Incomplete Brain Development in Autism: Causes & Treatment

8/14/2019 Incomplete Brain Development in Autism: Causes & Treatment

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Incomplete Brain Development inAutism: Causes and Treatment

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

Warrenville, IL


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Pf ei ff er Treatment Center

Ou tpatient medical facility

23,000 patients from all 50 states and 75foreign co u ntries.Collaboration between medical doctors andscientists.

Individ u alized Biochemical TherapyScientific Research501c3 P u blic Charity


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Pf ei ff er Autism Research

Chemistry Database St u dies

Metallothionein ResearchOx idative Damage-- Essential fats

-- Vasc u lar tiss u e-- Imm u ne cells (le uk ocytes)-- Brain tiss u e

Assays of a u tism/control brain tiss u es.


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Pf ei ff er Chemistry Database

10,600 Behavior & ADHD6,000 A u tism3,700 Schizophrenia & Bipolar

3,600 Depression


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Pf ei ff er Autism Database

Abou

t 90 to 150 assays of chemicalfactors in blood, u rine, or hair for morethan 6,000 patients

More than 1,000,000 separate chemicalanalyses


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Year 1999 Discovery

UndermethylationP resent in more than 90% o f

autism-spectrum children.


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Year 2000 Discovery

Greater than 99% o f ASD patients exhibitabnormal Cu and Zn levels in blood.Normally, Cu & Zn are homeostaticallycontrolled by metallothionein proteins.

Conclusion: Depressed metallothioneinactivity is a distinctive feature of autism.


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Autism Database Analysis

Major biochemical abnormalities observedthro u gho u t the a u tism spectr u m.The biochemical imbalances are moresevere than those for ADHD, violentbehavior, depression, and psychosis.Female a u tistics have more disorderedchemistry than male a u tistics.


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H igh Incidence BiochemicalAbnormalities in Autism

Elevated ser u m copper Elevated to x ic metalsDepressed zinc

UndermethylationPyrrole disorder Severe o x idative stress & damage


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Biochemical Abnormalities in Autism--- Continued ---

Depressed Methionine and SAMeElevated SAH and AdenosineHigh Urinary IsoprostanesDepressed Cysteine and Gl u tathione

Low Seleni u m LevelsDepressed Cer u loplasminElevated Levels of Free-Radicals


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E ach o f the Biochemical AbnormalitiesAre Associated With Oxidative Stress

1. Conclusion: Autism is a condition o f oxidative stress2. An oxidative stress model can explain

most symptoms o f autism3. Oxidative stress has become a leading

f ocus o f autism research.


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E xperimental Results andStatistical Analysis

Mean C u /Zn Ratio

Au tism Spectr u m (N=503) 1.63Controls (N=25) 1.15

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

American Psychiatric Association Ann u al MeetingNew O rleans, 2001.


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Insu ff icient Ceruloplasmin Levels inAutistic-Spectrum P atients

Autistics Controls

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

P < 0.01

Conclusion: Autistics exhibit excessivelevels of loosely bound or free-radical copper (high oxidative stress).


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Abnormally E levated Copper

1. Depletes metallothionein & gl u tathione2. Associated with inflammation &

e x cessive o x idative stress3. Can ca u se abnormal ne u rotransmitter

levels.


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Why is Metallothionein Important?

Req u ired for development of brain cells,Primary filter for Hg, Pb, and other metaltox ics at intestinal and blood/brain barriers,Req u ired for homeostasis of C u and Zn,S u pports imm u ne f u nction.

-- MT is a magnet for mercury, but MT activity isweak in autism-spectrum children.


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Autopsy Studies Show StructuralAbnormalities in Autistic Brains

Short, dense, u ndeveloped brain cells, Abnormalities observed primarily where MTlevels are highest (amygdala, hippocamp u s,P u r k inje cells, inferior olives, and pinealgland).

Conclusion : Incomplete maturation of autistic brains may be due to low MT levels.


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The Role of

Metallothionein in theDevelopment o f Brain Cells

MT-3 assists in the pr u ning of brain cells,which ma k es space for growth of new cells,MT-1 and MT-2 participate in the nat u ralgrowth (development) of brain cells,

MT-3 is the primary agent for termination of growth of f u lly-developed brain cells.


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Teamwork Between MT, GS H , SeThe Three Musketeers

GSH is first line of defense against Hg,Pb, etc, b u t has limited capacity for tox ic metals.When > 10% of GSH is bo u nd to to x icmetals, additional to x ics are transferredfrom GSH to MT.Se increases k inetics of the GSH/MTantio x idant system by more than 50%.For major e x pos u res, most to x ic metalsdepart the body bo u nd to MT.


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MT- P romotion Therapy

Form u lation of 22 n u trients that promote

genetic e x pression or f u nctioning of MT,inclu ding Zinc, Gl u tathione, and Seleni u m, Aimed at completion of brain mat u ration toenable gains in cognition, speech, andsocialization,Has res u lted in higher freq u ency of a u tismrecovery at Pfeiffer Treatment Center.

U.S. P atent 7,232,575 (issued June, 2007)


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Oxidative Damage Study 1

P u blished in O ctober, 2006. Archives of Neurology; Vol. 63:1161-1164. Au thors Pratico,Walsh, McGinnis, and Yao.

Findings: Elevated o x idative damage to fatsand vasc u lar tiss u es for a u tistic s u bjects,compared to controls.


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H igher i P Levels in Autismp < 0.01

0

1

2

3

4

5

6

iP

Autistics

Controls


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Oxidative Damage Study 2

American Journal of Biotechnology and Biochemistry; 4(2):61-72, 2008. Authors: E vans,McGinnis, Walsh, P erry, Salomon, Lewis, et. al.

F irst direct evidence o f oxidative damage in the

autistic brain.

E vidence o f neurodegeneration in autism


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Implications o f OxidativeDamage Studies

Untreated a u tism may be ne u rodegenerativewith o x idative damage ca u sing slow, grad u alloss of brain cells and IQ.

Antio x idant therapy may be necessarythro u gho u t the life of a person diagnosedwith an a u tism spectr u m disorder.


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Clinical E vidence (n=7,000) o f Neurodegeneration in Autism

Most yo u ng ASD patients appear q u ite bright

Many s u ccessf u lly treated children becomemainstreamed and academic leaders,

Most ad u lt a u tistics e x hibit mental severeretardation.


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Leukocyte Study

Altered Sulfur Amino Acid M etabolism inImmune Cells of Children Diagnosed with

Autism; J . Suh, W. Walsh, W. McGinnis, A.Lewis, and B. Ames .

American Journal o f Biochemistry &Biotechnology; 4 (2): 105-113, 2008.


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Leukocyte F indings f or 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

E vidence of increased inflammation,increased oxidative stress, and depressed immune function in autism.


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Urine P yrroles and Autism

Discerning the Mauve F actor, P art 1, 2.Alternative Therapies in H ealth and Medicine,Vol. 14, No. 2, March, 2008.W.McGinnis, T.A u dhya, W.Walsh, J.Jac k son,J.McLaren-Howard, A.Lewis, P.La u da, D.Bib u s,F.J u rna k , R.Lietha, A.Hoffer.

25-35% o f ASD patients exhibit elevated pyrroles.Urine H P L is a good marker f or oxidative stress.


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Correlation o f iP vs. Kp (corrected f or creatinine)

p = 0.0164

0123

456789

10

0 20 40 60 80 100

iP ng/mg

K

p m c g

/ m g


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Comparison o f E lemental Levels inAutism & Control Brains

Do u ble blind, controlled st u dy,

176 brain tiss u es & 22 peripheral samplesfrom U. of Marylands A u tism Brain Ban k ,Elemental analysis for 16 elements, incl u dingHg, Pb, C u , Zn, and Se u sing high-brilliancephotons at ANLs Advanced Photon So u rce),First elemental assays ever attempted for a u tism & control brain tiss u es.


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Brain Regions Studied

Cerebell u mS u perior Corte xDeep Corte xWhite Matter

Note: 20 autistic & 20 control tissue samplesfrom each brain region


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Autism/Control Tissue Array


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Summary o f F indings

Abnormal levels of Ca, S, Fe, Zn in a u tism brains,

The abnormalities are stri k ingly different for maleand female a u tistics, s u ggesting that male andfemale a u tism may have different genetic origins.

Merc u ry not detected (detection limit of abo u t 100ppb)

Note : Article prepared for Neurology.


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Distinctive F eatures o f Autism

Strong genetic predispositionO nset after environmental ins u ltHigh o x idative stressUndermethylation

Incomplete brain mat u ration


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Genetic Aspects o f Autism

Strong genetic predisposition

-- Higher concordance in siblings-- 60 to 80% concordance in identical twinsIn f luence o f environmental f actors

-- Identical twin concordance not 100%-- Major differences in many identical twins.


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Q UE STION: H ow Can There Be AnE pidemic o f a Genetic Condition?

ANSW E R :The genetic defect involves awea k ened ability to cope withenvironmental stresses


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Timing o f E nvironmentalInsults is Important

In Utero

Au tism evident at birth. Greater severity of symptoms. Mental retardation often present.

Af ter BirthRegressive a u tism. Symptoms depend on

developmental stage d u ring ins u lt.


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P oly-Gene Nature o f Autism

Cu rrent consens u s that a u tism res u lts frommany genetic defects, rather than from asingle gene.

A common factor in these genetic defectsmay be diminished ability to cope withoxidative stress .


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Consequences o f Oxidative StressMirror Classic Symptoms o f Autism

Hypersensitivity to Hg and other to x ic metals

Hypersensitivity to certain proteins (casein,glu ten, etc)Poor imm u ne f u nctionDisr u ption of the methylation cycle

Inflammation of the brain & G.I. tract.Depletion of gl u tathione & metallothioneinEx cessive amo u nts of u nbo u nd copper


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Most P opular Autism TherapiesE nhance Antioxidant P rotection

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

2. Methyl B-123. Metallothionein Promotion4. Transdermal or Injected Gl u tathione5.

Zn, Se, CoQ-10, Tau

rine, Vitamins A,C,D,E6. Alpha Lipoic Acid7. Risperdal


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Mercury Q uestions

What % of a u tism cases are triggered by Hg?Can old Hg stay in the brain and ca u secontin u ing damage?How serio u s is the contin u ing daily e x pos u reto Hg from the environment?


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Chelation and Oxidative Stress

DMSA and DMPS are powerf u l antio x idants.

Chelation can provide antio x idant benefitseven if to x ic metals are not present.For many patients, the primary benefits of chelation res u lt from antio x idant properties,and not from removal of Hg or other metals.

Antio x idant benefits from chelation appear tofade away after abo u t 2-4 wee k s.


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P rimary Bene f its o f Chelation

Rapid removal of to x ic metals fromperipheral soft tiss u es & blood, th u spreventing their access to the brain,

Powerf u

l antiox

idant


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Limitations o f Chelation

Does not fi x intestinal or blood/brain barriers,

rendering the patient v u lnerable to f u tu retox ic e x pos u res,

Antio x idant benefits are temporary, lastingonly 2-4 wee k s,May not remove to x ic metals from the brain,Complicates Zn management.


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Pf ei ff er Treatment P rotocolIdentification & individ u alized treatment of biochemical imbalances,MT-Promotion therapy,Selective u se of adj u nct therapies

- CF/GF diet

- Normalization of intestinal flora- Methylation therapies- Digestive enzymes- etc.


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MT P romotion TherapyP rimary Objective:

Advances in cognition, socialization,and speech by enhanced developmentof immat u re brain cells and new

synaptic connections.


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MT P romotion TherapySecondary Objectives

Elimination of to x ic metals & e x cess C uImproved imm u ne f u nctionHealing of the G.I. tractRed u ced food sensitivitiesImproved behavior control


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MT- P romotion F ormulationGenero u s amo u nts of Zn and GSH which are

essential to indu

ction and f u

nctioning of MT,Seleni u m, Vitamins B-6, C, E, which arek nown to promote MT,S u pplements of the 14 amino-acidconstit u ents of MT in the proportion theye x ist in MT proteins.


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Unique Advantageso f MT- P romotion

Directly aimed at development of brain cells& new synaptic connections,Potential for permanently correcting theintestinal and blood/brain barriers,Restores the nat u ral (and powerf u l) bodysystem for coping with to x ic metals,Potential for eliminating food sensitivities,yeast problems & intestinal inflammation.


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MT P romotion Challenges

Pre-loading with zinc is necessary to prevent

temporary side effects,Bu ilding u p tolerance to the MT Promoter form u lation can be a slow process for somechildren,

Commercial lab testing to determine MTstat u s is in its infancy.


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A Roadmap f or E nhanced Cognition,Speech, and Socialization

Elimination of to x ic metals and e x cessive

ox idative stress,Behavioral therapy to stim u late developmentof brain cells and synaptic connections,MT-Promotion therapy to enable completionof brain mat u ration.


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Summary

Ox idative stress may be the decisive factor in

a u tism-spectr u m disorders.Treatment protocols aimed at (1) red u ction of ox idative stresses and (2) development of new brain cells and synapses are highlypromising.Long-term antio x idant therapy may beneeded to prevent loss of brain cells andmental retardation.


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Incomplete Brain Development in Autism: Causes & Treatment

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