Download 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
What is Autism?
Autism is a label for people who have major
impairments in three areas:
speech/communication
social interaction/friendships
restricted, 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.
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
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
Early Onset vs. Regression
Data from Autism Research Institute (over 30,000 parental reports)
Incidence
In US, latest report by CDC cites 1 in 150 for
autism spectrum disorders (autism, PDDNOS, 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In UK, a new unpublished study by Simon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.
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 510% chance other children will have autism,
and 25% chance of major speech delay (so
carefully monitor siblings)
Genetic vulnerability + environmental exposure
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
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.
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
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
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?).
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
Oxidative Stress and transmethylation/transsulfuration
Methionine Methylation
THF
5,10CH2THF
1
MTHFR
Potential
SAM
MS
B12
oxidized
2
MTase
SAH
Cell Methylation
5CH3THF
Adenosine
1 Folate Cycle
2 Transmethylation
3 Transsulfuration
(SAM/SAH)
3
Homocystein
B6 CBS
e B6
Cystathionine
B6
Cysteine
GSH
GSSG
Antioxidant
Redox
Potential
(GSH/GSSG)
Intervention Trial with MethylB12 and Folinic Acid
Plasma Metabolite
Concentration
Autism
Pre-treatment
(n = 40)
Autism
Posttreatment
(n = 40)
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
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
GSSG (µmol/L)
b Signficantly different
p valuea
a Treatment
Maternal Methionine Cycle Metabolites:
Research by Jill James et al.
Autism Moms
Moms
(n = 46)
Control
(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
It would be a very good idea to ask your physician
to check your “total” homocysteine
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
0.30 ± 0.08*
0.24±0.04
GSSG (µM/L)
Total GSH/GSSG
*statistically significant
17 ± 8
31 ± 10*
Metabolite imbalance and the risk of
being a mother of a child with autism
Control
Mothers
Case
Mothers
(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
Stratified Group
(N=200)
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
IMPORTANT CAVEAT
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?
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
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.
Table 2. Summ ary o f materna l autoantibody reactivit y patterns for hu man fetal brain
proteins and their significant a ssociations.
Prevalence (%)
AU (n=61)
AU Reg (n=36)
AU EO (n=25)
TD (n=62)
DD (n=40)
37kD & 73kD
7 (12%)*
6 (17%)*
1 (4%)
0 (0%)
0 (0%)
37kD
15 (25%)*
10 (28%)*
5 (21%)
5 (8%)
2 (5%)
73kd
10 (17%)
9 (25%)*
1 (4%)
6 (9%)
7 (17%)
Heavy Chain
Significance (p-value)
AU vs TD
AU vs DD
Ê
AU Reg vs. AU EO
Ê
0.0061*
0.0401*
0.0086*
0.002*
0.2
0.79
0.223
0.777
0.106
Light Chain
Summary of maternal
antibodies to fetal
brain proteins :
• Researchers found a specific subset of
antibodies to fetal brain proteins in the blood
of a subset of mothers whose children have
autism.
• These antibodies occur most frequently in
those mothers who have children with
regressive autism.
• Similar findings have been demonstrated in
work by Zimmerman and Singer against both
rodent and human fetal brain.
The Autoimmune
Phenomenon
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.
Primate 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.
Mother preference task
• Increased
midline
crossings
• Demonstrated
no preference
for own mother
Social Dyad: Measure of stereotypic
episodes 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.
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.
Biomarkers
In 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.
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 = %)
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
Reduced Levels of Immunoglobulin in
Children with Autism Correlates with
Behavioral 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
Environmental Health
Reduced levels of IgG and IgM are indicative of an underlying
defect in the immune system of children with autism.
P=0.0001
• This study provides a novel association
between immune dysfunction and
behavioral parameters in autism.
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.
Regression Analysis – from DMSA study, Adams
et al
Compare severity of autism with glutathione and metal
tests
adjusted 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.
Regression Analysis – from Nutritional
Assessment study, Adams et al
Compare severity of autism with nutritional biomarkers
• ATEC:
adjusted R2
0.34
p=0.0003
Most significant factors
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)
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
Autism is TREATABLE!
Behavioral Therapies
Biomedical Therapies
Many children now greatly improve, and
some even recover, due to behavioral
and/or biomedical interventions
Autism Therapies
• Applied Behavior Analysis– most widely
accepted/used
• Relationship Development Intervention
(RDI) – new
• Other therapies
Biomedical Treatments for Autism
(based on the Defeat Autism Now! Guidelines)
•
•
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•
•
•
•
•
•
•
•
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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
Future Research Needs
Biomarkers
Focus 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.
Future Research (cont.)
Pre-Screening:
It is unlikely that a treatment will help all or even
most children. So, it is important to use biomarkers 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
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.
Future Research Needs
(continued)
Funding
We 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.