Septiembre 4-2013

Referencias seleccionadas actualizadas. Problemas médicos concomitantes al

diagnóstico de TEA, de competencia pediátrica clínica generalista (infancia y

adolescencia hasta 16 años) o médico clínico generalista (juventud y adultez). No se

presenta información sobre condiciones médicas neurológicas específicas en TEA(

epilepsia/convulsiones, trastornos de sueño y del movimiento).

-Gastrointestinales

PLoS One. 2013 Jun 18;8(6):e66155. Print 2013.

Markers of Celiac Disease and Gluten Sensitivity in Children with Autism.

Lau NM, Green PH, Taylor AK, Hellberg D, Ajamian M, Tan CZ, Kosofsky

BE, Higgins JJ, Rajadhyaksha AM, Alaedini A.

Source

Department of Medicine, Columbia University, New York, New York, United States of

America ; Celiac Disease Center, Columbia University, New York, New York, United

States of America.

Abstract

OBJECTIVE:

Gastrointestinal symptoms are a common feature in children with autism, drawing

attention to a potential association with celiac disease or gluten sensitivity. However,

studies to date regarding the immune response to gluten in autism and its association

with celiac disease have been inconsistent. The aim of this study was to assess immune

reactivity to gluten in pediatric patients diagnosed with autism according to strict

criteria and to evaluate the potential link between autism and celiac disease.

METHODS:

Study participants included children (with or without gastrointestinal symptoms)

diagnosed with autism according to both the AutismDiagnostic Observation Schedule

(ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) (n = 37), their

unaffected siblings (n = 27), and age-matched healthy controls (n = 76). Serum specimens

were tested for antibodies to native gliadin, deamidated gliadin, and transglutaminase 2

(TG2). Affected children were genotyped for celiac disease associated HLA-DQ2 and -

DQ8 alleles.

RESULTS:

Children with autism had significantly higher levels of IgG antibody to gliadin

compared with unrelated healthy controls (p<0.01). The IgG levels were also higher

compared to the unaffected siblings, but did not reach statistical significance. The IgG

anti-gliadin antibody response was significantly greater in the autistic children

with gastrointestinal symptoms in comparison to those without them (p<0.01). There

was no difference in IgA response to gliadin across groups. The levels of celiac disease-

specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ

between patients and controls. An association between increased anti-gliadin antibody

and presence of HLA-DQ2 and/or -DQ8 was not observed.

CONCLUSIONS:

A subset of children with autism displays increased immune reactivity to gluten,

the mechanism of which appears to be distinct from that in celiac disease. The

increased anti-gliadin antibody response and its association with GI symptoms

points to a potential mechanism involving immunologic and/or intestinal

permeability abnormalities in affected children.

http://www.ncbi.nlm.nih.gov/pubmed/23823064

Rocz Panstw Zakl Hig. 2013;64(1):1-12.

How nutritional status, diet and dietary supplements can affect autism. A review.

Kawicka A, Regulska-Ilow B.

Source

Department of Dietetics, Wroclaw Medical University, Wroclaw, Poland.

Abstract

Autism is a neurodevelopmental disorder with symptoms arising that are apparent

throughout the patient's lifespan. Autism Spectrum Disorders (ASD) are characterised

by impaired social and communication interactions as well as restricted, repetitive

interests and behaviour. Currently in Poland, about 50 000 people suffer from autism, of

which 1/5 are children. Epidemiological studies show that the incidence of autism is

increasing, which may be due to the diagnostic category of ASD having been

developed. Of vital importance in the treatment of autism, is early diagnosis which is

conducive to more rapidly improving the quality of patients' health. It is believed that

both genetic and environmental factors may affect the development of the disease.

Moreover, expert opinion emphasises the importance of making an adequate diagnosis

when the first symptoms of autism start appearing which can be both psychological,

gastro-intestinal and metabolic ones. Conventional treatment is based on the

combination of behavioural and dietary therapy together with pharmacotherapy. For

example, adapting an appropriate diet could help alleviate the disease severity, as well

as the psychological and gastrointestinal symptoms. Much scientific research has

indicated that pathogenesis of autism may have a beginning already in foetal life.

During pregnancy, specialists should take special heed of metabolic disorders, which

can increase the risk ofASD in children. One of the dietician's tasks are to properly

assess the nutritional status of mothers before and during pregnancy, thereby allowing

changes in nutrition to be made wherever necessary in order that metabolic indicators be

improved. Thus an important part of autism therapy is the improving patient's

nutritional status to prevent the onset of gastrointestinal symptoms. Adopting diets and

tailored to individual disease symptoms, is linked to the nutritional requirements and

food preferences of the patient. Specialists also emphasise that continual monitoring of

the diet and nutritional status of children with ASD is required. It is also essential to

start adequate dietary management in autistic patients with overweight, obesity or

wasting, caused by improper nutrition. Frequently only a dietary therapy is insufficient

to effectively treat autism. Many studies demonstrate the need to supplement the

nutritional deficiencies of autistic patients with fatty acids omega-3, probiotics,

vitamins and minerals in combination with medical and psychological

interventions. A properly designed elimination diet adapted to the patient's

individual may also lead to relief of the autism symptoms and the occurrence

of gastrointestinal disorders. Parents and caregivers should therefore be aware of

the benefits of nutritional therapy and need for proper monitoring the treatment

of patients with ASD. A review of nutritional factors, dietary treatments and diet

supplementation in patients with ASD is presented.

PLoS One. 2013;8(3):e58058. doi: 10.1371/journal.pone.0058058. Epub 2013 Mar 8.

Identification of unique gene expression profile in children with

regressive autism spectrum disorder (ASD) and ileocolitis.

Walker SJ, Fortunato J, Gonzalez LG, Krigsman A.

Source

Wake Forest Institute for Regenerative Medicine, Wake Forest University Health

Sciences, Winston Salem, North Carolina, United States of America.

swalker@wakehealth.edu

Abstract

Gastrointestinal symptoms are common in children

with autism spectrum disorder (ASD) and are often associated with mucosal

inflammatory infiltrates of the small and large intestine. Although distinct histologic and

immunohistochemical properties of this inflammatory infiltrate have been previously

described in this ASD(GI) group, molecular characterization of these lesions has not

been reported. In this study we utilize transcriptome profiling

of gastrointestinal mucosal biopsy tissue from ASD(GI) children and three non-ASD

control groups (Crohn's disease, ulcerative colitis, and histologically normal) in an

effort to determine if there is a gene expression profile unique to the ASD(GI) group.

Comparison of differentially expressed transcripts between the groups demonstrated

that non-pathologic (normal) tissue segregated almost completely from inflamed tissue

in all cases. Gene expression profiles in intestinal biopsy tissue from patients with

Crohn's disease, ulcerative colitis, and ASD(GI), while having significant overlap with

each other, also showed distinctive features for each group. Taken together, these

results demonstrate that ASD(GI) children have agastrointestinal mucosal

molecular profile that overlaps significantly with known inflammatory bowel

disease (IBD), yet has distinctive features that further supports the presence of an

ASD-associated IBD variant, or, alternatively, a prodromal phase of typical

inflammatory bowel disease. Although we report qPCR confirmation of representative

differentially expressed transcripts determined initially by microarray, these findings

may be considered preliminary to the extent that they require further confirmation in a

validation cohort.

http://www.ncbi.nlm.nih.gov/pubmed/23520485

Recommendations for evaluation and treatment of common gastrointestinal problems

in children with ASDs.

Buie T, Fuchs GJ 3rd, Furuta GT, Kooros K, Levy J, Lewis JD, Wershil BK, Winter H.

Pediatrics. 2010 Jan;125 Suppl 1:S19-29. doi: 10.1542/peds.2009-1878D.

http://www.ncbi.nlm.nih.gov/pubmed/20048084

Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with

ASDs: a consensus report.

Buie T, Campbell DB, Fuchs GJ 3rd, Furuta GT, Levy J, Vandewater J, Whitaker AH,

Atkins D, Bauman ML, Beaudet AL, Carr EG, Gershon MD, Hyman SL, Jirapinyo P,

Jyonouchi H, Kooros K, Kushak R, Levitt P, Levy SE, Lewis JD, Murray KF, Natowicz

MR, Sabra A, Wershil BK, Weston SC, Zeltzer L, Winter H.

Pediatrics. 2010 Jan;125 Suppl 1:S1-18. doi: 10.1542/peds.2009-1878C.

http://www.ncbi.nlm.nih.gov/pubmed/20048083

-Metabólicos y bioquímico-nutricionales

BMC Pediatr. 2011 Dec 12;11:111. doi: 10.1186/1471-2431-11-111.

Effect of a vitamin/mineral supplement on children and adults with autism.

Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W.

Source

Autism/Asperger's Research Program, Arizona State University, Tempe, AZ, USA.

jim.adams@asu.edu

Abstract

BACKGROUND:

Vitamin/mineral supplements are among the most commonly used treatments for autism, but

the research on their use for treatingautism has been limited.

METHOD: This study is a randomized, double-blind, placebo-controlled three month vitamin/mineral treatment study. The study involved 141 children and adults with autism, and pre and post symptoms of autism were assessed. None of the participants had taken a vitamin/mineral supplement in the two months prior to the start of the study. For a subset of the participants (53 children ages 5-16) pre and post measurements of nutritional and metabolic status were also conducted. RESULTS: The vitamin/mineral supplement was generally well-tolerated, and individually titrated to optimum benefit. Levels of many vitamins, minerals, and biomarkers improved/increased showing good compliance and absorption. Statistically significant improvements in metabolic status were many including: total sulfate (+17%, p = 0.001), S-adenosylmethionine (SAM; +6%, p = 0.003), reduced glutathione (+17%, p = 0.0008), ratio of oxidized glutathione to reduced glutathione (GSSG:GSH; -27%, p = 0.002), nitrotyrosine (-29%, p = 0.004), ATP (+25%, p = 0.000001), NADH (+28%, p = 0.0002), and NADPH (+30%, p = 0.001). Most of these metabolic biomarkers improved to normal or near-normal levels.The supplement group had significantly greater improvements than the placebo group on the Parental Global Impressions-Revised (PGI-R, Average Change, p = 0.008), and on the subscores for Hyperactivity (p = 0.003), Tantrumming (p = 0.009), Overall (p = 0.02), and Receptive Language (p = 0.03). For the other three assessment tools the difference between treatment group and placebo group was not statistically significant.Regression analysis revealed that the degree of improvement on the Average Change of the PGI-R was strongly associated with several biomarkers (adj. R2 = 0.61, p < 0.0005) with the initial levels of biotin and vitamin K being the most significant (p < 0.05); both biotin and vitamin K are made by beneficial intestinal flora. CONCLUSIONS: Oral vitamin/mineral supplementation is beneficial in improving the nutritional and metabolic status of children with autism, including improvements in methylation, glutathione, oxidative stress, sulfation, ATP, NADH, and NADPH. The supplement group had significantly greater improvements than did the placebo group on the PGI-R Average Change. This suggests that a

vitamin/mineral supplement is a reasonable adjunct therapy to consider for most children and adults with autism.

http://www.ncbi.nlm.nih.gov/pubmed/22151477 Nutr Metab (Lond). 2011 Jun 8;8(1):34. doi: 10.1186/1743-7075-8-34.

Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autismseverity. Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W. Source Arizona State University, Tempe, AZ, USA. jim.adams@asu.edu.

Abstract BACKGROUND: The relationship between relative metabolic disturbances and developmental disorders is an emerging research focus. This study compares the nutritional and metabolic status of children with autism with that of neurotypical children and investigates the possible association ofautism severity with biomarkers. METHOD: Participants were children ages 5-16 years in Arizona with Autistic Spectrum Disorder (n = 55) compared with non-sibling, neurotypical controls (n = 44) of similar age, gender and geographical distribution. Neither group had taken any vitamin/mineral supplements in the two months prior to sample collection. Autism severity was assessed using the Pervasive Development Disorder Behavior Inventory (PDD-BI), Autism Treatment Evaluation Checklist (ATEC), and Severity of Autism Scale (SAS). Study measurements included: vitamins, biomarkers of vitamin status, minerals, plasma amino acids, plasma glutathione, and biomarkers of oxidative stress, methylation, sulfation and energy production. RESULTS: Biomarkers of children with autism compared to those of controls using a t-test or Wilcoxon test found the following statistically significant differences (p < 0.001): Low levels of biotin, plasma glutathione, RBC SAM, plasma uridine, plasma ATP, RBC NADH, RBC NADPH, plasma sulfate (free and total), and plasma tryptophan; also high levels of oxidative stress markers and plasma glutamate. Levels of biomarkers for the neurotypical controls were in good agreement with accessed published reference ranges. In the Autism group, mean levels of vitamins, minerals, and most amino acids commonly measured in clinical care were within published reference ranges.A stepwise, multiple linear regression analysis demonstrated significant associations between several groups of biomarkers with all three autism severity scales, including vitamins (adjusted R2 of 0.25-0.57), minerals (adj. R2 of 0.22-0.38), and plasma amino acids (adj. R2 of 0.22-0.39). CONCLUSION: The autism group had many statistically significant differences in their nutritional and metabolic status, including biomarkers indicative of vitamin insufficiency, increased oxidative stress, reduced capacity for energy transport, sulfation and detoxification. Several of the biomarker groups were significantly associated with variations in the severity of autism. These nutritional and metabolic differences are generally in agreement with other published results and are likely amenable to nutritional supplementation. Research investigating treatment and its relationship to the co-morbidities and etiology of autism is warranted.

http://www.ncbi.nlm.nih.gov/pubmed/21651783 Research in Autism Spectrum Disorders Volume 7, Issue 10, October 2013, Pages 1228–1233 Comorbidity and autism: Trends, topics and future directions Johnny L. Matson, Rachel L. Goldin

Abstract

Autism spectrum disorders (ASD) are common, life-long disorders. Symptoms of ASD often co-

occur with other difficulties that also tend to be chronic and debilitating. Common co-occurring

difficulties include intellectual disabilities, physical conditions, comorbid psychopathologies and

challenging behaviors. However, the idea of comorbidities among individuals with ASD is still a

relatively new notion. Thus, a new field of research is developing examining comorbidities with

ASD. This field is developing rapidly but is still lacking. This paper highlights the most common

forms of comorbid disorders, and the future direction of research on comorbidities among

individuals with ASD is discussed.

Acta Neurobiol Exp (Wars). 2013;73(2):225-36.

The role of zinc and copper in autism spectrum disorders.

Bjorklund G. Abstract

Autism spectrum disorders (ASDs) are a group of developmental disabilities that can cause

significant social, communication and behavioral challenges. Several studies have suggested a

disturbance in the copper (Cu) and zinc (Zn) metabolism in ASDs. Zinc deficiency, excess Cu

levels, and low Zn/Cu ratio are common in children diagnosed with an ASD. The literature also

suggests that mercury accumulation may occur as a cause or consequence of

metallothionein (MT) dysfunction in children diagnosed with an ASD, which may be one

of the causes of Zn deficiency. MTs are proteins with important functions in

metal metabolism and protection. Zinc and Cu bind to and participate in the control of

the synthesis of MT proteins. Studies indicate that the GABAergic system may be

involved in ASDs, and that Zn and Cu may play a role in this system.

http://www.ncbi.nlm.nih.gov/pubmed/23823984

Transl Psychiatry. 2013 Jun 18;3:e273. doi: 10.1038/tp.2013.51.

Redox metabolism abnormalities in autistic children associated with mitochondrial disease.

Frye RE, Delatorre R, Taylor H, Slattery J, Melnyk S, Chowdhury N, James SJ.

Source

Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

REFrye@uams.edu

Abstract

Research studies have uncovered several metabolic abnormalities associated

with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal

redox metabolism. Despite the close connection between mitochondrial dysfunction and

oxidative stress, the relation between MD and oxidative stress in children with ASD has not

been studied. Plasma markers of oxidative stress and measures of cognitive and language

development and ASD behavior were obtained from 18 children diagnosed with ASD who met

criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and

gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD).

Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized

glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma

measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language

was measured using the preschool language scale or the expressive one-word vocabulary test

(depending on the age), adaptive behaviour was measured using the Vineland Adaptive

Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms

Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have

lower scores on the communication and daily living skill subscales of the VABS despite having

similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher

levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD,

suggesting an overall more favourable glutathione redox status in the ASD/MD group. However,

compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG,

demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had

higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the

ASD/MD group. Both ASD groups demonstrated significantly higher 3CT levels than control

subjects, suggesting that chronic inflammation was present in both groups of children with ASD.

Interestingly, 3NT was found to correlate positively with several measures of cognitive function,

development and behavior for the ASD/MD group, but not the ASD/NoMD group, such that

higher 3NT concentrations were associated with more favourable adaptive behaviour, language

and ASD-related behavior. To determine whether difference in receiving medications and/or

supplements could account for the differences in redox and inflammatory biomarkers across

ASD groups, we examined differences in medication and supplements across groups and their

effect of redox and inflammatory biomarkers. Overall, significantly more participants in the

ASD/MD group were receiving folate, vitamin B12, carnitine, co-enzyme Q10, B vitamins and

antioxidants. We then determined whether folate, carnitine, co-enzyme Q10, B vitamins and/or

antioxidants influenced redox or inflammatory biomarkers. Antioxidant supplementation was

associated with a significantly lower GSSG, whereas antioxidants, co-enzyme Q10 and B

vitamins were associated with a higher fGSH/GSSG ratio. There was no relation between folate,

carnitine, co-enzyme Q10, B vitamins and antioxidants with 3NT, 3CT or fGSH. Overall, our

findings suggest that ASD/MD children with a more chronic oxidized microenvironment have

better development. We interpret this finding in light of the fact that more active

mitochondrial can create a greater oxidized microenvironment especially when

dysfunctional. Thus, compensatory upregulation of mitochondria which are

dysfunctional may both increase activity and function at the expense of a more oxidized

microenvironment. Although more ASD/MD children were receiving certain supplements,

the use of such supplements were not found to be related to the redox biomarkers that

were related to cognitive development or behavior in the ASD/MD group but could

possibly account for the difference in glutathione metabolism noted between groups.

This study suggests that different subgroups of children with ASD have different redox

abnormalities, which may arise from different sources. A better understanding of the relationship

between mitochondrial dysfunction in ASD and oxidative stress, along with other factors that

may contribute to oxidative stress, will be critical to understanding how to guide treatment and

management of ASD children. This study also suggests that it is important to identify ASD/MD

children as they may respond differently to specific treatments because of their

specific metabolic profile.

http://www.ncbi.nlm.nih.gov/pubmed/23778583

Transl Psychiatry. 2013 Jan 22;3:e220. doi: 10.1038/tp.2012.143.

Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrumdisorder.

Frye RE, Melnyk S, Macfabe DF.

Source

Department of Pediatrics, Arkansas Children's Hospital Research Institute, Little Rock, AR,

USA. REFrye@uams.edu

Abstract

Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD).

Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to

explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of

children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which

propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria,

is infused intracerebroventricularly. This animal model shows validity as it demonstrates many

behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with

ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and

long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the

same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD,

the laboratory results from a large cohort of children with ASD (n=213) who underwent

screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in

a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be

abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these

abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD

demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific

acyl-carnitine species were consistently elevated across the individuals with consistently

abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not

medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal

acyl-carnitine panels-a pattern consistent with the PPA rodent ASD model. Examination of

electron transport chain function in muscle and fibroblast culture, histological and electron

microscopy examination of muscle and other biomarkers of mitochondrial metabolism revealed

a pattern consistent with the notion that PPA could be interfering with mitochondrial metabolism

at the level of the tricarboxylic-acid cycle (TCAC). The function of the fatty-acid oxidation

pathway in fibroblast cultures and biomarkers for abnormalities in non-mitochondrial fatty-acid

metabolism were not consistently abnormal across the subgroup of ASD children, consistent

with the notion that the abnormalities in fatty-acid metabolism found in this subgroup of children

with ASD were secondary to TCAC abnormalities. Glutathione metabolism was abnormal in the

subset of ASD individuals with consistent acyl-carnitine panel abnormalities in a pattern similar

to glutathione abnormalities found in the PPA rodent model of ASD. These data suggest that

there are similar pathological processes between a subset of ASD children and an animal model

of ASD with acquired mitochondrialdysfunction. Future studies need to identify additional

parallels between the PPA rodent model of ASD and this subset of ASD individuals with this

unique pattern of acyl-carnitine abnormalities. A better understanding of this animal model and

subset of children with ASD should lead to better insight in mechanisms behind environmentally

induced ASD pathophysiology and should provide guidance for developing preventive and

symptomatic treatments.

http://www.ncbi.nlm.nih.gov/pubmed/23340503

Zhongguo Dang Dai Er Ke Za Zhi. 2013 Aug;15(8):698-702.

[Relationship between vitamin D and autism spectrum disorder].

[Article in Chinese]

Duan XY, Jia FY, Jiang HY.

Source

Department of Pediatric Neurological Rehabilitation, First Hospital of Jilin University, Changchun

130031, China. 876695347@qq.com.

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, with multiple

genetic and environmental risk factors. The interplay between genetic and environmental factors

has become the subject of intensified research in the last several years. Vitamin D deficiency

has recently been proposed as a possible environmental risk factor for ASD. Vitamin D has a

unique role in brain homeostasis, embryogenesis and neurodevelopment, immunological

modulation (including the brain's immune system), antioxidation, antiapoptosis, neural

differentiation and gene regulation. Children with ASD had significantly lower serum levels

of 25-hydroxy vitamin D than healthy children.Therefore vitamin D deficiency during

pregnancy and early childhood may be an environmental trigger for ASD.

-Toxicológicos

Maedica (Buchar). 2012 Jan;7(1):38-48.

Toxic Metals and Essential Elements in Hair and Severity of Symptoms among Children with Autism.

Blaurock-Busch E, Amin OR, Dessoki HH, Rabah T.

Source

Lecturer and Advisor, International Board of Clinical Metal Toxicology & German Medical

Association of Clinical Metal Toxicology, Hersbruck, Germany.

Abstract

Objective: The objective of this study was to assess the levels of ten toxic metals and essential

elements in hair samples of children with autism, and to correlate the level of these elements

with the severity of autism.Method: The participants were 44 children, age 3 to 9 years,

with Autistic SpectrumDisorder (ASD) according to Diagnostic and Statistical Manual of Mental

Disorders 4th Edition, (DSM-IV). The severity of autistic symptomatology was measured by the

Childhood Autism Rating Scale (CARS). Hair analysis was performed to evaluate the long term

metal exposure and mineral level.Results: By comparing hair concentration of autistic vs

nonautistic children, elevated hair concentrations were noted for aluminum, arsenic, cadmium,

mercury, antimony, nickel, lead, and vanadium. Hair levels of calcium, iron, iodine, magnesium,

manganese, molybdenum, zinc, and selenium were considered deficient. There was a

significant positive correlation between lead & verbal communication (p = 0.020) and general

impression (p = 0.008). In addition, there was a significant negative correlation between zinc &

fear and nervousness (p = 0.022).Conclusion: Our data supports the historic evidence that

heavy metals play a role in the development of ASD. In combination with an inadequate

nutritional status the toxic effect of metals increase along with the severity of symptoms.

J Toxicol. 2013;2013:801517. doi: 10.1155/2013/801517. Epub 2013 Jun 9.

B-lymphocytes from a population of children with autism spectrum disorder and their unaffected siblings exhibit hypersensitivity to thimerosal.

Sharpe MA, Gist TL, Baskin DS.

Source

Department of Neurosurgery, The Methodist Neurological Institute, 6560 Fannin Street,

Scurlock Tower No. 944, Houston, TX 77030, USA.

Abstract

The role of thimerosal containing vaccines in the development

of autism spectrum disorder (ASD) has been an area of intense debate, as has the presence of

mercury dental amalgams and fish ingestion by pregnant mothers. We studied the effects

of thimerosal on cell proliferation and mitochondrial function from B-lymphocytes taken from

individuals with autism, their nonautistic twins, and their nontwin siblings. Eleven families were

examined and compared to matched controls. B-cells were grown with increasing levels

of thimerosal, and various assays (LDH, XTT, DCFH, etc.) were performed to examine the

effects on cellular proliferation and mitochondrial function. A subpopulation of eight individuals

(4 ASD, 2 twins, and 2 siblings) from four of the families showed thimerosal hypersensitivity,

whereas none of the control individuals displayed this response. The thimerosalconcentration

required to inhibit cell proliferation in these individuals was only 40% of controls. Cells

hypersensitive to thimerosal also had higher levels of oxidative stress markers, protein

carbonyls, and oxidant generation. This suggests certain individuals with a mild mitochondrial

defect may be highly susceptible to mitochondrial specific toxins like the vaccine

preservative thimerosal

http://www.ncbi.nlm.nih.gov/pubmed/23843785

J Inorg Biochem. 2013 Jul 19. pii: S0162-0134(13)00177-3. doi:

10.1016/j.jinorgbio.2013.07.022. [Epub ahead of print]

Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes.

Shaw CA, Li Y, Tomljenovic L.

Source

Dept. of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British

Columbia, Canada; Program in Experimental Medicine, University of British Columbia,

Vancouver, British Columbia, Canada; Program in Neuroscience, University of British Columbia,

Vancouver, British Columbia, Canada. Electronic address: cashawlab@gmail.com.

Abstract

Our previous ecological studies of autism spectrum disorder (ASD) has demonstrated a

correlation between increasing ASD rates and aluminium (Al) adjuvants in common use in

paediatric vaccines in several Western countries. The correlation between ASD rate and Al

adjuvant amounts appears to be dose-dependent and satisfies 8 of 9 Hill criteria for causality.

We have now sought to provide an animal model to explore potential behavioural phenotypes

and central nervous system (CNS) alterations using s.c. injections of Al hydroxide in early

postnatal CD-1 mice of both sexes. Injections of a "high" and "low" Al adjuvant levels were

designed to correlate to either the U.S. or Scandinavian paediatric vaccine schedules vs. control

saline-injected mice. Both male and female mice in the "high Al" group showed significant

weight gains following treatment up to sacrifice at 6months of age. Male mice in the "high Al"

group showed significant changes in light-dark box tests and in various measures of behaviour

in an open field. Female mice showed significant changes in the light-dark box at both doses,

but no significant changes in open field behaviours. These current data implicate Al injected in

early postnatal life in some CNS alterations that may be relevant for a better understanding of

the aetiology of AS

Immunol Res. 2013 Jul;56(2-3):304-16. doi: 10.1007/s12026-013-8403-1.

Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity.

Shaw CA, Tomljenovic L.

Source

Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences,

University of British Columbia (UBC), 828 W. 10th Ave., Vancouver, BC, V5Z 1L8, Canada.

cashawlab@gmail.com

Abstract

We have examined the neurotoxicity of aluminum in humans and animals under various

conditions, following different routes of administration, and provide an overview of the various

associated disease states. The literature demonstrates clearly negative impacts of aluminum on

the nervous system across the age span. In adults, aluminum exposure can lead to apparently

age-related neurological deficits resembling Alzheimer's and has been linked to this disease

and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models.

In addition, injection ofaluminum adjuvants in an attempt to model Gulf War syndrome and

associated neurological deficits leads to an ALS phenotype in young male mice. In young

children, a highly significant correlation exists between the number of

pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum

disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part,

from autoimmune reactions, as part of the ASIA syndrome.

Sci Rep. 2013;3:1199. doi: 10.1038/srep01199. Epub 2013 Feb 4.

Estimation of autistic children by metallomics analysis.

Yasuda H, Yasuda Y, Tsutsui T.

Source

La Belle Vie Research Laboratory, 8-4 Nihonbashi-Tomizawacho , Chuo-ku, Tokyo, Japan.

yasuda@lbv.co.jp

Erratum in

Sci Rep. 2013;3:2254. Kobayashi, Masahiro [removed].

Abstract

Clarification of the pathogenesis and treatment of autism spectrum disorders is one of the

challenges today. In this study, we examine scalp hair concentrations of 26 trace elements for

1,967 children with autistic disorders (1,553 males and 414 females). Five-hundred and eighty-

four (29.7%), 347 (17.6%) and 114 (5.8%) subjects was found deficient in zinc, magnesium and

calcium, respectively, and 2.0% or less in the other essential metals. The incidence rate of

mineral deficiency was highly observed in infants aged 0-3 year-old. In contrast, 339 (17.2%),

168 (8.5%) and 94 (4.8%) individuals was found suffering from high burden of aluminium,

cadmium and lead, and 2.8% or less from mercury and arsenic burden. These findings suggest

that infantile zinc- and magnesium-deficiency and/or toxic metal burdens may epigenetically

play principal roles as environmental factors inautistic disorders and that metallomics approach

may lead to early screening and prevention of the neurodevelopment disorders.

http://www.ncbi.nlm.nih.gov/pubmed/23383369 -Inmunes y autoinmunes

J Neuroimmune Pharmacol. 2013 Sep;8(4):900-20. doi: 10.1007/s11481-013-9462-8. Epub

2013 May 5.

Evidence for a dysregulated immune system in the etiology of psychiatric disorders.

Gibney SM, Drexhage HA.

Source

Department of Immunology, Na1101, Erasmus MC, Dr. Molewaterplein 50, Erasmus MC, 3015

GE, Rotterdam, The Netherlands, s.gibney@erasmusmc.nl.

Abstract

There is extensive bi-directional communication between the brain and the immune system in

both health and disease. In recent years, the role of an altered immune system in the etiology of

major psychiatric disorders has become more apparent. Studies have demonstrated that some

patients with major psychiatric disorders exhibit characteristic signs of immune dysregulation

and that this may be a common pathophysiological mechanism that underlies the development

and progression of these disorders. Furthermore, many psychiatric disorders are also often

accompanied by chronic medical conditions related to immune dysfunction such as

autoimmune diseases, diabetes and atherosclerosis. One of the major psychiatric disorders

that has been associated with an altered immune system is schizophrenia, with approximately

one third of patients with this disordershowing immunological abnormalities such as an altered

cytokine profile in serum and cerebrospinal fluid. An altered cytokine profile is also found in a

proportion of patients with major depressive disorder and is thought to be potentially related to

the pathophysiology of this disorder. Emerging evidence suggests that

altered immune parameters may also be implicated in the neurobiological etiology

of autism spectrum disorders. Further support for a role of immune dysregulation in the

pathophysiology of these psychiatric disorders comes from studies showing the

immunomodulating effects of antipsychotics and antidepressants, and the mood altering

effects of anti-inflammatory therapies. This review will not attempt to discuss all of the

psychiatric disorders that have been associated with an augmented immune system, but will

instead focus on several key disorders where dysregulation of this system has been implicated

in their pathophysiology including depression, schizophrenia and autism spectrum disorder.

Methods Mol Biol. 2012;934:219-40. doi: 10.1007/978-1-62703-071-7_12.

Autism spectrum disorders: from immunity to behavior.

Careaga M, Ashwood P.

Source

Department of Medical Microbiology and Immunology and the M.I.N.D. Institute, University of

California at Davis, Davis, CA, USA.

Abstract

Autism spectrum disorders (ASD) are complex and heterogeneous with a spectrum of diverse

symptoms. Mounting evidence from a number of disciplines suggests a link

between immune function and ASD. Although the causes of ASD have yet to be identified,

genetic studies have uncovered a host of candidate genes relating to immune regulation that

are altered in ASD, while epidemiological studies have shown a relationship with

maternal immune disturbances during pregnancy and ASD. Moreover, decades of research

have identified numerous systemic and cellular immuneabnormalities in individuals with

ASD and their families. These include changes in immune cell number, differences in

cytokine and chemokine production, and alterations of cellular function at rest and in

response to immunological challenge. Many of these changes in immune responses are

associated with increasing impairment in behaviors that are core features of ASD. Despite this

evidence, much remains to be understood about the precise mechanism by which

the immune system alters neurodevelopment and to what extent it is involved in the

pathogenesis of ASD. With estimates of ASD as high as 1% of children, ASD is a major public

health issue. Improvements in our understanding of the interactions between the nervous

and immune system during early neurodevelopment and how this interaction is different in ASD

will have important therapeutic implications with wide ranging benefits.

Brain Behav Immun. 2012 Mar;26(3):383-92. doi: 10.1016/j.bbi.2011.08.007. Epub 2011 Aug

28.

The role of immune dysfunction in the pathophysiology of autism.

Onore C, Careaga M, Ashwood P.

Source

Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA.

Abstract

Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders

encompassing impairments in communication, social interactions and restricted stereotypical

behaviors. Although a link between altered immune responses and ASD was first recognized

nearly 40 years ago, only recently has new evidence started to shed light on the complex

multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological

research in ASD has highlighted pathways involved in neural development, synapse plasticity,

structural brain abnormalities, cognition and behavior. At the same time, several lines of

evidence point to altered immune dysfunction in ASD that directly impacts some or all these

neurological processes. Extensive alterations in immune function have now been

described in both children and adults with ASD, including ongoing inflammation in brain

specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased

presence of brain-specific auto-antibodies and altered immune cell function.

Furthermore, these dysfunctional immune responses are associated with increased

impairments in behaviors characteristic of core features of ASD, in particular, deficits in

social interactions and communication. This accumulating evidence suggests

that immune processes play a key role in the pathophysiology of ASD. This review will

discuss the current state of our knowledge of immunedysfunction in ASD, how these findings

may impact on underlying neuro-immune mechanisms and implicate potential areas where the

manipulation of the immune response could have an impact on behavior and immunity in ASD.

J Neuroimmunol. 2012 Oct 15;251(1-2):94-102. doi: 10.1016/j.jneuroim.2012.07.001. Epub

2012 Jul 31.

Decreased levels of total immunoglobulin in children with autism are not a result of B cell dysfunction.

Heuer LS, Rose M, Ashwood P, Van de Water J.

Source

Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis,

USA.

Abstract

Autism spectrum disorders are a heterogeneous group of behaviorally defined disorders having

complex etiologies. We previously reported a direct correlation between lower plasma levels of

the immunoglobulins (Ig) IgG and IgM and increased severity of behavioral symptoms in

children withautism. Our current objective was to determine if these reduced plasma levels of

IgG and IgM are the result of defective B cell development, activation, or function. Results

suggest no differences in the B cell parameters measured, indicating that

decreased Ig in autism is not a result of B cell dysfunction and other immune cells might be

involved.

Arch Med Sci. 2012 May 9;8(2):324-31. doi: 10.5114/aoms.2012.28561.

Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old.

Wasilewska J, Kaczmarski M, Stasiak-Barmuta A, Tobolczyk J, Kowalewska E.

Source

Department of Paediatrics, Gastroenterology and Allergology, Medical University of Bialystok,

Poland.

Abstract

INTRODUCTION:

Immune system dysfunction is considered to be one of many medical disorders found in

children with autism. The primary objective of the study was to assess if blood tests reflecting

humoral immunity (IgA, IgG, IgM, IgE) are useful in identifying children with regressive autism.

The secondary objective was to evaluate a part of the cellular arm of immunity (CD4/CD25

Tregs, CD4/CD23 cells) in those children.

MATERIAL AND METHODS:

Using a clinical case-control design, the systemic levels of immunoglobulins and lymphocyte

subpopulations analysed by flow cytometry were compared in children aged 3-6 years old with a

new diagnosis of regressive autism (n = 24; mean age: 4.25 ±1.70 years; male 23/24) and in

sex- and age-matched healthy children (n = 24; aged 4.25 ±2.20 years; male 23/24).

RESULTS:

The humoral immunity profile, described by three binary variables, IgA < 0.97 g/l, IgE > 36

IU/ml, and IgG > 6.3 g/l, with a sensitivity of 79% and a specificity of 83% (p < 0.0001), was able

to identify children with autism. The highest risk of autism diagnosis was associated with IgA <

0.97g/l (OR - 23.0; p < 0.001). A higher number of CD19/CD23 was found in children diagnosed

with autism than in the control group (36.82 ±6.72% vs. 18.20 ±3.95%; p < 0.02). No correlation

between the number of CD23-positive cells and serum IgE levels was observed.

CONCLUSIONS:

A subtle shift of serum immunoglobulins consisting of low-normal IgA and B cell activation

expressed by an increase of CD23-positive cells may characterize children with

regressive autism aged 3-6 years old.

http://www.ncbi.nlm.nih.gov/pubmed/22662007

J Neuroimmunol. 2011 Sep 15;238(1-2):73-80. doi: 10.1016/j.jneuroim.2011.07.001. Epub 2011

Jul 30.

Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked

fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes.

Jyonouchi H, Geng L, Streck DL, Toruner GA.

Source

Division of Allergy/Immunology and Infection Diseases, Department of Pediatrics, University of

Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Ave,

Newark, NJ 07101-1709, USA. jyanouha@umdnj.edu

Abstract

Innate/adaptive immune responses and transcript profiles of peripheral blood monocytes were

studied in ASD children who exhibit fluctuating behavioral symptoms following infection and

other immune insults (ASD/Inf, N=30). The ASD/Inf children with persistent gastrointestinal

symptoms (ASD/Inf+GI, N=19), revealed less production of proinflammatory and counter-

regulatory cytokines with stimuli of innate immunity and marked changes in transcript profiles of

monocytes as compared to ASD/no-Inf (N=28) and normal (N=26) controls. This included a 4-

5 fold up-regulation of chemokines (CCL2 and CCL7), consistent with the production of

more CCL2 by ASD/Inf+GI cells. These results indicate dysregulated innate immune

defense in the ASD/Inf+GI children, rendering them more vulnerable to common

microbial infection/dysbiosis and possibly subsequent behavioral changes.

Expert Rev Clin Immunol. 2010 May;6(3):397-411. doi: 10.1586/eci.10.18.

Autism spectrum disorders and allergy: observation from a pediatric allergy/immunology clinic.

Jyonouchi H.

Source

Pediatrics, University of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey Medical

School (NJMS), 185 South Orange Ave, Newark, NJ 07101, USA. jyanouha@umdnj.edu

Abstract

IgE-mediated allergic diseases (e.g., allergic rhinoconjunctivitis, atopic asthma and food allergy)

are prevalent (up to 30%) in the general population and are increasing in developed countries.

In infants and young children, non-IgE-mediated food allergy is also prevalent. In addition to

easily recognized organ-specific symptoms, allergic diseases can cause neuropsychiatric

symptoms, such as irritability and hyperactivity, in otherwise healthy individuals. This is also

likely to occur in children with autism spectrum disorder (ASD). Moreover, the discomfort and

pain associated with allergic diseases could aggravate behavioral symptoms in ASD children.

Allergic conditions are easily treatable; however, ASD children may be underdiagnosed

and/or undertreated for allergic and other common childhood diseases, in part due to

their impaired communication skills. Practicing physicians should be aware of the

potential impact of allergic diseases on behavioral symptoms and cognitive activity in

ASD children. However, they also need to be aware that certain symptoms often

attributed to 'allergy' by caregivers may not be immune mediated and should understand

that behavioral symptoms can also be affected by many non-IgE-mediated causes.

-Inflamación

J Neuroinflammation. 2013 Apr 9;10:46. doi: 10.1186/1742-2094-10-46.

Focal brain inflammation and autism.

Theoharides TC, Asadi S, Patel AB.

Source

Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular

Physiology and Pharmacology, Tufts University School of Medicine, Suite J304, 136 Harrison

Avenue, Boston, MA 02111, USA. theoharis.theoharides@tufts.edu

Abstract

Increasing evidence indicates that brain inflammation is involved in the pathogenesis of

neuropsychiatric diseases. Autism spectrum disorders (ASD) are characterized by social and

learning disabilities that affect as many as 1/80 children in the USA. There is still no definitive

pathogenesis or reliable biomarkers for ASD, thus significantly curtailing the development of

effective therapies. Many children with ASD regress at about age 3 years, often after a

specific event such as reaction to vaccination, infection, stress or trauma implying some

epigenetic triggers, and may constitute a distinct phenotype. ASD children respond

disproportionally to stress and are also affected by food and skin allergies.

Corticotropin-releasing hormone (CRH) is secreted under stress and together with

neurotensin (NT) stimulates mast cells and microglia resulting in focal

brain inflammation and neurotoxicity. NT is significantly increased in serum of ASD

children along with mitochondrial DNA (mtDNA). NT stimulates mast cell secretion of

mtDNA that is misconstrued as an innate pathogen triggering an auto-inflammatory

response. The phosphatase and tensin homolog (PTEN) gene mutation, associated with

the higher risk of ASD, which leads to hyper-active mammalian target of rapamycin

(mTOR) signalling that is crucial for cellular homeostasis. CRH, NT and environmental

triggers could hyperstimulate the already activated mTOR, as well as stimulate mast cell and

microglia activation and proliferation. The natural flavonoid luteolin inhibits mTOR, mast cells

and microglia and could have a significant benefit in ASD.

J Neuroinflammation. 2012 Dec 11;9:265. doi: 10.1186/1742-2094-9-265.

Neuroinflammation in autism spectrum disorders.

El-Ansary A, Al-Ayadhi L.

Source

Biochemistry Department, Science College, King Saud University, P,O, Box 22452, 11495,

Riyadh, Saudi Arabia. elansary@ksu.edu.sa

Abstract

OBJECTIVES:

The neurobiological basis for autism remains poorly understood. However, research suggests

that environmentalfactors and neuroinflammation, as well as genetic factors, are contributors.

This study aims to test the role that might be played by heat shock protein (HSP)70,

transforming growth factor (TGF)-β2, Caspase 7 and interferon-γ (IFN-γ)in the pathophysiology

of autism.

MATERIALS AND METHODS:

HSP70, TGF-β2, Caspase 7 and INF-γ as biochemical parameters related to inflammation were

determined in plasma of 20 Saudi autistic male patients and compared to 19 age- and gender-

matched control samples.

RESULTS:

The obtained data recorded that Saudi autistic patients have remarkably higher plasma HSP70,

TGF-β2, Caspase 7 and INF-γ compared to age and gender-matched controls. INF-γ recorded

the highest (67.8%) while TGF-β recorded the lowest increase (49.04%). Receiver Operating

Characteristics (ROC) analysis together with predictiveness diagrams proved that the measured

parameters recorded satisfactory levels of specificity and sensitivity and all could be used as

predictive biomarkers.

CONCLUSION:

Alteration of the selected parameters confirm the role of neuroinflammation and

apoptosis mechanisms in the etiology of autismtogether with the possibility of the use of

HSP70, TGF-β2, Caspase 7 and INF-γ as predictive biomarkers that could be used to

predict safety, efficacy of a specific suggested therapy or natural supplements, thereby

providing guidance in selecting it for patients or tailoring its dose.

http://www.ncbi.nlm.nih.gov/pubmed/23231720

J Neuroinflammation. 2011 Nov 30;8:168. doi: 10.1186/1742-2094-8-168.

Neuro-inflammation, blood-brain barrier, seizures and autism.

Theoharides TC, Zhang B.

Source

Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular

Physiology and Pharmacology, Tufts University School of Medicine, 136 Harrison Avenue,

Boston, MA, USA. theoharis.theoharides@tufts.edu

Abstract

Many children with Autism Spectrum Diseases (ASD) present with seizure activity, but the

pathogenesis is not understood. Recent evidence indicates that neuro-inflammation could

contribute to seizures. We hypothesize that brain mast cell activation due to allergic,

environmental and/or stress triggers could lead to focal disruption of the blood-brain barrier and

neuro-inflammation, thus contributing to the development of seizures. Treating neuro-

inflammation may be useful when anti-seizure medications are ineffective.

http://www.ncbi.nlm.nih.gov/pubmed/22129087

-Microglial activation

Neuron Glia Biol. 2011 May;7(2-4):205-13. doi: 10.1017/S1740925X12000142. Epub 2012 Jul 6.

Evidence of microglial activation in autism and its possible role in brain underconnectivity.

Rodriguez JI, Kern JK.

Source

Stop Calling It Autism, Fort Worth, TX, USA.

Abstract

Evidence indicates that children with autism spectrum disorder (ASD) suffer from an ongoing

neuroinflammatory process in different regions of the brain involving microglial activation. When

microglia remain activated for an extended period, the production of mediators is sustained

longer than usual and this increase in mediators contributes to loss of synaptic connections and

neuronal cell death. Microglial activation can then result in a loss of connections or

underconnectivity. Underconnectivity is reported in many studies in autism. One way to control

neuroinflammation is to reduce or inhibit microglial activation. It is plausible that by reducing

brain inflammation and microglial activation, the neurodestructive effects of

chronicinflammation could be reduced and allow for improved developmental outcomes. Future

studies that examine treatments that may reduce microglial activation and neuroinflammation,

and ultimately help to mitigate symptoms in ASD, are warranted.

JAMA Psychiatry. 2013 Jan;70(1):49-58. doi: 10.1001/jamapsychiatry.2013.272.

Microglial activation in young adults with autism spectrum disorder.

Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K, Yoshihara Y, Omata K, Matsumoto K, Tsuchiya KJ, Iwata Y, Tsujii M, Sugiyama T,Mori N.

Source

Research Center for Child Mental Development, Hamamatsu University School of Medicine,

Hamamatsu, Japan.

Abstract

CONTEXT:

A growing body of evidence suggests that aberrant immunologic systems underlie the

pathophysiologic characteristics of autismspectrum disorder (ASD). However, to our knowledge,

no information is available on the patterns of distribution of microglial activation in the brain in

ASD.

OBJECTIVES:

To identify brain regions associated with excessively activated microglia in the whole brain, and

to examine similarities in the pattern of distribution of activated microglia in subjects with ASD

and control subjects.

DESIGN:

Case-control study using positron emission tomography and a radiotracer for microglia--

[11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide)

([11C](R)-PK11195).

SETTING:

Subjects recruited from the community.

PARTICIPANTS:

Twenty men with ASD (age range, 18-31 years; mean [SD] IQ, 95.9 [16.7]) and 20 age- and IQ-

matched healthy men as controls. Diagnosis of ASD was made in accordance with

the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised.

MAIN OUTCOME MEASURES:

Regional brain [11C](R)-PK11195 binding potential as a representative measure

of microglial activation.

RESULTS:

The [11C](R)-PK11195 binding potential values were significantly higher in multiple brain

regions in young adults with ASD compared with those of controls (P < .05, corrected). Brain

regions with increased binding potentials included the cerebellum, midbrain, pons, fusiform gyri,

and the anterior cingulate and orbitofrontal cortices. The most prominent increase was observed

in the cerebellum. The pattern of distribution of [11C](R)-PK11195 binding potential values in

these brain regions of ASD and control subjects was similar, whereas the magnitude of the

[11C](R)-PK11195 binding potential in the ASD group was greater than that of controls in all

regions.

CONCLUSIONS:

Our results indicate excessive microglial activation in multiple brain regions in young

adult subjects with ASD. The similar distribution pattern of regional microglial activity in

the ASD and control groups may indicate augmented but not

altered microglial activation in the brain in the subjects with ASD.

Biol Psychiatry. 2010 Aug 15;68(4):368-76. doi: 10.1016/j.biopsych.2010.05.024.

Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism.

Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J, Courchesne E, Everall IP.

Source

Department of Neuroscience, School of Medicine, University of California, San Diego, La Jolla,

CA 95817, USA. jtmorgan61@gmail.com

Abstract

BACKGROUND:

In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been

reported. However, it is unknown whethermicroglial somal volume or density are altered in the

cortex and whether any alteration is associated with age or other potential covariates.

METHODS:

Microglia in sections from the dorsolateral prefrontal cortex of nonmacrencephalic male cases

with autism (n = 13) and control cases (n = 9) were visualized via ionized calcium binding

adapter molecule 1 immunohistochemistry. In addition to a neuropathological

assessment, microglialcell density was stereologically estimated via optical fractionator and

average somal volume was quantified via isotropic nucleator.

RESULTS:

Microglia appeared markedly activated in 5 of 13 cases with autism, including 2 of 3 under age

6, and marginally activated in an additional 4 of 13 cases. Morphological alterations included

somal enlargement, process retraction and thickening, and extension of filopodia from

processes. Average microglial somal volume was significantly increased in white matter (p =

.013), with a trend in gray matter (p = .098). Microglial cell density was increased in gray matter

(p = .002). Seizure history did not influence any activation measure.

CONCLUSIONS:

The activation profile described represents a neuropathological alteration in a sizeable fraction

of cases with autism. Given its early presence, microglial activation may play a central role in

the pathogenesis of autism in a substantial proportion of patients. Alternatively, activationmay

represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal

network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple

cellular population

-Oxidative stress

Curr Med Chem. 2012;19(23):4000-5.

Glutathione-related factors and oxidative stress in autism, a review.

Ghanizadeh A, Akhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M, Firoozabadi A.

Source

Research Center for Psychiatry and Behavioral Sciences, Shiraz University of Medical

Sciences, School of Medicine, Shiraz, Iran. ghanizad@sina.tums.ac.ir

Abstract

Autism spectrum disorders are complex neuro-developmental disorders whose neurobiology is

proposed to be associated with oxidative stress which is induced by reactive oxygen species.

The process of oxidative stress can be a target for therapeutic interventions. In this study, we

aimed to review the role of oxidative stress, plasma glutathione (GSH), and related factors as

the potential sources of damage to the brain as well as the possible related factors which

reduce the oxidative stress. Methylation capacity, sulfates level, and the total glutathione level

are decreased in autism. On the other hand, both oxidized glutathione and the ratio of oxidized

to reduced glutathione are increased in autism. In addition, the activity of glutathione

peroxidase, superoxide dismutase, and catalase, as a part of the antioxidative stress system

are decreased. The current literature suggests an imbalance of oxidative and anti-oxidative

stress systems in autism. Glutathione is involved in neuro-protection against oxidative stress

and neuro-inflammation in autism by improving the anti-oxidative stress system. Decreasing the

oxidative stress might be a potential treatment for autism.

Mol Psychiatry. 2012 Apr;17(4):389-401. doi: 10.1038/mp.2011.165. Epub 2011 Dec 6.

A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation,inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures.

Rossignol DA, Frye RE.

Source

International Child Development Resource Center, Melbourne, FL 32934, USA. rossignolmd@gmail.com

Abstract

Recent studies have implicated physiological and metabolic abnormalities in autism spectrum

disorders (ASD) and other psychiatric disorders, particularly immune dysregulation

or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant

exposures ('four major areas'). The aim of this study was to determine trends in the literature on

these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was

performed in these four major areas in ASD with three objectives. First, publications were

divided by several criteria, including whether or not they implicated an association between the

physiological abnormality and ASD. A large percentage of publications implicated an

association between ASD and immune dysregulation/inflammation (416 out of 437 publications,

95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant

exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area

was computed using a validated scale. The strongest evidence was for immune

dysregulation/inflammation and oxidative stress, followed by toxicant exposures and

mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing

strong evidence for an association between the physiological abnormalities and ASD. Third, the

time trends in the four major areas were compared with trends in neuroimaging,

neuropathology, theory of mind and genetics ('four comparison areas'). The number of

publications per 5-year block in all eight areas was calculated in order to identify significant

changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and

51 in the four comparison areas (42 for genetics). For each 5-year period, the total number

of publications in the eight combined areas increased progressively. Most publications

(552 of 895, 62%) in the four major areas were published in the last 5 years (2006-2010).

Evaluation of trends between the four major areas and the four comparison areas

demonstrated that the largest relative growth was in immune dysregulation/inflammation,

oxidative stress, toxicant exposures, genetics and neuroimaging. Research on

mitochondrial dysfunction started growing in the last 5 years. Theory of mind and

neuropathology research has declined in recent years. Although most publications implicated an

association between the four major areas and ASD, publication bias may have led to an

overestimation of this association. Further research into these physiological areas may provide

insight into general or subset-specific processes that could contribute to the development of

ASD and other psychiatric disorders.

http://www.ncbi.nlm.nih.gov/pubmed/22143005 Síndrome de Asperger

J Neuroimmunol. 2009 Nov 30;216(1-2):108-12. doi: 10.1016/j.jneuroim.2009.09.015. Epub

2009 Oct 17.

Immune allergic response in Asperger syndrome.

Magalhães ES, Pinto-Mariz F, Bastos-Pinto S, Pontes AT, Prado EA, deAzevedo LC.

Source

Laboratory of Neurobiology & Clinical Neurophysiology, Neurology Section, Pediatric

Department, Fernandes Figueira Institute, FIOCRUZ, Brazil.

Abstract

Asperger's syndrome is a subgroup of autism characterized by social deficits without language

delay, and high cognitive performance. The biological nature of autism is still unknown but there

are controversial evidence associating an immune imbalance and autism. Clinical findings,

including atopic family history, serum IgE levels as well as cutaneous tests showed that

incidence of atopy was higher in the Asperger group compared to the healthy controls. These

findings suggest that atopy is frequent in this subgroup of autism implying that allergic

inflammation might be an important feature inAsperger syndrome.

J Psychiatr Res. 2012 Mar;46(3):394-401. doi: 10.1016/j.jpsychires.2011.10.004. Epub 2012

Jan 4.

Plasma antioxidant capacity is reduced in Asperger syndrome.

Parellada M, Moreno C, Mac-Dowell K, Leza JC, Giraldez M, Bailón C, Castro C, Miranda-Azpiazu P, Fraguas D, Arango C.

Source

Child and Adolescent Psychiatry, Department of Psychiatry, Hospital General Universitario

Gregorio Marañón, Centro de Investigación en Red de Salud Mental, CIBERSAM, Dr Esquerdo

46, Madrid, Spain. parellada@hggm.es

Abstract

Recent evidence suggests that children with autism have impaired detoxification capacity and

may suffer from chronic oxidative stress. To our knowledge, there has been no study focusing

on oxidative metabolism specifically in Asperger syndrome (a milder form of autism) or

comparing this metabolism with other psychiatric disorders. In this study, total antioxidant status

(TAOS), non-enzymatic (glutathione and homocysteine) and enzymatic (catalase, superoxide

dismutase, and glutathione peroxidase) antioxidants, and lipid peroxidation were measured in

plasma or erythrocyte lysates in a group of adolescent patients with Asperger syndrome, a

group of adolescents with a first episode of psychosis, and a group of healthy controls at

baseline and at 8-12 weeks. TAOS was also analyzed at 1 year. TAOS was reduced

in Asperger individuals compared with healthy controls and psychosis patients, after

covarying by age and antipsychotic treatment. This reduced antioxidant capacity did not

depend on any of the individual antioxidant variables measured. Psychosis patients had

increased homocysteine levels in plasma and decreased copper and ceruloplasmin at

baseline. In conclusion, Asperger patients seem to have chronic low detoxifying

capacity. No impaired detoxifying capacity was found in the first-episode psychosis

group in the first year of illness.

Pediatrics. 2012 Nov;130 Suppl 2:S62-8. doi: 10.1542/peds.2012-0900C.

Leadership in health care, research, and quality improvement for children and adolescents with autism spectrum disorders: Autism Treatment Network and Autism Intervention Research Network on Physical Health.

Lajonchere C, Jones N, Coury DL, Perrin JM.

Source

Autism Speaks, Los Angeles, California, USA.

http://www.ncbi.nlm.nih.gov/pubmed/23118255 La genética sólo explica el 1 % del riesgo del diagnóstico:

Hum Mol Genet. 2012 Nov 1;21(21):4781-92. doi: 10.1093/hmg/dds301. Epub 2012 Jul 26.

Individual common variants exert weak effects on the risk for autism spectrum disorderspi.

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Source

Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin

8, Ireland.

Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of

autism spectrum disorders (ASDs), the contribution of common variation to the risk of

developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of

the Autism Genome Project genome-wide association study, adding 1301 ASD families and

bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the

association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that

common variants, en masse, might affect the risk. Despite genotyping over a million SNPs

covering the genome, no single SNP shows significant association with ASD or selected

phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from

secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in

susceptibility for ASD. This SNP also shows modest association with age of word/phrase

acquisition in ASD subjects, of interest because features of language development are also

associated with other variation in CNTNAP2. In contrast, allele scores derived from the

transmission of common alleles to Stage 1 cases significantly predict case status in the

independent Stage 2 sample. Despite being significant, the variance explained by these

allele scores was small (Vm< 1%). Based on results from individual SNPs and their en

masse effect on risk, as inferred from the allele score results, it is reasonable to

conclude that common variants affect the risk for ASD but their individual effects are

modest.