NeuroRegeneration Dr. Joseph Pizzorno, ND Editor-in-Chief, Integrative Medicine: A Clinician’s Journal Founding President, Bastyr University Chair, Board of Directors, Institute for Functional Medicine Chair, Scientific Advisory Board, Bioclinic Naturals [email protected] Copyright © 2020 Overview 1. Worldwide Epidemic of Brain Disorders 2. Stop the Damage Neurotoxic Metals and Chemicals in Environment Loss of Blood Sugar Control Mitochondrial Dysfunction Neuroinflammation 3. Protect From Damage Antioxidants Glutathione 4. Support Normal Function Nutritional Deficiencies/Excesses are Rampant 5. Facilitate Regeneration 6. Condition-Specific Protocols WORLDWIDE EPIDEMIC OF NEUROLOGICAL DISORDERS Autism https://www.cdc.gov/ncbddd/autism/data.html (CDC data from 2000 to 2014) ADHD Parkinson’s Disease Lix LM, Hobson DE, Azimaee M, et al. Socioeconomic variations in the prevalence and incidence of Parkinson's disease: a population-based analysis. J Epidemiol Community Health. 2010 Apr;64(4):335-40 Alzheimer’s Disease https://www.cdc.gov/nchs/products/databriefs/db116.htm (Accessed July 2019) Virtually every disease and clinical condition caused by neurological damage has increased in every age group the past 50 years WHY? Neurotoxins Nutritional Deficiencies Depletion of Key Molecules in Food Supply Nutritional Excesses Loss of Blood Sugar Control Decreased Brain Regeneration Genomic Susceptibility CAUSES OF NEURODEGENERATION EPIDEMIC Neurological Degeneration Basic Mechanisms Common Etiologies ▪ Microglia overactivation • APOE e4 allele ▪ Mitochondrial damage • Lack of sleep ▪ Inflammation • Hyperhomocysteinemia ▪ Oxidative stress • Functional B12 deficiency ▪ Mis-folded proteins • Sugar dysregulation • Commonly prescribed drugs • Hypoxia • Psychological stress • Animal product consumption? • Environmental neurotoxins Microglia overactivation Neurotoxic Metals and Chemicals in Environment Loss of Blood Sugar Control Loss of Mitochondrial Function Neuroinflammation STOP THE DAMAGE Significant Clinical and/or Epidemiological Research Support for Neurotoxin Damage Diseases Conditions • Attention deficit hyperactive • Cognitive decline disorder (ADHD) • Dementia • Autism spectrum disorder (ASD) • Headache • Amyotrophic lateral sclerosis (ALS) • IQ loss (esp children) • Alzheimer’s disease (AD) • Mood disorders • Parkinson’s disease (PD) • Motor neuron disorders Crinnion W, Pizzorno J. Neurotoxicity in, Clinical Environmental Medicine. Elsevier, 2018 The Worst Neurotoxins(?) Prenatal Postnatal ▪ Methylmercury ▪ Arsenic ▪ Organophosphate pesticides ▪ Cadmium ▪ PCBs ▪ DDT/DDE ▪ Phthalates ▪ Lead ▪ Polyfluoroalkyl chemicals ▪ Mercury ▪ OCPs ▪ PCBs ▪ Particulate matter (Vehicular exhaust) ▪ Solvents Primary Mechanisms of Neuron Damage 1. Direct neurotoxicity 2. Oxidative stress 3. Inappropriate microglial activation 4. Mitochondrial damage 5. Methyl group depletion 6. Decreased production of BDNF 7. Impairment of microcirculation SOURCES OF NEUROTOXINS Sources of Neurotoxins • Farmed fish (POPs) • Large fish (Hg) • Chemically-grown foods (pesticides, Cd) • Food storage (BPA, phthalates) • Amalgam fillings (hg) • Arsenic in water • PM in air (PMs carry VOCs) • Lead in water, paint • Mold? (mycotoxins) • Common prescription drugs Mercury Exposure Common • Average exposure in non-industrial populations ▪ Amalgams: 10 ug/d ▪ Fish: 2.3 ug/d ▪ Water: 0.3 ug/d ▪ Air ▪ Vaccinations • Industrial Vimy, M.J., and Lorscheider, F.L (1990) Dental amalgam mercury daily dose estimated from intra-oral vapor measurements: A predictor of mercury accumulation in human tissues.]. Trace Elem. Exp. Med 3, 111-123 Hg From Fish • Total Hg urinary excretion proportional to amount of fish eaten • Impaired psychomotor performance ▪ R = 0.38 blood ▪ R = 0.77 urine • Huge variation in amount of Hg in fish Apostoli P, ICortesi I, Mangili A, et al. Assessment of reference values for mercury in urine: the results of an Italian polycentric study. The Science of the Total Environment 289 (2002)13-24 Carta P, et al. Sub-clinical neurobehavioral abnormalities associated with low level of mercury exposure through fish consumption. NeuroToxicology 24 (2003) 617–623 18 Amalgams Put Mercury Into the Brain • Mercury accumulates in the brain in proportion to surface area of amalgams • Study of 18 cadavers ▪ Hg in brain, thyroid and kidneys proportional to the number of amalgam surfaces ▪ For those with more than 12, Hg in brain disproportionately higher ▪ Suggests that at higher levels of exposure the brain’s mercury excretion pathways become overloaded. Guzzi 2006 Reinhardt JW. Side-Effects: Mercury contribution to body burden from dental amalgam. Adv Dent Res. 1992;6: 110 Guzzi G, et al. Dental amalgam and mercury levels in autopsy tissues. Am J Forensic Med Pathol. 2006 Mar;27(1):42-5 19 Mercury in the Air EPA-452/R-97-003 December 1997 Neurotoxins Daily Exposure to Daily Exposure Zeliger HI. Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases. Interdiscip Toxicol. 2013 Sep;6(3):103-10 PMID: 24678247 NEUROTOXICITY FETUS AND CHILDREN Prenatal Effects - Organophosphates • Prenatal exposure particularly harmful • Higher levels = poorer cognitive scores, (memory, processing speed, comprehension, and reasoning). • 7-point lower IQ (highest-lowest quintile) • 25% of pregnant US women have levels exceeding the median in this study • Children with higher levels of OP metabolites had up to 2x increased risk for ADHD, and the levels associated with risk were commonly found in the US population among children Rauh et al. 2011 Bouchard MF, et al. Prenatal Exposure to Organophosphate Pesticides and IQ in 7-Year Old Children. Environ Health Perspect. 2011 Aug;119(8):1189-95 Rauh V, et al. 7-Year Neurodevelopmental Scores and Prenatal Exposure to Chlorpyrifos, a Common Agricultural Pesticide. Environ Health Perspect. 2011 Apr 21. Bouchard MF,et al. Attention-deficit/hyperactivity disorder and urinary metabolites of organophosphate pesticides. Pediatrics. 2010 Jun;125(6):e1270-7 Polyfluoroalkyl Chemicals - Children • Developmental neurotoxicants • Associated with ADHD in children age 12-15 • Eliminated very slowly from the body – serum ½ life of 2 to 8.5 years • Gore-Tex, Scotchgard and STAINMASTER all PFCs • Serum levels directly associated with income (opposite of BPA, with higher levels seen in lower income) Hoffman K, et al. Exposure to polyfluoroalkyl chemicals and attention deficit/hyperactivity disorder in U.S. children 12-15 years of age. Environ Health Perspect. 2010 Dec;118(12):1762-7. Nelson JW, et al. Social disparities in exposures to bisphenol A and polyfluoroalkyl chemicals: a cross-sectional study within NHANES 2003-2006. Environ Health. 2012 Mar 6;11:10. Phthalates Prenatal exposure associated with conduct & attention • Fabjan et al. 2006 disorders (17050082) • Found in building materials, personal cosmetics, pharmaceuticals, nutritional supplements, solvents, adhesives, paints, lacquers, insecticides, air fresheners, shampoos, cleaning materials, children’s toys, and food packaging • May be listed as “fragrance” • Dietary sources – chickens and eggs had DEHP metabolites, suggesting chickens (vs. packaging) are contaminated Engel SM, et al. Prenatal phthalate exposure is associated with childhood behavior and executive functioning. Environ Health Perspect. 2010 Apr;118(4):565-71 Schettler T. Human exposure to phthalates via consumer products. Int J Androl. 2006 Feb;29(1):134-9; PBDE – Less Burns, BUT: Less IQ, More ADHD • Polybrominated diphenyl ethers • Prenatal exposure linked to lower IQ, and lower scores on tests of physical and mental development at 12-28, and 72 months • Postnatal exposure linked to poor social competence and attention deficit in 4 year old children She J, et al. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in breast milk from the Pacific Northwest. Chemosphere. 2007 Apr;67(9):S307-17 Gascon M, et al. Effects of pre and postnatal exposure to low levels of polybromodiphenyl ethers on neurodevelopment and thyroid hormone levels at 4 years of age. Environ Int. 2011 Apr;37(3):605-11. Herbstman JB, et al. Prenatal exposure to PBDEs and neurodevelopment. Environ Health Perspect. 2010 May;118(5):712-9 Lam J, Lanphear BP, Bellinger D, et al. Developmental PBDE Exposure and IQ/ADHD in Childhood: A Systematic Review and Meta-analysis. Environ Health Perspect. 2017 Aug 3;125(8):086001 PBDEs in Dust World-Wide • Polybrominated diphenylethers • Flame retardants • Presence in dust • UK especially high Aust Gov. Interim public health risk assessment of certain PBDE congeners. March 2007 NEUROTOXICITY ADULTS Organochlorine Pesticides and Dementia Kim KS, Lee YM, Lee HW, et al. Associations between organochlorine pesticides and cognition in U.S. elders: National Health and Nutrition Examination Survey 1999–2002. Environment International 2015;75: 87–92 Parkinson’s Disease • Measured atrazine, Atrazine simazine, alachlor, and metolachlor in 286 well water samples • For every 1.0 µg/L of total pesticide in groundwater, the risk of PD increased by 3% Chlorpyrifos James KA, Hall DA. Groundwater pesticide levels and the association with Parkinson disease. Int J Toxicol. 2015 May-Jun;34(3):266-73 PCB Levels Correlate with Parkinson’s Disease Hatcher-Martin JM, Gearing M, Steenland K, et al. Association between polychlorinated biphenyls and Parkinson's disease neuropathology. Neurotoxicology. 2012 Oct;33(5):1298-304. PMID: 22906799 Solvents Impair Neurological