The Cyanobacteria Derived Toxin Beta-N-Methylamino-L-Alanine and Amyotrophic Lateral Sclerosis

There is mounting evidence to suggest that environmental factors play a major role in the development of neurodegenerative diseases like ALS (Amyotrophic Lateral Sclerosis). The non-protein amino acid beta-N-methylamino-L-alanine (BMAA) was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam, and has been implicated as a potential environmental factor in ALS, Alzheimer’s disease, and other neurodegenerative diseases. BMAA has a number of toxic effects on motor neurons including direct agonist action on NMDA and AMPA receptors, induction of oxidative stress, and depletion of glutathione. As a non-protein amino acid, there is also the strong possibility that BMAA could cause intraneuronal protein misfolding, the hallmark of neurodegeneration. While an animal model for BMAA-induced ALS is lacking, there is substantial evidence to support a link between this toxin and ALS. The ramifications of discovering an environmental trigger for ALS are enormous. In this article, we discuss the history, ecology, pharmacology and clinical ramifications of this ubiquitous, cyanobacteria-derived toxin

Environmental And Occupational Exposures And Amyotrophic Lateral Sclerosis In New England

Background: Recent data provide support for the concept that potentially modifiable exposures are responsible for sporadic amyotrophic lateral sclerosis (ALS). Objective: To evaluate environmental and occupational exposures as risk factors for sporadic ALS. Methods: We performed a case control study of ALS among residents of New England, USA. The analysis compared questionnaire responses from 295 patients with a confirmed ALS diagnosis to those of 225 controls without neurodegenerative illness. Results: Self-reported job-or hobby-related exposure to one or more chemicals, such as pesticides, solvents, or heavy metals, increased the risk of ALS (adjusted OR 2.51; 95% CI 1.64-3.89). Industries with a higher toxicant exposure potential (construction, manufacturing, mechanical, military, or painting) were associated with an elevated occupational risk (adjusted OR 3.95; 95% CI 2.04-8.30). We also identified increases in the risk of ALS associated with frequent participation in water sports, particularly waterskiing (adjusted OR 3.89; 95% C11.97-8.44). Occupation and waterskiing both retained independent statistical significance in a composite model containing age, gender, and smoking status. Conclusions: Our study contributes to a growing body of literature implicating occupational-and hobby-related toxicant exposures in ALS etiology. These epidemiologic study results also provide motivation for future evaluation of water-body-related risk factors. (C) 2017 S. Karger AG, Base

Sleep matters: Neurodegeneration spectrum heterogeneity, combustion and friction ultrafine particles, industrial nanoparticle pollution, and sleep disorders—Denial is not an option

Sustained exposures to ubiquitous outdoor/indoor fine particulate matter (PM2.5), including combustion and friction ultrafine PM (UFPM) and industrial nanoparticles (NPs) starting in utero, are linked to early pediatric and young adulthood aberrant neural protein accumulation, including hyperphosphorylated tau (p-tau), beta-amyloid (Aβ1 − 42), α-synuclein (α syn) and TAR DNA-binding protein 43 (TDP-43), hallmarks of Alzheimer's (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). UFPM from anthropogenic and natural sources and NPs enter the brain through the nasal/olfactory pathway, lung, gastrointestinal (GI) tract, skin, and placental barriers. On a global scale, the most important sources of outdoor UFPM are motor traffic emissions. This study focuses on the neuropathology heterogeneity and overlap of AD, PD, FTLD, and ALS in older adults, their similarities with the neuropathology of young, highly exposed urbanites, and their strong link with sleep disorders. Critical information includes how this UFPM and NPs cross all biological barriers, interact with brain soluble proteins and key organelles, and result in the oxidative, endoplasmic reticulum, and mitochondrial stress, neuroinflammation, DNA damage, protein aggregation and misfolding, and faulty complex protein quality control. The brain toxicity of UFPM and NPs makes them powerful candidates for early development and progression of fatal common neurodegenerative diseases, all having sleep disturbances. A detailed residential history, proximity to high-traffic roads, occupational histories, exposures to high-emission sources (i.e., factories, burning pits, forest fires, and airports), indoor PM sources (tobacco, wood burning in winter, cooking fumes, and microplastics in house dust), and consumption of industrial NPs, along with neurocognitive and neuropsychiatric histories, are critical. Environmental pollution is a ubiquitous, early, and cumulative risk factor for neurodegeneration and sleep disorders. Prevention of deadly neurological diseases associated with air pollution should be a public health priority

Cyanotoxins and the Nervous System

Cyanobacteria are capable of producing a wide range of bioactive compounds with many considered to be toxins. Although there are a number of toxicological outcomes with respect to cyanobacterial exposure, this review aims to examine those which affect the central nervous system (CNS) or have neurotoxicological properties. Such exposures can be acute or chronic, and we detail issues concerning CNS entry, detection and remediation. Exposure can occur through a variety of media but, increasingly, exposure through air via inhalation may have greater significance and requires further investigation. Even though cyanobacterial toxins have traditionally been classified based on their primary mode of toxicity, increasing evidence suggests that some also possess neurotoxic properties and include known cyanotoxins and unknown compounds. Furthermore, chronic long-term exposure to these compounds is increasingly being identified as adversely affecting human health

Gene-Environment-Time Interactions in Neurodegenerative Diseases: Hypotheses and Research Approaches

Amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's diseases are age-related neurodegenerative diseases. ALS is not a single entity but a syndrome with many different causes. In all 3 diseases, gene mutations account for only 10-15% of cases. Many environmental and lifestyle factors have been implicated as risk factors for ALS, though none have been proven to cause the disease. It is generally believed that ALS results from interactions between environmental risk factors and genetic predisposing factors. The advent of next-generation sequencing and recent advances in research into environmental risk factors offer the opportunity to investigate these interactions. We propose a hypothesis to explain the syndrome of ALS based on the interaction of many individual environmental risk factors with many individual genetic predisposing factors. We hypothesize that there are many such combinations of individual, specific, genetic, and environmental factors, and that each combination can lead to the development of the syndrome of ALS. We also propose a hypothesis that explains the overlap between the age-related neurodegenerations and their genetic underpinnings. Age and duration of exposure are crucial factors in these age-related neurodegenerative diseases, and we consider how these may relate to gene-environment interactions. To date, genetic studies and environmental studies have investigated the causes of ALS separately. We argue that this univariate approach will not lead to discoveries of important gene-environment interactions. We propose new research approaches to investigating gene-environment interactions based on these hypotheses

Amyotrophic Lateral Sclerosis Risk, Family Income, and Fish Consumption Estimates of Mercury and Omega-3 PUFAs in the United States

Most amyotrophic lateral sclerosis (ALS) cases are considered sporadic, without a known genetic basis, and lifestyle factors are suspected to play an etiologic role. We previously observed increased risk of ALS associated with high nail mercury levels as an exposure biomarker and thus hypothesized that mercury exposure via fish consumption patterns increases ALS risk. Lifestyle surveys were obtained from ALS patients (n = 165) and n = 330 age- and sex-matched controls without ALS enrolled in New Hampshire, Vermont, or Ohio, USA. We estimated their annual intake of mercury and omega-3 polyunsaturated fatty acid (PUFA) via self-reported seafood consumption habits, including species and frequency. In our multivariable model, family income showed a significant positive association with ALS risk (p = 0.0003, adjusted for age, sex, family history, education, and race). Neither the estimated annual mercury nor omega-3 PUFA intakes via seafood were associated with ALS risk. ALS incidence is associated with socioeconomic status; however, consistent with a prior international study, this relationship is not linked to mercury intake estimated via fish or seafood consumption patterns

Amyotrophic Lateral Sclerosis Risk, Family Income, and Fish Consumption Estimates of Mercury and Omega-3 PUFAs in the United States

Most amyotrophic lateral sclerosis (ALS) cases are considered sporadic, without a known genetic basis, and lifestyle factors are suspected to play an etiologic role. We previously observed increased risk of ALS associated with high nail mercury levels as an exposure biomarker and thus hypothesized that mercury exposure via fish consumption patterns increases ALS risk. Lifestyle surveys were obtained from ALS patients ( n = 165) and n = 330 age- and sex-matched controls without ALS enrolled in New Hampshire, Vermont, or Ohio, USA. We estimated their annual intake of mercury and omega-3 polyunsaturated fatty acid (PUFA) via self-reported seafood consumption habits, including species and frequency. In our multivariable model, family income showed a significant positive association with ALS risk ( p = 0.0003, adjusted for age, sex, family history, education, and race). Neither the estimated annual mercury nor omega-3 PUFA intakes via seafood were associated with ALS risk. ALS incidence is associated with socioeconomic status; however, consistent with a prior international study, this relationship is not linked to mercury intake estimated via fish or seafood consumption patterns

Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases?

There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS) is caused by gene-environment interactions. Mutations in genes underlying familial ALS (fALS) have been discovered in only 5-10% of the total population of ALS patients. Relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron death leading to the syndrome of ALS, although exposure to chemicals including lead and pesticides, and to agricultural environments, smoking, certain sports, and trauma have all been identified with an increased risk of ALS. There is a need for research to quantify the relative roles of each of the identified risk factors for ALS. Recent evidence has strengthened the theory that chronic environmental exposure to the neurotoxic amino acid β-N-methylamino-L-alanine (BMAA) produced by cyanobacteria may be an environmental risk factor for ALS. Here we describe methods that may be used to assess exposure to cyanobacteria, and hence potentially to BMAA, namely an epidemiologic questionnaire and direct and indirect methods for estimating the cyanobacterial load in ecosystems. Rigorous epidemiologic studies could determine the risks associated with exposure to cyanobacteria, and if combined with genetic analysis of ALS cases and controls could reveal etiologically important gene-environment interactions in genetically vulnerable individuals

A new method for estimating under-recruitment of a patient registry: a case study with the Ohio Registry of Amyotrophic Lateral Sclerosis

We developed a disease registry to collect all incident amyotrophic lateral sclerosis (ALS) cases diagnosed during 2016–2018 in Ohio. Due to incomplete case ascertainment and limitations of the traditional capture-recapture method, we proposed a new method to estimate the number of cases not recruited by the Registry and their spatial distribution. Specifically, we employed three statistical methods to identify reference counties with normal case-population relationships to build a Poisson regression model for estimating case counts in target counties that potentially have unrecruited cases. Then, we conducted spatial smoothing to adjust outliers locally. We validated the estimates with ALS mortality data. We estimated that 119 total cases (95% CI [109, 130]) were not recruited, including 36 females (95% CI [31, 41]) and 83 males (95% CI [74, 99]), and were distributed unevenly across the state. For target counties , including estimated unrecruited cases increased the correlation between the case count and mortality count from r  = 0.8494 to 0.9585 for the total, from 0.7573 to 0.8270 for females, and from 0.6862 to 0.9292 for males. The advantage of this method in the spatial perspective makes it an alternative to capture-recapture for estimating cases missed by disease registries

Validation of a Droplet Digital PCR (ddPCR) Assay to Detect Cyanobacterial 16S rDNA in Human Lung Tissue

Cyanobacteria produce a variety of secondary metabolites, including toxins that may contribute to the development of disease. Previous work was able to detect the presence of a cyanobacterial marker in human nasal and broncoalveolar lavage samples; however, it was not able to determine the quantification of the marker. To further research the relationship between cyanobacteria and human health, we validated a droplet digital polymerase chain reaction (ddPCR) assay to simultaneously detect the cyanobacterial 16S marker and a human housekeeping gene in human lung tissue samples. The ability to detect cyanobacteria in human samples will allow further research into the role cyanobacteria plays in human health and disease