The Epidemiology of Amyotrophic Lateral SclerosisParkinsonismDementia Complex of Guam

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The Epidemiology of Amyotrophic Lateral
Sclerosis/Parkinsonism-Dementia Complex of Guam

• Stephen C. Waring, DVM, PhD
• Assistant Professor of Epidemiology
• UT-School of Public Health
• 713-500-9241
• swaring_at_sph.uth.tmc.edu

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Guam where and what?

• Mariana Archipelago
• Commonwealth of the Northern Mariana Islands
  (CNMI)
• Rota, Tinian, Saipan, and 11 other (unhabitated)
  islands north of Saipan
• Guam only island of the Marianas not in CMMI
• Western Pacific (13º N 144 ºE)
• 7,000 miles from US
• US Territory (unincorporated)
• Total area 210 sq. miles
• 4-12 mi. x 30 mi.

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Guam Population, 1990 US Census
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Guam ALS/PDC - history

• Early 1950s
• recognized ALS among indigenous population
• Incidence up to 100 times higher than rates for
  sporadic ALS in other parts of the world
• Evidence from death certificates dating back to
  1900
• Reference to lytico or paralytico
• NIH established a research center on Guam in late
  50s

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Guam ALS/PDC - history

• 1960s
• Began to recognize a change in spectrum of
  predominantly ALS to parkinsonism-dementia
  complex (PDC) in the indigenous population
• First documented case of PDC in 1936
• Incidence 50 - 100 times higher than rates for
  idiopathic PD in other parts of the world
• Reference to bodig or rayput

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Guam ALS/PDC - history

• 1970s
• Large scale case-control studies of risk factors
• Genetic-familial aggregation studies
• Began to see a decline in incidence of both ALS
  and PDC
• Extensive clinical and neuropathological studies
  to further characterize unique disease spectrum

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Guam ALS/PDC - history

• 1980s
• Purported link between Ca and
  hyperparathyroidism coupled with supposed
  disappearance of high incidence led to closure of
  the NIH Research Center on Guam in 1983
• New Yorker article describing the medical mystery
  of the Guam disease
• Leonard Kurland, MD, DrPH
• father of neuroepidemiology
• started the Rochester Epidemiology Project
• PHS Officer first assigned to project by NINDB
  in 1953, with orders stating mission should be
  complete in 4 weeks

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Guam ALS/PDC the nail in the coffin?
Disappearance of high-incidence amyotrophic
lateral sclerosis and parkinsonism-dementia on
Guam
Garruto, Yanagihara, Gajdusek Neurology, 1985
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Guam ALS/PDC - hypotheses

• Calcium and Vitamin D metabolism

Normal Aging, 1985
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Guam ALS/PDC - hypotheses

• Calcium metabolism/heavy metal

Neurology, 1995
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Guam ALS/PDC - hypotheses

• Cycadplant neurotoxin

Science, 1987
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Guam ALS/PDC - hypotheses

• Cycas circinalis
• False sago palm
• Federico palm
• Fadang

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Guam ALS/PDC - hypotheses

• Genetics

Am J Med Genetics, 1993
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Guam ALS/PDC - hypotheses
Science, 1993
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Guam ALS/PDC - Disease

• Amyotrophic lateral sclerosis (ALS)
• Parkinsonism-dementia complex (PDC)
• Marianas dementia
• Neurofibrillary tangle disease
• 50 of neurologically and cognitively normal
  Chamarros 50 years of age and older have NFTs

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Guam ALS/PDC - Histopathology

• Neurofibrillary tangles (NFTs)

Immunohistochemical stain
Ubiquitin stain
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Guam ALS/PDC - Histopathology

• Neurofibrillary tangles (NFTs) ALS/PDC vs AD

ALS/PDC brain AD brain
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ALS Measures of disease occurrence
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PDC Measures of disease occurrence
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ALSPDC Measures of disease occurrence
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ALS Age at Onset
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PDC Age at Onset
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ALSPDC Age at Onset
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ALS, PDC, and ALSPDC Age at Onset
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ALS/PDC Incidence by village of birth
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ALS/PDC Incidence by village of residence
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ALS/PDC Age-specific incidence/100,000
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ALS/PDC Age-specific incidence per 100,000
among five-year male birth cohorts
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ALSPDC Birth cohort effects on incidence
10-year cohorts
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Guam ALS/PDC - Epidemiology

• Methodological issues
• insidious onset
• latency
• ascertainment
• disease heterogeneity
• age of population at greatest risk

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Guam ALS/PDC - Epidemiology

• Etiologic clues
• familial aggregation
• North-South gradient
• lifestyle
• primary in Chamorros
• overlapping neuropathological features
• overlapping epidemiology
• changing spectrum
• increasing age at onset

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Guam ALS/PDC - Epidemiology

• Hypotheses
• Calcium deficiency/impaired mineral metabolism
• Neurotoxin from cycad plant
• Infectious
• Genetic
• Gene-envirionment interaction (multifactorial)

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Guam ALS/PDC - Epidemiology

• Risk factors
• Chamorro
• Age
• Male
• Living in southern villages
• Family history

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Guam ALS/PDC Epidemiology

• Analytic studies
• PDC patients significantly higher mean
  traditional food score compared to non-cases
  (Reed et al, Am J Epi 1987)
• PDC in lower subsistance level groups eating
  more fish and raw meat greater exposure to farm
  animals (Reed et al, Am J Epi 1975)
• Anthropological evidence - widespread use of
  cycad as food and medicinal use (poultice)
  primary use during famine/war

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Guam ALS/PDC - Genetics

• Genetic studies
• search for simple models of inheritance
  (Mendelian)
• pedigree study
• largest pedigree from Umatac (area of highest
  incidence)
• 95 of all individuals born since 1830
• traced all but one individual with disease to
  same pedigree
• conclusions supported
• dominant gene with reduced penetrance
• common founder (founder effect)

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Guam ALS/PDC - Genetics

• Genetic studies
• search for simple models of inheritance
• migration studies
• emigration effect - Chamorros still at higher
  risk for disease though not as high as on Guam
• migration to Guam
• no disease in Caucasians
• a few cases have been reported in Filipino
  immigrants, but not all have Guam pathology

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Guam ALS/PDC - Genetics

• Genetic risk factor studies
• superoxide dismutase (Ch21)
• apolipoprotein (APO- ?4)
• cytochrome P450 (CPY2D6, Ch22)
• Candidate gene studies
• Chromosome 4 (familial PD)
• Chromosome 17 (FTDP-17)
• ?-synuclein
• tau gene
• APP gene
• Chromosome 1
• Chromosome 14

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Guam ALS/PDC Gene-environment

• Support for genetic etiology
• Familial aggregation excess of affected first
  degree relatives compared to general population
  and to controls
• One inbred pedigree (1,450 members) accounted for
  51 of total population in Umatac and all but one
  of the cases from Umatac
• Segregation analysis of this pedigree consistent
  with autosomal dominant mode of inheritance with
  100 penetrance in males and 50 penetrance in
  females

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Guam ALS/PDC Gene-environment

• Support for environmental
• Decline in incidence
• Increased risk among spouses of patients
• Failure to find increase risk in offspring of
  patients

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Guam ALS/PDC Gene-environment

• Incorporation of environmental exposure data into
  segregation analyses
• Linkage analysis to map the susceptibility gene
• Case-control questionnaire
• Following of living first-degree relatives,
  particularly offspring, of patients
• California Chamorro project

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Is the Guam disease dying out?ALS
Garruto et al ALS below 5/100,000, sex ratio
approaching unity
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Is the Guam disease dying out?PDC
Garruto et al PDC below 5/100,000 sex ratio 11
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Methodological issues leading to grossly
underestimated rates

• Underascertainment of cases
• lag period from onset to recognition (up to 5
  years)
• may be different for males compared to females,
  hence the 11 ratio reported
• Overestimate of denominator
• Authors estimated 64,250 based on preliminary
  figures and their knowledge of the demographic
  changes on the island
• Actual 1980 census for Chamorros 47, 845 (1990
  census was 57,648)

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To the Chamorro people, whose indomitable spirit
and enduring determination are an inspiration for
those continuing the search for answers to
an elusive problem that has defied resolution for
too long