Title: Incomplete Brain Development in Autism: Causes and Treatment
1Incomplete Brain Development in Autism Causes
and Treatment
- William J. Walsh, Ph.D.
- Pfeiffer Treatment Center
- Warrenville, IL
2Pfeiffer Treatment Center
- Outpatient medical facility
- 23,000 patients from all 50 states and 75 foreign
countries. - Collaboration between medical doctors and
scientists. - Individualized Biochemical Therapy
- Scientific Research
- 501c3 Public Charity
3Pfeiffer Autism Research
- Chemistry Database Studies
- Metallothionein Research
- Oxidative Damage
- -- Essential fats
- -- Vascular tissue
- -- Immune cells (leukocytes)
- -- Brain tissue
- Assays of autism/control brain tissues.
4Pfeiffer Chemistry Database
- 10,600 Behavior ADHD
- 6,000 Autism
- 3,700 Schizophrenia Bipolar
- 3,600 Depression
5Pfeiffer Autism Database
- About 90 to 150 assays of chemical factors in
blood, urine, or hair for more than 6,000
patients - More than 1,000,000 separate chemical analyses
6Year 1999 Discovery
- Undermethylation
- Present in more than 90 of
- autism-spectrum children.
7Year 2000 Discovery
- Greater than 99 of ASD patients exhibit abnormal
Cu and Zn levels in blood. - Normally, Cu Zn are homeostatically controlled
by metallothionein proteins. - Conclusion Depressed metallothionein
activity is a distinctive feature of autism.
8Autism Database Analysis
- Major biochemical abnormalities observed
throughout the autism spectrum. - The biochemical imbalances are more severe than
those for ADHD, violent behavior, depression, and
psychosis. - Female autistics have more disordered chemistry
than male autistics.
9High Incidence Biochemical Abnormalities in Autism
- Elevated serum copper
- Elevated toxic metals
- Depressed zinc
- Undermethylation
- Pyrrole disorder
- Severe oxidative stress damage
10Biochemical Abnormalities in Autism ---
Continued ---
- Depressed Methionine and SAMe
- Elevated SAH and Adenosine
- High Urinary Isoprostanes
- Depressed Cysteine and Glutathione
- Low Selenium Levels
- Depressed Ceruloplasmin
- Elevated Levels of Free-Radicals
11Each of the Biochemical Abnormalities Are
Associated With Oxidative Stress
- Conclusion Autism is a condition of oxidative
stress - An oxidative stress model can explain most
symptoms of autism - Oxidative stress has become a leading focus of
autism research.
12Experimental Results and Statistical Analysis
- Mean Cu/Zn Ratio
- Autism Spectrum (N503) 1.63
- Controls (N25)
1.15 - t 8.77 (two-tailed t test) p lt 0.0001
- American Psychiatric Association Annual Meeting
- New Orleans, 2001.
13Insufficient Ceruloplasmin Levels in
Autistic-Spectrum Patients
-
Autistics Controls - Unbound Serum Cu 41 21
- Not bound to ceruloplasmin
- P lt 0.01
- Conclusion Autistics exhibit excessive levels
of loosely bound or free-radical copper (high
oxidative stress).
14Abnormally Elevated Copper
- Depletes metallothionein glutathione
- Associated with inflammation excessive
oxidative stress - Can cause abnormal neurotransmitter levels.
15Low Metallothionein Levels in Autismp lt 0.0092
16Why is Metallothionein Important?
- Required for development of brain cells,
- Primary filter for Hg, Pb, and other metal
toxics at intestinal and blood/brain barriers, - Required for homeostasis of Cu and Zn,
- Supports immune function.
- -- MT is a magnet for mercury, but MT activity
is weak in autism-spectrum children.
17Autopsy Studies Show Structural Abnormalities in
Autistic Brains
- Short, dense, undeveloped brain cells,
- Abnormalities observed primarily where MT levels
are highest (amygdala, hippocampus, Purkinje
cells, inferior olives, and pineal gland). - Conclusion Incomplete maturation of autistic
brains may be due to low MT levels.
18The Role of Metallothionein in the Development of
Brain Cells
- MT-3 assists in the pruning of brain cells, which
makes space for growth of new cells, - MT-1 and MT-2 participate in the natural growth
(development) of brain cells, - MT-3 is the primary agent for termination of
growth of fully-developed brain cells.
19Teamwork Between MT, GSH, SeThe Three
Musketeers
- GSH is first line of defense against Hg, Pb, etc,
but has limited capacity for toxic metals. - When gt 10 of GSH is bound to toxic metals,
additional toxics are transferred from GSH to MT. - Se increases kinetics of the GSH/MT antioxidant
system by more than 50. - For major exposures, most toxic metals depart the
body bound to MT.
20MT-Promotion Therapy
- Formulation of 22 nutrients that promote genetic
expression or functioning of MT, including Zinc,
Glutathione, and Selenium, - Aimed at completion of brain maturation to enable
gains in cognition, speech, and socialization, - Has resulted in higher frequency of autism
recovery at Pfeiffer Treatment Center. - U.S. Patent 7,232,575 (issued June, 2007)
21Oxidative Damage Study 1
- Published in October, 2006. Archives of
Neurology Vol. 631161-1164. Authors Pratico,
Walsh, McGinnis, and Yao. - Findings Elevated oxidative damage to fats and
vascular tissues for autistic subjects, compared
to controls.
22Higher iP Levels in Autismp lt 0.01
23Oxidative Damage Study 2
- American Journal of Biotechnology and
Biochemistry 4(2)61-72, 2008. Authors Evans,
McGinnis, Walsh, Perry, Salomon, Lewis, et. al. - First direct evidence of oxidative damage in the
autistic brain. - Evidence of neurodegeneration in autism
24Implications of Oxidative Damage Studies
- Untreated autism may be neurodegenerative with
oxidative damage causing slow, gradual loss of
brain cells and IQ. - Antioxidant therapy may be necessary throughout
the life of a person diagnosed with an autism
spectrum disorder.
25Clinical Evidence (n7,000) of Neurodegeneration
in Autism
- Most young ASD patients appear quite bright
- Many successfully treated children become
mainstreamed and academic leaders, - Most adult autistics exhibit mental severe
retardation.
26Leukocyte Study
- Altered Sulfur Amino Acid Metabolism in
Immune Cells of Children Diagnosed with Autism
J. Suh, W. Walsh, W. McGinnis, A. Lewis, and B.
Ames. - American Journal of Biochemistry
Biotechnology 4 (2) 105-113, 2008.
27Leukocyte Findings for ASD
- SAMe levels 36 lower,
- SAMe/SAH ratios 50 lower,
- Homocysteine 180 higher,
- Cysteine 40 lower,
- GSH 25-60 lower.
28Leukocyte Study Conclusion
- Evidence of increased inflammation, increased
oxidative stress, and depressed immune function
in autism.
29Urine Pyrroles and Autism
- Discerning the Mauve Factor, Part 1, 2.
Alternative Therapies in Health and Medicine,
Vol. 14, No. 2, March, 2008. - W.McGinnis, T.Audhya, W.Walsh, J.Jackson,
J.McLaren-Howard, A.Lewis, P.Lauda, D.Bibus,
F.Jurnak, R.Lietha, A.Hoffer. - 25-35 of ASD patients exhibit elevated pyrroles.
- Urine HPL is a good marker for oxidative stress.
30Correlation of iP vs. Kp(corrected for creatinine)
31(No Transcript)
32Comparison of Elemental Levels in Autism
Control Brains
- Double blind, controlled study,
- 176 brain tissues 22 peripheral samples from U.
of Marylands Autism Brain Bank, - Elemental analysis for 16 elements, including Hg,
Pb, Cu, Zn, and Se using high-brilliance photons
at ANLs Advanced Photon Source), - First elemental assays ever attempted for autism
control brain tissues.
33Brain Regions Studied
- Cerebellum
- Superior Cortex
- Deep Cortex
- White Matter
- Note 20 autistic 20 control tissue samples
- from each brain region
34Autism/Control Tissue Array
35Summary of Findings
- Abnormal levels of Ca, S, Fe, Zn in autism
brains, - The abnormalities are strikingly different for
male and female autistics, suggesting that male
and female autism may have different genetic
origins. - Mercury not detected (detection limit of about
100 ppb) - Note Article prepared for Neurology.
36Distinctive Features of Autism
- Strong genetic predisposition
- Onset after environmental insult
- High oxidative stress
- Undermethylation
- Incomplete brain maturation
37Genetic Aspects of Autism
- Strong genetic predisposition
- -- Higher concordance in siblings
- -- 60 to 80 concordance in identical twins
- Influence of environmental factors
- -- Identical twin concordance not 100
- -- Major differences in many identical twins.
38QUESTION How Can There Be An Epidemic of a
Genetic Condition?
- ANSWER
- The genetic defect involves a weakened ability
to cope with environmental stresses
39Timing of Environmental Insults is Important
- In Utero
- Autism evident at birth. Greater severity of
symptoms. Mental retardation often present. - After Birth
- Regressive autism. Symptoms depend on
developmental stage during insult.
40Severity of Environmental Insult Is Important
- Example Disruption of key brain proteins
- during development of speech
center. - Mild insult results in speech delay.
- Severe insult results in mutism.
41Poly-Gene Nature of Autism
- Current consensus that autism results from many
genetic defects, rather than from a single gene. - A common factor in these genetic defects may be
diminished ability to cope with oxidative stress.
42What is Autism?Oxidative Stress Theory of Autism
- Genetic tendency for depressed GSH, MT, Se, etc
at intestinal and blood/brain barriers, - Inability to prevent Hg, Pb, Cd, and reactive
oxygen specie from invading the brain. - -- destruction of brain cells
- -- interruption of brain maturation
process
43Consequences of Oxidative Stress Mirror Classic
Symptoms of Autism
- Hypersensitivity to Hg and other toxic metals
- Hypersensitivity to certain proteins (casein,
gluten, etc) - Poor immune function
- Disruption of the methylation cycle
- Inflammation of the brain G.I. tract.
- Depletion of glutathione metallothionein
- Excessive amounts of unbound copper
44Consequences of Oxidative Stress in the G.I. Tract
- Destroys digestive enzymes needed to break down
casein gluten proteins, - Promotes candida/yeast levels,
- Diminishes Zn levels and production of stomach
acid, - Produces inflammation,
- Ineffective barrier to toxic metals at the
intestinal mucosa.
45Most Popular Autism Therapies Enhance Antioxidant
Protection
- Chelation with DMSA, DMPS, EDTA, etc.
- Methyl B-12
- Metallothionein Promotion
- Transdermal or Injected Glutathione
- Zn, Se, CoQ-10, Taurine, Vitamins A,C,D,E
- Alpha Lipoic Acid
- Risperdal
46Mercury Questions
- What of autism cases are triggered by Hg?
- Can old Hg stay in the brain and cause
continuing damage? - How serious is the continuing daily exposure to
Hg from the environment?
47Chelation and Oxidative Stress
- DMSA and DMPS are powerful antioxidants.
- Chelation can provide antioxidant benefits even
if toxic metals are not present. - For many patients, the primary benefits of
chelation result from antioxidant properties, and
not from removal of Hg or other metals. - Antioxidant benefits from chelation appear to
fade away after about 2-4 weeks.
48Primary Benefits of Chelation
- Rapid removal of toxic metals from peripheral
soft tissues blood, thus preventing their
access to the brain, - Powerful antioxidant
49Limitations of Chelation
- Does not fix intestinal or blood/brain barriers,
rendering the patient vulnerable to future toxic
exposures, - Antioxidant benefits are temporary, lasting only
2-4 weeks, - May not remove toxic metals from the brain,
- Complicates Zn management.
50Pfeiffer Treatment Protocol
- Identification individualized treatment of
biochemical imbalances, - MT-Promotion therapy,
- Selective use of adjunct therapies
- - CF/GF diet
- - Normalization of intestinal flora
- - Methylation therapies
- - Digestive enzymes
- - etc.
51MT Promotion Therapy
- Primary Objective
- Advances in cognition, socialization, and
speech by enhanced development of immature brain
cells and new synaptic connections.
52MT Promotion Therapy
- Secondary Objectives
- Elimination of toxic metals excess Cu
- Improved immune function
- Healing of the G.I. tract
- Reduced food sensitivities
- Improved behavior control
53MT-Promotion Formulation
- Generous amounts of Zn and GSH which are
essential to induction and functioning of MT, - Selenium, Vitamins B-6, C, E, which are known
to promote MT, - Supplements of the 14 amino-acid constituents of
MT in the proportion they exist in MT proteins.
54Unique Advantages of MT-Promotion
- Directly aimed at development of brain cells
new synaptic connections, - Potential for permanently correcting the
intestinal and blood/brain barriers, - Restores the natural (and powerful) body system
for coping with toxic metals, - Potential for eliminating food sensitivities,
yeast problems intestinal inflammation.
55MT Promotion Challenges
- Pre-loading with zinc is necessary to prevent
temporary side effects, - Building up tolerance to the MT Promoter
formulation can be a slow process for some
children, - Commercial lab testing to determine MT status is
in its infancy.
56A Roadmap for Enhanced Cognition, Speech, and
Socialization
- Elimination of toxic metals and excessive
oxidative stress, - Behavioral therapy to stimulate development of
brain cells and synaptic connections, - MT-Promotion therapy to enable completion of
brain maturation.
57Summary
- Oxidative stress may be the decisive factor in
autism-spectrum disorders. - Treatment protocols aimed at (1) reduction of
oxidative stresses and (2) development of new
brain cells and synapses are highly promising. - Long-term antioxidant therapy may be needed to
prevent loss of brain cells and mental
retardation.
58THANK YOU!
- William J. Walsh, Ph.D.
- Pfeiffer Treatment Center
- Warrenville, Illinois
- www.hriptc.org