Neurodegenerative Disease

1. NeurodegenerativeDisease Dr Melvyn A Sydney-Smith. KGSJ. MBBS, PhD, Dip Gest Ther, Master Prac NLP, FACNEM. Australian College of Holistic Medicine Adjunct Professor, Nutrition Medicine RMIT University

2. Neurodegenerative Disease Excludes known disease: vascular, toxic, metabolic,infective and autoimmune disease Progressive, nerve cell dysfunction & apoptosis  eventuating in CNS atrophy & death Affects specific brain systems implies selective regionalnerve cell vulnerability Pathogenesis is ill-defined is apparently multifactorial ~related to~ genetic, environmental, metabolic and other aging factors Abnormal protein accumulation ~e.g. amyloid B plaques M. Flint Beal, AC. Ludolph (2005). Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics, Cambridge University Press.

3. Neurodegenerative Disease Dementia disordersAlzheimer’s DiseasePick’s Disease All share common characteristics Movement disordersParkinson’s DiseaseCerebellar AtaxiaMotor Neurone DiseaseMultiple System Atrophy Dementia + Movement disordersDiffuse Lewy Body Disease Alzheimer’s Disease Lewy Body variantHungtington’s Disease M. Flint Beal, AC. Ludolph (2005). Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics, Cambridge University Press.

4. Neurodegenerative Disease Increased tissue oxidative damage Reduced mitochondrial and axonal transport Increased Tau protein phosphorylation Common characteristics Progressive cell atrophy & apoptosis Accumulation of abnormal protein fragments Increased inflammatory cytokine production Decreased neurotransmitter production Progressive cell atrophy & apoptosis Increased inflammatory lipid mediators Skovronsky et al. 2006. "NEURODEGENERATIVE DISEASES … Ann Rev Path Mech Dis. 1(1)

5. Cognitive Disorder Dementia90 % sporadic10 % familial Pick’s disease ~more common below 60 yrs Alzheimer’s disease ~90% of dementia cases > 70 yrs Annual incidence Exponential 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 plaques Tau protein hyperphosphorylation~ neurofibrillary tangles Thomas & Fenech. 2007. A review of genome mutation and Alzheimer's disease. Mutagenesis22(1): 15-33. Mendez et al. 2008. Psychopathology of Frontotemporal Dementia: J Neuropsychiatry Clin Neurosci 20(2)

6. Alzheimer’s disease ~Classic dementia disorder& the commonestIncidence rises rapidly over 70 yrs age CVD is next commonest cause Neurofibrillary formation, Amyloid plaque deposition Lewy Bodies & Pick Bodies Insidious onset memory loss ~ progresses over 5~10 yrs impaired executive function, attentiveness, language, visual & motor processing and behaviour Neuronal Loss Brain Atrophy  Death Alzheimer’s Disease NormalAging Minati L, et al. 2008. Current Concepts in Alzheimer's Disease: A Multidisciplinary Review.. J Alzheimers Dis Other Demen.

7. Early Onset Familial Alzheimer’s Disease ~ accounts for < 5% of all Alzheimer patients ~ generally onsets between 50 ~ 60 yrs age Clinical Picture rapid & unrelenting progressionof cognitive deterioration 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 Thomas & Fenech. 2007. A review of genome mutation and Alzheimer's disease. Mutagenesis22(1): 15-33.

8. Increased risk with: • APO-E4 genotype  to 40~70% of cases • TNF-alpha polymorphism • Trisomy 21 Late Onset Alzheimer’s Disease 90% of all Alzheimer patientsabove age 70 yrsslow progressive disease • Risk Factors: • Aging, menopause • low education level • head trauma, • cerebral ischaemia • Risk Factors: • cardiovascular disease • obesity • diabetes • chronic inflammation Protective factors: anti-inflammatory drugs antioxidant agents oestrogen high educational level Minati L, et al. 2008. Current Concepts in Alzheimer's Disease: A Multidisciplinary Review..J Alzheimers Dis Other Demen.

9. Alzheimer’s Disease 3 Major processes Oxidantstress InsulinResistance Inflammation Emerit, J., M. Edeas, et al. (2004). "Neurodegenerative diseases and oxidative stress." Biomedicine & Pharmacotherapy 58(1): 39-46.

10. Inflammation Present at cellular level ~brain microglia activation ~ not systemic inflammation Increased cytokine production TNF-alphaIL-1 Exacerbated by*cerebral iron & copper* Vascular endothelial disease* APO E4 gene* Insulin Resistance Increased lipidmediators: Leukotrienes Reduced DHAimpairs Neuronal signalling Tan, Z. S., A. S. Beiser, et al. (2007). "Inflammatory markers and the risk of Alzheimer disease: The Framingham Study." Neurology68(22): 1902-1908. Lukiw, W. J. (2009). "Docosahexaenoic acid and Amyloid-beta Peptide Signaling in Alzheimer's Disease." World Rev Nutr Diet99: 55-70.

11. Oxidant Stressderives from EFA imbalanceomega-3-FA insufficiency InflammationAPO e4 gene TNF-alpha polymorphism Chronic inflammatory disease Low antioxidant status Ascorbate Bioflavonoids proanthocyanidins Environmental oxidant exposure Smoking Air pollution Heavy metals ~ Hg, Mn Insulin Resistance Cardiovascular Disease Diabetes Heavy metal overloadiron, coppermercury Yan, S. D., X. Chen, et al. (1996). "RAGE and amyloid-[beta] peptide neurotoxicity in Alzheimer's disease." Nature382(6593): 685-691. Emerit, J., M. Edeas, et al. (2004). "Neurodegenerative diseases and oxidative stress." Biomedicine & Pharmacotherapy 58(1): 39-46.

12. InsulinResistance Omega-3-EFA deficiencyinadequate intake of Fish & fish oils Obesity andOverweight • Mineral Depletion • Zinc • Magnesium • Chromium DIET High Carbohydrate intake High saturated fat intake Carbohydrate-responsive Gene PolymorphismsPPARS SREBP ChREBP ChronicInflammation Lack ofEXERCISE 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 Dementias23(2): 192-199.

13. Alzheimer’s Disease Causal Factors NutrientDepletion Heavy metal toxicity Oxidative damage Inflammatorycytokinerelease Mitochondrial dysfunction ObesityAdipokineproduction Reduced ATP genesis Neurotransmitterimbalance InsulinResistance InflammatoryLipidMediators NMDA- receptoractivation Glutamate toxicity Glucosetoxicity

14. Alzheimer’s Disease Useful Tests Cigarette Smoking APO E genotype Check Alcoholconsumption Full Blood Count & ESR High sensitivity CRPand ESR Glucose Tolerance Testwith insulin & cortisol Nutrient statusVit C, E & D Urinary MineralAnalysisCa, Mg, Zn Iron studyand ferritin Food Antibodiesboth IgG and IgE Red cell EFA analysis Neurotransmitterbalance Antioxidant Status& Co-Q10 Urinary Metabolite Analysis Bowel Dysbiosismarkers Hormone BalanceDHEA, OestrogenTestosterone DNA Oxidative damage Faecal Bacterial Analysismicrobial culture&/or DNA analysis Test for Heavy Metal Load Hair Analysis or Urinary Mercury Provocation

15. Alzheimer’s Disease TREATMENT DIGESTIVE SUPPORTGastric acid and Digestive enzymes DIETLow-allergy & Low Glycemic LoadHigh protein & vegetable intake Consider Paleolithic or ketogenic diet Primary Antioxidant TherapyVitamin C ~ mixed mineral ascorbatesMixed tocopherols & TocotrienolsMixed bioflavonoids Phytonutrient TherapyBlueberries Green tea Resveratrol Curcumin Pomegranate Essential Fatty Acid SupplementsDHA-rich omega-3-FAsalpha-Linolenic acid

16. Alzheimer’s Disease TREATMENT Toxic Mineral Removal Natural chelators N-acetylcysteine Garlic extracts Alpha-lipoic acid Green tea extract Pharmaceutical chelating agents EDTA chelation Clioquinol Desferrioxamine DMSA Mineral therapyCalcium Magnesium Selenium Chromium Zinc Vitamin therapyHigh dose: ActivatedB-Complex Folate & B12 Pyridoxal-5-phosphate NADH Neuronal stimulation Citicholine Phosphatidylserine L-arginine Adaptogenic Herbs Ginkgo biloba Korean GinsengAshagarwan

17. Alzheimer’s Disease THERAPY 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

18. Thank you • for your • care and attention

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