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 countries. Collaboration between medical doctors and

scientists. 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 patients

More than 1,000,000 separate chemical analyses

Year 1999 Discovery

UndermethylationPresent 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 psychosis.

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 stress

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 RatioAutism Spectrum (N=503) 1.63Controls (N=25) 1.15

t = 8.77 (two-tailed “t” test); p < 0.0001

American Psychiatric Association Annual MeetingNew Orleans, 2001.

Insufficient Ceruloplasmin Levels in Autistic-Spectrum Patients

Autistics Controls Unbound* Serum Cu 41 % 21 % *Not bound to ceruloplasmin

P < 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 < 0.0092

0

0.5

1

1.5

2

2.5

3

3.5

Metallothionein

AutisticsControls

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, Se“The Three Musketeers”

GSH is first line of defense against Hg, Pb, etc, but has limited capacity for toxic metals.

When > 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. 63:1161-1164. 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 < 0.01

0

1

2

3

4

5

6

iP

Autistics

Controls

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 (n=7,000) 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.

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.

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)

p = 0.0164

0123456789

10

0 20 40 60 80 100

iP ng/mg

Kp

mcg

/mg

Comparison of Elemental Levels in Autism & Control Brains

Double blind, controlled study, 176 brain tissues & 22 peripheral samples

from U. of Maryland’s Autism Brain Bank, Elemental analysis for 16 elements, including

Hg, Pb, Cu, Zn, and Se using high-brilliance photons at ANL’s Advanced Photon Source),

First elemental assays ever attempted for autism & control brain tissues.

Brain Regions Studied

CerebellumSuperior CortexDeep CortexWhite 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 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.

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?

ANSWER:

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 center.

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 process

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 acid, Produces inflammation, Ineffective barrier to toxic metals at the

intestinal mucosa.

Most Popular Autism Therapies Enhance Antioxidant Protection

1. Chelation with DMSA, DMPS, EDTA, etc.

2. Methyl B-12

3. Metallothionein Promotion

4. Transdermal or Injected Glutathione

5. Zn, Se, CoQ-10, Taurine, Vitamins A,C,D,E

6. Alpha Lipoic Acid

7. 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 exposures,

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 ObjectivesElimination of toxic metals & excess Cu Improved immune functionHealing of the G.I. tractReduced 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 children,

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

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.

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.

THANK YOU!

William J. Walsh, Ph.D.Pfeiffer Treatment Center

Warrenville, Illinoiswww.hriptc.org