Incomplete Brain Development in Autism: Causes and Treatment

1
Incomplete Brain Development in Autism Causes
and Treatment

• William J. Walsh, Ph.D.
• Pfeiffer Treatment Center
• Warrenville, IL

2
Pfeiffer 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

3
Pfeiffer Autism Research

• Chemistry Database Studies
• Metallothionein Research
• Oxidative Damage
• -- Essential fats
• -- Vascular tissue
• -- Immune cells (leukocytes)
• -- Brain tissue
• Assays of autism/control brain tissues.

4
Pfeiffer Chemistry Database

• 10,600 Behavior ADHD
• 6,000 Autism
• 3,700 Schizophrenia Bipolar
• 3,600 Depression

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Pfeiffer 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

6
Year 1999 Discovery

• Undermethylation
• Present in more than 90 of
• autism-spectrum children.

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Year 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.

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Autism 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.

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High Incidence Biochemical Abnormalities in Autism

• Elevated serum copper
• Elevated toxic metals
• Depressed zinc
• Undermethylation
• Pyrrole disorder
• Severe oxidative stress damage

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Biochemical 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

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Each of the Biochemical Abnormalities Are
Associated With Oxidative Stress

1. Conclusion Autism is a condition of oxidative
   stress
2. An oxidative stress model can explain most
   symptoms of autism
3. Oxidative stress has become a leading focus of
   autism research.

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Experimental 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.

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Insufficient 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).

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Abnormally Elevated Copper

1. Depletes metallothionein glutathione
2. Associated with inflammation excessive
   oxidative stress
3. Can cause abnormal neurotransmitter levels.

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Low Metallothionein Levels in Autismp lt 0.0092
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Why 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.

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Autopsy 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.

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The 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.

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Teamwork 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.

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MT-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)

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Oxidative 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.

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Higher iP Levels in Autismp lt 0.01
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Oxidative 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

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Implications 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.

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Clinical 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.

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Leukocyte 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.

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Leukocyte Findings for ASD

• SAMe levels 36 lower,
• SAMe/SAH ratios 50 lower,
• Homocysteine 180 higher,
• Cysteine 40 lower,
• GSH 25-60 lower.

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Leukocyte Study Conclusion

• Evidence of increased inflammation, increased
  oxidative stress, and depressed immune function
  in autism.

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Urine 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.

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Correlation of iP vs. Kp(corrected for creatinine)
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Comparison 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.

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Brain Regions Studied

• Cerebellum
• Superior Cortex
• Deep Cortex
• White Matter
• Note 20 autistic 20 control tissue samples
• from each brain region

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Autism/Control Tissue Array
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Summary 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.

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Distinctive Features of Autism

• Strong genetic predisposition
• Onset after environmental insult
• High oxidative stress
• Undermethylation
• Incomplete brain maturation

37
Genetic 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.

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QUESTION How Can There Be An Epidemic of a
Genetic Condition?

• ANSWER
• The genetic defect involves a weakened ability
  to cope with environmental stresses

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Timing 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.

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Severity 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.

41
Poly-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.
  

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What 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

43
Consequences 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

44
Consequences 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.

45
Most 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

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Mercury 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?

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Chelation 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.

48
Primary Benefits of Chelation

• Rapid removal of toxic metals from peripheral
  soft tissues blood, thus preventing their
  access to the brain,
• Powerful antioxidant

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Limitations 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.

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Pfeiffer 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.

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MT Promotion Therapy

• Primary Objective
• Advances in cognition, socialization, and
  speech by enhanced development of immature brain
  cells and new synaptic connections.

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MT 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

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MT-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.

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Unique 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.

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MT 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.

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A 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.

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Summary

• 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.

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THANK YOU!

• William J. Walsh, Ph.D.
• Pfeiffer Treatment Center
• Warrenville, Illinois
• www.hriptc.org