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#1
07-30-2015, 12:14 AM
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رابطة ضعف الاجتماعي والمعرفي والمؤشرات الحيوية في اضطرابات طيف التوحد
http://www.jneuroinflammation.com/content/11/1/4
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استشارى الادوية الطبيعيه وباحث وخبير فى علاجات التوحد 
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#2
07-30-2015, 12:17 AM
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استعراض طيف التوحد اضطرابات-a الوراثة
http://www.nature.com/gim/journal/v1...m9201151a.html
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استشارى الادوية الطبيعيه وباحث وخبير فى علاجات التوحد
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#3
07-30-2015, 12:22 AM
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السيتوكينات الالتهابية: المؤشرات الحيوية المحتملة من المناعية اختلال وظيفي في اضطرابات طيف التوحد
التوحد هو اضطراب المنشأ العصبي البيولوجي التي تتميز مشاكل في الاتصال والمهارات الاجتماعية والسلوك المتكرر. بعد أكثر من ستة عقود من البحث، ومسببات مرض التوحد ما زال مجهولا، وقد أثبتت المؤشرات الحيوية لا أن يكون سمة من سمات التوحد. وأظهر عدد من الدراسات أن مستويات خلوى في الدم والدماغ، والسائل النخاعي (CSF) من الموضوعات التوحد تختلف من أن الأفراد الأصحاء. على سبيل المثال، سلسلة من الدراسات تشير إلى أن انترلوكين 6 (IL-6)، نخر الورم α factor- (TNF- α)، وγ interferon- (IFN- γ) هي مرتفعة بشكل كبير في الأنسجة المختلفة في المواضيع التوحد. ومع ذلك، والتعبير عن بعض السيتوكينات، مثل IL-1، IL-2، وتحويل β النمو factor- (TGF- β)، وعامل تحفيز مستعمرة الكريات البيضاء بلعم (GM-CSF)، أمر مثير للجدل، والدراسات المختلفة لها العثور على نتائج مختلفة في الأنسجة المختلفة. في هذا الاستعراض، ركزنا على عدة أنواع من proinflammatory والمضادة للالتهابات السيتوكينات التي قد تؤثر على مختلف مسارات إشارة الخلية وتلعب دورا في آلية المرضية في جسم المريض من اضطرابات طيف التوحد.
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استشارى الادوية الطبيعيه وباحث وخبير فى علاجات التوحد
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#4
07-30-2015, 12:26 AM
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Did you mean: Protocadherin α (PCDHA) as a novel susceptibility gene for autism. J Psychiatry Neurosci. 2012 Oct 2;37(6):120058. doi: 10.1503/jpn.120058. [Epub ahead of print] Anitha A, Thanseem I, Nakamura K, Yamada K, Iwayama Y, Toyota T, Iwata Y, Suzuki K, Sugiyama T, Tsujii M, Yoshikawa T, Mori N. Abstract Background: Synaptic dysfunction has been shown to be involved in the pathogenesis of autism. We hypothesized that the protocadherin α gene cluster (PCDHA), which is involved in synaptic specificity and in serotonergic innervation of the brain, could be a suitable candidate gene for autism. Methods: We examined 14 PCDHA single nucleotide polymorphisms (SNPs) for genetic association with autism in DNA samples of 3211 individuals (841 families, including 574 multiplex families) obtained from the Autism Genetic Resource Exchange. Results: Five SNPs (rs251379, rs1119032, rs17119271, rs155806 and rs17119346) showed significant associations with autism. The strongest association (p < 0.001) was observed for rs1119032 (z score of risk allele G = 3.415) in multiplex families; SNP associations withstand multiple testing correction in multiplex families (p = 0.041). Haplotypes involving rs1119032 showed very strong associations with autism, withstanding multiple testing corrections. In quantitative transmission disequilibrium testing of multiplex fam - ilies, the G allele of rs1119032 showed a significant association (p = 0.033) with scores on the Autism Diagnostic Interview-Revised (ADI-R)_D (early developmental abnormalities). We also found a significant difference in the distribution of ADI-R_A (social interaction) scores between the A/A, A/G and G/G genotypes of rs17119346 (p = 0.002). Limitations: Our results should be replicated in an in - dependent population and/or in samples of different racial backgrounds. Conclusion: Our study provides strong genetic evidence of PCDHA as a potential candidate gene for autism. Predicting the diagnosis of autism spectrum disorder using gene pathway analysis. Mol Psychiatry. 2012 Sep 11. doi: 10.1038/mp.2012.126. [Epub ahead of print] Skafidas E, Testa R, Zantomio D, Chana G, Everall IP, Pantelis C. Abstract Autism spectrum disorder (ASD) depends on a clinical interview with no biomarkers to aid diagnosis. The current investigation interrogated single-nucleotide polymorphisms (SNPs) of individuals with ASD from the Autism Genetic Resource Exchange (AGRE) database. SNPs were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived pathways to identify affected cellular processes and develop a diagnostic test. This test was then applied to two independent samples from the Simons Foundation Autism Research Initiative (SFARI) and Wellcome Trust 1958 normal birth cohort (WTBC) for validation. Using AGRE SNP data from a Central European (CEU) cohort, we created a genetic diagnostic classifier consisting of 237 SNPs in 146 genes that correctly predicted ASD diagnosis in 85.6% of CEU cases. This classifier also predicted 84.3% of cases in an ethnically related Tuscan cohort; however, prediction was less accurate (56.4%) in a genetically dissimilar Han Chinese cohort (HAN). Eight SNPs in three genes (KCNMB4, GNAO1, GRM5) had the largest effect in the classifier with some acting as vulnerability SNPs, whereas others were protective. Prediction accuracy diminished as the number of SNPs analyzed in the model was decreased. Our diagnostic classifier correctly predicted ASD diagnosis with an accuracy of 71.7% in CEU individuals from the SFARI (ASD) and WTBC (controls) validation data sets. In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD. While SNPs differ across ethnic groups, our pathway approach identified cellular processes common to ASD across ethnicities. Our results have wide implications for detection, intervention and prevention of ASD.Molecular Psychiatry advance online publication, 11 September 2012; doi:10.1038/mp.2012.126. Use of artificial intelligence to shorten the behavioral diagnosis of autism. PLoS One. 2012;7(8):e43855. Epub 2012 Aug 27. Wall DP, Dally R, Luyster R, Jung JY, Deluca TF. Abstract The Autism Diagnostic Interview-Revised (ADI-R) is one of the most commonly used instruments for assisting in the behavioral diagnosis of autism. The exam consists of 93 questions that must be answered by a care provider within a focused session that often spans 2.5 hours. We used machine learning techniques to study the complete sets of answers to the ADI-R available at the Autism Genetic Research Exchange (AGRE) for 891 individuals diagnosed with autism and 75 individuals who did not meet the criteria for an autism diagnosis. Our analysis showed that 7 of the 93 items contained in the ADI-R were sufficient to classify autism with 99.9% statistical accuracy. We further tested the accuracy of this 7-question classifier against complete sets of answers from two independent sources, a collection of 1654 individuals with autism from the Simons Foundation and a collection of 322 individuals with autism from the Boston Autism Consortium. In both cases, our classifier performed with nearly 100% statistical accuracy, properly categorizing all but one of the individuals from these two resources who previously had been diagnosed with autism through the standard ADI-R. Our ability to measure specificity was limited by the small numbers of non-spectrum cases in the research data used, however, both real and simulated data demonstrated a range in specificity from 99% to 93.8%. With incidence rates rising, the capacity to diagnose autism quickly and effectively requires careful design of behavioral assessment methods. Ours is an initial attempt to retrospectively analyze large data repositories to derive an accurate, but significantly abbreviated approach that may be used for rapid detection and clinical prioritization of individuals likely to have an autism spectrum disorder. Such a tool could assist in streamlining the clinical diagnostic process overall, leading to faster screening and earlier treatment of individuals with autism. Use of machine learning to shorten observation-based screening and diagnosis of autism. Transl Psychiatry. 2012 Apr 10;2:e100. doi: 10.1038/tp.2012.10. Wall DP, Kosmicki J, Deluca TF, Harstad E, Fusaro VA. Abstract The Autism Diagnostic Observation Schedule-Generic (ADOS) is one of the most widely used instruments for behavioral evaluation of autism spectrum disorders. It is composed of four modules, each tailored for a specific group of individuals based on their language and developmental level. On average, a module takes between 30 and 60 min to deliver. We used a series of machine-learning algorithms to study the complete set of scores from Module 1 of the ADOS available at the Autism Genetic Resource Exchange (AGRE) for 612 individuals with a classification of autism and 15 non-spectrum individuals from both AGRE and the Boston Autism Consortium (AC). Our analysis indicated that 8 of the 29 items contained in Module 1 of the ADOS were sufficient to classify autism with 100% accuracy. We further validated the accuracy of this eight-item classifier against complete sets of scores from two independent sources, a collection of 110 individuals with autism from AC and a collection of 336 individuals with autism from the Simons Foundation. In both cases, our classifier performed with nearly 100% sensitivity, correctly classifying all but two of the individuals from these two resources with a diagnosis of autism, and with 94% specificity on a collection of observed and simulated non-spectrum controls. The classifier contained several elements found in the ADOS algorithm, demonstrating high test validity, and also resulted in a quantitative score that measures classification confidence and extremeness of the phenotype. With incidence rates rising, the ability to classify autism effectively and quickly requires careful design of assessment and diagnostic tools. Given the brevity, accuracy and quantitative nature of the classifier, results from this study may prove valuable in the development of mobile tools for preliminary evaluation and clinical prioritization-in particular those focused on assessment of short home videos of children--that speed the pace of initial evaluation and broaden the reach to a significantly larger percentage of the population at risk. Immune function genes CD99L2, JARID2 and TPO show association with autism spectrum disorder. Mol Autism. 2012 Jun 9;3(1):4. [Epub ahead of print] Ramos PS, Sajuthi S, Langefeld CD, Walker SJ. Abstract BACKGROUND: A growing number of clinical and basic research studies have implicated immunological abnormalities as being associated with and potentially responsible for the cognitive and behavioral deficits seen in autism spectrum disorder (ASD) children. Here we test the hypothesis that immune-related gene loci are associated with ASD. FINDINGS: We identified 2,012 genes of known immune-function via Ingenuity Pathway Analysis. Family-based tests of association were computed on the 22,904 single nucleotide polymorphisms (SNPs) from the 2,012 immune-related genes on 1,510 trios available at the Autism Genetic Resource Exchange (AGRE) repository. Several SNPs in immune-related genes remained statistically significantly associated with ASD after adjusting for multiple comparisons. Specifically, we observed significant associations in the CD99 molecule-like 2 region (CD99L2, rs11796490, P = 4.01 x 10-06, OR = 0.68 (0.58-0.80)), in the jumonji AT rich interactive domain 2 (JARID2) gene (rs13193457, P = 2.71 x 10-06, OR = 0.61 (0.49-0.75)), and in the thyroid peroxidase gene (TPO) (rs1514687, P = 5.72 x 10-06, OR = 1.46 (1.24- 1.72)). CONCLUSIONS: This study suggests that despite the lack of a general enrichment of SNPs in immune function genes in ASD children, several novel genes with known immune functions are associated with ASD.
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استشارى الادوية الطبيعيه وباحث وخبير فى علاجات التوحد
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#5
07-30-2015, 12:31 AM
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Did you mean: Neuroimmunology of Autism Spectrum Disorder. Neurotransmitters as predictive biomarkers of responsiveness to substance abuse treatment Neuroimmunology of Autism Spectrum Disorder. Addressing Adrenal Imbalance: The Future of Adrenal Health Avipaxin and Modulation of the Immune System. The Clinical Utility of Urinary Neurotransmitter Analysis: An Overview. Daxitrol Essential: A Novel Approach for Controlling Cravings. Hypersensitivity Reactions and Methods of Detection. Methylation: Fundamental to a Healthy Nervous System A Novel Top-down Strategy For Addressing Autonomic Imbalances. Download PDF NEUROIMMUNOLOGY OF AUTISM SPECTRUM DISORDER David Marc, MSa; Kelly Olson, PhD NeuroScience, Inc., 373 280th St., Osceola, WI 54020, United States address correspondence to: david.marc@neurorelief.com Abstract Autism is a developmental disorder characterized by immunological and neurological abnormalities. The role of cytokines in the pathophysiology of autism has been researched suggesting a relationship with altered blood-brain barrier permeability and subsequent neuroinflammation. Cytokine recruitment to the CNS may result in altered neurotransmitter signaling and the behavioral manifestation of autism symptoms. Other immune mediated events such as changes in the number and activity of natural killer cells, macrophages, immunoglobulins, and glutathione may contribute to altered neuronal signaling and neurotransmitter imbalances. The purpose of this overview is to examine the relationship between immune system and nervous system dysfunction to determine biomarkers for autism spectrum disorder. We will explore the utility of serum cytokines and urinary neurotransmitter analyses as biomarkers for autism. Introduction Autism is a pervasive developmental disorder characterized by impaired development of social interaction and communication, and a markedly restricted repertoire of activities and interests (American Psychiatric Association, 1994). The exact etiology of autism remains largely unknown, however, literature has emerged to suggest genetic, neurological, immunological, and environmental contributions. Immunological and environmental factors, such as diet, infection, and xenobiotics play critical roles in the development of autism. (Ivarsson, Bjerre, Vegfors, and Ahlfors, 1990; Wakefield et al., 1998; Edelson and Cantor, 2002; Fatemi et al., 2002; Kibersti and Roberts, 2002). Abnormalities in enzymatic function (Fatemi et al., 2002a), autoantibodies to brain proteins (Vojdani et al., 2002), and maternal infections during pregnancy (Shi et al., 2003) have been indicated in the autism population. Additionally, pathological alterations in genes involved in the patterning of the central nervous system, biochemical pathways, development of dendrites and synapses, and genes associated with the immune system have been observed in this population (Burber and Warren, 1998; Palmen, Engeland, Hof, and Schmitz, 2004; Polleux and Lauder, 2004; Cohen et al., 2005; Crawley, 2007; Glessner et al., 2009; Wang et al., 2009). Interestingly, an emerging body of evidence is growing concerning the link between abnormal immune function and neurological dysfunction with autism spectrum disorders. At critical times of infantile development, immune dysregulation may result in the release of immunomodulatory molecules, such as chemokines and cytokines, leading to altered neuronal development and neural function (Cohly & Panja, 2005). Chemokines and cytokines are proteins that manage immune cell trafficking and cellular arrangement of immune organs and determine appropriate immune responses (Borish & Steinke, 2003). Cytokines can be transported to and/or synthesized in the central nervous system (CNS) thereby establishing communication between peripheral immune cells and CNS neurons (Dunn, 2006). The purpose of this overview is to identify neurological and immunological abnormalities that exist in individuals with autism. Further, it will become critically apparent that neuroimmune biomarker testing for autism can identify these abnormalities and ensure therapeutic effectiveness. Cytokines and Neurotransmission Cytokines released by immune cells, particularly interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), communicate with the CNS to affect neural activity and modify behaviors, hormone release, and "normal" autonomic function (Dunn, 2006). Cytokines can enter the brain by various mechanisms including active transport or direct entry through a compromised blood-brain barrier. Active transport mechanisms that involve a saturable system have been documented for IL-1 and TNF-α (Dunn, 1992; Gutierrez, Banks, and Kastin, 1993; Gutierrez, Banks, Kastin, 1994). Additionally, Maier and colleagues (1998) found that cytokines may directly enter the central nervous system at circumventricular regions, predominantly the area postrema, where the blood brain barrier is less protective (Pavlov et al., 2003). Other circumventricular regions of potential cytokine entry include the pineal gland, subfornical organ, organum vasculosum of the lamina terminalis, choroid plexus, median eminence, subcommissural organ, and posterior pituitary (Ganong, 2000). Upon entry into the CNS, cytokines promote regulatory signals in the brain, through augmentation of hypothalamic-pituitary-adrenal (HPA) axis activity and vagal efferents, which can modify peripheral immune status. Enhanced HPA axis release of epinephrine and cortisol can decrease the release of pro-inflammatory cytokines from macrophages in the periphery (Pavlov et al., 2003). In addition, enhanced vagal efferent activity can trigger the release of acetylcholine from peripheral parasympathetic nerve endings, decreasing the release of pro-inflammatory cytokines (Pavlov et al., 2003). It is therefore evident that the immune system and nervous system communicate to maintain homeostasis, yet under excessive immune challenges alterations in neuronal signaling can develop. Studies have shown that peripheral activation of cytokines can lead to CNS release of various neurotransmitters. Specifically, IL-1 administration may promote CNS release of norepineprhine, serotonin, dopamine, glutamate, and gamma-amino-butyric-acid (GABA) (Dunn, 1992; Zalcman et al., 1994; Casamenti et al., 1999; Luk et al., 1999; Huang and O'Banion, 1998). With enhanced turnover of these neurotransmitters, significant neurological and behavioral alterations transpire. Research has shown how immune challenges can alter neurotransmission leading to behavioral changes and psychiatric disorders (Kronfol & Remick, 2000). For example, elevated levels of interleukin-6 (IL-6) have been associated with depressive symptoms (Bob et al., 2009). In Autism, alteration in immune system function may contribute to impaired neurological signaling. A possible mechanism contributing to neuronal dysfunction in the autistic brain is the transport of noxious substances across the blood-brain barrier into the CNS leading to autoimmunity. Studies have shown how cytokines, chemokines, immunoglobulins, and natural killer cells promote the recruitment of noxious chemicals in the brains of autistic individuals, as well as contribute to autoimmunity (Ashwood et al., 2006). Proinflammatory chemokines, such as monocyte chemotactic protein-1 (MCP-1) and thymus activation-regulated chemokine (TARC), along with cytokines, such as TNF-α, were consistently elevated in the brains of individuals with autism (Cohly & Panja, 2005). The transport or synthesis of cytokines in the brain may contribute to neuroinflammation and possible neurotransmitter imbalances (Cohly & Panja, 2005). Furthermore, Ashwood and colleagues (2008) found that reduced levels of the modulatory cytokine, transforming growth factor-β1 (TGF-β1), in autistic children contributed to the dysregulation of adaptive behaviors and predisposal for autoimmune responses. Autoimmunity can be detrimental to normal neuronal signaling and result in significant behavioral abnormalities (Ashwood et al., 2006). Vojdani and colleagues (2008) reported decreased natural killer cell activity in autistic children with low intracellular levels of glutathione, IL-2, and IL-15. Decreased natural killer cell activity has been associated with autoimmunity through alteration of cytokine production (Johansson et al, 2005). Lastly, Entrom and colleagues (2009) demonstrated elevated immunoglobulin G4 (IgG4) production in children with autism. Elevated IgG antibodies have been identified against brain-specific proteins in the hypothalamus and thalamus of autistic children, again suggesting autoimmunity (Cabanlit et al., 2007). Although limited studies on autism and autoimmunity exist, it has been hypothesized that the excess transport and synthesis of proinflammatory chemokines, cytokines, and immunoglobulins from the periphery to the CNS contribute to the development of autoimmune responses (Cohly & Panja, 2005). Autoimmunity may lead to dysregulated neuronal signaling causing behavioral manifestation of autism symptoms. Therefore, assessment of immune and nervous system function may provide biochemical targets to treat patients with these behavioral abnormalities. Nervous System Biomarkers and Autism Biomarkers are substances used as indicators of a biologic state. Research has revealed the clinical utility of urinary neurotransmitters as practical biomarkers to associate with neurotransmission (Kusaga et al., 2002; Hughes et al., 2004). Urinary neurotransmitter analysis is an innovative, minimally invasive method to assess peripheral neurotransmitter levels, and has a breadth of data to support its usefulness in clinical practice. In the 1950's, research uncovered correlations between urinary catecholamine levels and psychiatric symptoms, such as depression and anxiety (Bergsman, 1959; Carlsson et al., 1959). Recent research has examined the utility of urinary neurotransmitter analysis to categorize subsets of depression and anxiety, and to determine pharmaceutical intervention(s) (Hughes et al., 2004; Otte et al., 2005). Notwithstanding, urinary neurotransmitter analysis can further be used to assess Attention-Deficit-Hyperactivity Disorder (ADHD). Subjects with ADHD tend to have decreased urinary monoamine neurotransmitter levels (specifically, beta-phenylethylamine (PEA)) that can impair mood and attention (Kusaga et al., 2002). What's more, decreased beta-PEA levels may contribute to symptoms of inattentiveness (Berry, 2004). Overall, urinary neurotransmitter assessment can be a useful tool in any clinical practice, especially those managing psychiatric disorders. Urinary neurotransmitter analysis can identify neurotransmitter abnormalities that may contribute to behavioral changes, and thereby allow more appropriate treatment selection (Kahane, 2009). In autism, urinary neurotransmitter analysis has been utilized to examine biochemical abnormalities. As such, urinary serotonin has been the primary urinary neurotransmitter evaluated in autistic individuals. Abnormalities in urinary serotonin have been linked to immunological disturbances. A recent study found consistent elevations in the number of mast cells, along with elevated levels of urinary serotonin, in autistic patients (Castellani et al., 2009). Food, stress, or viruses can stimulate mast cells in the intestines and brains of young children. Localized and systemic immune activation can lead to enhanced cytokine and serotonin release from mast cells and disruption in the lining of the intestines and the blood-brain barrier causing altered neuronal signaling (Castellani et al., 2009). As mentioned previously, a compromised blood-brain barrier permits noxious substances entry into the brain and contribute to neuroinflammation. CNS neurotransmitter abnormalities may result from neuroinflammation leading to behavioral changes. As identified in autistic individuals, raised peripheral glutamate levels may also result from a compromised blood-brain barrier (Moreno-Fuenmayor, et al, 1996, Yip, 2007). Elevated plasma glutamate has been attributed to decreased levels of its rate- limiting enzyme glutamic acid decarboxylase (GAD) in autistic individuals (Shinohe, 2006, Yip, 2007). Specifically, Fatemi and colleagues (2002a) and Yip and others (2007) reported a reduced number of GAD 65 and 67 proteins in Purkinje cells in autistic cerebella. The decreased GAD may be due to autoantibodies specific for GAD, which has been detected in various neurological disorders (Manto et al., 2007). These autoantibodies attack the body's own cells, tissues, and/or organs, causing inflammation and tissue damage. Because GAD converts glutamate to gamma-immunobutyric acid (GABA), a decrease in this enzyme will cause subsequent increases in glutamate levels (Yip, 2007). Clinically, high glutamate levels can be excitotoxic and may lead to neurodegeneration and cognitive dysfunction (Ha et al., 2009). Studies have demonstrated that particular biochemical measurements, such as in plasma amino acid levels, are elevated in children with autism when compared to controls. Autistic children demonstrated elevated levels of plasma glutamate and aspartic acid along with taurine, phenylalanine, asparagine, tyrosine, alanine, and lysine (Moreno-Fuenmayor, Borjas, arrieta, Valera, and Socorro-Candanoza, 1996; Aldred, Moore, Fitzgerald, and Waring, 2003). These amino acid alterations may be caused by immune mediated events, vitamin insufficiency, alterations in neurotransmitter transport, or metabolic derangement. Imaging studies have further revealed abnormalities in autistic individuals, which suggest that abnormal brain growth in many major brain structures such as cerebellum, cerebral cortex, amygdala, hippocampus, corpus collosum, basal ganglia, and brain stem may contribute to behavioral abnormalities in autism (Courchesne et al., 2001; Acosta and Pearl, 2004). Moreover, research shows that reduced cerebellar volume in the autistic brain is due to decreased numbers of Purkinje cells located in the cerebellum. Altered Purkinje cell population can eventually lead to disrupted and weakened motor coordination (Palmen, Engeland, Hof, & Schmitz, 2004). Taken together, abnormal brain growth could be another factor that can contribute to peripheral neurotransmitter imbalances and behavioral manifestation of symptoms. What's more, abnormal neural development and function may result from cytokine recruitment to the CNS and therefore amino acid and neurotransmitter alterations (Cohly & Panja, 2005). Changes in amino acid levels may lead to elevated or insufficient neurotransmitter activity and thus can interfere with normal cognitive development (Aldred, et al., 2003). During infancy and adolescence, maintenance of optimal neuronal signaling is essential to ensure normal development of attentional processes, memory, and overall cognitive function, lending credence to the importance of early intervention through laboratory analysis of neurotransmitters and cytokines. Conclusion Immune system and nervous system activity must be viewed and examined as one system functioning in parallel. It is well established that neurological and immunological abnormalities exist in autistic individuals, however, the relationship between neural and immune function has just recently been emphasized. Food, stress, and viruses can activate immune cells in the periphery and result in CNS disruptions. This may lead to inflammation in the brain and eventually to behavior changes (Castellani et al., 2009). Healthcare practitioners should understand and evaluate the status of the nervous system together with the immune system to best optimize therapeutic intervention(s). Through the development of innovative laboratory tests to analyze neurotransmitters and cytokines, comprehensive information can be obtained to determine neurological and immunological abnormalities. These biochemical measures can serve as biomarkers for clinical symptoms, as well as provide significant guidance for therapeutic selection to reestablish physiological homeostasis and to benefit overall health and wellbeing. References Acosta, M.T., & Pearl, P.L. (2004). Imaging data in autism: From structure to malfunction. Seminars in Pediatric Neurology, 11, 205-213. Aldred, S., Moore, K.M., Fitzgerald, M., & Waring, R.H. (2003). Plasma amino acid levels in children with autism and their families. Journal of Autism and Developmental Disorders, 33, 93-97. American Psychiatric Association. Diagnostic and statistical manual of metal disorders. DSM-IV. 4th ed. Washington, DC: American Psychiatric Association, 1994. Ashwood, P., Enstrom, A., Krakowiak, P., Hertz-Picciotto, I., Hansen, R.L., Croen, L.A., et al. (2008). Decreased transforming growth factor beta1 in autism: A potential link between immune dysregulation and impairment in clinical behavioral outcomes. Journal of Neuroimmunology, 204(1-2), 149-153. Ashwood, P., Willis, S., & Van de Water, J. (2006). The immune response in autism: a new frontier for autism research. Journal of Leukocyte Biology, 80, 1-15. Bergsman, A. (1959) The urinary excretion of adrenaline and noradrenaline in some mental diseases; a clinical and experimental study. Acta psychiatrica Scandinavica. Supplementum, 133, 1-107. Berry, M.D. (2004a) Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. Journal of Neurochemistry, 90(2), 257-271. Bob, P., Raboch, J., Maes, M., Susta, M., Pavlat, J., Jasova, D. et al. (2009). Depression, traumatic stress and interleukin-6. Journal of Affective Disorders, [Epub ahead of print]. Borish, L.C., & Steinke, J.W. (2003). 2. Cytokines and chemokines. Journal of Allergy and Clinical Immunology, 111(2), S460-S475. Burger, R.A., & Warren, R.P. (1998). Possible immunogenetic basis for autism. 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Cohen, D., Pichard, N., Tordjman, S., Baumann, C., Burglen, L., Excoffier, E., Lazar, G., Mazet, P., Pinquier, C., Verloes, A., & Heron, D. (2005). Specific genetic disorders and autism: Clinical contribution towards their identification. Journal of Autism and Developmental Disorders, 35, 103-116. Cohly, H.H., & Panja, A. (2005) Immunological findings in autism. International Review of Neurobiology, 71, 317-341. Courchesne, E., Karns, C.M., Davis, H.R., Ziccardi, R., Carper, R.A., Tigue, Z.D., Chisum, H.J., Moses, P., Pierce, K., Lord, C., et al. (2001). Unusual brain growth patterns in early life in patients with autistic disorder: An MRI study. Neurology, 57, 245-254. Crawley, J.N. (2007). Testing hypotheses about autism. Science, 318, 56-57. Dunn, A.J. (1992). Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: Comparison with interleukin-1. Journal of Pharmacology and Experimental Therapeutics, 261, 964-969. Dunn, A.J. (2006). Effects of cytokines and infections on brain neurochemistry. Clinical Neuroscience Research, 6(1-2), 52-68. Edelson, S.B., & Cantor, D.S. (2000). The neurotoxic etiology of the autistic spectrum disorder: A replicative study. Toxicology and Industrial Health, 16, 239-247. Ek, M., Kurosawa, M., Lundeberg, T., et al. (1998). Activation of vagal afferents after intravenous injection of interleukin-1β: Role of endogenous prostaglandins. Journal of Neuroscience, 18, 9471-9479. Enstrom, A., Krakowiak, P., Onore, C., Pessah, I.N., Hertz-Picciotto, I., Hansen, R.L. et al. (2009). Increased IgG4 levels in children with autism disorder. Brain, Behavior, and Immunity, 23(3), 389-395. Fatemi, S.H., Earle, J., Kanodia, R., Kist, D., Emamian, E.S., Patterson, P.H., Shi, L., & Sidwell, R. (2002). Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: Implications for genesis of autism and schizophrenia. Cellular and Molecular Neurobiology, 22, 25-33. Fatemi, et al. 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Iversson, S.A., Bjerre, L., Vegfors, P., & Ahlfors, K. (1990). Autism as one of several abnormalities in two children with congenital cytomegalovirus infection. Neuropediatrics, 21, 102-103. Johansson, S., Berg, L., Hall, H., & Hoglund, P. (2005). NK cells: Elusive players in autoimmunity. Trends in Immunology, 26, 613-618. Kahane, A. (2009). Urinary Neurotransmitter Analysis as a Biomarker for Psychiatric Disorders. Townsend Letter, 1, 70-72. Kibersti, P., & Roberts, L. (2002). It's Not Just the Genes. Science, 296, 685. Kronfol, Z., & Remick, D. (2000). Cytokines and the brain: implications for clinical psychiatry. American Journal of Psychiatry, 158(7), 1163-1164. Kusaga, A., Yamashita, Y., Koeda, T., Hiratani, M., Kaneko, M., Yamada, S., & Matsuishi, T. (2002) Increased urine phenylethylamine after methylphenidate treatment in children with ADHD. Annals of Neurology, 52(3), 372-374. Layé, S., Bluthé, R.M., Kent, S. et al. (1995). Subdiphragmatic vagotomy blocks induction of Il-1 mRNA in mice brain in response to peripheral LPS. American Journal of Physiology, 268, R1327-R1331. Luk, W.P, Zhang, Y., White, T.D. et al. (1999). Adenosine. A mediator of interleukin-1β ??induced hippocampol synaptic inhibition. Journal of Neuroscience, 19, 4238-4244. Manto, M.U., Laute, M.A., Aguera, M., Rogemond, V., Pandolfo, M., & Honnorat, J. (2007). Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases. Annals of Neurology, 61(6), 544-551. Maier, S.F., Goehler, L.E., Fleshner, M. et al. (1998). The role of the vagus nerve in cytokine-to-brain communication. Annals of the New York Academy of Sciences, 840, 289-300. Moreno-Fuenmayor, H., Borjas, L., Arrieta, A., Valera, V., & Socorro-Candanoza, L. (1996). Plasma excitatory amino acids in autism. The Journal of Clinical Investigation, 37(2), 113-128. Otte, C., Neylan, T.C., Pipkin, S.S., Browner, W.S., & Whooley, M.A. (2005) Depressive symptoms and 24-hour urinary norepinephrine excretion levels in patients with coronary disease: findings from the Heart and Soul Study. American Journal of Psychiatry, 162(11), 2139-2145. Palmen, S., Engelan, H., Hof, P.R., & Schmitz, C. (2004). Neuropathological findings in autism. Brain, 127, 2572-2583. Pavlov, V.A., Wang, H., Czura, C.J., Friedman, S.G., & Tracey, K.J. (2003). The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Molecular Medicine, 9(5-8), 125-134. Polleux, F., & Lauder, J.M. (2004). Toward a developmental neurobiology of autism. Mental Retardation and Developmental Disabilities Research Reviews, 10, 303-317. Shi, L., Fatemi, S.H., Sidwell, R.W. & Patterson, P.H. (2003). Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. Journal of Neuroscience, 23, 297-302. Shinohe, et al. (2006). Increased serum levels of glutamate in adult patients with autism. Progress in Neuro-Psychopharmacology and Biological Psychiastry, 30, 1472-1477. Yip, J., Soghomonia, J.J., & Blatt, G.J. (2007). Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: Pathophysiological implications. Acta Neuropathology, 113, 559-568. Vojdani, A., Campbell, A.W., Anyanwu, E., Kashanian, A., Bock, K. & Vojdani, E. (2002). Antibodies to neuron-specific antigens in children with autism: Possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Stretoccoccus group A. Journal of Neuroimmunology, 129, 168-177. Vojdani, A., Mumper, E., Granpeesheh, D., Mielke, L., Traver, D., Bock, K., et al. (2008). Low natural killer cell cytotoxic activity in autism: The role of glutathione, IL-2 and IL-15. Journal of Neuroimmunology, 205(1-2), 148-154. Wakefield, A.J., Murch, S.H., Anthony, A., Linnell, J., Casson, D.M., Malik, M., Berelowitz, M., Dhillon, A.P., Thomson, M.A., Valentine, A., Davies, S.E., & Walker-Smith, J.A. (1998). Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet, 351, 637-641. Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J.T., Abrahams, B.S., et al. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorder. Nature, [Epub ahead of print] Zalcman, S., Gree-Johnson, J.M., Murray, L. et al. (1994). Cytokine-specific central monoamine alterations induced by interleukin-1-2, and -6. Brain Research, 15, 287-290.
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Did you mean: Neuroimmunology of Autism Spectrum Disorder. Neurotransmitters as predictive biomarkers of responsiveness to substance abuse treatment Neuroimmunology of Autism Spectrum Disorder. Addressing Adrenal Imbalance: The Future of Adrenal Health Avipaxin and Modulation of the Immune System. The Clinical Utility of Urinary Neurotransmitter Analysis: An Overview. Daxitrol Essential: A Novel Approach for Controlling Cravings. Hypersensitivity Reactions and Methods of Detection. Methylation: Fundamental to a Healthy Nervous System A Novel Top-down Strategy For Addressing Autonomic Imbalances. Download PDF NEUROIMMUNOLOGY OF AUTISM SPECTRUM DISORDER David Marc, MSa; Kelly Olson, PhD NeuroScience, Inc., 373 280th St., Osceola, WI 54020, United States address correspondence to: david.marc@neurorelief.com Abstract Autism is a developmental disorder characterized by immunological and neurological abnormalities. The role of cytokines in the pathophysiology of autism has been researched suggesting a relationship with altered blood-brain barrier permeability and subsequent neuroinflammation. Cytokine recruitment to the CNS may result in altered neurotransmitter signaling and the behavioral manifestation of autism symptoms. Other immune mediated events such as changes in the number and activity of natural killer cells, macrophages, immunoglobulins, and glutathione may contribute to altered neuronal signaling and neurotransmitter imbalances. The purpose of this overview is to examine the relationship between immune system and nervous system dysfunction to determine biomarkers for autism spectrum disorder. We will explore the utility of serum cytokines and urinary neurotransmitter analyses as biomarkers for autism. Introduction Autism is a pervasive developmental disorder characterized by impaired development of social interaction and communication, and a markedly restricted repertoire of activities and interests (American Psychiatric Association, 1994). The exact etiology of autism remains largely unknown, however, literature has emerged to suggest genetic, neurological, immunological, and environmental contributions. Immunological and environmental factors, such as diet, infection, and xenobiotics play critical roles in the development of autism. (Ivarsson, Bjerre, Vegfors, and Ahlfors, 1990; Wakefield et al., 1998; Edelson and Cantor, 2002; Fatemi et al., 2002; Kibersti and Roberts, 2002). Abnormalities in enzymatic function (Fatemi et al., 2002a), autoantibodies to brain proteins (Vojdani et al., 2002), and maternal infections during pregnancy (Shi et al., 2003) have been indicated in the autism population. Additionally, pathological alterations in genes involved in the patterning of the central nervous system, biochemical pathways, development of dendrites and synapses, and genes associated with the immune system have been observed in this population (Burber and Warren, 1998; Palmen, Engeland, Hof, and Schmitz, 2004; Polleux and Lauder, 2004; Cohen et al., 2005; Crawley, 2007; Glessner et al., 2009; Wang et al., 2009). Interestingly, an emerging body of evidence is growing concerning the link between abnormal immune function and neurological dysfunction with autism spectrum disorders. At critical times of infantile development, immune dysregulation may result in the release of immunomodulatory molecules, such as chemokines and cytokines, leading to altered neuronal development and neural function (Cohly & Panja, 2005). Chemokines and cytokines are proteins that manage immune cell trafficking and cellular arrangement of immune organs and determine appropriate immune responses (Borish & Steinke, 2003). Cytokines can be transported to and/or synthesized in the central nervous system (CNS) thereby establishing communication between peripheral immune cells and CNS neurons (Dunn, 2006). The purpose of this overview is to identify neurological and immunological abnormalities that exist in individuals with autism. Further, it will become critically apparent that neuroimmune biomarker testing for autism can identify these abnormalities and ensure therapeutic effectiveness. Cytokines and Neurotransmission Cytokines released by immune cells, particularly interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), communicate with the CNS to affect neural activity and modify behaviors, hormone release, and "normal" autonomic function (Dunn, 2006). Cytokines can enter the brain by various mechanisms including active transport or direct entry through a compromised blood-brain barrier. Active transport mechanisms that involve a saturable system have been documented for IL-1 and TNF-α (Dunn, 1992; Gutierrez, Banks, and Kastin, 1993; Gutierrez, Banks, Kastin, 1994). Additionally, Maier and colleagues (1998) found that cytokines may directly enter the central nervous system at circumventricular regions, predominantly the area postrema, where the blood brain barrier is less protective (Pavlov et al., 2003). Other circumventricular regions of potential cytokine entry include the pineal gland, subfornical organ, organum vasculosum of the lamina terminalis, choroid plexus, median eminence, subcommissural organ, and posterior pituitary (Ganong, 2000). Upon entry into the CNS, cytokines promote regulatory signals in the brain, through augmentation of hypothalamic-pituitary-adrenal (HPA) axis activity and vagal efferents, which can modify peripheral immune status. Enhanced HPA axis release of epinephrine and cortisol can decrease the release of pro-inflammatory cytokines from macrophages in the periphery (Pavlov et al., 2003). In addition, enhanced vagal efferent activity can trigger the release of acetylcholine from peripheral parasympathetic nerve endings, decreasing the release of pro-inflammatory cytokines (Pavlov et al., 2003). It is therefore evident that the immune system and nervous system communicate to maintain homeostasis, yet under excessive immune challenges alterations in neuronal signaling can develop. Studies have shown that peripheral activation of cytokines can lead to CNS release of various neurotransmitters. Specifically, IL-1 administration may promote CNS release of norepineprhine, serotonin, dopamine, glutamate, and gamma-amino-butyric-acid (GABA) (Dunn, 1992; Zalcman et al., 1994; Casamenti et al., 1999; Luk et al., 1999; Huang and O'Banion, 1998). With enhanced turnover of these neurotransmitters, significant neurological and behavioral alterations transpire. Research has shown how immune challenges can alter neurotransmission leading to behavioral changes and psychiatric disorders (Kronfol & Remick, 2000). For example, elevated levels of interleukin-6 (IL-6) have been associated with depressive symptoms (Bob et al., 2009). In Autism, alteration in immune system function may contribute to impaired neurological signaling. A possible mechanism contributing to neuronal dysfunction in the autistic brain is the transport of noxious substances across the blood-brain barrier into the CNS leading to autoimmunity. Studies have shown how cytokines, chemokines, immunoglobulins, and natural killer cells promote the recruitment of noxious chemicals in the brains of autistic individuals, as well as contribute to autoimmunity (Ashwood et al., 2006). Proinflammatory chemokines, such as monocyte chemotactic protein-1 (MCP-1) and thymus activation-regulated chemokine (TARC), along with cytokines, such as TNF-α, were consistently elevated in the brains of individuals with autism (Cohly & Panja, 2005). The transport or synthesis of cytokines in the brain may contribute to neuroinflammation and possible neurotransmitter imbalances (Cohly & Panja, 2005). Furthermore, Ashwood and colleagues (2008) found that reduced levels of the modulatory cytokine, transforming growth factor-β1 (TGF-β1), in autistic children contributed to the dysregulation of adaptive behaviors and predisposal for autoimmune responses. Autoimmunity can be detrimental to normal neuronal signaling and result in significant behavioral abnormalities (Ashwood et al., 2006). Vojdani and colleagues (2008) reported decreased natural killer cell activity in autistic children with low intracellular levels of glutathione, IL-2, and IL-15. Decreased natural killer cell activity has been associated with autoimmunity through alteration of cytokine production (Johansson et al, 2005). Lastly, Entrom and colleagues (2009) demonstrated elevated immunoglobulin G4 (IgG4) production in children with autism. Elevated IgG antibodies have been identified against brain-specific proteins in the hypothalamus and thalamus of autistic children, again suggesting autoimmunity (Cabanlit et al., 2007). Although limited studies on autism and autoimmunity exist, it has been hypothesized that the excess transport and synthesis of proinflammatory chemokines, cytokines, and immunoglobulins from the periphery to the CNS contribute to the development of autoimmune responses (Cohly & Panja, 2005). Autoimmunity may lead to dysregulated neuronal signaling causing behavioral manifestation of autism symptoms. Therefore, assessment of immune and nervous system function may provide biochemical targets to treat patients with these behavioral abnormalities. Nervous System Biomarkers and Autism Biomarkers are substances used as indicators of a biologic state. Research has revealed the clinical utility of urinary neurotransmitters as practical biomarkers to associate with neurotransmission (Kusaga et al., 2002; Hughes et al., 2004). Urinary neurotransmitter analysis is an innovative, minimally invasive method to assess peripheral neurotransmitter levels, and has a breadth of data to support its usefulness in clinical practice. In the 1950's, research uncovered correlations between urinary catecholamine levels and psychiatric symptoms, such as depression and anxiety (Bergsman, 1959; Carlsson et al., 1959). Recent research has examined the utility of urinary neurotransmitter analysis to categorize subsets of depression and anxiety, and to determine pharmaceutical intervention(s) (Hughes et al., 2004; Otte et al., 2005). Notwithstanding, urinary neurotransmitter analysis can further be used to assess Attention-Deficit-Hyperactivity Disorder (ADHD). Subjects with ADHD tend to have decreased urinary monoamine neurotransmitter levels (specifically, beta-phenylethylamine (PEA)) that can impair mood and attention (Kusaga et al., 2002). What's more, decreased beta-PEA levels may contribute to symptoms of inattentiveness (Berry, 2004). Overall, urinary neurotransmitter assessment can be a useful tool in any clinical practice, especially those managing psychiatric disorders. Urinary neurotransmitter analysis can identify neurotransmitter abnormalities that may contribute to behavioral changes, and thereby allow more appropriate treatment selection (Kahane, 2009). In autism, urinary neurotransmitter analysis has been utilized to examine biochemical abnormalities. As such, urinary serotonin has been the primary urinary neurotransmitter evaluated in autistic individuals. Abnormalities in urinary serotonin have been linked to immunological disturbances. A recent study found consistent elevations in the number of mast cells, along with elevated levels of urinary serotonin, in autistic patients (Castellani et al., 2009). Food, stress, or viruses can stimulate mast cells in the intestines and brains of young children. Localized and systemic immune activation can lead to enhanced cytokine and serotonin release from mast cells and disruption in the lining of the intestines and the blood-brain barrier causing altered neuronal signaling (Castellani et al., 2009). As mentioned previously, a compromised blood-brain barrier permits noxious substances entry into the brain and contribute to neuroinflammation. CNS neurotransmitter abnormalities may result from neuroinflammation leading to behavioral changes. As identified in autistic individuals, raised peripheral glutamate levels may also result from a compromised blood-brain barrier (Moreno-Fuenmayor, et al, 1996, Yip, 2007). Elevated plasma glutamate has been attributed to decreased levels of its rate- limiting enzyme glutamic acid decarboxylase (GAD) in autistic individuals (Shinohe, 2006, Yip, 2007). Specifically, Fatemi and colleagues (2002a) and Yip and others (2007) reported a reduced number of GAD 65 and 67 proteins in Purkinje cells in autistic cerebella. The decreased GAD may be due to autoantibodies specific for GAD, which has been detected in various neurological disorders (Manto et al., 2007). These autoantibodies attack the body's own cells, tissues, and/or organs, causing inflammation and tissue damage. Because GAD converts glutamate to gamma-immunobutyric acid (GABA), a decrease in this enzyme will cause subsequent increases in glutamate levels (Yip, 2007). Clinically, high glutamate levels can be excitotoxic and may lead to neurodegeneration and cognitive dysfunction (Ha et al., 2009). Studies have demonstrated that particular biochemical measurements, such as in plasma amino acid levels, are elevated in children with autism when compared to controls. Autistic children demonstrated elevated levels of plasma glutamate and aspartic acid along with taurine, phenylalanine, asparagine, tyrosine, alanine, and lysine (Moreno-Fuenmayor, Borjas, arrieta, Valera, and Socorro-Candanoza, 1996; Aldred, Moore, Fitzgerald, and Waring, 2003). These amino acid alterations may be caused by immune mediated events, vitamin insufficiency, alterations in neurotransmitter transport, or metabolic derangement. Imaging studies have further revealed abnormalities in autistic individuals, which suggest that abnormal brain growth in many major brain structures such as cerebellum, cerebral cortex, amygdala, hippocampus, corpus collosum, basal ganglia, and brain stem may contribute to behavioral abnormalities in autism (Courchesne et al., 2001; Acosta and Pearl, 2004). Moreover, research shows that reduced cerebellar volume in the autistic brain is due to decreased numbers of Purkinje cells located in the cerebellum. Altered Purkinje cell population can eventually lead to disrupted and weakened motor coordination (Palmen, Engeland, Hof, & Schmitz, 2004). Taken together, abnormal brain growth could be another factor that can contribute to peripheral neurotransmitter imbalances and behavioral manifestation of symptoms. What's more, abnormal neural development and function may result from cytokine recruitment to the CNS and therefore amino acid and neurotransmitter alterations (Cohly & Panja, 2005). Changes in amino acid levels may lead to elevated or insufficient neurotransmitter activity and thus can interfere with normal cognitive development (Aldred, et al., 2003). During infancy and adolescence, maintenance of optimal neuronal signaling is essential to ensure normal development of attentional processes, memory, and overall cognitive function, lending credence to the importance of early intervention through laboratory analysis of neurotransmitters and cytokines. Conclusion Immune system and nervous system activity must be viewed and examined as one system functioning in parallel. It is well established that neurological and immunological abnormalities exist in autistic individuals, however, the relationship between neural and immune function has just recently been emphasized. Food, stress, and viruses can activate immune cells in the periphery and result in CNS disruptions. This may lead to inflammation in the brain and eventually to behavior changes (Castellani et al., 2009). Healthcare practitioners should understand and evaluate the status of the nervous system together with the immune system to best optimize therapeutic intervention(s). Through the development of innovative laboratory tests to analyze neurotransmitters and cytokines, comprehensive information can be obtained to determine neurological and immunological abnormalities. These biochemical measures can serve as biomarkers for clinical symptoms, as well as provide significant guidance for therapeutic selection to reestablish physiological homeostasis and to benefit overall health and wellbeing. References Acosta, M.T., & Pearl, P.L. (2004). Imaging data in autism: From structure to malfunction. Seminars in Pediatric Neurology, 11, 205-213. Aldred, S., Moore, K.M., Fitzgerald, M., & Waring, R.H. (2003). Plasma amino acid levels in children with autism and their families. Journal of Autism and Developmental Disorders, 33, 93-97. American Psychiatric Association. Diagnostic and statistical manual of metal disorders. DSM-IV. 4th ed. Washington, DC: American Psychiatric Association, 1994. Ashwood, P., Enstrom, A., Krakowiak, P., Hertz-Picciotto, I., Hansen, R.L., Croen, L.A., et al. (2008). Decreased transforming growth factor beta1 in autism: A potential link between immune dysregulation and impairment in clinical behavioral outcomes. 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(2002a). Glutamic acid decarbosylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biological Psychiatry, 52, 805-810. Ganong, W.F. (2000). Circumventricular organs: Definition and role in the regulation of endocrine and autonomic function. Clinical and Experimental Pharmacology and Physiology, 27(5-6), 422-427. Glessner, J.T., Wang, K., Cai, G., Korvatska, O., Kim, C.E., Wood, S., et al. (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature, [Epub ahead of print]. Goehler, L.E., Gaykema, R.P., Nguyen, K.T. et al. (1999). Interleukin-1β in immune cells of the abdominal vagus nerve: A link between the immune and nervous systems? Journal of Neuroscience, 19, 2799-2806. Gutierrez, E.G., Banks, W.A., & Kastin, A.J. (1993). Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. Journal of Neuroimmunology, 47, 169-176. Gutierrez, E.G., Banks, W.A., & Kastin, A.J. (1994). Blood-borne interleukin-1 receptor antagonist crosses the blood brain barrier. Journal of Neuroimmunology, 55, 153-160. Ha, J.S., Leem C.S., Maeng, J.S., Kwon, K.S., & Park, S.S. (2009). Chronic glutamate toxicity in mouse cortical neuron culture. Brain Research, [Epub ahead of print]. Hansen, M.K., Taishi, P., Chen, Z. et al. (1998). Vagotomy blocks the induction of interleukin-1β (IL-1β) mRNA in the brain of rats in response to systemic IL-1β. Journal of Neuroscience, 18, 2247-2253. Huang, T.L., & O'Banion, M.K. (1998). Interleukin-1β and tumor necrosis factor-alpha suppress dexamethasone induction of glutamine synthetase in primary mouse astrocytes. Journal of Neuroscience, 71, 1436-1442. Hughes, J.W., Watkins, L., Blumenthal, J.A., Kuhn, C., & Sherwood, A. (2004) Depression and anxiety symptoms are related to increased 24-hour urinary norepinephrine excretion among healthy middle-aged women. Journal of Psychosomatic Research, 57(4), 353-358. Iversson, S.A., Bjerre, L., Vegfors, P., & Ahlfors, K. (1990). Autism as one of several abnormalities in two children with congenital cytomegalovirus infection. Neuropediatrics, 21, 102-103. Johansson, S., Berg, L., Hall, H., & Hoglund, P. (2005). NK cells: Elusive players in autoimmunity. Trends in Immunology, 26, 613-618. Kahane, A. (2009). Urinary Neurotransmitter Analysis as a Biomarker for Psychiatric Disorders. Townsend Letter, 1, 70-72. Kibersti, P., & Roberts, L. (2002). It's Not Just the Genes. Science, 296, 685. Kronfol, Z., & Remick, D. (2000). Cytokines and the brain: implications for clinical psychiatry. American Journal of Psychiatry, 158(7), 1163-1164. Kusaga, A., Yamashita, Y., Koeda, T., Hiratani, M., Kaneko, M., Yamada, S., & Matsuishi, T. (2002) Increased urine phenylethylamine after methylphenidate treatment in children with ADHD. Annals of Neurology, 52(3), 372-374. Layé, S., Bluthé, R.M., Kent, S. et al. (1995). 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Otte, C., Neylan, T.C., Pipkin, S.S., Browner, W.S., & Whooley, M.A. (2005) Depressive symptoms and 24-hour urinary norepinephrine excretion levels in patients with coronary disease: findings from the Heart and Soul Study. American Journal of Psychiatry, 162(11), 2139-2145. Palmen, S., Engelan, H., Hof, P.R., & Schmitz, C. (2004). Neuropathological findings in autism. Brain, 127, 2572-2583. Pavlov, V.A., Wang, H., Czura, C.J., Friedman, S.G., & Tracey, K.J. (2003). The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Molecular Medicine, 9(5-8), 125-134. Polleux, F., & Lauder, J.M. (2004). Toward a developmental neurobiology of autism. Mental Retardation and Developmental Disabilities Research Reviews, 10, 303-317. Shi, L., Fatemi, S.H., Sidwell, R.W. & Patterson, P.H. (2003). Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. Journal of Neuroscience, 23, 297-302. Shinohe, et al. (2006). Increased serum levels of glutamate in adult patients with autism. Progress in Neuro-Psychopharmacology and Biological Psychiastry, 30, 1472-1477. Yip, J., Soghomonia, J.J., & Blatt, G.J. (2007). Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: Pathophysiological implications. Acta Neuropathology, 113, 559-568. Vojdani, A., Campbell, A.W., Anyanwu, E., Kashanian, A., Bock, K. & Vojdani, E. (2002). Antibodies to neuron-specific antigens in children with autism: Possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Stretoccoccus group A. Journal of Neuroimmunology, 129, 168-177. Vojdani, A., Mumper, E., Granpeesheh, D., Mielke, L., Traver, D., Bock, K., et al. (2008). Low natural killer cell cytotoxic activity in autism: The role of glutathione, IL-2 and IL-15. Journal of Neuroimmunology, 205(1-2), 148-154. Wakefield, A.J., Murch, S.H., Anthony, A., Linnell, J., Casson, D.M., Malik, M., Berelowitz, M., Dhillon, A.P., Thomson, M.A., Valentine, A., Davies, S.E., & Walker-Smith, J.A. (1998). Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet, 351, 637-641. Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J.T., Abrahams, B.S., et al. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorder. Nature, [Epub ahead of print] Zalcman, S., Gree-Johnson, J.M., Murray, L. et al. (1994). Cytokine-specific central monoamine alterations induced by interleukin-1-2, and -6. Brain Research, 15, 287-290.
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استشارى الادوية الطبيعيه وباحث وخبير فى علاجات التوحد
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#7
07-30-2015, 01:21 AM
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ضعف الجهاز الهضمي في اضطراب طيف التوحد: دور الميتوكوندريا وmicrobiome المعوي
http://www.microbecolhealthdis.net/i...cle/view/27458
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استشارى الادوية الطبيعيه وباحث وخبير فى علاجات التوحد
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#8
07-30-2015, 01:23 AM
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شبكة الوضع الافتراضي في الشباب الذكور البالغين الذين يعانون من اضطراب طيف التوحد: العلاقة مع سمات التوحد
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استشارى الادوية الطبيعيه وباحث وخبير فى علاجات التوحد
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#9
07-30-2015, 01:26 AM
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عوامل الخطر الوراثية وNonheritable لاضطرابات طيف التوحد
http://epirev.oxfordjournals.org/content/24/2/137.full
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استشارى الادوية الطبيعيه وباحث وخبير فى علاجات التوحد
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#10
07-30-2015, 01:30 AM
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التوحد والإجهاد التأكسدي التدخلات: التأثير على سلوك التوحد
http://austinpublishinggroup.com/pha...-v2-id1015.php
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استشارى الادوية الطبيعيه وباحث وخبير فى علاجات التوحد
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