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A new meta-analysis investigates possible environmental causes of ALS

A new meta-analysis investigates possible environmental causes of ALS

Graphic illustration of chemicals on a molecular level.
January 27, 2022

Amyotrophic lateral sclerosis is a progressive neuromuscular disorder that can affect up to 30,000 Americans. It has been a hundred and fifty years since its discovery. The disease is still unknown and devastating, and strikes without warning.

Researchers have struggled to find the cause of this complex disorder. Some ALS and other neurodegenerative diseases, such as ALS, have a genetic component.Alzheimer’s diseaseResearchers have identified a wide range of environmental agents that could be risk factors.
Graphic illustration of chemicals on a molecular level.A range of chemicals that can appear in the environment, including -N-methylamino-L-alanine (BMAA), formaldehyde, selenium, manganese, mercury, zinc and copper, are examined for their possible links to ALS.
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Professor Deutsch conducted a new meta-analysis on all the available ALS literature. Rolf HaldenTwo doctoral students from Arizona State University Biodesign Institute investigate environmental influences that could be linked to the disease. They use rigorous quantitative methods. The study also examines ALS distribution over space and time, correlating geographic data to exposure risks and lifestyle or occupational hazards.

Researchers will use the new findings to help fill in the gaps in the full picture of this disease. The study projects that it will affect approximately 22,650 Americans by 2040.

Melanie Newell, a doctoral candidate and the lead author for the study, says that narrowing potential risk factors to a probable subset will speed up the work required to determine if they are actually causal or merely related to ALS. Patients and caregivers could see a significant improvement in the reality of this terrible disease by reducing the delay in diagnosis and avoiding occupational and non-occupational exposures early on.

Halden, director of TheBiodesign Center for Environmental Health EngineeringMoreover, he says that environmental factors play a significant role in many diseases, not just those involving neurodegenerative diseases like ALS. Many diseases in industrialized nations are rising rapidly and to a large extent. This cannot be explained by slow genetic changes. Studying the environment is crucial to improve U.S. health outcomes and global health outcomes.

The reviewRecently, this article was published in Science of the Total Environment.

Rolf Halden is director of the Biodesign center for environmental health engineering.

The brain under attack

Lou Gehrigs disease, also known by the name ALS, is a form of paralysis that results in progressive degeneration of motor nerve cells in both the brain and spinal cord (upper motor neurons) in the brain. Other symptoms include twitching or cramping of the muscles, loss in motor control in hands and arms, weakness, fatigue and difficulty breathing.

Researchers are still trying to figure out why the disease is more common among men than among women. ALS usually strikes between 55 and 75 years of age. Most ALS patients will die within three to five years of being diagnosed.

Familial ALS accounts for around 510% of all cases. It occurs when two or three family members are affected. These patients are more likely to succumb to the disease sooner than ALS patients not related to them. Although gene mutations have been linked to ALS, they only account for 12% of all cases. The overwhelming majority (98%) of ALS cases do not have a clear cause. There have been three possible causes: injury, diet, and exposures to a wide variety of potentially hazardous chemicals. These are the main focus of the current overview.

A new take on ALS

The large-scale review of all available literature on ALS covered 1,710 papers. It identified 258 papers that met the strict criteria to be included in the study. To reduce the possibility of errors, two methodologies were used for data analysis. The review included 83 environmental chemicals. The combined results of the two methods showed that seven chemicals were identified as causing an increase in the risk of developing ALS.

The top environmental hazards that require further investigation include chemicalsN-methylamino-L-alanine (BMAA), formaldehyde, selenium and four heavy metals: manganese, mercury, zinc and copper (in order of decreasing significance). Researchers face many challenges when trying to identify the culprits behind this mysterious disorder.

The study shows that ALS cases do not occur in an evenly distributed manner around the world. Historical data has identified some geographic hot spots, especially in the Western Pacific region.

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These data suggest that environmental factors in certain areas could be contributing to the ALS burden. The Chamorros people from the Mariana Islands, which includes Guam, are just a few examples. In 1956, the area saw 100 ALS cases per 100,000 people. New Guinea had the highest prevalence of ALS ever recorded in 1963 with 147 cases per 100,000 people. New Guinea rates are still well above the global average. Screening has strongly implicated environmental correlations in these cases.

Hidden threats

As toxic chemicals build up in the environment, they can be causative agents in ALS and other neurological diseases. This is because they have been identified in associative research and further are known to trigger epigenetic and genetic changes in the body. The picture is blurred when the effects of exposures to known neurotoxins, such as metals and solvents, pharmacological agent or mixtures thereof, are influenced by endogenous factors, including genetic predispositions and gene expression.

The Bradford Hill criteria is a tool that allows researchers at ASU to identify confounding factors and to better measure, weigh, and interpret disease risks. It examines the interaction of multiple causal factors. Nine conditions must be met for a given chemical compound (or group of chemicals) to be considered causative (not merely related) to ALS. A literature search of geographic exposure events was also performed to validate the results.

Only BMAA was among the top seven chemicals that had strong associations with ALS. However, other chemicals are strongly implicated and need further research. Exposure to toxic chemicals can increase the risk of developing ALS. This is why certain occupations that make liberal use of these chemicals are cited. These include construction, paperwork, electrical work and military service.

BMAA was identified as the most dangerous chemical. Exposures can be caused by seafood consumed from waters contaminated by cyanobacteria, or from eating cycad, which contains both BMAA (a neurotoxin) and cycasin (a second neurotoxin). A positive association was found between known chemical exposure and ALS incidence in a variety other occupations than fishing and farming.

Assembling ALS’s puzzle

The U.S. is experiencing an increase in ALS prevalence. The National Amyotrophic Lateral Systrophy Registry estimates that 5,000 people are diagnosed annually with ALS. However, current modeling predicts that over 6,400 additional diagnoses could be made each year. The number of ALS cases is expected to rise to 22,654 by 2040 and 209,830 by 2240 in the United States. Globally, ALS cases are expected to rise the most in India, the U.S., and China.

Because of the complex interplay between factors, such as exposure to multiple chemicals, occupational risks, lifestyle choices, age, sex, and genetic predispositions, it will be difficult to identify a clear pattern of causality, especially in the absence early diagnostic signs or biomarkers for ALS. Based on the literature analysis, hypothesis-driven research may be possible to examine known risk factors and their impact on disease incidence. This research provides hope and a productive pathway forward to battling this perplexing, devastating disorder.

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