Prevention Of Autism Research Articles

The effects of postnatal erythropoietin and nano-erythropoietin on behavioral alterations by mediating K-Cl co-transporter 2 in the valproic acid-induced rat model of autism.

In this study, based on the excitatory/inhibitory imbalance theory of autism, the time window of GABA switch, the role of K-Cl co-transporter 2 (KCC2) in adjustment GABA switch, and brain permeability to erythropoietin (EPO), the effects of postnatal -EPO and- nano- erythropoietin (NEPO) have been evaluated in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism at gestational day (GD) 12.5 (600 mg/kg). Male offsprings were injected with EPO and NEPO in a clinically proper postnatal dosing regimen on postnatal days (PND) 1-5, and autistic-like behaviors were tested at the end of the first month. Then animals were sacrificed, and neuron morphology and KCC2 expression were examined by Nissl staining and Western blot. According to our findings, high-dose NEPO improved autism-associated phenotypes. Neuroprotective effects of EPO and NEPO have been shown in the hippocampus. Postnatal NEPO treatment reversed KCC2 expression abnormalities induced by prenatal VPA. Our results might support the role of KCC2 in ASD and the excitatory/inhibitory imbalance hypothesis. We suggested Nano- erythropoietin and other KCC2 interventions as a new approach to the early treatment and prevention of autism.

Role of JAK-STAT and PPAR-Gamma Signalling Modulators in the Prevention of Autism and Neurological Dysfunctions.

The Janus-kinase (JAK) and signal transducer activator of transcription (STAT) signalling pathways regulate gene expression and control various factors involved in normal physiological functions such as cell proliferation, neuronal development, and cell survival. JAK activation phosphorylates STAT3 in astrocytes and microglia, and this phosphorylation has been linked to mitochondrial damage, apoptosis, neuroinflammation, reactive astrogliosis, and genetic mutations. As a regulator, peroxisome proliferator-activated receptor gamma (PPAR-gamma), in relation to JAK-STAT signalling, prevents this phosphorylation and aids in the treatment of the above-mentioned neurocomplications. Changes in cellular signalling may also contribute to the onset and progression of autism. Thus, PPAR-gamma agonist upregulation may be associated with JAK-STAT signal transduction downregulation. It may also be responsible for attenuating neuropathological changes by stimulating SOCS3 or involving RXR or SMRT, thereby reducing transcription of the various cytokine proteins and genes involved in neuronal damage. Along with JAK-STAT inhibitors, PPAR-gamma agonists could be used as target therapeutic interventions for autism. This research-based review explores the potential involvement and mutual regulation of JAK-STAT and PPAR-gamma signalling in controlling multiple pathological factors associated with autism.

AN OBSERVATIONAL STUDY TO ASSESS THE PARENTAL DOSHA PRAKRITI OF AUTISTIC CHILDREN

Prakriti refers to the genetically determined physical and mental constitution of an individual. Autism is a lifelong disability identified by impaired communication, social interaction and repetitive behaviours. The genetic, envi- ronmental and immunological factors play an important role in generating autism. Genetic factors are more pre- dominant in autism pathogenesis than the environmental factors that would modulate the phenotype. Until now, no interventions have proven widely effective in providing complete relief to autism. Therefore, the prevention of autism needs supreme attention. To a greater extent, prakriti of an individual can determine proneness to particu- lar diseases. To assess the prakriti of both parents of 30 diagnosed cases of autistic children attending the OPD and IPD of Govt. Ayurveda College, Kannur were randomly selected. They are subjected to detailed history taking based on specially prepared proforma and assessments were recorded. Their prakriti assessment was done using a validated computer-assisted questionnaire software Ayusoft developed by C-DAC Pune. The data was statistically analysed. In this study, Vata pitta prakriti was significantly seen in mothers of autistic children. Keywords: Prakriti, Autism

Socioeconomic characteristics of autistic children: a comparative study

Background: Prevalence of autism is increasing and growing as an important public health problem. Prevention of autism is still a complicated issue. Thus, the management and rehabilitation of autistic children socially could be the main option. For which the role of socio-economic factors of the autistic children needs to be considered.Methods: This was a cross-sectional comparative study conducted among the autistic and non-autistic children to compare their socioeconomic characteristics. A total of 90 autistic children from two specialized schools and age-matched 180 non-autistic children from nearby schools were included in this study.Results: Overall the mean age of the children was 8.01±2.974 years. More than fourth-fifths (84.4%) of the autistic children were male. In comparison to non-autistic children, significantly (p<0.05) autistic children had small family size (4.79) and higher family income (Taka=34588). Higher education of both father and mother was also found to be significantly associated with autistic children. However, logistic regression analysis revealed that post-graduate education of the father had the strongest (6.4 times) ability to predict the occurrence of autism. The mean age of the mother at birth of autistic children was significantly higher (31.16 years) and logistic regression analysis revealed that higher age of the mother at birth had 1.3 times ability to predict the occurrence of autism. Moreover, the analysis revealed that mothers who were housewife 2.3 times more likely to predict the occurrence of autism.Conclusions: The study revealed that some socio-economic factors were significantly related to autistic children compared to those of non-autistic children.

The Neurochemistry of Autism.

Autism spectrum disorder (ASD) refers to complex neurobehavioral and neurodevelopmental conditions characterized by impaired social interaction and communication, restricted and repetitive patterns of behavior or interests, and altered sensory processing. Environmental, immunological, genetic, and epigenetic factors are implicated in the pathophysiology of autism and provoke the occurrence of neuroanatomical and neurochemical events relatively early in the development of the central nervous system. Many neurochemical pathways are involved in determining ASD; however, how these complex networks interact and cause the onset of the core symptoms of autism remains unclear. Further studies on neurochemical alterations in autism are necessary to clarify the early neurodevelopmental variations behind the enormous heterogeneity of autism spectrum disorder, and therefore lead to new approaches for the treatment and prevention of autism. In this review, we aim to delineate the state-of-the-art main research findings about the neurochemical alterations in autism etiology, and focuses on gamma aminobutyric acid (GABA) and glutamate, serotonin, dopamine, N-acetyl aspartate, oxytocin and arginine-vasopressin, melatonin, vitamin D, orexin, endogenous opioids, and acetylcholine. We also aim to suggest a possible related therapeutic approach that could improve the quality of ASD interventions. Over one hundred references were collected through electronic database searching in Medline and EMBASE (Ovid), Scopus (Elsevier), ERIC (Proquest), PubMed, and the Web of Science (ISI).

The putative etiology and prevention of autism.

Since the initial psychological report by Leo Kanner in 1943, relatively little formal biochemical/neurological research on the cause of autism, other than peripheral searches for genomic mutations, had been carried until the end of the 20th century. As a result of studies on twin sets and the conclusion that autism was largely a hereditary defect, numerous investigations have sought various genetic faults in particular. However, such studies were able to reveal a plausible etiology for this malady in only a small percentage of instances.Key bio-molecular characteristics of this syndrome have been uncovered when the potential roles of the glia were studied in depth. Findings related to biochemical deficiencies appearing early in the newborn, such as depressed IGF-1 (insulin-like growth factor #1) in neurogenesis/myelination, are becoming emphasized in many laboratories. Progress leading to timely diagnoses and subsequent prevention of central nervous system dysconnectivity now seems plausible. The tendency for an infant to develop autism may currently be determinable and preventable before irreversible psychosocial disturbances become established.These discussions about glial function will be inter-spersed with comments about their apparent relevance to autism. The concluding portion of this presentation will be a detailed review and summation of this diagnosis and prevention proposition.

IGF – Autism prevention/amelioration

Autism continues to be a significant cause of psychosocial pathology in affected children and adults. Until recently, the predominant research thrust to uncover the cause of this condition has been the search for a major nuclear mutation. Although a small percentage of cases do demonstrate such a DNA fault, recent effort has come to emphasize problems in the biochemistry of its sufferers. In particular, insulin-like growth factor-1 (IGF) has become the center of concern in many laboratories. A deficiency in this growth factor, leading to insufficient neuron myelination and defective synapse function, appears to result in brain dysconnectivity during the first year of postpartum life, and cause social malfunction in childhood years and beyond. At least three approaches have been reported by which this deficiency can be corrected in neonates before irreversible damage has been caused. The overall purpose of this report is to bring together related observations and to evolve a coherent, plausible explanation of the cause and prevention of autism.

Perfil sensorial e sua relação com risco psíquico, prematuridade e desenvolvimento motor e de linguagem por bebês de 12 meses

Objetivo: Analisar a correlação entre perfil sensorial do bebê, idade gestacional e risco psíquico e seus efeitos na avaliação motora e de linguagem. Método: a amostra foi composta por 40 bebês, 20 prematuros e 20 nascidos a termo, com 10 bebês com risco psíquico e 10 sem risco em cada grupo, identificados a partir dos sinais PREAUT e dos Indicadores Clínicos de Referência ao Desenvolvimento Infantil e avaliados pelo DENVER II, na faixa etária de 12 meses a 12 meses e 29 dias. A análise estatística foi realizada pelos programas STATISTICA 9.1 e PASW 17.0. Resultados: Foi identificada significância estatística nas correlações entre testes sensoriais e protocolo de risco psíquico, bem como no fator de risco prematuridade. Os resultados não demonstraram significância estatística com os resultados em motricidade e linguagem no teste DENVER II. Conclusão: Alterações no perfil sensorial estiveram relacionadas a risco psíquico e idade gestacional menor, mas não se correlacionaram ao desenvolvimento motor e linguístico.

The absolute quantitative analysis of cingulate cortex metabolites in preschool children with autism spectrum disorder using proton MR spectroscopy

Objective To investigate the metabolite changes in the preschool children with autism spectrum disorder (ASD) using MR spectroscopy (MRS) and explore the associations between image findings and clinical variables, which may provide a noninvasive brain biochemical method for the early diagnosis and prevention of autism. Methods Twenty one cases of preschool ASD children (3-6 years old) and age-and sex-matched 20 preschool healthy controls underwent single voxel short (SVS) short TE (TE=30 ms) MRS. The absolute metabolite concentrations in the anterior cingulate cortex (ACC), anterior middle anterior cingulate cortex (aMCC) and posterior cingulate (PCC) were quantitatively analyzed using LCModel software. Two independent sample t tests were used for analysis. The relationships between metabolite concentrations and diagnostic and statistical manual of mental disorders (DSM-IV), childhood autism rating scale (CARS) and autism behavior checklist (ABC) were analyzed by Pearson correlation analysis. Results Compared to control subjects, ASD patients had significantly lower N-acetylaspartate (NAA) values (4.35±0.80, 6.34±0.82, 8.04±0.97 mmol/L respectively) in ACC, aMCC and PCC (t=2.640, P=0.012; t=2.182, P=0.035; t=3.343, P=0.002), had significantly lower choline (Cho) 1.32±0.22 mmol/L (t=2.905, P=0.006) and glutamine and glutamate complex (Glx) 10.02±0.88 mmol/L (t=2.090, P=0.043) in PCC. Cho, total creatine (tCr), myo-Inositol (MI) and Glx levels did not differ between groups in other aforementioned regions (P>0.05). Negative correlations between the NAA ualues in the PCC and CARS (r=-0.504, P=0.020) were detected, and no significant correlation among DSM-IV, CARS, ABC and other metabolite values (P>0.05). Conclusions The biochemical changes in the preschool children with ASD in cingulate reflect the neuronal loss, structural or functional damage and cell membrane enzyme metabolic dysfunctions, may reveal the pathological basis of ASD. These results may provide noninvasive and quantitative methods for the diagnosis and prognosis evaluation of ASD child. Key words: Autism spectrum disorder; Magnetic resonance spectroscopy; Cingulate cortex; Child

Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring.

Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism.

38. Prenatal zinc prevents mTOR disturbance in a rat model of autism induced by prenatal lipopolysaccharide

Previous investigations by our group have shown that prenatal exposure to lipopolysaccharide (LPS), which mimics infection with Gram-negative bacteria, on gestational day 9.5 induces autistic-like behavior. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism spectrum disorder (ASD). We selected zinc as the prenatal treatment because LPS induces hypozincaemia. Epidemiological findings and animal models have indicated that excessive signaling through the mammalian target of rapamycin (mTOR) pathway lead to increased risk of ASD. Because mTOR is considered an important biomarker of autism, we evaluated mTOR protein levels in the striatum and substatia nigra of rats prenatally exposed to LPS and zinc via western blotting. Prenatal LPS exposure increased 30% the mTOR levels in the striatum compared to the control group (LPS + SAL group versus SAL + SAL group, p < 0.01). Zinc prenatal treatment was able to reduce 40% the mTOR levels in the striatum even after the LPS exposure (LPS + Zn versus LPS + SAL, p < 0.001). Prenatal zinc after LPS returned the mTOR levels to the same levels of the control group. The analyses in the substantia nigra revealed no differences in the mTOR levels between all the groups. Together with our data of benefits in autistic-like behaviors after prenatal zinc treatment, zinc has a potential beneficial effect in the prevention of autism with regard to the mTOR pathway. CAPES and FAPESP.

Should Children with Autism Continue Taking Folic Acid Supplement?

Elevated levels of homocysteine have been linked with autism. Despite evidence that folic acid supplementation reduces the homocysteine level. There is a need for clinical trials to specifically study the role of folic acid in the primary and secondary prevention of autism. Sporadic evidence from childhood practices that there is a benefit for folic acid supplementation for autistic children and those patients are encouraged to take folic acid as a medication. Meta-analysis studies are needed to study the cause-specific effect of folic acid deficiency and/or hyperhomocysteinemia on the autism incidence.

A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism.

We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.

Diagnosis, Treatment and Prevention of Autism via Meridian Theory

A twelve-week pilot study was conducted on 11 male children, aged five to 19 years, who had ASD (autistic symptom disorder) of varying degrees of severity. These eleven subjects were each examined three times in the 12-week period: at the first week, 6th week, and 12th week. During each examination, two sets of full-body thermographs were taken of each child, before and fifteen minutes after drinking a solution of stable water clusters with a double helix configuration. This solution of stable water clusters is called double helix water (DHW). In the before thermographs, a consistent thermal pattern of six hot regions of body surface temperature were identified. They are: left and right upper forehead region of the face; left and right area in front of the center of the ear; left and right area of the inner extreme point of the eye; left and right collarbone region; left and right side neck region; and left and right armpit region. These areas may be interpreted as regions surrounding various acupoints along the GB, BL, ST, SI, SJ meridians. These meridians are yang meridians that on one end reach the head, and hence have branches reaching into the brain, and on the other end reach to the gastrointestinal tract and urinary bladder system. Thus, they can be considered to explain the major clinical symptoms of ASD. These thermal patterns, if confirmed in a larger clinical study, may lead to a new way to diagnose ASD, and to test the effectiveness of any treatment. When such a thermal pattern is discovered early, say around the age of 18 months, preventive action can be initiated before observation of any behavior disorder. We simultaneously studied the healing effect of stable water clusters with double helix configuration (DHW) on these subjects. The quantitative reduction of maximum temperature at these six regions was calculated. A consistent reduction was noted and suggests a positive healing effect taking place within a very short time period (fifteen minutes), and lasting over a long time period (12 weeks). Quantitative evaluation by the parents over the 12-week period showed that eight out of 11 children had physiological and behavioral improvement. Our findings with these small numbers suggest a reliable method of early diagnosis/detection and also an effective treatment of ASD. We therefore conclude that a study of larger numbers of children with ASD should be conducted.

Association of hypomelanotic skin disorders with autism: links to possible etiologic role of vitamin-D levels in autism?

Vitamin D is crucial for several key physiological processes, including brain development, DNA repair, and regulation of many genes. Much evidence indicates prenatal and early postnatal vitamin-D deficiency increases autism risk, probably through multiple effects, including impaired brain development and increased de novo mutations. High autism rates in several genetically based hypomelanotic skin disorders are puzzling, because ultraviolet-B radiation (UVB) in sunlight acting on skin is a key source of vitamin-D, and lighter skin protects against vitamin-D deficiency, especially at high latitudes. We consider two hypotheses to help explain autism's co-morbidity with hypomelanosis. 1) Because genetic and epigenetic variants that produce hypomelanosis help protect against vitamin-D deficiency, they increase reproductive fitness of individuals who also have other autism risk factors. 2) Hypomelanotic children have increased autism risk because photosensitivity and skin-cancer concerns lead families to excessively reduce children's sun exposure. Hypothesis testing could involve studies comparing genomes, epigenetic markers, skin pigmentation, and vitamin-D levels in autistic individuals with and without hypomelanosis, their relatives and controls. Conducting such studies in samples from regions that differ widely in UVB availability would provide particularly valuable data. Support for either hypothesis would elucidate vitamin-D's role in autism and suggest vitamin-D enhancement may aid treatment and prevention of autism.