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Nutrients Feb 2024Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological... (Review)
Review
Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence.
Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.
Topics: Humans; Diet, Ketogenic; Autism Spectrum Disorder; Dysbiosis; Epilepsy; Diet, Carbohydrate-Restricted; Ketone Bodies; Cognitive Dysfunction; Mood Disorders
PubMed: 38398876
DOI: 10.3390/nu16040553 -
Translational Psychiatry Oct 2023Autism is a neurodevelopmental disorder characterized by early-onset social behavioral deficits and repetitive behaviors. Chromodomain helicase DNA-binding protein...
Autism is a neurodevelopmental disorder characterized by early-onset social behavioral deficits and repetitive behaviors. Chromodomain helicase DNA-binding protein (CHD8) is among the genes most strongly associated with autism. In addition to the core behavioral symptoms of autism, affected individuals frequently present with gastrointestinal symptoms that are also common among individuals harboring mutations in the gene encoding CHD8. However, little is known regarding the mechanisms whereby CHD8 affects gut function. In addition, it remains unknown whether gastrointestinal manifestations contribute to the behavioral phenotypes of autism. The current study found that mice haploinsufficient for the large isoform of Chd8 (Chd8L) exhibited increased intestinal permeability, transcriptomic dysregulation in gut epithelial cells, reduced tuft cell and goblet cell counts in the gut, and an overall increase in microbial load. Gut epithelial cell-specific Chd8 haploinsufficiency was associated with increased anxiety-related behaviors together with a decrease in tuft cell numbers. Antibiotic treatment of Chd8L haploinsufficient mice attenuated social behavioral deficits. Together, these results suggest Chd8 as a key determinant of autism-related gastrointestinal deficits, while also laying the ground for future studies on the link between GI deficits and autism-related behaviors.
Topics: Mice; Animals; Autistic Disorder; Brain-Gut Axis; Gene Expression Regulation, Developmental; DNA-Binding Proteins; Autism Spectrum Disorder; Epithelial Cells
PubMed: 37783686
DOI: 10.1038/s41398-023-02611-2 -
Nutrients Jul 2023Autism Spectrum Disorder (ASD) is characterized by varying degrees of difficulty in social interaction and communication. These deficits are often associated with... (Review)
Review
Autism Spectrum Disorder (ASD) is characterized by varying degrees of difficulty in social interaction and communication. These deficits are often associated with gastrointestinal symptoms, indicating alterations in both intestinal microbiota composition and metabolic activities. The intestinal microbiota influences the function and development of the nervous system. In individuals with ASD, there is an increase in bacterial genera such as , as well as species involved in the synthesis of branched-chain amino acids (BCAA) like . Conversely, decreased amounts of and spp. are observed. Epigallocatechin-3-gallate (EGCG) is one of the polyphenols with the greatest beneficial activity on microbial growth, and its consumption is associated with reduced psychological distress. Therefore, the objective of this review is to analyze how EGCG and its metabolites can improve the microbial dysbiosis present in ASD and its impact on the pathology. The analysis reveals that EGCG inhibits the growth of pathogenic bacteria like and . Moreover, it increases the abundance of spp. and spp. As a result, EGCG demonstrates efficacy in increasing the production of metabolites involved in maintaining epithelial integrity and improving brain function. This identifies EGCG as highly promising for complementary treatment in ASD.
Topics: Humans; Child; Autism Spectrum Disorder; Dysbiosis; Gastrointestinal Microbiome; Bacteria
PubMed: 37513683
DOI: 10.3390/nu15143265 -
NeuroImage Mar 2024Autism spectrum disorder is a common neurodevelopmental condition that manifests as a disruption in sensory and social skills. Although it has been shown that the brain...
Autism spectrum disorder is a common neurodevelopmental condition that manifests as a disruption in sensory and social skills. Although it has been shown that the brain morphology of individuals with autism is asymmetric, how this differentially affects the structural connectome organization of each hemisphere remains under-investigated. We studied whole-brain structural connectivity-based brain asymmetry in individuals with autism using diffusion magnetic resonance imaging obtained from the Autism Brain Imaging Data Exchange initiative. By leveraging dimensionality reduction techniques, we constructed low-dimensional representations of structural connectivity and calculated their asymmetry index. Comparing the asymmetry index between individuals with autism and neurotypical controls, we found atypical structural connectome asymmetry in the sensory and default-mode regions, particularly showing weaker asymmetry towards the right hemisphere in autism. Network communication provided topological underpinnings by demonstrating that the inferior temporal cortex and limbic and frontoparietal regions showed reduced global network communication efficiency and decreased send-receive network navigation in the inferior temporal and lateral visual cortices in individuals with autism. Finally, supervised machine learning revealed that structural connectome asymmetry could be used as a measure for predicting communication-related autistic symptoms and nonverbal intelligence. Our findings provide insights into macroscale structural connectome alterations in autism and their topological underpinnings.
Topics: Humans; Autistic Disorder; Autism Spectrum Disorder; Connectome; Magnetic Resonance Imaging; Brain
PubMed: 38340881
DOI: 10.1016/j.neuroimage.2024.120534 -
Neuroscience and Biobehavioral Reviews Sep 2023There is now good evidence that behavioural signs of autism spectrum conditions (autism) emerge over the first two years of life. Identifying clear developmental... (Review)
Review
There is now good evidence that behavioural signs of autism spectrum conditions (autism) emerge over the first two years of life. Identifying clear developmental differences early in life may facilitate earlier identification and intervention that can promote longer-term quality of life. Here we present a systematic review of studies investigating behavioural markers of later autism diagnosis or symptomology taken at 0-6 months. The following databases were searched for articles published between 01/01/2000 and 15/03/2022: Embase, Medline, Scopus, PubMed, PsycINFO, CINAHL, Web of Science and Proquest. Twenty-five studies met inclusion criteria: assessment of behaviour at 0-6 months and later assessment of autism symptomology or diagnosis. Studies examined behaviours of attention, early social and communication behaviours, and motor behaviours, as well as composite measures. Findings indicated some evidence of measures of general attention, attention to social stimuli, and motor behaviours associated with later autism diagnosis or symptomology. Findings were inconsistent regarding social and communication behaviours, with a lack of repeated or validated measures limiting drawing firm conclusions. We discuss implications of the findings and suggest recommendations for future research.
Topics: Humans; Autistic Disorder; Quality of Life; Autism Spectrum Disorder; Communication
PubMed: 37406749
DOI: 10.1016/j.neubiorev.2023.105304 -
Brain Research Jun 2024Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by social deficits, repetitive behaviours and lack of empathy. Its significant genetic... (Review)
Review
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by social deficits, repetitive behaviours and lack of empathy. Its significant genetic heritability and potential comorbidities often lead to diagnostic and therapeutic challenges. This review addresses the biological basis of ASD, focusing on the sex differences in gene expression and hormonal influences. ASD is more commonly diagnosed in males at a ratio of 4:1, indicating a potential oversight in female-specific ASD research and a risk of underdiagnosis in females. We consider how ASD manifests differently across sexes by exploring differential gene expression in female and male brains and consider how variations in steroid hormones influence ASD characteristics. Synaptic function, including excitation/inhibition ratio imbalance, is influenced by gene mutations and this is explored as a key factor in the cognitive and behavioural manifestations of ASD. We also discuss the role of micro RNAs (miRNAs) and highlight a novel mutation in miRNA-873, which affects a suite of key synaptic genes, neurexin, neuroligin, SHANK and post-synaptic density proteins, implicated in the pathology of ASD. Our review suggests that genetic predisposition, sex differences in brain gene expression, and hormonal factors significantly contribute to the presentation, identification and severity of ASD, necessitating sex-specific considerations in diagnosis and treatments. These findings advocate for personalized interventions to improve the outcomes for individuals with ASD.
Topics: Humans; Autism Spectrum Disorder; Sex Characteristics; Female; Male; Brain; MicroRNAs; Genetic Predisposition to Disease
PubMed: 38513995
DOI: 10.1016/j.brainres.2024.148877 -
Journal of Autism and Developmental... Aug 2023Prior studies suggest autism-specific and general developmental screens are complementary for identifying both autism and developmental delay (DD). Parents completed...
Prior studies suggest autism-specific and general developmental screens are complementary for identifying both autism and developmental delay (DD). Parents completed autism and developmental screens before 18-month visits. Children with failed screens for autism (n = 167) and age, gender, and practice-matched children passing screens (n = 241) completed diagnostic evaluations for autism and developmental delay. When referral for autism and/or DD was considered, overall false positives from the autism screens were less frequent than for referral for autism alone. Presence of a failed communication subscale in the developmental screen was a red flag for autism and/or DD. An ordinally-scored autism screen had more favorable characteristics when considering autism and/or DD, yet none of the screens achieved recommended standards at 18 months, reinforcing the need for recurrent screening as autism emerges in early development.
Topics: Child; Humans; Infant; Autistic Disorder; Autism Spectrum Disorder; Surveys and Questionnaires; Parents; Mass Screening
PubMed: 35579791
DOI: 10.1007/s10803-022-05541-y -
Cerebral Cortex (New York, N.Y. : 1991) May 2024We evaluated functional connectivity (FC) in patients with adult autism spectrum disorder (ASD) using resting-state functional MRI (rs-fMRI) and diffusion kurtosis...
We evaluated functional connectivity (FC) in patients with adult autism spectrum disorder (ASD) using resting-state functional MRI (rs-fMRI) and diffusion kurtosis imaging (DKI). We acquired rs-fMRI data from 33 individuals with ASD and 33 healthy controls (HC) and DKI data from 18 individuals with ASD and 17 HC. ASD showed attenuated FC between the right frontal pole (FP) and the bilateral temporal fusiform cortex (TFusC) and enhanced FC between the right thalamus and the bilateral inferior division of lateral occipital cortex, and between the cerebellar vermis and the right occipital fusiform gyrus (OFusG) and the right lingual gyrus, compared with HC. ASD demonstrated increased axial kurtosis (AK) and mean kurtosis (MK) in white matter (WM) tracts, including the right anterior corona radiata (ACR), forceps minor (FM), and right superior longitudinal fasciculus (SLF). In ASD, there was also a significant negative correlation between MK and FC between the cerebellar vermis and the right OFusG in the corpus callosum, FM, right SLF and right ACR. Increased DKI metrics might represent neuroinflammation, increased complexity, or disrupted WM tissue integrity that alters long-distance connectivity. Nonetheless, protective or compensating adaptations of inflammation might lead to more abundant glial cells and cytokine activation effectively alleviating the degeneration of neurons, resulting in increased complexity. FC abnormality in ASD observed in rs-fMRI may be attributed to microstructural alterations of the commissural and long-range association tracts in WM as indicated by DKI.
Topics: Humans; Autism Spectrum Disorder; Male; Adult; Magnetic Resonance Imaging; Female; Young Adult; Brain; Neural Pathways; White Matter; Brain Mapping; Adolescent; Diffusion Tensor Imaging
PubMed: 38012112
DOI: 10.1093/cercor/bhad451 -
JAMA Network Open Jul 2023Maternal labor epidural analgesia (LEA) and oxytocin use for labor and delivery have been reported to be associated with child autism spectrum disorders (ASD). However,...
IMPORTANCE
Maternal labor epidural analgesia (LEA) and oxytocin use for labor and delivery have been reported to be associated with child autism spectrum disorders (ASD). However, it remains unclear whether these 2 common medications used during labor and delivery have synergistic associations with ASD risk in children.
OBJECTIVE
To assess the independent associations of LEA and oxytocin during labor and delivery with ASD, as well as outcome modification associated with the concurrent use of both interventions.
DESIGN, SETTING, AND PARTICIPANTS
Data for this cohort study included 205 994 singleton births with vaginal deliveries in a single integrated health care system in Southern California from calendar years 2008 to 2017. Children were followed up to December 31, 2021. Data on use of LEA and oxytocin, covariates, and ASD outcome in children were obtained from electronic medical records. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) adjusting for covariates.
EXPOSURES
Labor epidural analgesia and/or oxytocin use during labor and delivery.
MAIN OUTCOMES AND MEASURES
A child's clinical diagnosis of ASD during follow-up and at age of diagnosis.
RESULTS
Among the cohort, 153 880 children (74.7%) were exposed to maternal LEA and 117 808 children (57.2%) were exposed to oxytocin during labor and delivery. The population of children was approximately half boys and half girls. The median (IQR) age of the mothers was 30.8 (26.8-34.5) years for those not exposed to LEA, 30.0 (25.9-33.8) years for those exposed to LEA, 30.4 (26.5-34.1) years for those unexposed to oxytocin, and 30.0 (25.9-33.9) years for those exposed to oxytocin during labor and delivery. A total of 5146 children (2.5%) had ASD diagnosed during follow-up. Oxytocin exposure was higher among LEA-exposed (67.7%) than -unexposed (26.1%) children. The ASD risk associated with LEA was independent of oxytocin exposure (HR, 1.28; 95% CI, 1.18-1.38); however, the ASD risk associated with oxytocin was not significant after adjusting for LEA exposure (HR, 1.05; 95% CI, 0.99-1.12). A significant interaction of LEA and oxytocin on child ASD risk was found (P = .02 for interaction). Compared with no exposure, HRs were 1.20 (95% CI, 1.09-1.32) for LEA alone, 1.30 (95% CI, 1.20-1.42) for both LEA and oxytocin, and 0.90 (95% CI, 0.78-1.04) for oxytocin alone.
CONCLUSIONS AND RELEVANCE
The findings of this cohort study suggest an association between maternal LEA and ASD risk in children, and the risk appeared to be further increased if oxytocin was also administered. Oxytocin exposure without LEA exposure was not associated with ASD risk in children. These findings must be interpreted with caution. Further studies are needed to replicate or refute the study results and examine biological plausibility.
Topics: Pregnancy; Male; Female; Child; Humans; Adult; Autism Spectrum Disorder; Cohort Studies; Analgesia, Epidural; Oxytocin; Labor, Obstetric; Analgesics
PubMed: 37477919
DOI: 10.1001/jamanetworkopen.2023.24630 -
JCI Insight Oct 2023Germline de novo missense variants of the CACNA1D gene, encoding the pore-forming α1 subunit of Cav1.3 L-type Ca2+ channels (LTCCs), have been found in patients with...
Germline de novo missense variants of the CACNA1D gene, encoding the pore-forming α1 subunit of Cav1.3 L-type Ca2+ channels (LTCCs), have been found in patients with neurodevelopmental and endocrine dysfunction, but their disease-causing potential is unproven. These variants alter channel gating, enabling enhanced Cav1.3 activity, suggesting Cav1.3 inhibition as a potential therapeutic option. Here we provide proof of the disease-causing nature of such gating-modifying CACNA1D variants using mice (Cav1.3AG) containing the A749G variant reported de novo in a patient with autism spectrum disorder (ASD) and intellectual impairment. In heterozygous mutants, native LTCC currents in adrenal chromaffin cells exhibited gating changes as predicted from heterologous expression. The A749G mutation induced aberrant excitability of dorsomedial striatum-projecting substantia nigra dopamine neurons and medium spiny neurons in the dorsal striatum. The phenotype observed in heterozygous mutants reproduced many of the abnormalities described within the human disease spectrum, including developmental delay, social deficit, and pronounced hyperactivity without major changes in gross neuroanatomy. Despite an approximately 7-fold higher sensitivity of A749G-containing channels to the LTCC inhibitor isradipine, oral pretreatment over 2 days did not rescue the hyperlocomotion. Cav1.3AG mice confirm the pathogenicity of the A749G variant and point toward a pathogenetic role of altered signaling in the dopamine midbrain system.
Topics: Humans; Animals; Mice; Autism Spectrum Disorder; Mutation; Dopamine; Phenotype; Calcium Channels, L-Type
PubMed: 37698939
DOI: 10.1172/jci.insight.162100