Neurodegenerative Disease

NeurodegenerativeDisease

Dr Melvyn A Sydney-Smith. KGSJ.MBBS, PhD, Dip Gest Ther, Master Prac NLP, FACNEM.

Australian College of Holistic MedicineAdjunct Professor, Nutrition Medicine

RMIT University

Neurodegenerative Disease

Progressive, nerve cell dysfunction &

apoptosis eventuating in CNS

atrophy & death

Excludes known disease: vascular,

toxic, metabolic,infective and autoimmune

disease

Affects specific brain systems

implies selective regional

nerve cell vulnerabilityAbnormal protein

accumulation ~e.g. amyloid B plaques

Pathogenesis is ill-defined

is apparently multifactorial ~related to~

genetic, environmental,

metabolic and other aging factors

M. Flint Beal, AC. Ludolph (2005). Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics,

Cambridge University Press.


Dementia disorders

Alzheimer’s DiseasePick’s Disease

Movement disorders

Parkinson’s DiseaseCerebellar AtaxiaMotor Neurone

DiseaseMultiple System

Atrophy

Dementia + Movement disorders

Diffuse Lewy Body Disease

Alzheimer’s Disease Lewy Body variant

Hungtington’s Disease

All share common characteristics

M. Flint Beal, AC. Ludolph (2005). Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics,

Cambridge University Press.


Common character

istics

Reduced mitochondrial

and axonal transport

Progressive cell atrophy &

apoptosis

Increased tissue

oxidative damage

Increased inflammatory

cytokine production

Accumulation of abnormal

protein fragments

Increased Tau protein

phosphorylation

Decreased neurotransmitter

productionIncreased

inflammatory lipid mediators

Progressive cell atrophy &

apoptosisSkovronsky et al. 2006. "NEURODEGENERATIVE DISEASES … Ann Rev

Path Mech Dis. 1(1)

Cognitive DisorderCognitive Disorder

Alzheimer’s disease ~

90% of dementia cases > 70 yrs

Pick’s disease ~ more common below 60 yrs

Dementia

90 % sporadic

10 % familial

Annual incidenceExponential increase with age

40 to 60 yrs ~ 2.4 / 100,000 80 yrs ~ 127 / 100,000

4th or 5th leading cause of death

Amyloid-B-peptide Accumulation

Insoluble amyloid plaquesTau protein

hyperphosphorylation~ neurofibrillary tanglesThomas & Fenech. 2007. A review of genome mutation and Alzheimer's

disease. Mutagenesis 22(1): 15-33.Mendez et al. 2008. Psychopathology of Frontotemporal Dementia: J

Neuropsychiatry Clin Neurosci 20(2)

Alzheimer’s disease ~

Classic dementia disorder

& the commonestIncidence rises rapidly

over 70 yrs age

CVD is next commonest

cause

Minati L, et al. 2008. Current Concepts in Alzheimer's Disease: A Multidisciplinary Review.. J Alzheimers Dis Other Demen.

Insidious onset memory loss ~ progresses over 5~10 yrs impaired executive function, attentiveness, language, visual & motor

processing and behaviour

Neurofibrillary formation, Amyloid plaque deposition

Lewy Bodies & Pick Bodies

Normal

Aging

Alzheimer’s Diseas

e

Neuronal Loss Brain Atrophy Death

Early Onset Familial Alzheimer’s Disease~ accounts for < 5% of all Alzheimer patients~ generally onsets between 50 ~ 60 yrs age

Genetic form of Alzheimer’s Disease~ multiple polymorphisms on 3 genes~ autosomal dominant inheritance

presenilin 1 (PSEN1) ch-14,presenilin 2 (PSEN2) ch-1

Aβ precursor protein (APP) ch-21

Clinical Picturerapid & unrelenting

progressionof cognitive deterioration

Thomas & Fenech. 2007. A review of genome mutation and Alzheimer's disease. Mutagenesis 22(1): 15-33.

Late Onset Alzheimer’s Disease

90% of all Alzheimer patientsabove age 70 yrs

slow progressive diseaseRisk Factors:

Aging, menopauselow education

levelhead trauma,

cerebral ischaemia

Protective factors:

anti-inflammatory drugs

antioxidant agentsoestrogen

high educational level

Risk Factors: cardiovascular

diseaseobesity

diabeteschronic inflammation

Increased risk with:

APO-E4 genotype to 40~70% of cases

TNF-alpha polymorphismTrisomy 21

Minati L, et al. 2008. Current Concepts in Alzheimer's Disease: A Multidisciplinary Review.. J Alzheimers Dis Other Demen.

Inflammation

Inflammation

Oxidantstress

Oxidantstress

Insulin

ResistanceInsulin

Resistance

Alzheimer’s Disease

3 Major processes

Emerit, J., M. Edeas, et al. (2004). "Neurodegenerative diseases and oxidative stress." Biomedicine & Pharmacotherapy 58(1): 39-46.

InflammationInflammationPresent at cellular level~brain microglia activation

~ not systemic inflammation

Increased cytokine

productionTNF-alpha

IL-1

Tan, Z. S., A. S. Beiser, et al. (2007). "Inflammatory markers and the risk of Alzheimer disease: The Framingham Study." Neurology 68(22): 1902-1908.

Lukiw, W. J. (2009). "Docosahexaenoic acid and Amyloid-beta Peptide Signaling in Alzheimer's Disease." World Rev Nutr Diet 99: 55-70.

Increased lipid

mediators:Leukotrienes

Reduced DHAimpairs

Neuronal signalling

Exacerbated by

* cerebral iron & copper* Vascular endothelial

disease* APO E4 gene

* Insulin Resistance

Oxidant Stressderives

from

Oxidant Stressderives

from

Insulin Resistance

Cardiovascular DiseaseDiabetes

EFA imbalanceomega-3-FA insufficiency

Heavy metal overload

iron, coppermercury

InflammationAPO e4 gene

TNF-alpha polymorphism

Chronic inflammatory

disease

Low antioxidant

statusAscorbate

Bioflavonoidsproanthocyani

dins

Environmental oxidant

exposureSmoking

Air pollutionHeavy metals

~ Hg, MnYan, S. D., X. Chen, et al. (1996). "RAGE and amyloid-[beta] peptide neurotoxicity in Alzheimer's disease." Nature 382(6593): 685-691.

Emerit, J., M. Edeas, et al. (2004). "Neurodegenerative diseases and oxidative stress." Biomedicine & Pharmacotherapy 58(1): 39-46.

InsulinResistance

InsulinResistance

DIETHigh

Carbohydrate intake

High saturated fat intake

Carbohydrate-responsive

Gene Polymorphism

sPPARSSREBP

ChREBP

Mineral Depletion

• Zinc• Magnesium• Chromium

Omega-3-EFA deficiencyinadequate

intake ofFish & fish oils Obesity and

Overweight

Lack ofEXERCISE

ChronicInflammation

Sabayan, B., F. Foroughinia, et al. (2008). "Role of Insulin Metabolism Disturbances in the Development of Alzheimer Disease: Mini Review." American Journal of Alzheimer's Disease and Other Dementias 23(2): 192-199.


Causal FactorsOxidativ

e damage

Heavy metal

toxicity

NMDA- receptoractivation

Mitochondrial

dysfunction

Neurotransmitterimbalance

Glutamate toxicity

InsulinResistance

Reduced ATP

genesis

Glucosetoxicity

Inflammatorycytokinerelease

InflammatoryLipid

Mediators

ObesityAdipokineproduction

NutrientDepletio

n


Useful Tests

Check Alcoholconsumption

Cigarette Smoking

High sensitivity CRPand ESR

Full Blood Count & ESR

Faecal Bacterial Analysismicrobial culture

&/or DNA analysis

Food Antibodiesboth IgG and IgE

Red cell EFA analysis

Antioxidant Status& Co-Q10

APO E genotype

Glucose Tolerance Testwith insulin & cortisol

Urinary MineralAnalysis

Ca, Mg, Zn

DNA Oxidative damage

Nutrient statusVit C, E & D

Iron studyand ferritin

Test for Heavy Metal LoadHair Analysis or

Urinary Mercury Provocation

Urinary Metabolite Analysis

Hormone BalanceDHEA, Oestrogen

Testosterone

Neurotransmitterbalance

Bowel Dysbiosismarkers


TREATMENT

DIGESTIVE SUPPORTGastric acid and Digestive enzymes

DIETLow-allergy & Low Glycemic

LoadHigh protein & vegetable intake

Consider Paleolithic or ketogenic diet

Essential Fatty Acid Supplements

DHA-rich omega-3-FAs

alpha-Linolenic acid

Primary Antioxidant Therapy

Vitamin C ~ mixed mineral ascorbates

Mixed tocopherols & Tocotrienols

Mixed bioflavonoidsPhytonutrient

TherapyBlueberriesGreen tea

ResveratrolCurcumin

Pomegranate


TREATMENT

Vitamin therapyHigh dose:

Activated B-ComplexFolate & B12Pyridoxal-5-phosphate

NADH

Mineral therapyCalcium

MagnesiumSeleniumChromium

Zinc

Toxic Mineral Removal

Natural chelatorsN-acetylcysteineGarlic extracts

Alpha-lipoic acidGreen tea extract

Pharmaceutical chelating agents

EDTA chelationClioquinol

DesferrioxamineDMSANeuronal

stimulationCiticholine

PhosphatidylserineL-arginine

Adaptogenic Herbs

Ginkgo bilobaKorean Ginseng

Ashagarwan

Alzheimer’s DiseaseTHERAPY NEEDS TO BE

Multimodal & Integrated~ targeting identified metabolic dysfunctions

Initiated at earliest sign of cognitive dysfunction

Persistent ~ long-term administration of therapeutic agents

Clinically Monitored ~ on an ongoing basis

Thank you for your

care and attention

REFERENCES:Samuel, T. H. (2004). "High carbohydrate diets and Alzheimer's disease."

Medical hypotheses 62(5): 689-700.Van der Auwera, I., S. Wera, et al. (2005). "A ketogenic diet reduces amyloid beta 40 and 42 in a

mouse model of Alzheimer's disease." Nutr Metab (Lond).Sabayan, B., F. Foroughinia, et al. (2008). "Role of Insulin Metabolism Disturbances in the

Development of Alzheimer Disease: Mini Review." American Journal of Alzheimer's Disease and Other Dementias 23(2): 192-199.

Mosconi, L., A. Pupi, et al. (2008). "Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer's disease." Ann N Y Acad Sci 1147: 180-95.

Freund-Levi, Y., M. Eriksdotter-Jonhagen, et al. (2006). "{omega}-3 Fatty Acid Treatment in 174 Patients With Mild to Moderate Alzheimer Disease: OmegAD Study: A Randomized Double-blind Trial." Arch Neurol 63(10): 1402-1408.

Nurk, E., C. A. Drevon, et al. (2007). "Cognitive performance among the elderly and dietary fish intake: the Hordaland Health Study." Am J Clin Nutr 86(5): 1470-1478.

Lukiw, W. J. (2009). "Docosahexaenoic acid and Amyloid-beta Peptide Signaling in Alzheimer's Disease." World Rev Nutr Diet 99: 55-70.

Yehuda, S., S. Rabinovtz, et al. (1996). "Essential Fatty Acids Preparation (Sr-3) Improves Alzheimer's Patients Quality of Life." International Journal of Neuroscience 87(3): 141-149.

REFERENCESBowman, G. L., H. Dodge, et al. (2009). "Ascorbic Acid and rates of cognitive decline in Alzheimer's

disease." J Alzheimers Dis 16(1): 93-8. Morris, M. C., D. A. Evans, et al. (2005). "Relation of the tocopherol forms to incident Alzheimer

disease and to cognitive change." Am J Clin Nutr 81(2): 508-514. Chandan K. Sen, S. K. S. R. (2004). "Tocotrienol: The Natural Vitamin E to Defend the Nervous

System?" Annals of the New York Academy of Sciences 1031(Vitamin E and Health): 127-142.Maczurek, A., K. Hager, et al. (2008). "Lipoic acid as an anti-inflammatory and neuroprotective

treatment for Alzheimer's disease." Adv Drug Deliv Rev 60(13-14): 1463-70.Abdul, H. M. and D. A. Butterfield (2007). "Involvement of PI3K/PKG/ERK1/2 signaling pathways in

cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease." Free Radic Biol Med 42(3): 371-84.

Holmquist, L., G. Stuchbury, et al. (2007). "Lipoic acid as a novel treatment for Alzheimer's disease and related dementias." Pharmacol Ther 113(1): 154-64.

Maczurek, A., K. Hager, et al. (2008). "Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease." Adv Drug Deliv Rev 60(13-14): 1463-70.

Bruce N. Ames, J. L. (2004). "Delaying the Mitochondrial Decay of Aging with Acetylcarnitine." Annals of the New York Academy of Sciences 1033(Carnitine The Science behind a Conditionally Essential Nutrient): 108-116.

REFERENCESOrly, W., M. Silvia, et al. (2004). "Neurological mechanisms of green tea polyphenols in Alzheimer's

and Parkinson's diseases." The Journal of nutritional biochemistry 15(9): 506-516.Rezai-Zadeh, K., D. Shytle, et al. (2005). "Green Tea Epigallocatechin-3-Gallate (EGCG) Modulates

Amyloid Precursor Protein Cleavage and Reduces Cerebral Amyloidosis in Alzheimer Transgenic Mice." J. Neurosci. 25(38): 8807-8814.

Vingtdeux, V., U. Dreses-Werringloer, et al. (2008). "Therapeutic potential of resveratrol in Alzheimer's disease." BMC Neurosci 9 Suppl 2: S6.

Zhu, Y., P. C. Bickford, et al. (2008). "Blueberry Opposes ß-Amyloid Peptide-Induced Microglial Activation Via Inhibition of p44/42 Mitogen-Activation Protein Kinase." Rejuvenation Research 11(5): 891-901.

Papandreou, M. A., A. Dimakopoulou, et al. (2008). "Effect of a polyphenol-rich wild blueberry extract on cognitive performance of mice, brain antioxidant markers and acetylcholinesterase activity." Behavioural Brain Research.

Francis, C. L., S.-H. Barbara, et al. (2005). "The beneficial effects of fruit polyphenols on brain aging." Neurobiology of aging 26(1): 128-132.

Hartman, R. E., A. Shah, et al. (2006). "Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer's disease." Neurobiology of Disease 24(3): 506-515.

REFERENCESIsingrini, E., T. Desmidt, et al. (2009). "Endothelial dysfunction: A potential therapeutic target for

geriatric depression and brain amyloid deposition in Alzheimer's disease?" Curr Opin Investig Drugs 10(1): 46-55.

Monnet-Tschudi, F., M. G. Zurich, et al. (2006). "Involvement of environmental mercury and lead in the etiology of neurodegenerative diseases." Rev Environ Health 21(2): 105-17.

Mutter, J., J. Naumann, et al. (2004). "Alzheimer disease: mercury as pathogenetic factor and apolipoprotein E as a moderator." Neuro Endocrinol Lett 25(5): 331–339.

Bush,A.I. (2002) Metal complexing agents as therapies for Alzheimer’s disease. Neurobiol. Aging, 23, 1031–1038.

Chen, D., Q. C. Cui, et al. (2007). "Clioquinol, a Therapeutic Agent for Alzheimer's Disease, Has Proteasome-Inhibitory, Androgen Receptor-Suppressing, Apoptosis-Inducing, and Antitumor Activities in Human Prostate Cancer Cells and Xenografts." Cancer Res 67(4): 1636-1644.

Neurodegenerative Disease

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