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Incomplete Brain Development in Autism: Causes and Treatment


Pfeiffer Chemistry Database 10,600 Behavior & ADHD 6,000 Autism 3,700 ... Oxidative Stress Theory of Autism Consequences of Oxidative Stress Mirror ... – PowerPoint PPT presentation

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Title: Incomplete Brain Development in Autism: Causes and Treatment

Incomplete Brain Development in Autism Causes
and Treatment
  • William J. Walsh, Ph.D.
  • Pfeiffer Treatment Center
  • Warrenville, IL

Pfeiffer Treatment Center
  • Outpatient medical facility
  • 23,000 patients from all 50 states and 75 foreign
  • Collaboration between medical doctors and
  • Individualized Biochemical Therapy
  • Scientific Research
  • 501c3 Public Charity

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.

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

Pfeiffer Autism Database
  • About 90 to 150 assays of chemical factors in
    blood, urine, or hair for more than 6,000
  • More than 1,000,000 separate chemical analyses

Year 1999 Discovery
  • Undermethylation
  • Present in more than 90 of
  • autism-spectrum children.

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.

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
  • Female autistics have more disordered chemistry
    than male autistics.

High Incidence Biochemical Abnormalities in Autism
  • Elevated serum copper
  • Elevated toxic metals
  • Depressed zinc
  • Undermethylation
  • Pyrrole disorder
  • Severe oxidative stress damage

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

Each of the Biochemical Abnormalities Are
Associated With Oxidative Stress
  1. Conclusion Autism is a condition of oxidative
  2. An oxidative stress model can explain most
    symptoms of autism
  3. Oxidative stress has become a leading focus of
    autism research.

Experimental Results and Statistical Analysis
  • Mean Cu/Zn Ratio
  • Autism Spectrum (N503) 1.63
  • Controls (N25)
  • t 8.77 (two-tailed t test) p lt 0.0001
  • American Psychiatric Association Annual Meeting
  • New Orleans, 2001.

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).

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

Low Metallothionein Levels in Autismp lt 0.0092
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.

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.

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.

Teamwork Between MT, GSH, SeThe Three
  • 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.

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)

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.

Higher iP Levels in Autismp lt 0.01
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

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.

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

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.
  • American Journal of Biochemistry
    Biotechnology 4 (2) 105-113, 2008.

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

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

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.

Correlation of iP vs. Kp(corrected for creatinine)
(No Transcript)
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.

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

Autism/Control Tissue Array
Summary of Findings
  • Abnormal levels of Ca, S, Fe, Zn in autism
  • The abnormalities are strikingly different for
    male and female autistics, suggesting that male
    and female autism may have different genetic
  • Mercury not detected (detection limit of about
    100 ppb)
  • Note Article prepared for Neurology.

Distinctive Features of Autism
  • Strong genetic predisposition
  • Onset after environmental insult
  • High oxidative stress
  • Undermethylation
  • Incomplete brain maturation

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.

QUESTION How Can There Be An Epidemic of a
Genetic Condition?
  • The genetic defect involves a weakened ability
    to cope with environmental stresses

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.

Severity of Environmental Insult Is Important
  • Example Disruption of key brain proteins
  • during development of speech
  • Mild insult results in speech delay.
  • Severe insult results in mutism.

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.

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

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

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
  • Produces inflammation,
  • Ineffective barrier to toxic metals at the
    intestinal mucosa.

Most Popular Autism Therapies Enhance Antioxidant
  • 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

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?

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.

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

Limitations of Chelation
  • Does not fix intestinal or blood/brain barriers,
    rendering the patient vulnerable to future toxic
  • Antioxidant benefits are temporary, lasting only
    2-4 weeks,
  • May not remove toxic metals from the brain,
  • Complicates Zn management.

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.

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

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

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.

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.

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
  • Commercial lab testing to determine MT status is
    in its infancy.

A Roadmap for Enhanced Cognition, Speech, and
  • 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.

  • 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

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