The Autism studies/research thread

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Abstract
Methods
The study was conducted using a repeated measures research design. Retrospective chart review data were collected from 62 individuals with autism, age (M=8.65, SD=4.53), all of whom were level two autistic and required moderate support in communication, socialization, and daily life. These individuals received ABA treatment over five months. The study measured cumulative target behaviors using a repeated measures design, which allowed for the identification of statistically significant differences across 12 time points. This robust methodology ensures the validity and reliability of the study's findings.

Results
Mixed repeated measures analysis of variance (ANOVA) indicated statistical significance (sphericity assumed), F(11,495) = 55.432, p < 0.001 (time). Multiple comparisons using bootstrapped paired t-tests showed p < 0.05 on time points 1-8 and non-significance (p > 0.05) on time points 9-12. There was a significant interaction effect (sphericity assumed) with time x (age category), F(44,495) = 2.338, p < 0.001. Interaction contrasts indicated statistically significant differences over time, mainly within the one-year to four-year-old, five to eight-year-old, and most in the nine to 12-year-old age groups. There was some significance within the 13- to 16-year-old age group and no significance within the 17- to 26-year-old age group.

Conclusions
Over five months, individuals with autism who underwent ABA treatments demonstrated a statistically significant enhancement in general target behaviors. This finding is crucial as it underscores the effectiveness of ABA treatments in a naturalistic environment. Moreover, the study's discovery of a significant interaction between time and age in these behaviors provides valuable insights into the impact of age on treatment outcomes. Extensive large-N studies of general ABA broad effectiveness and repeated measures designs are lacking and can lead to further research to improve quality and outcomes. These findings contribute to the body of empirical evidence and emphasize the importance of replicative efficacy studies in ensuring the reliability of research findings.

The incidence of autism spectrum disorder was higher among children exposed to topiramate in the second half of pregnancy than in the general population, but not relative to other children born to women with epilepsy, a study of 4 million pregnant women and their children showed.

At age 8, 1.89% of children who had never been prenatally exposed to an antiseizure medication were diagnosed with autism spectrum disorder, reported Sonia Hernández-Díaz, MD, DrPH, of the Harvard T.H. Chan School of Public Health in Boston, and co-authors.

For children born to mothers with epilepsy, however, the crude incidence of autism at age 8 was 4.21% with no prenatal exposure to an antiseizure medication, 6.15% with exposure to topiramate, 10.51% with exposure to valproate, and 4.08% with exposure to lamotrigine, the researchers wrote in the New England Journal of Medicine

After adjusting for indication and other variables, only valproate was associated with additional autism risk, Hernández-Díaz and colleagues said. Compared with no exposure to antiseizure medication, weighted average hazard ratios (HRs) were 0.96 (95% CI 0.56-1.65) for topiramate exposure, 2.67 (95% CI 1.69-4.20) for valproate, and 1.00 (95% CI 0.69-1.46) for lamotrigine.

"Overall, results suggest no substantially increased risk of autism spectrum disorder after prenatal exposure to either topiramate or lamotrigine (the negative control group) and a dose-dependent increased risk of autism spectrum disorder associated with prenatal valproate exposure (the positive control group)," the researchers wrote.

Valproate is a known teratogen; its label carries a boxed warningopens in a new tab or window that prenatal exposure may lead to cognitive deficits or physical birth defects. Most studies of other antiseizure medications have not shown increased risksopens in a new tab or window of neurodevelopmental disorders.

A recent Nordic studyopens in a new tab or window, however, reported an increased incidence of autism after prenatal exposure to topiramate, triggering a safety reviewopens in a new tab or window of the drug by U.K. health authorities. Last year, the European Medicines Agency's safety committee recommended new measures to avoid topiramate exposureopens in a new tab or window in pregnancy.

In the U.S., the FDA has warned of an increased risk of oral cleftsopens in a new tab or window in infants born to women treated with topiramate.

However, a full understanding of potential neuropsychological risks of topiramate and many other antiseizure medications requires further basic and clinical investigations," Meador pointed out. "Fetal exposure to topiramate has been associated with an increased incidence of congenital malformationsopens in a new tab or window (3.9 to 4.1% among exposed infants vs 3% in the general population) and of small size for gestational age."

Teratogenic risks for many other antiseizure medications remain unknown "and the pace of advancement is painfully slow," he continued. The need for more research is underscored by the substantial costs associated with fetal medication exposures, he added: "The lifetime financial costs of just cognitive deficits related to fetal exposure to valproate in the United States in 2006 alone were estimated to be $626 million."

Hernández-Díaz and co-authors studied pregnancy cohorts nested in Medicaid data from 2000 through 2018 and in MarketScan commercial health insurance data from 2003 through 2020. Records included 4.2 million children eligible at birth; more than 400,000 children were followed for at least 8 years. The median follow-up was 2 years.

The study had several limitations, the researchers said. Though the cohort remained large, many children were lost to follow-up by age 8. Filled prescriptions were used as a proxy for actual medication use. Due to the relatively small number of cases of autism, confidence intervals for hazard ratios were wide.

Chemicals found in common household items could be damaging our brains, scientists have warned, with potential links to a range of neurological conditions including multiple sclerosis and autism.

On a daily basis, we are exposed to hundreds of different chemicals, the health effects of which are mostly unknown. To explore these effects, a team of researchers from Case Western Reserve University's School of Medicine analyzed over 1,800 household chemicals found in common household cleaners, beauty products and flame retardants.

Most previous studies on the effects of these chemicals on brain health have focused on neuronal cells in the brain, which basically act like the brain's wiring. But much less is known about the effects of these chemicals on the brain's supporting cells. Thus, the team decided to focus it efforts on the cells that wrap around our neurons and improve their ability to transmit information. Called oligodendrocytes, they form the brain's white matte and function like the colorful cable insulation we see around copper wires.

Using oligodendrocytes isolated from mice and cultured human cells, the team found that 292 of the chemicals tested were deadly to these insulating brain cells, with a further 47 inhibiting oligodendrocyte generation. Their results were published in the journal Nature Neuroscience.

Autism has proven to be one of the most difficult-to-treat indications, but troublesome symptoms may someday find new relief. Last week, Roche Holdings (NASDAQOTH: RHHBY) announced it had received breakthrough therapy status from the Food and Drug Administration for balovaptan, a potential therapy for autism spectrum disorder.

If future trials confirm balovaptan's promise, it could improve social interaction and communication in people with autism.

The drug that may help someday
In midstage studies, Roche's balovaptan has shown promise that it may help improve social behavior in autistic adults.

Balovaptan is a V1a vasopressin receptor antagonist that blocks or dampens the biological response to vasopressin, a hormone. Historically, vasopressin is known for its role in regulating the volume of water in the body and influencing blood pressure. However, researchers increasingly believe that vasopressin imbalances may contribute to autism, particularly in boys, in whom high levels of vasopressin have been connected to anxiety and aggression.

At the International Meeting for Autism Research in San Francisco last year, trial data was presented showing that balovaptan taken once daily for 12 weeks significantly improved socialization and communication abilities, as measured by the Vineland Adaptive Behavior Scales. Specifically, study participants who took intermediate and high doses of balovaptan saw their scores on this scale improve by roughly four to five points, results that researchers said were "above the threshold for what we consider a minimum clinically important difference."

What’s Next
The FDA designation of breakthrough status can accelerate balovaptan's development, but there's still a lot of work to be done.

Before the FDA will consider approving balovaptan, Roche needs to complete its ongoing study in children between the ages of 5 to 17 years. If results from that study are also positive, then Roche can sit down with regulators to discuss whether any additional trials will be necessary before filing for approval. According to ClinicalTrials.gov, we have some waiting to do; the estimated completion date for the children's study isn't until April 2019. Based on that timeline, we're still a couple of years away from knowing that balovaptan is a safe and effective treatment for symptoms associated with autism.

Key Points
Question What are the sex-specific etiological origins of autism spectrum disorder?

Findings In this cohort study including 1 047 649 Swedish children, 12 226 (1.17%) received a diagnosis of autism spectrum disorder; heritability was estimated at 87.0% for males and 75.7% for females, a statistically significant difference.

Meaning These findings suggest that variation in the occurrence of autism spectrum disorder in the population differs between males and females, indicating that some of the underlying causes and prevalence of the condition may differ between the 2 sexes.

Abstract
Importance Autism spectrum disorder (ASD) is a neurodevelopmental disorder more prevalent in males than in females. The cause of ASD is largely genetic, but the association of genetics with the skewed sex ratio is not yet understood. To our knowledge, no large population-based study has provided estimates of heritability by sex.

Objective To estimate the sex-specific heritability of ASD.

Design, Setting, and Participants. This was a population-based, retrospective analysis using national health registers of nontwin siblings and cousins from Sweden born between January 1, 1985, and December 31, 1998, with follow-up to 19 years of age. Data analysis occurred from August 2022 to November 2023.

Main Outcomes and Measures Models were fitted to estimate the relative variance in risk for ASD occurrence owing to sex-specific additive genetics, shared environmental effects, and a common residual term. The residual term conceptually captured other factors that promote individual behavioral variation (eg, maternal effects, de novo variants, rare genetic variants not additively inherited, or gene-environment interactions). Estimates were adjusted for differences in prevalence due to birth year and maternal and paternal age by sex.

Results The sample included 1 047 649 individuals in 456 832 families (538 283 males [51.38%]; 509 366 females [48.62%]). Within the entire sample, 12 226 (1.17%) received a diagnosis of ASD, comprising 8128 (1.51%) males and 4098 (0.80%) females. ASD heritability was estimated at 87.0% (95% CI, 81.4%-92.6%) for males and 75.7% (95% CI, 68.4%-83.1%) for females with a difference in heritability estimated at 11.3% (95% CI, 1.0%-21.6%). There was no support for shared environmental contributions.

Conclusions and Relevance These findings suggest that the degree of phenotypic variation attributable to genetic differences (heritability) differs between males and females, indicating that some of the underlying causes of the condition may differ between the 2 sexes. The skewed sex ratio in ASD may be partly explained by differences in genetic variance between the sexes.

Researchers at the University of California San Diego School of Medicine have shed new light on the changes in metabolism that occur between birth and the presentation of autism spectrum disorder (ASD) later in childhood. The researchers discovered that a small number of biochemical pathways are responsible for the majority of these changes, which could help inform new early detection and prevention strategies for autism.

"At birth, the physical appearance and behavior of a child who will develop autism over the next few years are indistinguishable from that of a neurotypical child. Indeed, in most cases the fate of the child with regard to autism is not set at birth," said Robert Naviaux, M.D., Ph.D., professor in the Departments of Medicine, Pediatrics and Pathology at UC San Diego School of Medicine.

"We're starting to learn about the governing dynamics that regulate the transition from risk to the actual appearance of the first symptoms of ASD. Early diagnosis opens the possibility of early intervention and optimal outcomes."

While autism is known to have strong genetic risk factors, there are also environmental risk factors that play a role in the development and severity of ASD. Naviaux and other researchers are discovering that the development of autism is governed by the real-time interaction of these varied factors. By studying the developmental biology of metabolism and how it differs in autism, new insights are emerging in ASD and other complex developmental disorders.

"Behavior and metabolism are linked—you cannot separate them," added Naviaux.

To learn more about the early metabolic changes that occur in children with autism, researchers studied two cohorts of children. One cohort consisted of newborn children, in whom autism can't be detected. The second cohort consisted of 5-year-old children, some of whom had been diagnosed with autism.

When comparing the metabolic profiles of children in the cohort who were eventually diagnosed with autism to those who developed neurotypically, they found striking differences. Of the 50 different biochemical pathways the researchers investigated, just 14 were responsible for 80% of the metabolic impact of autism.

The pathways that were most changed are related to the cell danger response, a natural and universal cellular reaction to injury or metabolic stress. The body has biochemical safeguards in place that can shut down the cell danger response once the threat has passed, and Naviaux hypothesizes that autism occurs when these safeguards fail to develop normally. The result is heightened sensitivity to environmental stimuli, and this effect contributes to sensory sensitivities and other symptoms associated with autism.

"Metabolism is the language that the brain, gut and immune system use to communicate, and autism occurs when the communication between these systems is changed," added Naviaux.

The cell danger response is primarily regulated by adenosine triphosphate (ATP) the body's chemical energy currency. While these ATP-signaling pathways do not develop normally in autism, they may be partially restorable with existing pharmaceutical drugs. In 2017, Naviaux and his team completed early clinical testing for suramin, the only drug approved in humans that can target ATP signaling and which is normally used to treat African sleeping sickness.

Now, the researchers hope that by revealing the specific ATP-related pathways that are altered in autism, their work will help scientists develop more drugs that target these pathways to manage the symptoms of ASD.

"Suramin is just one drug that targets the cell danger response," he said. "Now that we're closely interrogating how metabolism changes in ASD, we could be at the beginning of a drug renaissance that will create new options for treatment that never existed before."

The study is published in the journal Communications Biology.

Biomarkers for ASD
Prior research has identified metabolic and biochemical markers for ASD in children and adults, varying with age, sex, and symptom severity. Many of these markers are involved in the structure and function of the brain, immune system, autonomic nervous system, and microbiome. Nevertheless, no single genetic or environmental factor accounts for all ASD cases among children.

The CDR model
The cell danger response (CDR) model depicts metabolic pathways connecting environmental and genetic stressors to altered development and ASD. The CDR flows from the point of impact of the stressor outwards, following various changes in metabolic, inflammatory, autonomic, endocrine, and neurological responses to these injuries or stresses.

ASD is more likely to follow CDR when stressors operate in intrauterine life or early childhood. These impact four areas that are part of the CDR, including the mitochondria, oxidative stress, innate immunity, and microbiomes. Extracellular adenosine triphosphate (eATP) is the fundamental regulator in all CDR pathways.

ATP as a signaling molecule
ATP is the energy currency for all life on earth. About 90% of ATP is generated within the intracellular mitochondria and is used for all metabolic pathways.

Outside the cell, eATP functions as an information molecule. To this end, eATP binds to purine-responsive receptors on the cell to warn of danger, altered metabolism, and induce a generalized CDR response.

Beginning with innate immunity activation, the sequence continues through acute localized responses to trauma or infection that ultimately become remote organ-level or systemic responses. In some cases, this could affect human neurodevelopment.

ATP in ASD metabolism
Dysregulated purine metabolism and purinergic signaling in response to ATP have been identified in experimental and human studies of ATP and confirmed in multi-omics analyses. The role of eATP is key to multiple aspects of neurological development altered in ASD, including mast cells and microglia, neuronal sensitization, and neuroplasticity.

Mitochondria generate ATP and are crucial for processing data, providing early warning, and initiating timely responses to changes in the environment. Mitochondria conduct almost 800 metabolic reactions independently, including those involved in child development, growth and differentiation, healing, stress adaptation, and aging, over half of which are regulated by ATP and its congeners.

Chronic mitochondrial dysfunction in ASD impairs metabolic pathways and gene expression, thereby disrupting neurodevelopment trajectories.

What did the study show?
Infants in the pre-ASD or typically developing (TD) groups did not exhibit any differences in their exposure to environmental factors during pregnancy and infancy. About 50% of children in the pre-ASD group exhibited regression of development at one or more points as compared to 2% in the TD group. The average age at ASD diagnosis was 3.3 years.

Metabolites were increased above the mean level in the newborn ASD cohort and continued to increase by more than half by five years as compared to the newborn cohort. These metabolites included stress molecules and the purine 7-methylguanine that caps newly formed messenger ribonucleic acid (mRNA),

In newborns, the most significant increase was observed with four sphingolipids, with a corresponding decrease in sphingomyelins, their source molecules. Similarly, 7-methylguanosine was increased, and guanine decreased.

Conversely, metabolites that were decreased in the newborn cohort were reduced by 120% more by five years of age. These included antioxidants, neurotransmitters like dopamine, and one-carbon molecules.

Among five-year-olds, several phospholipids were increased, whereas cardiolipins involved in the production of mitochondria and ATP decreased. Purine 7-methylguanine levels remained high, while several vitamins and serotonin were reduced.

Differentiating ASD from TD newborns
Using six or seven of the identified biomarkers, pre-ASD was distinguished from TD newborns and five-year-olds with an accuracy of 75% and 90%, respectively. Several important classes of metabolites changed their trajectories between birth and five years.

Bile acids, phosphatidylserine (PS), phosphatidylcholine (PC) lipids, and sphingomyelins decreased with age, whereas purines and fatty acid oxidation levels were unaffected. Comparatively, the levels of mRNA capping purines and several lipids, such as acyl-carnitine linoleylcarnitine, increased.

Exploring network interactions between metabolites in TD newborns and TD five-year-olds showed an 18-fold reversal of the ratio of positive to negative correlations from 5.5 to 0.3 in purine metabolic pathways. In ASD, the expected reversal failed to occur, thus indicating failed development.

Neuronal γ-aminobutyric acid (GABA) signaling typically reverses from net excitatory at birth to inhibitory at two to three years of age. This accompanies a reduced vulnerability to environmental factors and a concomitant reduction in the risk of ASD.

Negative correlations with purines were lost with time in the ceramide and phospholipid hubs. The eicosanoid hub exhibited fourfold higher positive and threefold higher negative correlations in ASD as compared to TD.

Despite similar positive-to-negative correlation ratios, there were qualitative differences in the ASD hypercorrelator hub between study groups. For example, asparagine, which mediates mitochondrial signaling pathways for cell growth, was negatively correlated with eicosanoids at multiple points.

The TD hypercorrelator hub showed different positive and negative correlations. Lipids accounted for 13 of the top 15 metabolites in the TD hypercorrelator hub but lost 90% of their correlations in the ASD metabolome.

Metabolic growth rate
In the TD cohort, Vnet, a measure of metabolic growth rate, increased by 173% between birth and five years of age, whereas Vnet was stable in the pre-ASD cohort, thus indicating development arrest. The low connectivity in the metabolic network in ASD might be due to CDR signaling, which inhibits remote signal reception, causing impaired coordination of chemical signals across the body’s various systems.

Potential ASD mechanisms
The current study identified the most prominent changes in children who developed ASD by five years of age as affecting specific groups of complex lipids. About 80% of the metabolic shift was traceable to 14 metabolic pathways observed both in the newborn pre-ASD and five-year ASD cohorts.

Ceramides are lipids that can cause cell death and loss of mitochondrial function. The loss of negative correlations between ceramides and purines leads to their accumulation in ASD. The result is mitochondrial dysfunction and apoptosis of many cells, even without lethal exposures.

The primary impact of this correlation was reflected as lower anti-inflammatory activity, less antioxidant reserve, and more stress response activity, all of which increased with age. Repeated activation of the CDR might cause increased oxygen utilization within the mitochondria.

With higher dissolved oxygen in the cell, cellular membranes undergo oxidative damage. Although this response allows for excess dissolved oxygen to be sequestered, it also stiffens the membranes, limits mitochondrial function and synaptogenesis, and delays responses to environmental stressors in ASD.

Conclusions
The study findings confirm that ASD is linked to metabolic profiles that are distinct from those of TD children, though varying by age, sex, and disease severity. These changes are reflected in the abnormal neurobiology of ASD.

Taken together, the data may indicate that the failure of normal reversal of the purine network causes failure to reverse the GABA-ergic network. The loss of inhibitory connections reduces natural dampening, thereby allowing excessive excitatory calcium signaling in the ASD network.

Therefore, cells tend to remain excited and respond excessively to sensory signals in ASD. This could explain the need for an unchanging routine with ASD children to avoid anxiety induced by unexpected changes.

Future studies can utilize these findings, as well as those obtained from previous reports, to generate better screening tools for newborns and infants to identify those at risk for ASD. This could aid in early detection and intervention for affected children, ultimately improving patient outcomes and reducing the incidence of ASD.