N‐acetyltransferase (AANAT) is the rate‐limiting step enzyme in the melatonin biosynthetic pathway. We found that AANAT expression is significantly decreased in the pineal gland and the striatum of HD patients compared to normal controls. In the R6/2 mouse forebrain, AANAT protein expression was decreased in synaptosomal, but not nonsynaptosomal, mitochondria and was associated with decreased synaptosomal melatonin levels compared to wild type mice. We also demonstrate sequestration of AANAT in mutant‐huntingtin protein aggregates likely resulting in decreased AANAT bioavailability. Paradoxically, AANAT mRNA expression is increased in tissues where AANAT protein expression is decreased, suggesting a potential feedback loop that is, ultimately unsuccessful. In conclusion, we demonstrate that pineal, extrapineal, and synaptosomal melatonin levels are compromised in the brains of HD patients and R6/2 mice due, at least in part, to protein aggregation. [ABSTRACT FROM AUTHOR]

An individual's autism symptom severity level can change across childhood. The prevalence and direction of change, however, are still not well understood. Nor are the characteristics of children that experience change. Symptom severity trajectories were evaluated from early to middle childhood (approximately ages 3–11) for 182 autistic children. Symptom severity change was evaluated using individual change scores and the Reliable Change Index. Fifty‐one percent of participants experienced symptom severity change: 27% of children decreased in severity, 24% increased and 49% were stable. Symptom severity decreases were more common during early childhood. Severity increases occurred at both early and middle childhood but increase in social affect severity was especially prominent during middle childhood. Most children experienced significant change during only one period and remained stable during the other. Girls decreased more and increased less in symptom severity than boys. Children that increased in severity decreased in adaptive functioning across childhood. Exploratory analyses indicated that a decrease in severity was associated with higher parental education level and older parental age at the time of the child's birth. Conversely, increase in autism severity was associated with lower parental education level and younger parental age at the child's birth. These findings extend recent observations that symptom severity change is more likely than previously appreciated. An understanding of the role of both biological and sociodemographic factors in determining a child's symptom trajectory may factor into future decisions on allocation and type of interventions distributed to young autistic children. Lay Summary: We studied whether a child's autism severity changed from initial diagnosis until middle childhood (ages 3–11). We found that 27% of the children decreased in severity, 24% increased and the rest stayed the same. Symptom severity decreases were more common during early childhood while severity increases were more prominent during middle childhood. We also found that girls were more likely to decrease than boys. Whether a child decreased or increased is related, in part, to parental characteristics. [ABSTRACT FROM AUTHOR]

One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2–19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajectories. In this Mini Review, we summarize findings to date from the APP cohort and describe progress made toward identifying meaningful subgroups of autism. [ABSTRACT FROM AUTHOR]

Objective: To evaluate how distinct presentations of anxiety symptoms and intellectual impairment influence the measurement and estimated rate of clinically significant anxiety in autism spectrum disorder (ASD). Method: The sample included 75 children (ages 9–13 years) with ASD and varied IQ and 52 typically developing (TD) controls and parents. Parents completed anxiety symptom scales and a diagnostic interview, designed to (1) differentiate anxiety and ASD and (2) examine DSM-specified and unspecified ("distinct") anxiety presentations in each child, including fears of change, special interests, idiosyncratic stimuli and social confusion rather than evaluation. Children completed standard intellectual and ASD diagnostic assessments. Results: 69% of those with ASD had clinically-significant anxiety, including 21% DSM-specified anxiety disorders, 17% distinct anxiety, and 31% both. Only 8% of TD children had clinically-significant anxiety, all DSM-specified. DSM-specified anxiety disorders in children with ASD and intellectual impairment (IQ<70) were predominantly specific phobias. DSM-specified anxiety other than specific phobia was significantly less common in children with, versus without, intellectual impairment; this was not the case for distinct anxiety. The sensitivities of anxiety scales were moderate to poor, particularly in cases with intellectual impairment. Conclusions: ASD is associated with more frequent and varied presentations of clinical anxiety, which may align with and differ from the specified anxiety disorders of the DSM. Standard parent report anxiety scales have reduced sensitivity to detect clinical anxiety in ASD, particularly in children with intellectual impairment. [ABSTRACT FROM AUTHOR]

Atypical responses to fearful stimuli and the presence of various forms of anxiety are commonly seen in children with autism spectrum disorder (ASD). The fear potentiated startle paradigm (FPS), which has been studied both in relation to anxiety and as a probe for amygdala function, was carried out in 97 children aged 9–14 years including 48 (12 female) with ASD and 49 (14 female) with typical development (TD). In addition, exploratory analyses were conducted examining the association between FPS and amygdala volume as assessed with magnetic resonance imaging in a subset of the children with ASD with or without an anxiety disorder with available MRI data. While the startle latency was increased in the children with ASD, there was no group difference in FPS. FPS was not significantly associated with traditional Diagnostic and Statistical Manual (DSM) or "autism distinct" forms of anxiety. Within the autism group, FPS was negatively correlated with amygdala volume. Multiple regression analyses revealed that the association between FPS and anxiety severity was significantly moderated by the size of the amygdala, such that the association between FPS and anxiety was significantly more positive in children with larger amygdalas than smaller amygdalas. These findings highlight the heterogeneity of emotional reactivity associated with ASD and the difficulties in establishing biologically meaningful probes of altered brain function. Lay summary Many children with autism spectrum disorder (ASD) have additional problems such as anxiety that can greatly impact their lives. How these co‐occurring symptoms develop is not well understood. We studied the amygdala, a region of the brain critical for processing fear and a laboratory method called fear potentiated startle for measuring fear conditioning, in children with ASD (with and without an anxiety disorder) and typically developing children. Results showed that the connection between fear conditioning and anxiety is dependent on the size of the amygdala in children with ASD. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) symptoms are frequently reported in children with autism spectrum disorder (ASD). We evaluated the frequency and severity of GI symptoms in preschool‐aged children with ASD compared to participants with typical development (TD). Our goal was to ascertain whether GI symptoms are associated with differences in sex or developmental and behavioral measures. Participants were between 2 and 3.5 years of age and included 255 children with ASD (184 males/71 females) and 129 age‐matched TD controls (75 males/54 females). A parent interview was used to assess GI symptoms (abdominal pain, gaseousness/bloating, diarrhea, constipation, pain on stooling, vomiting, difficulty swallowing, blood in stool or in vomit). Children with GI symptoms in each diagnostic group were compared to children without GI symptoms on measures of developmental, behavioral, and adaptive functioning. GI symptoms were reported more frequently in children with ASD compared to the TD group (47.8% vs. 17.8%, respectively). Children with ASD were also more likely to experience multiple GI symptoms (30.6% vs. 5.4%). GI symptoms were equally common in males and females across both diagnostic groups. There were no statistically significant differences in developmental or adaptive measures based on presence of GI symptoms in either ASD or TD children. Co‐occurring GI symptoms were, however, associated with increased self‐injurious behaviors, restricted stereotyped behaviors, aggressive behaviors, sleep problems and attention problems in both ASD and TD children. In children with ASD, a higher number of GI symptoms was associated with an increase in self‐injurious behaviors, somatic complaints, reduced sleep duration, and increased parasomnias. Lay Summary ASD is characterized by challenges in social communication and repetitive behaviors. But, people with autism have many other difficulties including gastrointestinal problems. Children with ASD were three times more likely to experience GI symptoms than typically developing peers. Increased GI symptoms are associated with increased problem behaviors such as sleep problems, self‐injury, and body aches. Since GI symptoms are often treatable, it is important to recognize them as soon as possible. Both clinicians and parents should become more aware of the high occurrence of GI problems in autistic people. Autism Res 2020, 13: 1778–1789. © 2020 International Society for Autism Research and Wiley Periodicals LLC [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS) cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs), neural progenitor cells (NPCs) and neurons suggests that (I) iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii) Neural stem cells have impaired differentiation when infected by HCMV; (iii) NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv) most iPS-derived neurons are not permissive to HCMV infection; and (v) infected neurons have impaired calcium influx in response to glutamate. [ABSTRACT FROM AUTHOR]

Of the 1 in 36 individuals in the United States who are diagnosed with autism spectrum disorder, nearly 40% also have intellectual disability (ID). The cortex has been widely implicated in neural processes underlying autistic behaviors as well as intellectual ability. Thus, neuroimaging features such as cortical thickness are of particular interest as a possible biomarkers of the condition. However, neuroimaging studies often fail to include autistic individuals with ID. As a result, there are few studies of cortical thickness in autistic individuals across the entire range of intellectual abilities. This study used MRI to evaluate cortical thickness in young autistic children (n = 88, mean age 5.37 years) with a large range of intellectual ability (IQ 19-133) as well as nonautistic, nondevelopmentally delayed (referred to here as typically developing [TD]) peers (n = 53, mean age 5.29 years). We first investigated associations between full scale IQ and cortical thickness in both autistic and TD children. Autistic children had significant negative associations (i.e., thinner cortex, higher IQ) in bilateral entorhinal cortex, right fusiform gyrus, superior, middle and inferior temporal gyri, and right temporal pole that were not present in TD children. Significantly thicker cortex was also observed in these regions for autistic children with ID (i.e., IQ ≤ 70) compared with those without. Last, given the reported correspondence between the severity of autism symptoms and intellectual ability, we compared cortical thickness associations with both IQ and ADOS Calibrated Severity Scores and found these patterns overlapped to a significant degree across the cortex., (© 2025 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Background: We extended our study of trajectories of intellectual development of autistic individuals in early (mean age 3 years; T1), and middle childhood (mean age 5 years, 7 months; T2) into later middle childhood/preadolescence (mean age 11 years, 6 months; T3) in the longitudinal Autism Phenome Project cohort. Participants included 373 autistic children (115 females)., Methods: Multivariate latent class growth analysis was used to identify distinct IQ trajectory subgroups. Baseline and developmental course group differences and predictors of trajectory membership were assessed using linear mixed effects models with repeated measures with pairwise testing, multinomial logistic regression models, and sensitivity analyses., Results: We isolated three IQ trajectories between T1 and T3 for autistic youth that were similar to those found in our prior work. These included a group with persistent intellectual disability (ID; 45%), a group with substantial increases in IQ (CHG; 39%), and a group with persistently average or above IQs (P-High; 16%). By T3, the groups did not differ in ADOS-2 calibrated severity scores (CSS), and there were no group differences between Vineland (VABS) communication scores in CHG and P-High. T1-T3 externalizing behaviors declined significantly for CHG, however, there were no significant T3 group differences between internalizing or externalizing symptoms. T1 correlates for CHG and P-High versus ID group membership included higher VABS communication and lower ADOS-2 CSS. A T1 to T2 increase in VABS communication scores and a decline in externalizing predicted CHG versus ID group membership at T3, while T1 to T2 improvement in VABS communication and reduction in ADOS-2 CSS predicted P-High versus ID group membership., Conclusions: Autistic youth exhibit consistent IQ developmental trajectories from early childhood through preadolescence. Factors associated with trajectory group membership may provide clues about prognosis, and the need for treatments that improve adaptive communication and externalizing symptoms., Competing Interests: Conflicts of Interest Drs. Solomon, Iosif, Nordahl, Cho, Heath, and Ferrer and Mr. Srivastav report no biomedical financial interests or potential conflicts of interest. Dr. Amaral is on the Scientific Advisory Board of Stemina Biomaker Discovery and Axial Biotherapeutics.

An individual's autism symptom severity level can change across childhood. The prevalence and direction of change, however, are still not well understood. Nor are the characteristics of children that experience change. Symptom severity trajectories were evaluated from early to middle childhood (approximately ages 3-11) for 182 autistic children. Symptom severity change was evaluated using individual change scores and the Reliable Change Index. Fifty-one percent of participants experienced symptom severity change: 27% of children decreased in severity, 24% increased and 49% were stable. Symptom severity decreases were more common during early childhood. Severity increases occurred at both early and middle childhood but increase in social affect severity was especially prominent during middle childhood. Most children experienced significant change during only one period and remained stable during the other. Girls decreased more and increased less in symptom severity than boys. Children that increased in severity decreased in adaptive functioning across childhood. Exploratory analyses indicated that a decrease in severity was associated with higher parental education level and older parental age at the time of the child's birth. Conversely, increase in autism severity was associated with lower parental education level and younger parental age at the child's birth. These findings extend recent observations that symptom severity change is more likely than previously appreciated. An understanding of the role of both biological and sociodemographic factors in determining a child's symptom trajectory may factor into future decisions on allocation and type of interventions distributed to young autistic children. LAY SUMMARY: We studied whether a child's autism severity changed from initial diagnosis until middle childhood (ages 3-11). We found that 27% of the children decreased in severity, 24% increased and the rest stayed the same. Symptom severity decreases were more common during early childhood while severity increases were more prominent during middle childhood. We also found that girls were more likely to decrease than boys. Whether a child decreased or increased is related, in part, to parental characteristics., (© 2022 International Society for Autism Research and Wiley Periodicals LLC.)

Atypical responses to fearful stimuli and the presence of various forms of anxiety are commonly seen in children with autism spectrum disorder (ASD). The fear potentiated startle paradigm (FPS), which has been studied both in relation to anxiety and as a probe for amygdala function, was carried out in 97 children aged 9-14 years including 48 (12 female) with ASD and 49 (14 female) with typical development (TD). In addition, exploratory analyses were conducted examining the association between FPS and amygdala volume as assessed with magnetic resonance imaging in a subset of the children with ASD with or without an anxiety disorder with available MRI data. While the startle latency was increased in the children with ASD, there was no group difference in FPS. FPS was not significantly associated with traditional Diagnostic and Statistical Manual (DSM) or "autism distinct" forms of anxiety. Within the autism group, FPS was negatively correlated with amygdala volume. Multiple regression analyses revealed that the association between FPS and anxiety severity was significantly moderated by the size of the amygdala, such that the association between FPS and anxiety was significantly more positive in children with larger amygdalas than smaller amygdalas. These findings highlight the heterogeneity of emotional reactivity associated with ASD and the difficulties in establishing biologically meaningful probes of altered brain function. LAY SUMMARY: Many children with autism spectrum disorder (ASD) have additional problems such as anxiety that can greatly impact their lives. How these co-occurring symptoms develop is not well understood. We studied the amygdala, a region of the brain critical for processing fear and a laboratory method called fear potentiated startle for measuring fear conditioning, in children with ASD (with and without an anxiety disorder) and typically developing children. Results showed that the connection between fear conditioning and anxiety is dependent on the size of the amygdala in children with ASD., (© 2020 International Society for Autism Research, Wiley Periodicals LLC.)

Gastrointestinal (GI) symptoms are frequently reported in children with autism spectrum disorder (ASD). We evaluated the frequency and severity of GI symptoms in preschool-aged children with ASD compared to participants with typical development (TD). Our goal was to ascertain whether GI symptoms are associated with differences in sex or developmental and behavioral measures. Participants were between 2 and 3.5 years of age and included 255 children with ASD (184 males/71 females) and 129 age-matched TD controls (75 males/54 females). A parent interview was used to assess GI symptoms (abdominal pain, gaseousness/bloating, diarrhea, constipation, pain on stooling, vomiting, difficulty swallowing, blood in stool or in vomit). Children with GI symptoms in each diagnostic group were compared to children without GI symptoms on measures of developmental, behavioral, and adaptive functioning. GI symptoms were reported more frequently in children with ASD compared to the TD group (47.8% vs. 17.8%, respectively). Children with ASD were also more likely to experience multiple GI symptoms (30.6% vs. 5.4%). GI symptoms were equally common in males and females across both diagnostic groups. There were no statistically significant differences in developmental or adaptive measures based on presence of GI symptoms in either ASD or TD children. Co-occurring GI symptoms were, however, associated with increased self-injurious behaviors, restricted stereotyped behaviors, aggressive behaviors, sleep problems and attention problems in both ASD and TD children. In children with ASD, a higher number of GI symptoms was associated with an increase in self-injurious behaviors, somatic complaints, reduced sleep duration, and increased parasomnias. LAY SUMMARY: ASD is characterized by challenges in social communication and repetitive behaviors. But, people with autism have many other difficulties including gastrointestinal problems. Children with ASD were three times more likely to experience GI symptoms than typically developing peers. Increased GI symptoms are associated with increased problem behaviors such as sleep problems, self-injury, and body aches. Since GI symptoms are often treatable, it is important to recognize them as soon as possible. Both clinicians and parents should become more aware of the high occurrence of GI problems in autistic people. Autism Res 2020, 13: 1778-1789. © 2020 International Society for Autism Research and Wiley Periodicals LLC., (© 2020 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)