Disclosures: None Insights on Occupational & Environmental - PDF document

Disclosures: None Insights on Occupational & Environmental Causes of Neurodegenerative Disease Updates in Occupational and Environmental Medicine 2017 Samuel M. Goldman, MD, MPH Associate Professor, UCSF Department of Neurology SFVAMC, Division of Occupational & Environmental Medicine “Primary” Neurodegenerative Disorders: Neurodegenerative Diseases: Classification Clinical Classification  Etiology  Primary dementing disorders (may manifest parkinsonism) • “Primary”: Genetic or idiopathic • Alzheimer Disease (AD) • “Secondary”: Acquired • Frontotemporal dementias (FTD, FTLD)  Clinical features • Dementia with Lewy Bodies (DLB) • Motoric: pyramidal; extrapyramidal: parkinsonism, chorea, dystonia • Others: Argyrophilic grain disease, Pick’s Disease • Sensory  Primary parkinsonian disorders (may manifest dementia and/or dystonia) • Cognitive • Parkinson Disease (PD)  Clinical course • Atypical parkinsonisms: Multiple System Atrophy (MSA, OPCA, SND, Shy-Drager); Progressive Supranuclear Palsy (PSP); Corticobasal Ganglionic Degeneration (CBD) • Onset: acute, subacute, gradual  Choreiform disorders (may manifest dementia & parkinsonism) • Course: static, progressive • Huntington’s Disease • Response to therapy • Spinocerebellar ataxias  Pathology • Others: Neurodegeneration with Brain Iron Accumulation; Primary prion disorders; Wilson’s Disease • Anatomic distribution: focal/diffuse  Neuromuscular disorders • Cell types: neuron, glia, immune • Amyotrophic Lateral Sclerosis (ALS) • Molecular:  -amyloid, tau,  -synuclein, TDP-43, huntingtin, prion • primary lateral sclerosis, spinal/bulbar muscular atrophy 1

Primary Neurodegenerative Disorders “Secondary” Causes of Neurodegeneration Histological Classification • Solvents  Infections   -amyloidoidosis: AD, DLB • Metals  Trauma • Pesticides  Autoimmune  Tauopathies: AD, PSP, CBD, ALS-PDC of Guam, • Drugs  Hypoxic Pick’s….many others • Toxins  Metabolic  Synucleinopathies: PD, PDD, DLB, MSA • Toxicants • Radiation  TDP-43; FUS: ALS, FTLD Neurodegenerative Diseases: Mechanisms Distinguishing between Primary & Secondary Neurodegenerative & Neurotoxic Conditions Mechanisms common to primary (and secondary) neurodegenerative disorders Isn’t always easy…..  Inflammation Primary Acquired Characteristic Neurodegeneration Neurodegeneration  Oxidative stress Onset Gradual Rapid/intermediate/gradual  Energy Course Progressive May improve or plateau impairment/mitochondrial Symmetry Usually asymmetric Often symmetric dysfunction Focality Variable Often diffuse  Protein mishandling Response to therapy Disease-specific +/-  Impaired autophagy Imaging Specific tracers available for Variable, often some (PIB, DatSCAN) uninformative  Apoptosis Biological Few biomarkers currently Toxicology Exposure history ?? Essential From Perry et al, in Molecular Pathology of Dementia & Movement Disorders, Dickson ed, 2011 2

Parkinsonism: A Clinical Syndrome Challenges in Studying Neurodegenerative Diseases Clinical Syndrome: Bradykinesia, resting tremor, rigidity, postural reflex impairment  Few or no diagnostic tests Neural substrate: Nigrostriatal system  Clinically heterogeneous Pharmacology: Disrupted nigrostriatal  Etiologically heterogeneous dopaminergic neurotransmission  Diseases of aging: long pre-clinical period  Exposures may occur years before symptoms  Competitive mortality  Limited ability to diagnose prodromal disease  E.g., high prevalence “incidental” Lewy bodies Parkinsonism Types: Clinical Distinctions Parkinson’s Disease  Acute/Subacute Onset:  Most common cause of parkinsonism • Causes: Typically due to a discrete, identifiable injury  Affects ~ 1 million in U.S. • Minimal or no progression  50,000-70,000 new cases annually • Reversible Forms: Antipsychotic use most common, other drugs, possibly some toxicants or infections  Depicted in ancient texts: • Irreversible Forms: Vascular, infectious, traumatic, toxicant  Maimonides 1200s Spain  Called “kampavata” in Indian Ayurveda  Gradual Onset:  Described fully by James Parkinson in 1817 • Causes: Genetic, toxicant, mostly unknown (likely multifactorial) • Commonly progressive  ~ 2% prevalence > 65 years of age • Neurodegenerative forms here: PD, MSA, PSP, CBD 3

PD Pathology: Loss of Pigmented Dopaminergic Age-Specific PD Incidence Neurons in the Substantia Nigra pars compacta 200 180 PD Incidence per 100,000 160 Male Female 140 120 100 80 60 40 But….PD is a 20 systemic disease 0 30-39 40-49 50-59 60-69 70-79 80+ Age Synuclein pathology in Synuclein pathology myenteric plexus in olfactory bulb Kaiser Permanente Northern CA, Van den Eeden, Am J Epidem, 2003. Projected Increase of PD PD Incidence may be increasing over time 2005-2030 Dorsey, et al, 2007, Neurology Savica et al, JAMA Neurol , 2016 4

Twins: Nature's Controlled Study The Great Genetics vs. Environment Debate • Identical twins share 100% of genes • Fraternal twins share ~ 50% of genes Hypothesis: “…paralysis agitans is not a family disease” If PD is primarily a genetic disorder, MZ concordance should be >> DZ concordance. Charcot, 1877 Results: Similar concordance in MZ & DZ twin pairs “Many patients with the disease have a strong family NAS/NRC WWII Heritability > age 50 only 7% VETERAN TWINS ROSTER history…” 31,848 TWINS BORN 1917 - 1927 Gowers, 1888 Conclusion: Environment is a major contributor to the cause of PD Tanner, Goldman et al, JAMA, 1999 Designer Drug Lab, Watsonville, CA MPTP parkinsonism vs. idiopathic PD • Patients were regular iv drug users • All had injected a “synthetic heroin” 2-6 weeks prior Feature MPTP parkinsonism Parkinson’s disease Cardinal signs + + Onset Rapid Gradual L-dopa response + + Treatment-related dyskinesias + + Nigrostriatal DA deficits + + Progressive +/- + Pigmented nigral DA cell death + + Lewy bodies ? + Toxicant identified: 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) 5

Mechanism of MPTP Toxicity: Causes of secondary parkinsonism Do Toxicants Cause PD? – Drugs • Dopamine receptor blocking (neuroleptics, metoclopramide, prochlorperazine) • Dopamine depleting (reserpine,  ‐ methyl ‐ dopa) • Calcium channel blockers • Antiarrhythmics (amiodarone, procaine) • Anticonvulsants (valproate, phenytoin) • Immunosuppressants (cyclosporine, vincristine, adriamycin) • lithium – Infection • encephalitis lethargica, von Economo’s disease (influenza?) • West Nile, Japanese B encephalitis, EBV • HIV • Syphilis • Lyme, TB, Malaria – Vascular: basal ganglia – Trauma – Toxicant • Manganese (occupational; ephedrone) • Carbon monoxide • Carbon disulfide (rayon manufacturing; grain fumigant) • Hydrocarbon solvents Goldman, Ann Rev Pharmacol Toxicol, 2014 • MPTP Solvents & PD: specific agents rarely studied Solvents & Parkinson’s Disease Study Design Exposure Association  Acute solvent intoxications can cause parkinson ism Hertzman et al, 1994 Case-control Solvents: Self-reported 2.2 (1.1-4.4) • methanol (Guggenheim et al, 1971) Seidler et al, 1996 Case-control Solvents: Self-reported 1.8 (1.2-2.7) Solvents: IH inferred ns • n ‐ hexane (Pezzoli et al, 1989) Pals et al, 2003 Case-control Toluene: Self-reported 7.8 (1.0-59) • hydrocarbon and solvent mixtures (McCrank et al, 1989; McDonnell, 2003 Industrial cohort Solvents: IH job hx review 1.5 (0.81-2.9) Tetrud et al, 1994; Uitti et al, 1994) Park et al, 2005 National mortality Occupation-based “solvent 1.07 (1.0-1.13) database exposure index”  Associations with idiopathic PD are not consistent Dick et al, 2007 Case-control Solvents: IH inferred ns Tanner et al, 2009 Case-control Task-based history: Glue or adhesive use 1.3 (0.85-2.0) Cleaning with solvents ns Firestone et al, 2009 Case-control Solvents: self-report or IH Men ns Women 1.7 (0.98-3.0) 6