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Persico A.M.,Biomedical University of Rome | Persico A.M.,Mafalda Luce Center for Pervasive Developmental Disorders | Merelli S.,Mafalda Luce Center for Pervasive Developmental Disorders
Key Issues in Mental Health | Year: 2015

Multiple observations indicate that environmental and epigenetic factors play an important role in the emergence of autism spectrum disorders (ASD). Growing ASD incidence rates, the incomplete penetrance of many rare variants linked to autism, and increased exposure to environmental contaminants all strongly support the role of gene × environment interactions in a substantial fraction of autistic patients. Within this framework, genetically susceptible individuals exposed to detrimental environmental factors at critical times during neurodevelopment might undergo disrupted brain morphogenesis, neuronal connectivity, and synaptic functioning consequently yielding ASD. Several teratogenic drugs and prenatal viral infections are able to cause autism in humans, as supported by case reports, cohort studies, and animal models. Moreover, recent studies have shown that some newly identified potential neurotoxicants may negatively affect developmental trajectories, leading to altered cognitive, attentive, behavioral, and motor performances, as well as to systemic abnormalities frequently seen in autistic individuals. A variety of mechanisms are potentially involved, ranging from oxidative and inflammatory brain damage to altered gene expression and impaired signal transduction. More research is needed to thoroughly investigate the effects of these compounds on neurodevelopment, to validate their involvement specifically in ASD, to study gene × environment interactions in potentially susceptible individuals, and to plan targeted prevention strategies. © 2015 S. Karger AG, Basel. Source

Gabriele S.,Biomedical University of Rome | Sacco R.,Biomedical University of Rome | Altieri L.,Biomedical University of Rome | Altieri L.,Imperial College London | And 9 more authors.
Autism Research | Year: 2016

The uremic toxin p-cresol (4-methylphenol) is either of environmental origin or can be synthetized from tyrosine by cresol-producing bacteria present in the gut lumen. Elevated p-cresol amounts have been previously found in the urines of Italian and French autism spectrum disorder (ASD) children up until 8 years of age, and may be associated with autism severity or with the intensity of abnormal behaviors. This study aims to investigate the mechanism producing elevated urinary p-cresol in ASD. Urinary p-cresol levels were thus measured by High Performance Liquid Chromatography in a sample of 53 Italian ASD children assessed for (a) presence of Clostridium spp. strains in the gut by means of an in vitro fecal stool test and of Clostridium difficile-derived toxin A/B in the feces, (b) intestinal permeability using the lactulose/mannitol (LA/MA) test, (c) frequent use of antibiotics due to recurrent infections during the first 2 years of postnatal life, and (d) stool habits with the Bristol Stool Form Scale. Chronic constipation was the only variable significantly associated with total urinary p-cresol concentration (P < 0.05). No association was found with presence of Clostridium spp. in the gut flora (P = 0.92), augmented intestinal permeability (P = 0.18), or frequent use of antibiotics in early infancy (P = 0.47). No ASD child was found to carry C. difficile in the gut or to release toxin A/B in the feces. In conclusion, urinary p-cresol levels are elevated in young ASD children with increased intestinal transit time and chronic constipation. Autism Res 2016, 9: 752–759. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. Source

Gabriele S.,Biomedical University of Rome | Sacco R.,Biomedical University of Rome | Persico A.M.,Biomedical University of Rome | Persico A.M.,Mafalda Luce Center for Pervasive Developmental Disorders
European Neuropsychopharmacology | Year: 2014

Elevated blood serotonin (5-HT) levels were the first biomarker identified in autism research. Many studies have contrasted blood 5-HT levels in autistic patients and controls, but different measurement protocols, technologies, and biomaterials have been used through the years. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and between-study heterogeneity, while verifying whether and to what extent different methodological approaches influence the strength of this association. Our literature search strategy identified 551 papers, from which 22 studies providing patient and control blood 5-HT values were selected for meta-analysis. Significantly higher 5-HT levels in autistic patients compared to controls were recorded both in whole blood (WB) [O.R.=4.6; (3.1-5.2); P=1.0×10-12], and in platelet-rich plasma (PRP) [O.R.=2.6 (1.8-3.9); P=2.7×10-7]. Predictably, studies measuring 5-HT levels in platelet-poor plasma (PPP) yielded no significant group difference [O.R.=0.54 (0.2-2-0); P=0.36]. Altogether, elevated 5-HT blood levels were recorded in 28.3% in WB and 22.5% in PRP samples of autistic individuals, as reported in 15 and 4 studies, respectively. Studies employing HPLC vs fluorometric assays yield similar cumulative effect sizes, but the former display much lower variability. In summary, despite some limitations mainly due to small study sample sizes, our results significantly reinforce the reliability of elevated 5-HT blood levels as a biomarker in ASD, providing practical indications potentially useful for its inclusion in multi-marker diagnostic panels for clinical use. © 2014 Elsevier B.V. and ECNP. Source

Sacco R.,Biomedical University of Rome | Gabriele S.,Biomedical University of Rome | Persico A.M.,Biomedical University of Rome | Persico A.M.,Mafalda Luce Center for Pervasive Developmental Disorders
Psychiatry Research - Neuroimaging | Year: 2015

Macrocephaly and brain overgrowth have been associated with autism spectrum disorder. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and statistical significance for both head circumference and total brain volume in autism. Our literature search strategy identified 261 and 391 records, respectively; 27 studies defining percentages of macrocephalic patients and 44 structural brain imaging studies providing total brain volumes for patients and controls were included in our meta-analyses. Head circumference was significantly larger in autistic compared to control individuals, with 822/5225 (15.7%) autistic individuals displaying macrocephaly. Structural brain imaging studies measuring brain volume estimated effect size. The effect size is higher in low functioning autistics compared to high functioning and ASD individuals. Brain overgrowth was recorded in 142/1558 (9.1%) autistic patients. Finally, we found a significant interaction between age and total brain volume, resulting in larger head circumference and brain size during early childhood. Our results provide conclusive effect sizes and prevalence rates for macrocephaly and brain overgrowth in autism, confirm the variation of abnormal brain growth with age, and support the inclusion of this endophenotype in multi-biomarker diagnostic panels for clinical use. © 2015 Elsevier Ireland Ltd. Source

Chakrabarti B.,University of Reading | Persico A.,Biomedical University of Rome | Persico A.,Mafalda Luce Center for Pervasive Developmental Disorders | Battista N.,University of Teramo | And 2 more authors.
Neurotherapeutics | Year: 2015

Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the “endocannabinoid (eCB) system”, a rather complex ensemble of lipid signals (“endocannabinoids”), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD. © 2015, The American Society for Experimental NeuroTherapeutics, Inc. Source

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