Abstract
Seventy years of research on Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia Complex (ALS/PDC) have provided invaluable data on the etiology, molecular pathogenesis and latency of this disappearing, largely environmental neurodegenerative disease. ALS/PDC is linked to genotoxic chemicals (notably methylazoxymethanol, MAM) derived from seed of the cycad plant (Cycas spp.) that were used as a traditional food and/or medicine in all three disease-affected Western Pacific populations. MAM, nitrosamines and hydrazines generate methyl free radicals that damage DNA (in the form of O6-methylguanine lesions) that can induce mutations in cycling cells and degenerative changes in post-mitotic cells, notably neurons. This paper explores exposures to naturally occurring and manmade sources of nitrosamines and hydrazines in association with sporadic forms of ALS (with or without frontotemporal degeneration), progressive supranuclear palsy, and Alzheimer disease. Research approaches are suggested to examine whether these associations might have etiological significance.Lay SummaryUnknown environmental exposures are thought to be risk factors for non-inherited forms of certain progressive brain diseases, such as sporadic forms of amyotrophic lateral sclerosis (sALS), progressive supranuclear palsy (sPSP), and Alzheimer's disease (sAD). Related progressive and fatal brain disorders coalesce in a single neurodegenerative disease of largely environmental origin (ALS-Parkinsonism-dementia Complex) that has affected three genetically distinct populations residing in islands of the Western Pacific region. Prolonged study of this prototypical neurodegenerative disease has provided invaluable information on the probable environmental cause (specific chemical genotoxins) and molecular mechanisms (unrepaired nerve cell DNA-damage) by which brain degeneration begins, evolves and, years or decades later, clinical signs appear, and progress. This information is used as a foundation to explore whether chemically related genotoxins (nitrosamines, hydrazines) are possible risk factors for sALS, sPSP, and sAD. Methods to test this hypothesis in the field and laboratory are proposed.
Highlights
There is wide acceptance that environmental exposures contribute to an unknown extent to the genesis of sporadic neurodegenerative disorders. such as amyotrophic lateral sclerosis, progressive supranuclear palsy, and Alzheimer disease
Three genetically distinct populations in the Western Pacific region have experienced a very high incidence of ALS: Chamorro and other residents of Guam and Rota in the Mariana Islands; Japanese residents in two regions of the Kii Peninsula of Honshu Island, Japan, and Auyu and Jaqai linguistic groups on the island of New Guinea in Papua, Indonesia. These geographic isolates of ALS are associated with a high incidence of atypical parkinsonism (P) and dementia (D), such that they are described as the Western Pacific ALS/P-D Complex (ALS/PDC)
One 3year-old Japanese subject who migrated from the southern highrisk ALS/PDC area in the Kii Peninsula developed pyramidal signs, parkinsonian symptoms, and mildly impaired cognitive function 73 years later [7], and a member of the U.S Air Force stationed on Guam for only 4 months was diagnosed with ALS 10–20 years later [2]
Summary
There is wide acceptance that environmental exposures contribute to an unknown extent to the genesis of sporadic neurodegenerative disorders. such as amyotrophic lateral sclerosis (sALS), progressive supranuclear palsy (sPSP), and Alzheimer disease (sAD). Three genetically distinct populations in the Western Pacific region have experienced a very high incidence of ALS: Chamorro and other residents of Guam and Rota in the Mariana Islands; Japanese residents in two regions of the Kii Peninsula of Honshu Island, Japan, and Auyu and Jaqai linguistic groups on the island of New Guinea in Papua, Indonesia. One 3year-old Japanese subject who migrated from the southern highrisk ALS/PDC area in the Kii Peninsula developed pyramidal signs, parkinsonian symptoms, and mildly impaired cognitive function 73 years later [7], and a member of the U.S Air Force stationed on Guam for only 4 months was diagnosed with ALS 10–20 years later [2] Taken together, these data suggest that exposure to an environment with high-incidence ALS/PDC is a risk factor for motorsystem disease that appears clinically years or decades after exposure. The subclinical cerebellar abnormalities found in some Guamanian and Japanese ALS/PDC cases may represent biological markers of early-life exposure to cycad toxins or chemically related substances (see below)
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