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Page 1: Current State of Autism Research

Current State of Autism Research

James B. Adams, Ph.D.Professor, Arizona State University

Science Director, Autism Research Institute/Defeat Autism Now!Parent of a 17-year-old girl with autism

Page 2: Current State of Autism Research

What is Autism?Autism is a label for people who have major

impairments in three areas:speech/communicationsocial interaction/friendshipsrestricted, repetitive, stereotypic behaviors

Autism is a spectrum disorder:Autism / PDD-NOS/ Aspergers

Impairment in social skills is common to all

Likely due to multiple causes.

Page 3: Current State of Autism Research

Research Tools for Diagnosing Autism

• Autism Diagnostic Interview – Revised (ADI-Revised): 2-4 hour interview with parents of child’s history

• Autism Diagnostic Observation Schedule (ADOS) – 1 hour structured interaction with child

Primarily used for research, not by clinicians

Page 4: Current State of Autism Research

Co-occurring symptoms• Mental Retardation – but must be tested with

non-verbal IQ test• Seizures: 25% (and 60% without seizures have

subclinical seizures)• Diarrhea/Constipation: 50%• Sleep problems: 50%• Low muscle tone: 30%• Pica: eating non-food items: 30%• Sensory Sensitivies: touch, vision, sound, taste,

smell, pain; under- and/or over-sensitive

Page 5: Current State of Autism Research

Early Onset vs. Regression

Data from Autism Research Institute (over 30,000 parental reports)

Page 6: Current State of Autism Research

Incidence

In US, latest report by CDC cites 1 in 150 for autism spectrum disorders (autism, PDD-NOS, Asperger’s).

In UK, a new unpublished study by Simon Baron-Cohen at Cambridge University found 1 in 100, and estimates the actual rate at 1 in 60.

Page 7: Current State of Autism Research

Genetic or Environmental Cause?

• Studies of identical twins reveal:– Co-occurrence is roughly 60% for autism, and

roughly 90% for speech delays; if 100%, then only due to genes; so genes are important, but so are unknown environmental factors.

• If a couple has one child with autism, then 5-10% chance other children will have autism, and 25% chance of major speech delay (so carefully monitor siblings)

Genetic vulnerability + environmental exposure

Page 8: Current State of Autism Research

Which Genes?

• Many genetics studies of autism, but they generally disagree, since too few subjects and too many genes

• Probably 10-20 genes involved in complex manner

• In 2 similar conditions, Fragile X and Rett’s Syndrome, a single gene has been identified for each

Page 9: Current State of Autism Research

Known Genetic Factors

There are several rare genetic disorders that greatly increase the risk of developing autism. These disorders include PKU, creatine formation/transport deficiency (uncommon), adenylosuccinate lyase deficiency, Angelman’s syndrome, Fragile X, Rett’s syndrome, neurofibromatosis, tuberous sclerosis, and others.

However, these disorders account for only roughly 5-10% of the cases of autism.

Page 10: Current State of Autism Research

Which Environmental Causes?

• No general agreement• Possible causes with limited scientific data include:

– Impaired methylation– Oxidative stress– Mercury/toxic metals poisoning (due to limited excretion

because of low glutathione)– Pesticide exposure (esp. organophosphates and

organochlorides)– Excessive oral antibiotic usage– Vaccine damage (especially MMR)– Lack of essential minerals (sulfate, iodine, lithium)– Other unknown factors

Page 11: Current State of Autism Research

Rapid increase in incidence• 1970’s: 2-3 per 10,000• 2008: 1 per 150 (autism spectrum); • Now affects about 1 in 94 boys, since 4:1 boy:girl ratio• In California (which has best statistics), autism now accounts for

45% of all new developmental disabilities

• Arizona: – 1996: 633 people with moderate/severe autism served by DDD– 1999: 1057– 2003: 1917– 2005: 2500– 2009: 3500

Page 12: Current State of Autism Research

Why rising rate of autism?

• Partly due to better awareness/diagnosis, but that is only modest effect (per study by MIND Institute)

• Not due to genetics alone – gene pool normally changes very slowly, although environmental toxicants can cause permanent genetic changes/damage

• So, primary reason is increased exposure to environmental factor (toxid metals, pesticides, antibiotics, MMR, iodine deficiency, other?).

Page 13: Current State of Autism Research

New Research on Risk of Autism

Preliminary research by Jill James et al on abnormalities in methylation cycle and glutathione in MOTHERS of children with autism

Page 14: Current State of Autism Research

SAM

SAH

Homocysteine B6

Oxidative Stress and transmethylation/transsulfuration

Cystathionine

Cysteine

GSH GSSG

Methionine

Adenosine

B6

B6

5-CH3THF

THF

5,10-CH2THF

Cell Methylation1

1

2

3

Folate Cycle

Transmethylation

Transsulfuration

2

3 Antioxidant Redox Potential (GSH/GSSG)

CBS

MTase

Methylation Potential (SAM/SAH)

MS

MTHFRB12 oxidized

Page 15: Current State of Autism Research

Intervention Trial with MethylB12 and Folinic AcidPlasma Metabolite Concentration

Autism Pre-treatment

(n = 40)

Autism Post-

treatment(n = 40)

p valuea

Methionine 21 ± 4b 22 ± 3 ns

SAM (nmol/L) 66 ± 13b 69 ± 12 ns

SAH (nmol/L) 15.2 ± 5 14.8 ± 4 ns

SAM/SAH (µmol/L) 4.7 ± 1.5b 5.0 ± 2.0 ns

Homocysteine (µmol/L) 4.8 ± 1.8 5.3 ± 1.1 0.04

Cysteine (µmol/L) 191 ± 24b 215 ± 19 0.001

Total Glutathione (µmol/L)

5.4 ± 1.3b 6.2 ± 1.2 0.001

Free Glutathione (µmol/L)

1.5 ± 0.4b 1.8 ± 0.4 0.008

GSSG (µmol/L) 0.28 ± 0.08b 0.22 ± 0.06 0.001

tGSH/GSSG 21 ± 6b 30 ± 9 0.001

fGSH/GSSG 6 ± 2b 9 ± 3 0.001

b Signficantly different from

age- matched control

children

a Treatment effect

Page 16: Current State of Autism Research

Research by Jill James et al. Autism Moms Control Moms (n = 46) (n= 200)

Methionine (µM/L) 24 ± 5 26 ± 6

SAM (nM/L) 80 ± 19 83 ± 13

SAH (nM/L) 33 ± 14* 23 ± 8.4 SAM/SAH Ratio 3.1 ± 1.7* 4.0 ± 1.4

Homocysteine (µM/L) 11 ± 3.9* 7.6 ± 1.6

*statistically significant

Maternal Methionine Cycle Metabolites:

It would be a very good idea to ask your physician to check your “total” homocysteine

Page 17: Current State of Autism Research

Maternal Transsulfuration Metabolites

Autism Moms ControlMoms Cysteine (µM/L) 232 ± 40 231 ± 20

Total GSH (µM/L) 5.1 ± 1.7* 7.3 ± 1.5

Free GSH (µM/L) 1.5 ± 0.5* 2.6 ± 0.6

GSSG (µM/L) 0.30 ± 0.08* 0.24±0.04

Total GSH/GSSG 17 ± 8 31

± 10* *statistically significant

Page 18: Current State of Autism Research

Metabolite imbalance and the risk of being a mother of a child with

autism

Stratified Group

ControlMothers

(N=200)

CaseMothers

(N=46)

Odds Ratio (Risk)

SAH >30µMol/L) 14% 54% 6.9

SAM/SAH <2.5 10% 54% 10.7

tGSH/GSSG <20 11% 65% 15.2

SAM/SAH <2.5 and tGSH/GSSG <20

3% 41% 46

In other words, 41% of ASD mothers had a 46x higher chance of having a child with autism, associated with abnormal methylation and oxidative stress

Page 19: Current State of Autism Research

It is not possible to determine from this data whether the abnormal metabolic profile in parents is genetically determined or whether it simply reflects the stress of living with an autistic child

Question: Would testing for abnormal methylation/glutathione in mothers and/or newborns, and treating it, reduce the risk of autism? Is this one possible method for preventing autism?

IMPORTANT CAVEAT

Page 20: Current State of Autism Research

Vulnerable to Toxins

• Decreased glutathione would make fetus more vulnerable to toxins, including toxic metals and pesticides

• Consistent with studies linking toxic metals (Windham et al 2006) and pesticide exposure (Roberts et al 2007) to risk of developing autism

Page 21: Current State of Autism Research

New research on possible cause of 12% of cases of autism by Judy van de Water and

colleagues at Mind Institute

A study of the mothers of children with autism (n=61) found that 12% of them had antibodies to fetal brain tissue. These antibodies were not found in any typical children (n=62).

Larger study of 300 children ongoing, and results are similar.

Page 22: Current State of Autism Research

Heavy Chain

Light Chain

Page 23: Current State of Autism Research

Summary of maternal Summary of maternal antibodies to fetal antibodies to fetal

brain proteins :brain proteins :

• Researchers found a specific subset of Researchers found a specific subset of antibodies to fetal brain proteins in the blood antibodies to fetal brain proteins in the blood of a subset of mothers whose children have of a subset of mothers whose children have autism.autism.

• These antibodies occur most frequently in These antibodies occur most frequently in those mothers who have children with those mothers who have children with regressive autism.regressive autism.

• Similar findings have been demonstrated in Similar findings have been demonstrated in work by Zimmerman and Singer against both work by Zimmerman and Singer against both rodent and human fetal brain. rodent and human fetal brain.

Page 24: Current State of Autism Research

The Autoimmune The Autoimmune PhenomenonPhenomenon

Question: Are the antibodies pathogenic?

Researchers currently have both primate and murine (mouse) models underway to determine the potential effect of exposure to IgG from the autistic maternal population during gestation on behavioral outcome.

Page 25: Current State of Autism Research

Primate model--Pilot studyPrimate model--Pilot study

• The gestating dams were exposed to 3 IV injections of IgG beginning late 1st trimester with 2 additional injections during the second trimester. – Group A exposed animals had 4 live births.– Group B exposed animals had 2 live births and will be

repeated.

• The offspring were monitored for several developmental criteria including motor coordination, mother preference test, and social interaction.

Page 26: Current State of Autism Research

Mother preference task

• Increased midline crossings

• Demonstrated no preference for own mother

Page 27: Current State of Autism Research

Social Dyad: Social Dyad: Measure of stereotypic Measure of stereotypic episodes with familiar pairingsepisodes with familiar pairings

• The weaned animals were placed in the observation cage with either a familiar monkey from their social group or an unfamiliar monkey.

• The AU treated offspring demonstrated severe stereotypies when placed in this environment.

Page 28: Current State of Autism Research

Summary

• It appears that 12% of mothers of children with autism have antibodies to fetal brain tissue.

• When injected into pregnant monkeys, those antibodies cause autistic-like behavior in their offspring.

• Currently working on commercialization of this test, so that mothers can know if they have this risk factor.

• Unknown what causes this abnormal antibody production in mothers.

Page 29: Current State of Autism Research

BiomarkersIn autism, there are many abnormalities in many organs and

systems, including the immune system, GI tract, brain, nutrition, metabolism, and detoxification.

The challenge is to determine which are primary, and which are secondary consequences, so that we know which to treat.

One way to do this is by focusing on biomarkers that correlate with the severity of autism.

However, it is unlikely that any one biomarker will cover all cases; rather, we expect several biomarkers for different causes and phenotypes of autism.

Page 30: Current State of Autism Research

Biomarkers (cont.)Biomarkers that correlate with the severity of autism include:

Urinary opioid peptides Total IgG (Heuer et al, 2008) R = -0.33, p<0.0001 (ABC)Porphyrins (Geier et al, 2008) R=0.28-0.31, p<0.05 (CARS)Serotonin (Adams et al, unpublished) R= - 0.37 (3 tests)Plasma Sulfate (Adams et al, unpublished) R=-0.42 (3 tests)Lysozyme (Adams et al, unpublished) R=0.47 (ATEC)Gut symptoms (Adams et al, unpublished) R=0.66 (ATEC)

In other words, many systems are affected in autism, and each contributes to the severity of autism, on average, with a lot of variation between children.

Note: R=0.33 means it explains about 10% of the variation in autism severity (R2 = %)

Page 31: Current State of Autism Research

GI Severity

• Overall GI symptom severity (GISS) correlates highly with autism severity (ATEC), R=0.66

• Lysozymes (a marker of GI inflammation) correlates strongly with autism severity (ATEC), R=0.47

• So, gut inflammation and GI symptoms have an important connection to autism

Page 32: Current State of Autism Research

Reduced Levels of Immunoglobulin in Reduced Levels of Immunoglobulin in Children with Autism Correlates with Children with Autism Correlates with

Behavioral SymptomsBehavioral Symptoms

•Heuer, Luke*1, 7,8, Ashwood, Paul*2, 7,8 , Schauer, Joseph 1, 7,8, Goines, Paula 1, 7,8,, , Hertz-Picciotto, Irva3,7,8, Hansen, Robin4,7,8, Croen, Lisa A5, Pessah, Isaac N6,7,8, Van de Water, Judy**1,7,8,

•As part of the Children’s Center for As part of the Children’s Center for Environmental HealthEnvironmental Health

Page 33: Current State of Autism Research

Reduced levels of IgG and IgM are indicative of an underlying defect in the immune system of children with autism.

Total IgG

Autism ASD Typical Delayed0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

20.0

22.5

N=105 N=24 N=96 N=32

* *

* *

Diagnosis

Total IgM

Autism ASD Typical Delayed0

1

2

3

4

N=116 N=27 N=92 N=29

*

Diagnosis

Total IgA

Autism ASD Typical Delayed0.00

0.25

0.50

0.75

1.00

1.25

1.50

1.75

N=116 N=27 N=92 N=29Diagnosis

Total IgE

Autism ASD Typical Delayed0

500

1000

1500

2000

N=116 N=27 N=92 N=29Diagnosis

A. B.

C.D.

P=0.0001

Page 34: Current State of Autism Research

• This study provides a novel association This study provides a novel association between immune dysfunction and between immune dysfunction and behavioral parameters in autism.behavioral parameters in autism.

Page 35: Current State of Autism Research

Biomarkers (continued)

To determine which correlations are the most important, it is possible to use Regression Analysis (multiple correlations)

ex. Autism Severity = a (peptides) + b (porphyrins) + c (glutathione)

We have used regression analysis in two studies, and found that we can explain approximately half the severity of autism in each study.

Page 36: Current State of Autism Research

Regression Analysis – from DMSA study, Adams et al

Compare severity of autism with glutathione and metal testsadjusted R2 Most significant metals

• ATEC: 0.22 p=0.003 Pb-9, Sb-b• SAS: 0.36 p=0.002 Pb-b• PDD-BI: 0.25 p= 0.004 Sb-9, W-b, Sn-9

• ADOS: 0.49 p=0.0003 Hg-b, Al-b, Hg-9

All four scales of autism severity can be partially explained in terms of heavy metal excretion, with a very high statistical significance.

Suggests 22-49% of autism severity appears to be due to toxic metals, especially lead, antimony, and mercury.

Page 37: Current State of Autism Research

Regression Analysis – from Nutritional Assessment study, Adams et al

Compare severity of autism with nutritional biomarkers

adjusted R2 Most significant factors• ATEC: 0.34 p=0.0003 Serotonin, ATP, NADH

free carnitine

• SAS: 0.27 p=0.001 Serotonin, free sulfate

• PDD-BI: 0.20 p<0.002 Serotonin, free sulfate

All three scales of autism severity can be partially explained in terms of these factors, with a very high statistical significance.

Suggests part of autism severity related to abnormalities in serotonin, free sulfate, and mitochondrial factors (ATP, NADH, carnitine)

Page 38: Current State of Autism Research

Prognosis?Two major lifetime studies for adults – note that most of

these adults had little or no behavioral or medical intervention:

Autism: 90% of adults unable to work, unable to live independently, < 1 social interaction/month

Asperger’s (50% with college degrees):similar prognosis – social skills limit use of intellectual abilities

Grim prognosis if untreated, but many treatments now available, and there is MUCH more hope

Page 39: Current State of Autism Research

Autism is TREATABLE!

Behavioral Therapies

Biomedical Therapies

Many children now greatly improve, and some even recover, due to behavioral and/or biomedical interventions

Page 40: Current State of Autism Research

Autism Therapies

• Applied Behavior Analysis– most widely accepted/used

• Relationship Development Intervention (RDI) – new

• Other therapies

Page 41: Current State of Autism Research

Biomedical Treatments for Autism (based on the Defeat Autism Now! Guidelines)

• Improve Diet• Food Allergies• GFCF Diet (no wheat, no dairy)• Vitamin/Mineral Supplements• High-Dose Vitamin B6 and Magnesium• Essential Fatty Acids• Amino Acids• Gut Treatments• Thyroid Supplements• Sulfation• Glutathione • Detoxification• Anti-Viral Treatments• Immune System Regulation

Page 42: Current State of Autism Research

Future Research Needs

BiomarkersFocus on biomarkers, especially those that correlate with

severity of autism (need to integrate medical studies with behavioral assessments)

Focus on treatments that relate to biomarkers that correlate with severity of autism. We have many treatment options, but need to rigorously assess the efficacy of each.

Determine risk factors for autism, so that we learn how to prevent it.

Page 43: Current State of Autism Research

Future Research (cont.)

Pre-Screening:It is unlikely that a treatment will help all or even most children. So, it is important to use bio-markers to determine who is most likely to benefit.

Example: a treatment study with essential fatty acids (EFA) – only enroll children with low levels (we found that those who consumed little or no seafood were much more likely to improve than those who consumed 3+ seafood servings/month

Page 44: Current State of Autism Research

Future Research Needs (cont.)Multi-Treatments:

Almost all studies look at the effect of only 1 treatment, which usually helps only a subset of children, to a limited extent.

Since our goal is 100% recovery of the child, we need to investigate treating all of their known problems, instead of only one of them.

Example: We are planning a multi-treatment study that will test most of the DAN! guidelines, tailored to the individual based on testing. It will include a personalized special diet, vitamins/minerals, amino acids, essential fatty acids, gut treatments, methyl-B12/folinic acid, thyroid testing, etc. The goal is to assess the effect of the total, integrated set of treatments.

Page 45: Current State of Autism Research

Future Research Needs (continued)

FundingWe need to shift public and private funding from unsuccessful, over-funded areas (genetics, brain research) to new areas that directly relate to prevention and treatment

ARI appreciates the support of many donors, which have allowed it to fund many studies on the causes of autism and how to treat and prevent it.


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