Disclosures: None Insights on Occupational & Environmental - - PDF document

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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

Disclosures: None

Neurodegenerative Diseases: Classification

• Etiology
• “Primary”: Genetic or idiopathic
• “Secondary”: Acquired
• Clinical features
• Motoric: pyramidal; extrapyramidal: parkinsonism, chorea, dystonia
• Sensory
• Cognitive
• Clinical course
• Onset: acute, subacute, gradual
• Course: static, progressive
• Response to therapy
• Pathology
• Anatomic distribution: focal/diffuse
• Cell types: neuron, glia, immune
• Molecular: -amyloid, tau, -synuclein, TDP-43, huntingtin, prion

“Primary” Neurodegenerative Disorders: Clinical Classification

• Primary dementing disorders (may manifest parkinsonism)
• Alzheimer Disease (AD)
• Frontotemporal dementias (FTD, FTLD)
• Dementia with Lewy Bodies (DLB)
• Others: Argyrophilic grain disease, Pick’s Disease
• Primary parkinsonian disorders (may manifest dementia and/or dystonia)
• Parkinson Disease (PD)
• Atypical parkinsonisms: Multiple System Atrophy (MSA, OPCA, SND, Shy-Drager); Progressive

Supranuclear Palsy (PSP); Corticobasal Ganglionic Degeneration (CBD)

• Choreiform disorders (may manifest dementia & parkinsonism)
• Huntington’s Disease
• Spinocerebellar ataxias
• Others: Neurodegeneration with Brain Iron Accumulation; Primary prion disorders; Wilson’s Disease
• Neuromuscular disorders
• Amyotrophic Lateral Sclerosis (ALS)
• primary lateral sclerosis, spinal/bulbar muscular atrophy

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Primary Neurodegenerative Disorders Histological Classification

• -amyloidoidosis: AD, DLB
• Tauopathies: AD, PSP, CBD, ALS-PDC of Guam,

Pick’s….many others

• Synucleinopathies: PD, PDD, DLB, MSA
• TDP-43; FUS: ALS, FTLD

“Secondary” Causes of Neurodegeneration

• Solvents
• Metals
• Pesticides
• Drugs
• Toxins
• Toxicants
• Radiation
• Infections
• Trauma
• Autoimmune
• Hypoxic
• Metabolic

Distinguishing between Primary & Secondary Neurodegenerative & Neurotoxic Conditions

Characteristic Primary Neurodegeneration Acquired Neurodegeneration Onset Gradual Rapid/intermediate/gradual Course Progressive May improve or plateau Symmetry Usually asymmetric Often symmetric Focality Variable Often diffuse Response to therapy Disease-specific +/- Imaging Specific tracers available for some (PIB, DatSCAN) Variable, often uninformative Biological Few biomarkers currently Toxicology Exposure history ?? Essential

Isn’t always easy…..

Neurodegenerative Diseases: Mechanisms

• Inflammation
• Oxidative stress
• Energy

impairment/mitochondrial dysfunction

• Protein mishandling
• Impaired autophagy
• Apoptosis

Mechanisms common to primary (and secondary) neurodegenerative disorders

From Perry et al, in Molecular Pathology of Dementia & Movement Disorders, Dickson ed, 2011

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Challenges in Studying Neurodegenerative Diseases

• Few or no diagnostic tests
• Clinically heterogeneous
• Etiologically heterogeneous
• 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: A Clinical Syndrome

Clinical Syndrome: Bradykinesia, resting tremor, rigidity, postural reflex impairment Neural substrate: Nigrostriatal system Pharmacology: Disrupted nigrostriatal dopaminergic neurotransmission

Parkinsonism Types: Clinical Distinctions

• Acute/Subacute Onset:
• Causes: Typically due to a discrete, identifiable injury
• Minimal or no progression
• Reversible Forms: Antipsychotic use most common, other drugs,

possibly some toxicants or infections

• Irreversible Forms: Vascular, infectious, traumatic, toxicant
• Gradual Onset:
• Causes: Genetic, toxicant, mostly unknown (likely multifactorial)
• Commonly progressive
• Neurodegenerative forms here: PD, MSA, PSP, CBD

Parkinson’s Disease

• Most common cause of parkinsonism
• Affects ~ 1 million in U.S.
• 50,000-70,000 new cases annually
• Depicted in ancient texts:
• Maimonides 1200s Spain
• Called “kampavata” in Indian Ayurveda
• Described fully by James Parkinson in 1817
• ~ 2% prevalence > 65 years of age

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20 40 60 80 100 120 140 160 180 200 30-39 40-49 50-59 60-69 70-79 80+ PD Incidence per 100,000

Age-Specific PD Incidence

Male Female

Age

Kaiser Permanente Northern CA, Van den Eeden, Am J Epidem, 2003.

PD Pathology: Loss of Pigmented Dopaminergic Neurons in the Substantia Nigra pars compacta

But….PD is a systemic disease

Synuclein pathology in myenteric plexus Synuclein pathology in olfactory bulb

Projected Increase of PD 2005-2030

Dorsey, et al, 2007, Neurology

PD Incidence may be increasing over time

Savica et al, JAMA Neurol, 2016

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The Great Genetics vs. Environment Debate

“…paralysis agitans is not a family disease”

Charcot, 1877

“Many patients with the disease have a strong family history…”

Gowers, 1888

Twins: Nature's Controlled Study

• Identical twins share 100% of genes
• Fraternal twins share ~ 50% of genes

Hypothesis:

If PD is primarily a genetic disorder, MZ concordance should be >> DZ concordance.

NAS/NRC WWII VETERAN TWINS ROSTER 31,848 TWINS BORN 1917 - 1927

Results:

Similar concordance in MZ & DZ twin pairs Heritability > age 50 only 7%

Conclusion: Environment is a major contributor to the cause of PD

Tanner, Goldman et al, JAMA, 1999

Designer Drug Lab, Watsonville, CA

Toxicant identified: 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)

• 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 ? +

MPTP parkinsonism vs. idiopathic PD

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Mechanism of MPTP Toxicity: Do Toxicants Cause PD?

Goldman, Ann Rev Pharmacol Toxicol, 2014

Causes of secondary parkinsonism

– 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
• MPTP

Solvents & Parkinson’s Disease

• Acute solvent intoxications can cause parkinsonism
• methanol (Guggenheim et al, 1971)
• n‐hexane (Pezzoli et al, 1989)
• hydrocarbon and solvent mixtures (McCrank et al, 1989;

Tetrud et al, 1994; Uitti et al, 1994)

• Associations with idiopathic PD are not consistent

Solvents & PD: specific agents rarely studied

Study Design Exposure Association

Hertzman et al, 1994 Case-control Solvents: Self-reported 2.2 (1.1-4.4) Seidler et al, 1996 Case-control Solvents: Self-reported Solvents: IH inferred 1.8 (1.2-2.7) ns Pals et al, 2003 Case-control Toluene: Self-reported 7.8 (1.0-59) McDonnell, 2003 Industrial cohort Solvents: IH job hx review 1.5 (0.81-2.9) Park et al, 2005 National mortality database Occupation-based “solvent exposure index” 1.07 (1.0-1.13) Dick et al, 2007 Case-control Solvents: IH inferred ns Tanner et al, 2009 Case-control Task-based history: Glue or adhesive use Cleaning with solvents 1.3 (0.85-2.0) ns Firestone et al, 2009 Case-control Solvents: self-report or IH Men Women ns 1.7 (0.98-3.0)

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Trichloroethylene (TCE) & PD

Guehl et al, 1999 Case‐report (n=1)

• 7 years exposure house cleaner, plastics

Kochen et al, 2003 Case‐series (n=3)

• 3 unrelated workers 10‐25 years exposure
• work histories not described

Gash et al, 2008 Cluster

• industrial plant metal degreasing
• PD in 3 co‐workers > 25 years exposure
• mild parkinsonian signs/symptoms in others
• Common exposures since the 1920s
• Degreasing metal parts (85%), computer circuits
• Dry-cleaning
• Surgical anesthetic (until 1977)
• Decaffeinated coffee (until 1977)
• Typewriter correction fluids, adhesives, paints,

carpet cleaners, spot removers…..

• Most frequently reported organic

contaminant in groundwater

TCE (trichloroethylene)

Occupational Solvent Exposures in PD- discordant twins. Goldman et al, Ann Neurol, 2012

Compound Odds ratio ever/never 95% Confidence Interval p‐value 1 or more a priori solvents 1.7 0.80‐3.7 0.16 N‐hexane 1.3 0.40‐4.1 0.69 Toluene 1.3 0.49‐3.3 0.61 Xylene 2.2 0.43‐12 0.34 CCl4 2.3 0.88‐6.1 0.088 TCE 6.1 1.2‐33 0.034 PERC 10.5 0.97‐113 0.053

Oral TCE causes selective dose-related degeneration

• f dopaminergic neurons in rat substantia nigra

Liu, et al, J Neurochem 2010

(a) (b) (c)

• Fig. 1 TCE-induced dopaminergic neuron

degeneration in a dose-dependent manner. (a) Representative TH immunostaining in the substantia nigra of 6-week TCE (200, 500 and 1000 mg/kg) and vehicle-treated

• rats. Scale bar = 500 l m. (b) Unbiased

stereological cell counting showed a signif- icant reduction in the total number of TH- positive neurons in the substantia nigra of 500 and 1000 mg/kg TCE-treated rats as compared with vehicle treatment. *p < 0.05, **p < 0.01 vs. vehicle, n = 6 per group. (c) Silver staining revealed degenerating neu- rons with metallic silver deposits (arrow) and the surrounding

• f

glia-like cells (arrowheads) in the substantia nigra after 6- week 1000 mg/kg TCE treatment. Scale bar = 50 l m.

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• 1‐trichloromethyl‐1,2,3,4‐tetrahydro‐‐carboline (TaCLO)
• Dopaminergic neurotoxin
• MPTP analogue
• potent mitochondrial complex 1 inhibitor

TaClo Hypothesis (Bringmann, 1995)

TCE PERC TaClo

CYP2E1 Tryptamine

MPTP

Pesticides & PD

• Pesticide use has been

associated with PD in >40 studies worldwide

• Insecticides, herbicides,

fungicides, rodenticides, piscicides, acaricides.

• Specific compounds rarely

associated

Van der Mark et al, EHP, 2012

• 84,000 pesticide applicators & spouses
• Iowa & North Carolina
• 600 in-home exams
• Lifetime environmental history interviews

Pesticide PD Risk P-value Rotenone 2.8 0.005 Paraquat 2.5 0.004

• Professional pesticide applicators (mostly farmers) & spouses
• 110 PD cases, 358 controls
• Asked about use of 31 specific pesticides
• Very good historians!
• Only 2 pesticides were significantly associated with PD

FAME Study: PD in Agricultural Health Study

Tanner, Kamel Goldman, et al, EHP, 2011

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Common Toxic Mechanisms

MPTP Paraquat Rotenone Mitochondrial poison + + + Oxidative stress + + + -synuclein protein + + + Parkinsonism in animal models + + + Nigrostriatal injury + + +

GSTT1 present, no PQ GSTT1 null, no PQ GSTT1 present, yes PQ GSTT1 null, yes PQ

Risk of PD

OR 1.1 OR 1.5

OR 11.1

Reference

}

G * E

Gene * Environment interaction:

Risk of PD from Paraquat exposure in GSTT1 null pesticide applicators

Goldman et al, Movement Disorders, 2012

Metals & PD

• Impaired iron homeostasis well-described in PD: Increased nigral

free iron & reduced ferritin

• Impaired copper homeostasis in PD
• Rare genetic forms of parkinsonism due to metals mishandling
• Neuromelanin binds metals in substantia nigra
• Dopamine oxidation enhanced by iron & other metals: generation
• f free radicals
• Many metals enhance the aggregation of -synuclein protein
• May cause secondary forms of parkinsonism (Mn, Hg)

Metals & PD: Limited Epidemiologic Evidence

• Lead in bone
• Weisskopf et al, EHP, 2010
• Airborne metals
• Palacios et al, EHP, 2014
• Nurses Health Study

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PD mortality

• dds by SOC code

Park et al, AJIM, 2005

• Death certificates 1992-8
• 2.6 million deaths
• PD n=33,678

Occupational Categories Associated with PD Mortality Odds Ratio Administrative support 1.2 Biological, medical scientists 2.0 Bus drivers 1.2 Clergy 1.8 Farming 1.1 Financial records processing 1.2 Horticultural specialists 1.7 Scheduling clerks 1.2 Painters, sculptors 1.2 Religious workers 1.7 Secretaries 1.4 Social workers 1.4 Teachers 1.6 Technical 1.2

Primary Occupation & PD in three movement disorders clinics (n=2,249) Manganese-induced parkinsonism

• Well-recognized cause of secondary parkinsonism (Couper, 1837)
• PD studies largely negative (Mortimer et al, Neurology, 2012)

Ephedrone (methcathinone)

https://erowid.org/chemicals/cathinon e/methcathinone_faq.shtml

Smoking & PD

• > 50 studies find inverse

association with smoking

• Risk ~ 0.5 in prospective,

retrospective, and twin study designs

• Dose-response: ~ 20% risk

reduction/10 pack-years smoked

• Causal?

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Coffee Drinking & PD Risk

Hernan et al, Ann Neurol, 2002

Mouse model of TBI: increased -synuclein in striatum

Uryu, et al, Experimental Neurol, 2003

PD & Head Injury

• Human epidemiology

is mostly consistent

PD Risk Factor Associations

Demographic factors Increasing age Male sex White race Family history of Parkinson’s disease Lifestyle Head trauma Diet (dairy products, animal fats) Biometric & comorbid conditions Lower blood cholesterol Lower serum uric acid Oophorectomy Environmental exposures MPTP Pesticides (paraquat, rotenone, 2,4-D, dieldrin, maneb) Industrial agents (PCBs) Solvents (TCE, PERC) Metals (lead, iron) Rural residence Drinking well water Pulp mills Cigarette smoking and tobacco use Coffee and tea drinking History of gout Diet “Mediterrenean” diet polyunsaturated fats uricogenic diet High physical activity Medications Calcium-channel blockers Nonsteroidal anti-inflammatory drugs Statins

Reduced Risk Increased Risk

From Goldman & Tanner, in Parkinson’s Disease & Movement Disorders, Jankovic & Tolosa eds, 2015. Occupations: health care, teaching, woodworking/carpentry, legal work, religious work, farming

Alzheimer’s Disease: Overview

• > 5 million Americans
• 6% > age 60, 30% > 85
• 50% with AD also have
• ther neuropathologies
• Most common neurodegenerative disease
• 60-80% of dementias
• Other common causes: vascular, DLB, FTLD, PD, CTE

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Changes in US causes of death (all ages) between 2000-2010.

National Center for Health Statistics

Biomarker detection of AD pathology

Jack et al, Lancet Neurol, 2013

AD heritability is estimated at 50-70%

Scheltens et al, Lancet, 2015

Environment & AD: Studies to date

From Yegambaram 2015

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Associations of Occupational Exposures & Dementia

• Few consistent findings
• Studies of highly variable

quality

• Inverse association with
• ccupational complexity
• Essential to adjust for

education, and/or SES From Killin et al, BMC Geriatrics 2016

Occupational Metals Exposure & Risk of Non-Vascular Dementia

Koeman et al, AJIM, 2015 Swedish Mortality Study. Census-based linkage with job-exposure matrices.

Metals

AD & Specific Metals

Metal Strength of evidence Human studies Animal/in vitro

Aluminum ++ +++ Arsenic + + Cadmium + ++ Cobalt + ? Copper + ++ Iron + + Lead + ++ Manganese ? + Mercury ? + Selenium ? + Zinc ? + (U-shaped)

AD & Aluminum

• High levels in brain regions with extensive pathology (Crapper et al,

Science, 1973)

• Al deposits in neurofibrillary tangles in AD (Perl et al, J Alz Dis,2006)
• Rats fed high Al develop cognitive dysfunction & hippocampal

accumulation (Walton, J Alz Dis, 2012)

• Human epidemiology is controversial

‒ Walton, J Alz Dis, 2014: “Chronic aluminum intake causes Alzheimer's disease: applying Sir Austin Bradford Hill's causality criteria.” ‒ Lidsky, JOEM, 2014: “Is the Aluminum Hypothesis dead?” ‒ Perl: “It is highly unlikely that aluminum represents an etiologic agent for

• AD. However….. aluminum does represent a constituent of the

neurofibrillary tangle and, as such, likely plays a role in the pathogenetic process leading to the disease.”

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AD & Aluminum

From: Kawahara, Int J Alz Dis, 2011

Occupational Solvent Exposure & AD. Specific

compounds rarely studied.

Study Design Exposure Association

Tyas et al, 2001 Small prospective Canadian cohort. Baseline questionnaire “Ever exposed” to solvent/degreaser 0.9 (0.3-2.5) Graves et al, 1991 Pooled 4 case-control studies Self-reported ever use of

• cc solvents/degreasers

0.76 (0.5-1.2) Park et al, 2005 US mortality database Occupation-based “solvent exposure index” 1.09 (1.3-1.15) Kukull et al, 2005 HMO-nested case- control; proxy- interviews for all Occ use of any solvent “daily or almost daily” Men Women 6.0 (2.1-17.2) ns Koeman et al, 2015 Dutch mortality cohort; Census-linked to JEM Total Solvents Aromatics Chlorinated (Q4 vs Q1) ns ns 1.6 (1.1-2.3), p-trend 0.01

Occupational Pesticide Exposure & AD

Study Design Exposure Association

Tyas et al, 2001 Small prospective Canadian cohort. Baseline questionnaire “Ever exposed” to solvent/degreaser 0.9 (0.3-2.5) Graves et al, 1991 Pooled 4 case-control studies Self-reported ever use of

• cc solvents/degreasers

0.76 (0.5-1.2) Park et al, 2005 US mortality database Occupation-based “solvent exposure index” 1.09 (1.3-1.15) Kukull et al, 2005 HMO-nested case- control; proxy- interviews for all Occ use of any solvent “daily or almost daily” Men Women 6.0 (2.1-17.2) ns Koeman et al, 2015 Dutch mortality cohort; Census-linked to JEM Any Pesticides High pesticides Insecticides High Herbicides High Fungicides ns ns ns 5.3 (1.3-21.4) 2.8 (0.9-9.2)

Occupational Pesticide Exposure & AD

Yan et al, Scientific Reports, 2016

Koeman et al, AJIM, 2015 Dutch mortality cohort; Census-linked to JEM Any Pesticides High pesticides Insecticides High Herbicides High Fungicides ns ns ns 5.3 (1.3-21.4) 2.8 (0.9-9.2)

Meta-analysis: AD & pesticides

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Electromagnetic field (EMF) exposure & AD

Meta-analysis of 49 studies, Vergara et al, JOEM, 2013

AD & Pollution

• Several recent compelling papers
• Recently feature in Science: http://www.sciencemag.org/news/2017/01/brain-

pollution-evidence-builds-dirty-air-causes-alzheimer-s-dementia

Calderon-Garcideunas 2004, Toxicol Pathol

Air pollution & Ab42 accumulation in cognitively normal residents of Mexico city

Proximity to roads in Canada is associated with incident dementia risk

Chen et al, 2017, Lancet

Source: Citation Here

PM2.5 & Cortical Pathology in Mouse: Gene * environment interaction

Cacciottolo et al, 2017, Translational Psychiatry

Source: Citation Here

Cortical A from nPM is greater in ApoE4 than ApoE3 mouse Hazard for PM2.5 >12ug/m3 (3-yr avg) in women, stratified by ApoE genotype

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Amyotrophic Lateral Sclerosis (ALS)

• ALS comprises 90% of Motor Neuron Diseases (MND)
• Others: progressive bulbar palsy; progressive muscular atrophy; primary

lateral sclerosis; pseudobulbar palsy

• First described by Charcot in 1869
• Clinical Features
• Degeneration of corticospinal and/or bulbar upper motor neurons

& spinal lower motor neurons

• Spasticity & secondary muscle weakness, wasting
• Mean survival ~3 years
• Incidence 1-2/100,000 p-y, prevalence 5/100,000
• Median age at onset 65-70
• Men at ~40% higher risk at all ages

ALS Pathology

• Clinically & pathologically

heterogeneous

• 14% meet criteria for FTD
• Pathologic subtypes
• SOD1 aggregates (usually

familial)

• TDP-43 cytoplasmic

inclusions (common, usually sporadic)

• Dinucleotide-repeat

pathology (usually familial)

SOD TDP-43

C9orf72 repeat pathology

90% of ALS is sporadic. Gene mutations identified in 75% of familial ALS, but only 10% of sporadic

Morgan et al, Br Med Bull, 2016

(TDP‐43)

Twins studies estimate heritability of sporadic ALS ~ 60%

ALS Incidence May Be Increasing

Dorsey, et al, 2007, Neurology

Fang et al, 2009, Arch Neurol

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ALS, Physical Activity & Injury

Many prior reports of association with sports, athletes, physical injury Pupillo et al, Ann Neurol, 2014

• Large European Registry
• Consistent methods, well-controlled
• Inverse associations with leisure and

work-related physical activity

• Single outlier is “professional sports”

Seals et al, AJE, 2016

• Danish ALS Register
• 3500 cases, 350,000 controls
• Hospitalization for any trauma before

age 55 (but not after) significantly associated with ALS risk (in lagged analysis)

• OR 1.22 (1.08-1.37)

But….

ALS & Occupations. Peters et al, OEM, 2017

• Swedish nested case-control; ALS dx 1991-2010; Occ hx from Census in 1970, 1980, 1990

Metals & ALS. Reviewed by Callaghan et al, Neurodegen Diseases, 2011

• Mercury, selenium: few case reports; epidemiology limited, inconsistent
• Lead: Consistent & extensive epidemiology

XRF bone lead:

t1/2 = 3-5 years (trabecular), 15-25 years (cortical) Kamel, 2002 (Wang et al, JOEM, 2014)

Pesticides & ALS

Meta-analysis of occupational pesticide exposure.

Kamel et al, Neurotoxicology, 2012

Kamel 2012 Pesticides & ALS in the Ag Health Study: Aldrin, Dieldrin, DDT, Toxaphene, Trifluralin

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• Seals et al, Epidemiology, 2016
• Danish population-based study 1982-2009
• Military service linked to national patient register
• 3,500 ALS cases matched to 350,000 controls
• No assoc w/ calendar year or duration of service

Military Service & ALS

• Beard et al, Environ Intl, 2016
• US Registry of Veterans w/ ALS, VA controls
• 621 cases (identified 2005-10), 958 controls
• No association with branch of service
• Risk increased for service in WWII, Korea,

and total years of deployment

• Association of ALS & military-related factors reported in 5 of 7 studies on 1990-1

Gulf War Veterans (see Beard & Kamel, Epidemiol Rev, 2015)

Exposure OR Ever took pyridostigmine bromide 2.7 (1.05-7) Exhaust from heaters/generators 1.8 (1.05-2.9) Mixing/applying burning agents 7.8 (1.9-31) Agent Orange exposure 2.8 (1.4-5.4) Ground level fumigation (Gulf) 8.5 (1.05-70)

EMF & ALS

• > 20 studies on EMF, “electrical” jobs, electric shock
• Early studies often positive, later higher quality studies & meta-analyses less

supportive Fischer et al, Epidemiology, 2015

• Population-nested Swedish case-control, 5,000 cases, 25,000 controls
• Census-linked JEMs for EMF, shock, electrical occupations
• No associations with occupations, shocks, or EMF

ALS-parkinsonism dementia complex of Guam (“lytico-bodig”). Reviewed by McGeer & Steele, Prog Neurobiol, 2011

• Extremely high rates of ALS & dementia in

indigenous Chomorros of Guam & Kii peninsula

• f Japan after WWII
• First recognized by US navy physicians
• Epidemiology characterized by Leonard

Kurland 1950s

• Highly familial
• Prominent neurofibrillary tau tangles at

autopsy (also TDP-43 & LRRK2)

• Dramatic reduction past 50 years suggests

removal of a toxin

The Cycad hypothesis & -methylamino-L-alanine (BMAA)

• Cycad hypothesis proposed by Whiting 1963
• BMAA in cycad seed identified by Spencer (Science, 1987)
• a non-proteinogenic amino acid produced by cyanobacteria
• glutamate receptor agonist, toxic at high levels
• Immediately debunked: very low levels in cycad seed flour would require

eating impossibly large amounts (Duncan, Lancet, 1988)

• But….bioconcentrated by

bats (flying foxes) (Cox & Sacks, Neurology, 2002)

• Still highly controversial
• A possible cause of AD &

ALS?

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Chronic traumatic encephalopathy (CTE): tau pathology

Question 1:

Increased risk of Parkinson’s disease has been associated with which of the following agents? a) Paraquat b) Rotenone c) Trichloroethylene (TCE) d) All of the above

Question 2:

Which genetic risk factor explains the largest proportion of Alzheimer’s risk? a) A-synuclein b) ApoE c) TDP-43 d) BMAA

Question 3:

Epidemiologic data are most supportive of a relationship between ALS and which of the following metals? a) Cadmium b) Mercury c) Iron d) Lead