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"No Evidence of Any Link"

Posted Sep 12 2008 11:30am
[UPDATE: This link is becoming quite popular, so I will just start archiving studies that support the vaccine/autism link here. I will be adding the links to the studies to the top section, and I have added about 25 abstracts following Kirby's list.]

[FINAL UPDATE: So I have been adding to the list slowly and have 33 studies, and i will keep adding new ones that come out, but TACA has blown my puny list out of the water with their master list that is approaching 600 citations. So if you have exhausted my list, and are hungry for more, they should keep you busy for quite some time.

And I don't want to hear "No evidence of any link" ever again!]

If you have heard any media on the hearings this week, you have heard a doctor say that there is "No Evidence of Any Link", several times. This is an untrue statement. The court would not be hearing the case unless there was something for them to present. David Kirby, during interviews about his book, Evidence of Harm, has to respond to this claim from doctors repeatedly. Here is his response:

I have to counter that argument all the time. I have prepared the list below and sent it to NPR today.


EVIDENCE FOR THE PETITIONERS –

For their side of the argument, family lawyers will present thousands of pages of published "biological" science, as opposed to epidemiology. They will examine data from animal models, test tube studies, and examinations of children with autism; they will try to present a plausible biological mechanism by which mercury (and to a lesser extent, MMR) could cause autistic-like symptoms -- at the molecular, cellular, and clinical level.

Among this evidence is research suggesting that:

1. Many children with autism, probably due to genetics, are deficient in certain sulfur-based proteins that defend against heavy metal accumulation in humans. The proteins, which include glutathione, are called "thiols," and sometimes "mercaptans," from the Latin mercurium captans, or literally "mercury capturers."

UNIVERSITY OF ARKANSAS – ARKANSAS CHILDREN’S HOSPITAL

PUBLISHED IN BIOLOGY



2. Many children with autism show signs of heavy metal accumulation, including elevated levels of proteins called "prophyrins" a bio-marker of lead and mercury toxicity. They also present with low levels of mercury in baby haircuts, (versus control children) suggesting a heavy metal "efflux disorder" that prevents the proper metabolism and excretion of heavy metals.

LABORATOIRE PHILIPPE AUGUSTE, PARIS, FRANCE

PUBLISHED IN TOXICOLOGY AND APPLIED PHARMACOLOGY


Porphyrinuria in childhood autistic disorder: Implications for environmental toxicity


Toxicology and Applied Pharmacology, 2006

Robert Natafa, Corinne Skorupkab, Lorene Ametb, Alain Lama, Anthea Springbettc and Richard Lathed, aLaboratoire Philippe Auguste, Paris, France, Association ARIANE, Clichy, France, Department of Statistics, Roslin Institute, Roslin, UK, Pieta Research,

This new study from France utilizes a new and sophisticated measurement for environmental toxicity by assessing porphyrin levels in autistic children. It provides clear and unequivocal evidence that children with autism spectrum disorders are more toxic than their neurotypical peers.

Excerpt: "Coproporphyrin levels were elevated in children with autistic disorder relative to control groups...the elevation was significant. These data implicate environmental toxicity in childhood autistic disorder."

Abstract: To address a possible environmental contribution to autism, we carried out a retrospective study on urinary porphyrin levels, a biomarker of environmental toxicity, in 269 children with neurodevelopmental and related disorders referred to a Paris clinic (2002–2004), including 106 with autistic disorder. Urinary porphyrin levels determined by high-performance liquid chromatography were compared between diagnostic groups including internal and external control groups. Coproporphyrin levels were elevated in children with autistic disorder relative to control groups. Elevation was maintained on normalization for age or to a control heme pathway metabolite (uroporphyrin) in the same samples. The elevation was significant (P < 0.001). Porphyrin levels were unchanged in Asperger's disorder, distinguishing it from autistic disorder. The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder (P < 0.001) but not significantly in Asperger's. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) with a view to heavy metal removal. Following DMSA there was a significant (P = 0.002) drop in urinary porphyrin excretion. These data implicate environmental toxicity in childhood autistic disorder.

3) Exposure to extremely low doses (micromolars) of thimerosal, previously thought to be safe, shut down 25% of brain stem cells, in one lab study.

UNIVERISTY OF ROCHESTER

PUBLISHED IN PLoS BIOLOGY



4. In another, low-level exposures of a few minutes duration killed many of the immune system's "dendritic" cells, disrupted production of immune-system messenger chemicals called "cytokines," and caused inflammation.

UNIVERSITY OF CALIFORNIA AT DAVIS

PUBLISHED IN ENVIRONMENTAL HEALTH PERSPECTIVES (NIH)


Uncoupling of ATP-mediated Calcium Signaling and Dysregulated IL-6 Secretion in Dendritic Cells by Nanomolar Thimerosal

Environmental Health Perspectives, July 2006.

Samuel R. Goth, Ruth A. Chu Jeffrey P. Gregg

This study demonstrates that very low-levels of Thimerosal can contribute to immune system disregulation.

Excerpt: "Our findings that DCs primarily express the RyR1 channel complex and that this complex is uncoupled by very low levels of THI with dysregulated IL-6 secretion raise intriguing questions about a molecular basis for immune dyregulation and the possible role of the RyR1 complex in genetic susceptibility of the immune system to mercury."


5. Mmany children with autism show signs of immune deficiency AND hyperactivity, as well as cytokine imbalances and inflammation, (they also show signs of chronic autoimmunity, where the immune system attacks the body and brain).

U.C. DAVIS M.I.N.D. INSTITUTE

POSTER PRESENTATION AT THE 2005 INTERNATIONAL MEETING FOR AUTISM RESEARCH (IMFAR)


6. Organic ethylmercury from thimerosal crosses the blood-brain barrier in primates, where it quickly converts to inorganic mercury, which can remain trapped in the brain for decades.

UNIVERSITY OF WASHINGTON PRIMATE CENTER

PUBLISHED IN ENVIRONMENTAL HEALTH PERSPECTIVES (NIH), 2005

Comparison of Blood and Brain Mercury Levels in Infant Monkeys Exposed to Methylmercury or Vaccines Containing Thimerosal

Environmental Health Perspectives, Aug 2005.

Thomas Burbacher, PhD [University of Washington].

This study demonstrates clearly and unequivocally that ethyl mercury, the kind of mercury found in vaccines, not only ends up in the brain, but leaves double the amount of inorganic mercury as methyl mercury, the kind of mercury found in fish. This work is groundbreaking because little is known about ethyl mercury, and many health authorities have asserted that the mercury found in vaccines is the "safe kind." This study also delivers a strong rebuke of the Institute of Medicine's recommendation in 2004 to no longer pursue the mercury-autism connection.

Excerpt: "A recently published IOM review (IOM 2004) appears to have abandoned the earlier recommendation [of studying mercury and autism] as well as back away from the American Academy of Pediatrics goal [of removing mercury from vaccines]. This approach is difficult to understand, given our current limited knowledge of the toxicokinetics and developmental neurotoxicity of thimerosal, a compound that has been (and will continue to be) injected in millions of newborns and infants."

7. Inorganic mercury trapped in primate brains caused neuro-inflammation (ie, rapid brain growth) by activating "glial" cells in the brain.

Increases in the number of reactive glia in the visual cortex of Macaca fascicularis following subclinical long-term methyl mercury exposure.

Toxicology and Applied Pharmacology, 1994

Charleston JS, Bolender RP, Mottet NK, Body RL, Vahter ME, Burbacher TM., Department of Pathology, School of Medicine, University of Washington

The number of neurons, astrocytes, reactive glia, oligodendrocytes, endothelia, and pericytes in the cortex of the calcarine sulcus of adult female Macaca fascicularis following long-term subclinical exposure to methyl mercury (MeHg) and mercuric chloride (inorganic mercury; IHg) has been estimated by use of the optical volume fractionator stereology technique. Four groups of monkeys were exposed to MeHg (50 micrograms Hg/kg body wt/day) by mouth for 6, 12, 18, and 12 months followed by 6 months without exposure (clearance group). A fifth group of monkeys was administered IHg (as HgCl2; 200 micrograms Hg/kg body wt/day) by constant rate intravenous infusion via an indwelling catheter for 3 months. Reactive glia showed a significant increase in number for every treatment group, increasing 72% in the 6-month, 152% in the 12-month, and 120% in the 18-month MeHg exposed groups, and the number of reactive glia in the clearance group remained elevated (89%). The IHg exposed group showed a 165% increase in the number of reactive glia. The IHg exposed group and the clearance group had low levels of MeHg present within the tissue; however, the level of IHg was elevated in both groups. These results suggest that the IHg may be responsible for the increase in reactive glia. All other cell types, including the neurons, showed no significant change in number at the prescribed exposure level and durations. The identities of the reactive glial cells and the implications for the long-term function and survivability of the neurons due to changes in the glial population following subclinical long-term exposure to mercury are discussed.
8. Autopsies on autistic human brains found chronic inflammation, apparently linked to the brain's immune system and produced by activation of its "glial" cells.

JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE

PUBLISHED IN ANNALS OF NEUROLOGY



Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism

Annals of Neurology, Feb 2005.

Diana L. Vargas, MD [Johns Hopkins University].

This study, performed independently and using a different methodology than Dr. Herbert (see above) reached the same conclusion: the brains of autistic children are suffering from inflammation.

Excerpt: "Because this neuroinflammatory process appears to be associated with an ongoing and chronic mechanism of CNS dysfunction, potential therapeutic interventions should focus on the control of its detrimental effects and thereby eventually modify the clinical course of autism."

9. Another autopsy study also showed ongoing neuro-inflammation, possibly from heavy metal exposure, and signs of autoimmunity. (Other studies have found rapid brain growth in infants with autism.)

HARVARD UNIVERSITY

PUBLISHED IN CLINICAL NEUROPSYCHIATRY
Autism: A Brain Disorder, or A Disorder That Affects the Brain?

Clinical Neuropsychiatry, 2005

Martha R. Herbert M.D., Ph.D., Harvard University

Autism is defined behaviorally, as a syndrome of abnormalities involving language, social reciprocity and hyperfocus or reduced behavioral flexibility. It is clearly heterogeneous, and it can be accompanied by unusual talents as well as by impairments, but its underlying biological and genetic basis in unknown. Autism has been modeled as a brain-based, strongly genetic disorder, but emerging findings and hypotheses support a broader model of the condition as a genetically influenced and systemic. These include imaging, neuropathology and psychological evidence of pervasive (and not just specific) brain and phenotypic features; postnatal evolution and chronic persistence of brain, behavior and tissue changes (e.g. inflammation) and physical illness symptomatology (e.g. gastrointestinal, immune, recurrent infection); overlap with other disorders; and reports of rate increases and improvement or recovery that support a role for modulation of the condition by environmental factors (e.g. exacerbation or triggering by toxins, infectious agents, or others stressors, or improvement by treatment). Modeling autism more broadly encompasses previous work, but also encourages the expansion of research and treatment to include intermediary domains of molecular and cellular mechanisms, as well as chronic tissue, metabolic and somatic changes previously addressed only to a limited degree. The heterogeneous biologies underlying autism may conceivably converge onto the autism profile via multiple mechanisms on the one hand and processing and connectivity abnormalities on the other may illuminate relevant final common pathways and contribute to focusing on the search for treatment targets in this biologically and etiologically heterogeneous behavioral syndrome.

10. Thimerosal can disrupt a chemical process called "methylation," critical for gene expression, neural function, memory and attention, and the production of sulfur-based "thiol" proteins like glutathione.

NORTHEASTERN UNIVERSITY

PUBLISHED IN MOLECULAR PSYCHIATRY



Activation of Methionine Synthase by Insulin-like Growth Factor-1 and Dopamine: a Target for Neurodevelopmental Toxins and Thimerosal

Molecular Psychiatry, July 2004.

Richard C. Deth, PhD [Northeastern University].

This study demonstrates how Thimerosal inhibits methylation, a central driver of cellular communication and development. Excerpt:

"The potent inhibition of this pathway [methylation] by ethanol, lead, mercury, aluminum, and thimerosal suggests it may be an important target of neurodevelopmental toxins."


11. Plaintiff lawyers will also show data from a study of birthday videos proving that many kids with autism were meeting or exceeding developmental milestones at age one, only to have tumbled into a wordless, autistic world by age two. They will also show home videos of plaintiff children, before and after their own regression, and in many cases, of the same children a few years after experimental treatments -- including chelation (for heavy metal removal) and methyl B-12 (for repair of methylation) -- that seem to have vastly improved their condition.

UNIVERSITY OF WASHINGTON

PUBLISHED IN ENVIRONMENTAL HEALTH PERSPECTIVES (NIH)

Validation of the Phenomenon of Autistic Regression Using Home Videotapes

Archives of General Psychiatry, 2005

Emily Werner, PhD; Geraldine Dawson, PhD, University of Washington

Objective To validate parental report of autistic regression using behavioral data coded from home videotapes of children with autism spectrum disorder (ASD) vs typical development taken at 12 and 24 months of age.

Design Home videotapes of 56 children’s first and second birthday parties were collected from parents of young children with ASD with and without a reported history of regression and typically developing children. Child behaviors were coded by raters blind to child diagnosis and regression history. A parent interview that elicited information about parents’ recall of early symptoms from birth was also administered.

Setting Participants were recruited from a multidisciplinary study of autism conducted at a major university.

Participants Fifteen children with ASD with a history of regression, 21 children with ASD with early-onset autism, and 20 typically developing children and their parents participated.

Main Outcome Measures Observations of children’s communicative, social, affective, repetitive behaviors, and toy play coded from videotapes of the toddlers’ first and second birthday parties.

Results Analyses revealed that infants with ASD with regression show similar use of joint attention and more frequent use of words and babble compared with typical infants at 12 months of age. In contrast, infants with ASD with early onset of symptoms and no regression displayed fewer joint attention and communicative behaviors at 12 months of age. By 24 months of age, both groups of toddlers with ASD displayed fewer instances of word use, vocalizations, declarative pointing, social gaze, and orienting to name as compared with typically developing 24-month-olds.

Parent interview data suggested that some children with regression displayed difficulties in regulatory behavior before the regression occurred.

Conclusion This study validates the existence of early autistic regression.


UPDATE: Since the Poling Case, this has become a popular link, so I will update it with more research and better information so that you can actually find and read the articles. Below is a partial list that I will keep adding to.

12. Blood Levels of Mercury Are Related to Diagnosis of Autism: A Reanalysis of an Important Data Set

Journal of Child Neurology, Vol. 22, No. 11, 1308-1311 (2007)

M. Catherine DeSoto, PhD, Robert T. Hitlan, PhD -Department of Psychology, University of Northern Iowa, Cedar Falls, Iowa

Excerpt: “We have reanalyzed the data set originally reported by Ip et al. in 2004 and have found that the original p value was in error and that a significant relation does exist between the blood levels of mercury and diagnosis of an autism spectrum disorder. Moreover, the hair sample analysis results offer some support for the idea that persons with autism may be less efficient and more variable at eliminating mercury from the blood.”



13. Developmental Regression and Mitochondrial Dysfunction in a Child With Autism

Journal of Child Neurology / Volume 21, Number 2, February 2006
Jon S. Poling, MD, PhD, Department of Neurology and Neurosurgery
Johns Hopkins Hospital

This article showed that 38% of Kennedy Krieger Institute autism patients studied had one marker for impaired oxidative phosphorylation (mitochondrial dysfunction), and 47% had a second marker.

Excerpt: "Children who have (mitochondrial-related) dysfunctional cellular energy metabolism might be more prone to undergo autistic regression between 18 and 30 months of age if they also have infections or immunizations at the same time.”



14. Oxidative Stress in Autism: Elevated Cerebellar 3-nitrotyrosine Levels

American Journal of Biochemistry and Biotechnology 4 (2): 73-84, 2008

Elizabeth M. Sajdel-Sulkowska, - Dept of Psychiatry, Harvard Medical School

Shows a potential link between mercury and the autopsied brains of young people with autism. A marker for oxidative stress was 68.9% higher in autistic brain issue than controls (a statistically significant result), while mercury levels were 68.2% higher.

Excerpt: The preliminary data suggest a need for more extensive studies of oxidative stress, its relationship to the environmental factors and its possible attenuation by antioxidants in autism.”



15. Large Brains in Autism: The Challenge of Pervasive Abnormality

The Neuroscientist, Volume 11, Number 5, 2005.

Martha Herbert, MD, PhD [Harvard University].

This study helps refute the notion that the brains of autistic children are simply wired differently and notes, "neuroinflammation appears to be present in autistic brain tissue from childhood through adulthood." Dr. Herbert suggests that chronic disease or an external environmental source (like heavy metals) may be causing the inflammation.

Excerpt: "Oxidative stress, brain inflammation, and microgliosis have been much documented in association with toxic exposures including various heavy metals...the awareness that the brain as well as medical conditions of children with autism may be conditioned by chronic biomedical abnormalities such as inflammation opens the possibility that meaningful biomedical interventions may be possible well past the window of maximal neuroplasticity in early childhood because the basis for assuming that all deficits can be attributed to fixed early developmental alterations in neural architecture has now been undermined."



16. Evidence of Toxicity, Oxidative Stress, and Neuronal Insult in Autism

Journal of Toxicology and Environmental Health, Nov-Dec 2006.

Janet Kern, Anne Jones

"This article discusses the evidence for the case that some children with autism may become autistic from neuronal cell death or brain damage sometime after birth as result of insult; and addresses the hypotheses that toxicity and oxidative stress may be a cause of neuronal insult in autism... the article discusses what may be happening over the course of development and the multiple factors that may interplay and make these children more vulnerable to toxicity, oxidative stress, and neuronal insult."



17. Oxidative Stress in Autism

Pathophysiology, 2006.

Abha Chauhan, Ved Chauhan

This study provides a helpful overview of the growing evidence supporting the link between oxidative stress and autism.

Excerpt: "Upon completion of this article, participants should be able to: 1. Be aware of laboratory and clinical evidence of greater oxidative stress in autism. 2. Understand how gut, brain, nutritional, and toxic status in autism are consistent with greater oxidative stress. 3. Describe how anti-oxidant nutrients are used in the contemporary treatment of autism."



18. Thimerosal Neurotoxicity is Associated with Glutathione Depletion: Protection with Glutathione Precursors

Neurotoxicology, Jan 2005.

S. Jill James, PhD [University of Arkansas].

This recent study demonstrates that Thimerosal lowers or inhibits the body's ability to produce Glutathione, an antioxidant and the body's primary cellular-level defense against mercury.

Excerpt: "Thimerosal-induced cytotoxicity was associated with depletion of intracellular Glutathione in both cell lines...The potential effect of Glutathione or N-acetylcysteine against mercury toxicity warrants further research as possible adjunct therapy to individuals still receiving Thimerosal-containing vaccines."



19. Aluminum adjuvant linked to gulf war illness induces motor neuron death in mice

Neuromolecular Medicine, 2007

Christopher Shaw, Ph.D. [Department of Ophthalmology and Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada]

This study demonstrates the extreme toxicity of the aluminum adjuvant used as a preservative in vaccines.

Excerpt: "testing showed motor deficits in the aluminum treatment group that expressed as a progressive decrease in strength measured...Significant cognitive deficits in water-maze learning were observed in the combined aluminum and squalene group...Apoptotic neurons were identified in aluminum-injected animals that showed significantly increased activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor cortex (192%) compared with the controls. Aluminum-treated groups also showed significant motor neuron loss (35%) and increased numbers of astrocytes (350%) in the lumbar spinal cord.



20. Environmental mercury release, special education rates, and autism disorder: an ecological study of Texas

Health & Place, 2006

Raymond F. Palmer, University of Texas Health Science Center

This study demonstrated the correlation between environmental mercury and autism rates in Texas.

Excerpt: "On average, for each 1,000 lb of environmentally released mercury, there was a 43% increase in the rate of special education services and a 61% increase in the rate of autism. The association between environmentally released mercury and special education rates were fully mediated by increased autism rates. This ecological study suggests the need for further research regarding the association between environmentally released mercury and developmental disorders such as autism."



21. Autism Spectrum Disorders in Relation to Distribution of Hazardous Air Pollutants in the SF Bay Area

Environmental Health Perspectives – Vol. 114 No. 9, September, 2006

Gayle Windham, Div. of Environmental and Occupational Disease Control, California Department of Health Services

284 ASD children & 657 controls, born in 1994 in Bay Area, were assigned exposure levels by birth tract for 19 chemicals. Risks for autism were elevated by 50% in tracts with the highest chlorinated solvents and heavy metals. The highest risk compounds were mercury, cadmium, nickel, trichloroethylene, and vinyl chloride, and the risk from heavy metals was almost twice as high as solvents.

Excerpt: “Our results suggest a potential association between autism and estimated metal concentrations, and possibly solvents, in ambient air around the birth residence.”



22. A Case Series of Children with Apparent Mercury Toxic Encephalopathies Manifesting with Clinical Symptoms of Regressive Autistic Disorder

Journal of Toxicology and Environmental Health, 2007

David A. Geier, Mark R. Geier

This study reviewed the case histories and medical profiles of nine autistic children and concluded that eight of the nine children were mercury toxic and this toxicity manifested itself in a manner consistent with Autism Spectrum Disorders.

Excerpt: "...these previously normally developing children suffered mercury toxic encephalopathies that manifested with clinical symptoms consistent with regressive ASDs. Evidence for mercury intoxication should be considered in the differential diagnosis as contributing to some regressive ASDs."



23. Attention-deficit hyperactivity disorder and blood mercury level: a case-control study in chinese children

Neuropediatrics, August 2006 - P.R. Kong [Department of Pediatrics and Adolescent Medicine, The University of Hong Kong].

This study demonstrates that blood mercury levels are higher for children with ADHD.

Excerpt: "There was significant difference in blood mercury levels between cases and controls, which persists after adjustment for age, gender and parental occupational status. The geometric mean blood mercury level was also significantly higher in children with inattentive and combined subtypes of ADHD. High blood mercury level was associated with ADHD. Whether the relationship is causal requires further studies."



24. The Changing Prevalence of Autism In California

Journal of Autism and Developmental Disorders, April 2003
Mark Blaxill, MBA

This study helps to refute the supposition made by some researchers that autism's epidemic may only be due to "diagnostic substitution".

Excerpt: "They have suggested that 'diagnostic substitution' accounts for an apparent increase in the incidence of autism in California that is not real. This hypothesized substitution is not supported by proper and detailed analyses of the California data."


25. Mitochondrial Energy-Deficient Endophenotype in Autism

American Journal of Biochemistry and Biotechnology 4 (2): 198-207, 2008

J. Jay Gargus and Faiqa Imtiaz
Department of Physiology and Biophysics and Department of Pediatrics, Section of Human Genetics, School of Medicine, University of California, Irvine, Arabian Diagnostics Laboratory, King Faisal Specialist Hospital and Research Centre

Abstract: While evidence points to a multigenic etiology of most autism, the pathophysiology of the disorder has yet to be defined and the underlying genes and biochemical pathways they subserve remain unknown. Autism is considered to be influenced by a combination of various genetic, environmental and immunological factors; more recently, evidence has suggested that increased
vulnerability to oxidative stress may be involved in the etiology of this multifactorial disorder.
Furthermore, recent studies have pointed to a subset of autism associated with the biochemical endophenotype of mitochondrial energy deficiency, identified as a subtle impairment in fat and carbohydrate oxidation. This phenotype is similar, but more subtle than those seen in classic mitochondrial defects. In some cases the beginnings of the genetic underpinnings of these mitochondrial defects are emerging, such as mild mitochondrial dysfunction and secondary carnitine deficiency observed in the subset of autistic patients with an inverted duplication of chromosome 15q11-q13. In addition, rare cases of familial autism associated with sudden infant death syndrome (SIDS) or associated with abnormalities in cellular calcium homeostasis, such as malignant hyperthermia or cardiac arrhythmia, are beginning to emerge. Such special cases suggest that the pathophysiology of autism may comprise pathways that are directly or indirectly involved in mitochondrial energy production and to further probe this connection three new avenues seem worthy of exploration: 1) metabolomic clinical studies provoking controlled aerobic exercise stress to expand the biochemical phenotype, 2) high-throughput expression arrays to directly survey activity of the genes underlying these biochemical pathways and 3) model systems, either based upon neuronal stem cells or model genetic organisms, to discover novel genetic and environmental inputs into these pathways.



26. Bridging from Cells to Cognition in Autism Pathophysiology: Biological
Pathways to Defective Brain Function and Plasticity


American Journal of Biochemistry and Biotechnology 4 (2): 167-176, 2008

Matthew P. Anderson, Brian S. Hooker and Martha R. Herbert
Departments of Neurology and Pathology, Harvard Medical School/Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, High Throughput Biology Team, Fundamental Science Directorate, Pacific Northwest National Laboratory, Pediatric Neurology/Center for Morphometric Analysis, Massachusetts General Hospital/Harvard Medical School, and
Center for Child and Adolescent Development, Cambridge Health Alliance/Harvard Medical School

Abstract: We review evidence to support a model where the disease process underlying autism may begin when an in utero or early postnatal environmental, infectious, seizure, or autoimmune insult triggers an immune response that increases reactive oxygen species (ROS) production in the brain that leads to DNA damage (nuclear and mitochondrial) and metabolic enzyme blockade and that these inflammatory and oxidative stressors persist beyond early development (with potential further exacerbations), producing ongoing functional consequences. In organs with a high metabolic demand such as the central nervous system, the continued use of mitochondria with damaged DNA and impaired metabolic enzyme function may generate additional ROS which will cause persistent activation of the innate immune system leading to more ROS production. Such a mechanism would self-sustain and possibly progressively worsen. The mitochondrial dysfunction and altered redox signal transduction pathways found in autism would conspire to activate both astroglia and microglia. These activated cells can then initiate a broad-spectrum proinflammatory gene response. Beyond the direct effects of ROS on neuronal function, receptors on neurons that bind the inflammatory mediators may serve to inhibit neuronal signaling to protect them from excitotoxic damage during various pathologic
insults (e.g., infection). In autism, over-zealous neuroinflammatory responses could not only influence neural developmental processes, but may more significantly impair neural signaling involved in cognition in an ongoing fashion. This model makes specific predictions in patients and experimental animal models and suggests a number of targets sites of intervention. Our model of potentially reversible pathophysiological mechanisms in autism motivates our hope that effective therapies may soon appear on the horizon.



27. Heavy-Metal Toxicity—With Emphasis on Mercury

John Neustadt, ND, and Steve Pieczenik, MD, PhD

Research Review

Conclusion: Metals are ubiquitous in our environment, and exposure to them is inevitable. However, not all people accumulate toxic levels of metals or exhibit symptoms of metal toxicity, suggesting that genetics play a role in their potential to damage health. Metal toxicity creates multisystem dysfunction, which appears to be mediated primarily through mitochondrial damage from glutathione depletion.
Accurate screening can increase the likelihood that patients with potential metal toxicity are identified. The most accurate screening method for assessing chronic-metals exposure and metals load in the body is a provoked urine test.



28. Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment

American Journal of Biochemistry and Biotechnology 4 (2): 208-217, 2008

Daniel A. Rossignol, J. Jeffrey Bradstreet, International Child Development Resource Center,

Abstract: Classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits. However, in many cases of autism, there is evidence of mitochondrial dysfunction (MtD) without the classic features associated with mitochondrial disease. MtD appears to be more common in autism and presents with less severe signs and symptoms. It is not associated with discernable mitochondrial pathology in muscle biopsy specimens despite objective evidence of lowered mitochondrial functioning. Exposure to environmental toxins is the likely etiology for MtD in autism. This dysfunction then contributes to a number of diagnostic symptoms and comorbidities observed in autism including: cognitive impairment, language deficits, abnormal energy metabolism, chronic gastrointestinal problems, abnormalities in fatty acid oxidation, and increased oxidative stress. MtD and oxidative stress may also explain the high male to female ratio found in autism due to increased male vulnerability to these dysfunctions.
Biomarkers for mitochondrial dysfunction have been identified, but seem widely under-utilized despite available therapeutic interventions. Nutritional supplementation to decrease oxidative stress along with factors to improve reduced glutathione, as well as hyperbaric oxygen therapy (HBOT) represent supported and rationale approaches. The underlying pathophysiology and autistic symptoms of affected individuals would be expected to either improve or cease worsening once effective treatment for MtD is implemented.



29. Proximity to point sources of environmental mercury release as a predictor of autism prevalence

Health & Place, 2008

Raymond F. Palmer, Stephen Blanchard, Robert Wood
University of Texas Health Science Center, San Antonio Department of Family and Community Medicine, Our Lady of the Lake University, San Antonio Texas, Chair, Department of Sociology

This study should be viewed as hypothesis-generating - a first step in examining the potential role of environmental mercury and childhood developmental disorders. Nothing is known about specific exposure routes, dosage, timing, and individual susceptibility. We suspect that persistent low-dose exposures to various environmental toxicants, including mercury, that occur during critical windows of neural development among genetically susceptible children (with a diminished capacity for metabolizing accumulated toxicants) may increase the risk for developmental disorders such as autism. Successfully identifying the specific combination of environmental exposures and genetic susceptibilities can inform the development of targeted prevention intervention strategies.



30. Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical characterization, and medical conditions

Developmental Medicine & Child Neurology, 2007

Guiomar Oliveira MD PhD, Centro de Desenvolvimento da Criança, Hospital Pediátrico de Coimbra; Assunção Ataíde BSc, Direcção Regional de Educação do Centro Coimbra;
Carla Marques MSc, Centro de Desenvolvimento da Criança, Hospital Pediátrico de Coimbra; Teresa S Miguel BSc, Direcção Regional de Educação do Centro, Coimbra;
Ana Margarida Coutinho BSc, Instituto Gulbenkian de Ciência, Oeiras; Luísa Mota-Vieira PhD, Unidade de Genética e Patologia moleculares, Hospital do Divino Espírito Santo, Ponta Delgada, Açores; Esmeralda Gonçalves PhD; Nazaré Mendes Lopes PhD, Faculdade de Ciências e Tecnologia, Universidade de Coimbra; Vitor Rodrigues MD PhD; Henrique Carmona da Mota MD PhD, Faculdade de Medicina, Universidade de Coimbra, Coimbra; Astrid Moura Vicente PhD, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
*Correspondence to first author at Hospital Pediátrico de Coimbra, Av Bissaya Barreto, 3000-076 Coimbra, Portugal. E-mail: guiomar@hpc.chc.min-saude.pt

Abstract: The objective of this study was to estimate the prevalence of autistic spectrum disorder (ASD) and identify its clinical characterization, and medical conditions in a paediatric population in Portugal. A school survey was conducted in elementary schools, targeting 332 808 school-aged children in the mainland and 10 910 in the Azores islands. Referred children were directly assessed using the Diagnostic and Statistical Manual of Mental Disorders (4th edn), the Autism Diagnostic Interview–Revised, and the Childhood Autism Rating Scale. Clinical history and a laboratory investigation was performed. In parallel, a systematic multi-source search of children known to have autism was carried out in a restricted region. The global prevalence of ASD per 10 000 was 9.2 in mainland, and 15.6 in the Azores, with intriguing regional differences. A diversity of associated medical conditions was documented in 20%, with an unexpectedly high rate of mitochondrial respiratory chain disorders.



31. Thimerosal induces neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing factor release from mitochondria.

International Journal of Molecular Medicine, 2006

Yel L, Brown LE, Su K, Gollapudi S, Gupta S.Department of Medicine, University of California, Irvine, CA 92697, USA. lyel@uci.edu
There is a worldwide increasing concern over the neurological risks of thimerosal (ethylmercury thiosalicylate) which is an organic mercury compound that is commonly used as an antimicrobial preservative. In this study, we show that thimerosal, at nanomolar concentrations, induces neuronal cell death through the mitochondrial pathway. Thimerosal, in a concentration- and time-dependent manner, decreased cell viability as assessed by calcein-ethidium staining and caused apoptosis detected by Hoechst 33258 dye. Thimerosal-induced apoptosis was associated with depolarization of mitochondrial membrane, generation of reactive oxygen species, and release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol. Although thimerosal did not affect cellular expression of Bax at the protein level, we observed translocation of Bax from cytosol to mitochondria. Finally, caspase-9 and caspase-3 were activated in the absence of caspase-8 activation. Our data suggest that thimerosal causes apoptosis in neuroblastoma cells by changing the mitochondrial microenvironment.

32. Mitochondrial mediated thimerosal-induced apoptosis in a human neuroblastoma cell line (SK-N-SH).

Neurotoxicology. 2005

Humphrey ML, Cole MP, Pendergrass JC, Kiningham KK. Department of Pharmacology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25704-9388, USA.
Environmental exposure to mercurials continues to be a public health issue due to their deleterious effects on immune, renal and neurological function. Recently the safety of thimerosal, an ethyl mercury-containing preservative used in vaccines, has been questioned due to exposure of infants during immunization. Mercurials have been reported to cause apoptosis in cultured neurons; however, the signaling pathways resulting in cell death have not been well characterized. Therefore, the objective of this study was to identify the mode of cell death in an in vitro model of thimerosal-induced neurotoxicity, and more specifically, to elucidate signaling pathways which might serve as pharmacological targets. Within 2 h of thimerosal exposure (5 microM) to the human neuroblastoma cell line, SK-N-SH, morphological changes, including membrane alterations and cell shrinkage, were observed. Cell viability, assessed by measurement of lactate dehydrogenase (LDH) activity in the medium, as well as the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, showed a time- and concentration-dependent decrease in cell survival upon thimerosal exposure. In cells treated for 24 h with thimerosal, fluorescence microscopy indicated cells undergoing both apoptosis and oncosis/necrosis. To identify the apoptotic pathway associated with thimerosal-mediated cell death, we first evaluated the mitochondrial cascade, as both inorganic and organic mercurials have been reported to accumulate in the organelle. Cytochrome c was shown to leak from the mitochondria, followed by caspase 9 cleavage within 8 h of treatment. In addition, poly(ADP-ribose) polymerase (PARP) was cleaved to form a 85 kDa fragment following maximal caspase 3 activation at 24 h. Taken together these findings suggest deleterious effects on the cytoarchitecture by thimerosal and initiation of mitochondrial-mediated apoptosis.


33. Possible Immunological Disorders in Autism: Concomitant Autoimmunity and Immune Tolerance

The Egyptian Journal of Immunology, 2006

Maha I. Sh. Kawashti, Omnia R. Amin Nadia G. Rowehy

Microbiology Department, Faculty of Medicine (For Girls), Al Azhar University, Cairo, Egypt, Psychiatry Department, Faculty of Medicine, Cairo University, Cairo, Egypt and Serology Lab King Fahad General Hospital, Jeddah, K.S.A.

Abstract: Autism is a pervasive developmental disorder that affect children early in their life. Immunological disorders is one of several contributing factors that have been suggested to cause autism. Thirty autistic children aged 3-6 years and thirty non-autistic psychologically-free siblings were studied. Circulating IgA and IgG autoantibodies to casein and gluten dietary proteins were detected by enzyme-immunoassays (EIA). Circulating IgG antibodies to measles, mumps and rubella vaccine (M.M.R) and cytomeglovirus were investigated by EIA. Results revealed high seropositivity for autoantibodies to casein and gluten: 83.3% and 50% respectively in autistic children as compared to 10% and 6.7% positivity in the control group. Surprisingly, circulating anti-measles, anti-mumps and anti-rubella IgG were positive in only 50%, 73.3% and 53.3% respectively as compared to 100% positivity in the control group. Anti-CMV IgG was positive in 43.3% of the autistic children as compared to 7% in the control group. It is concluded that, autoimmune response to dietary proteins and deficient immune response to measles, mumps and rubella vaccine antigens might be associated with autism, as a leading cause or a resulting event. Further research is needed to confirm these findings.

34. Pediatric Vaccines Influence Primate Behavior, and Amygdala Growth and Opioid Ligand Binding Friday, May 16, 2008: IMFAR

L. Hewitson , Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA B. Lopresti , Radiology, University of Pittsburgh, Pittsburgh, PA C. Stott , Thoughtful House Center for Children, Austin, TX J. Tomko , Pittsburgh Development Center, University of Pittsburgh, Pittsburgh, PA L. Houser , Pittsburgh Development Center, University of Pittsburgh, Pittsburgh, PA E. Klein , Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA C. Castro , Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA G. Sackett , Psychology, Washington National Primate Research Center, Seattle, WA S. Gupta , Medicine, Pathology & Laboratory Medicine, University of California - Irvine, Irvine, CA D. Atwood , Chemistry, University of Kentucky, Lexington, KY L. Blue , Chemistry, University of Kentucky, Lexington, KY E. R. White , Chemistry, University of Kentucky, Lexington, KY A. Wakefield , Thoughtful House Center for Children, Austin, TX

Background: Macaques are commonly used in pre-clinical vaccine safety testing, but the combined childhood vaccine regimen, rather than individual vaccines, has not been studied. Childhood vaccines are a possible causal factor in autism, and abnormal behaviors and anomalous amygdala growth are potentially inter-related features of this condition.

Objectives: The objective of this study was to compare early infant cognition and behavior with amygdala size and opioid binding in rhesus macaques receiving the recommended childhood vaccines (1994-1999), the majority of which contained the bactericidal preservative ethylmercurithiosalicylic acid (thimerosal).

Methods: Macaques were administered the recommended infant vaccines, adjusted for age and thimerosal dose (exposed; N=13), or saline (unexposed; N=3). Primate development, cognition and social behavior were assessed for both vaccinated and unvaccinated infants using standardized tests developed at the Washington National Primate Research Center. Amygdala growth and binding were measured serially by MRI and by the binding of the non-selective opioid antagonist [11C]diprenorphine, measured by PET, respectively, before (T1) and after (T2) the administration of the measles-mumps-rubella vaccine (MMR).

Results: Compared with unexposed animals, significant neurodevelopmental deficits were evident for exposed animals in survival reflexes, tests of color discrimination and reversal, and learning sets. Differences in behaviors were observed between exposed and unexposed animals and within the exposed group before and after MMR vaccination. Compared with unexposed animals, exposed animals showed attenuation of amygdala growth and differences in the amygdala binding of [11C]diprenorphine. Interaction models identified significant associations between specific aberrant social and non-social behaviors, isotope binding, and vaccine exposure.

Conclusions: This animal model, which examines for the first time, behavioral, functional, and neuromorphometric consequences of the childhood vaccine regimen, mimics certain neurological abnormalities of autism. The findings raise important safety issues while providing a potential model for examining aspects of causation and disease pathogenesis in acquired disorders of behavior and development.

35. Thimerosal exposure in infants and neurodevelopmental disorders: An assessment of computerized medical records in the Vaccine Safety Datalink.

Young HA, Geier DA, Geier MR.

The George Washington University School of Public Health and Health Services, Department of Epidemiology and Biostatistics, United States.

The study evaluated possible associations between neurodevelopmental disorders (NDs) and exposure to mercury (Hg) from Thimerosal-containing vaccines (TCVs) by examining the automated Vaccine Safety Datalink (VSD). A total of 278,624 subjects were identified in birth cohorts from 1990-1996 that had received their first oral polio vaccination by 3 months of age in the VSD. The birth cohort prevalence rate of medically diagnosed International Classification of Disease, 9th revision (ICD-9) specific NDs and control outcomes were calculated. Exposures to Hg from TCVs were calculated by birth cohort for specific exposure windows from birth-7 months and birth-13 months of age. Poisson regression analysis was used to model the association between the prevalence of outcomes and Hg doses from TCVs. Consistent significantly increased rate ratios were observed for autism, autism spectrum disorders, tics, attention deficit disorder, and emotional disturbances with Hg exposure from TCVs. By contrast, none of the control outcomes had significantly increased rate ratios with Hg exposure from TCVs. Routine childhood vaccination should be continued to help reduce the morbidity and mortality associated with infectious diseases, but efforts should be undertaken to remove Hg from vaccines. Additional studies should be conducted to further evaluate the relationship between Hg exposure and NDs.



36. Glutathione, oxidative stress and neurodegeneration

Schulz JB, Lindenau J, Seyfried J, Dichgans J.
Neurodegeneration Laboratory, Department of Neurology, University of Tübingen, Germany.

Eur J Biochem. 2000 Aug;267(16):4904-11.

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species and mitochondrial dysfunction. Here, we review the evidence for a disturbance of glutathione homeostasis that may either lead to or result from oxidative stress in neurodegenerative disorders. Glutathione is an important intracellular antioxidant that protects against a variety of different antioxidant species. An important role for glutathione was proposed for the pathogenesis of Parkinson's disease, because a decrease in total glutathione concentrations in the substantia nigra has been observed in preclinical stages, at a time at which other biochemical changes are not yet detectable. Because glutathione does not cross the blood-brain barrier other treatment options to increase brain concentrations of glutathione including glutathione analogs, mimetics or precursors are discussed.



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