Neurodegenerative Disease

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

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

Pathogenesis is illdefined is apparently multifactorial
implies selective regional nerve cell vulnerability

~related to~ e.g. amyloid B plaques M. Flint Beal, AC. Ludolph (2005). Neurodegenerative Diseases: Neurobiology, genetic, environmental, Pathogenesis and Therapeutics, metabolic and other Cambridge University Press. aging factors

Abnormal protein accumulation ~

Dementia disorders

All share common characteri Dementia + Movement stics disorders

Diffuse Lewy Body Disease Alzheimers Disease Lewy Body variant Hungtingtons Disease

Alzheimers Disease Picks Disease

Neurodegen erative Disease

Movement disorders

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

Parkinsons Disease Cerebellar Ataxia Motor Neurone Disease Multiple System Atrophy

Neurodegenerative Disease
Reduced mitochondrial and axonal transport Progressive cell atrophy & apoptosis

Increased tissue oxidative damage

Increased Tau protein phosphorylation

Decreased neurotransmitter production Progressive cell atrophy & apoptosis

Common characteris tics

Skovronsky et al. 2006. "NEURODEGENERATIVE DISEASES Ann Rev Path Mech Dis. 1(1)

Accumulation of abnormal protein fragments Increased inflammatory cytokine production Increased inflammatory lipid mediators

Cognitive Disorder
Picks disease ~
more common below 60 yrs

Dementia
90 % sporadic 10 % familial

Alzheimers disease ~
90% of dementia cases > 70 yrs

Amyloid-B-peptide Accumulation
Insoluble amyloid plaques

Annual incidence Exponential increase with a

Tau protein hyperphosphorylation

40 to 60 yrs ~ 2.4 / 100,000 80 yrs ~ 127 / 100,000 4th or 5th leading cause of dea

Thomas & Fenech. 2007. A review of genome mutation and Alzheimer's disease. ~ neurofibrillary tangles Mutagenesis 22(1): 15-33. Mendez et al. 2008. Psychopathology of Frontotemporal Dementia: J Neuropsychiatry Clin Neurosci 20(2)

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

Alzheimers disease ~

arly Onset Familial Alzheimers Disease

accounts for < 5% of all Alzheimer patients generally onsets between 50 ~ 60 yrs age

Clinical Picture

rapid & unrelenting progression of cognitive deterioration

Genetic form of Alzheimers Disease

~ multiple polymorphisms on 3 genes ~ autosomal dominant inheritance

presenilin 1 (PSEN1) ch-14, presenilin 2 (PSEN2) ch-1 A precursor protein (APP) chThomas & Fenech. 2007. A review of genome mutation and Alzheimer's disease. Mutagenesis 22(1): 15-33.

Onset Alzheimers Disease

Increased risk with:

APO-E4 genotype to 40~70% of cases TNF-alpha polymorphism Trisomy 21

0% of all Alzheimer patients above age 70 yrs slow progressive disease

Risk Factors: Risk Factors: Aging, menopause Protective factors: cardiovascular disease low education level nti-inflammatory drugs obesity head trauma, antioxidant agents diabetes cerebral ischaemia oestrogen chronic inflammation high educational level
Minati L, et al. 2008. Current Concepts in Alzheimer's Disease: A Multidisciplinary Review.. J Alzheimers Dis Other Demen.

Alzheimers Disease 3 Major processes

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

Inflammation
Exacerbated by * cerebral iron &

Present at cellular level

~brain microglia activation not systemic inflammation Increased

cytokine production Increased lipid mediators:

TNF-alpha IL-1

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

copper * Vascular Reduced DHA endothelial Leukotrienes impairs disease Neuronal signalling * APO E4 gene * Insulin 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. Resistance

Low antioxidant status Ascorbate Bioflavonoids Environmental proanthocyanidin oxidant exposure s Smoking Heavy metal Air pollution overload Heavy metals ~ iron, copper Hg, Mn mercury Yan, 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.

Oxidant Stress derives from

EFA imbalance omega-3-FA insufficiency Inflammation APO e4 gene TNF-alpha polymorphism Chronic inflammatory disease Insulin Resistance Cardiovascular Disease Diabetes

Omega-3-EFA deficiency inadequate intake of Fish & fish oils Mineral Depletion Zinc Magnesium Chromium Chronic Inflammation

Obesity and Overweight DIET High Carbohydrate intake High saturated fatLack intake of EXERCISE

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.

Carbohydrateresponsive Gene Polymorphisms PPARS SREBP ChREBP

Mitochond rial Inflammatory Obesity dysfunctio Reduced cytokine Adipokine n ATP release production Neurotransmitter genesis imbalance Insulin NMDA- receptor Inflammatory Resistance activation Lipid Glutamate Glucose Mediators toxicity toxicity

Alzheimers Disease Causal Factors

Nutrient Depletion Oxidative damage

Heavy metal toxicity

Alzheimers Disease
Useful Tests
Urinary Mineral Analysis Ca, Mg, Zn

APO E genotype Full Blood Count & ESR

Cigarette Smoking Check Alcohol consumption

High sensitivity CRP Glucose Tolerance Test and ESR with insulin & cortisol Nutrient status Iron study Food Antibodies Vit C, E & D and ferritin both IgG and IgE Red cell EFA analysis Urinary Metabolite Analysis Hormone Balance DHEA, Oestrogen Testosterone Neurotransmitter balance Bowel Dysbiosis markers Faecal Bacterial Analysis microbial culture &/or DNA analysis

Antioxidant Status & Co-Q10

DNA Oxidative damage

Test for Heavy Metal Load Hair Analysis or Urinary Mercury Provocation

Alzheimers Disease
TREATMENT

DIGESTIVE SUPPORT Gastric acid and Digestive enzy

DIET Low-allergy & Low Glycemic Load High protein & vegetable intake Primary Antioxidant Consider Therapy Paleolithic or ketogenic diet Vitamin C ~ mixed mineral ascorbates Mixed tocopherols & Tocotrienols Phytonutrient Therapy Essential Fatty Acid Mixed bioflavonoids Blueberries Supplements Green tea DHA-rich omega-3-FAs Resveratrol alpha-Linolenic acid Curcumin Pomegranate

Natural chelators N-acetylcysteine TREATMENT Garlic extracts Mineral therapy Alpha-lipoic acid Calcium Vitamin therapy Green tea extract Magnesium High dose: Pharmaceutical chelating Activated B-Complex Selenium agents Chromium Folate & B12 EDTA chelation Pyridoxal-5-phosphate Zinc Clioquinol NADH Desferrioxamine DMSA Neuronal stimulation Adaptogenic Herbs Citicholine Ginkgo biloba Phosphatidylserine Korean Ginseng L-arginine Ashagarwan

Alzheimers Disease

Toxic Mineral Removal

Alzheimers 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

Thank you for your care and attention

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