neurodegenerative disease
DESCRIPTION
noneTRANSCRIPT
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.
Neurodegenerative Disease
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.
Neurodegenerative Disease
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.
Alzheimer’s Disease
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
Alzheimer’s Disease
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
Alzheimer’s Disease
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
Alzheimer’s Disease
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.