Physical Activity as an Exogenous Risk Factor for ALS

Abstract and Introduction

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. The only established epidemiological risk factors for ALS are male sex and increasing age. The role of physical activity has been debated as an environmental risk factor. Over the last decade multiple studies have attempted to delineate the architecture of ALS. These have not yet established definite risk factors, often due to low-powered studies, lack of focus on at-risk genotypes and sub-optimal methodology.

We have conducted a review of all the studies published between 2009 and December 2021. The free text search terms were [(motor neuron disease) OR (MND) OR (Amyotrophic Lateral Sclerosis) OR (ALS)] AND [(Exercise) or (Physical Activity) or (PA) or (sport)]. We identified common themes, for example soccer, head injury and the physiological mechanisms that differ in ALS patients. We have analysed the relevant, available studies (n = 93), highlighting the underlying reasons for any reported discrepancies.

Overall, we have found that the more highly powered studies using validated exposure methodologies, linked strenuous, anaerobic physical activity as a risk factor for ALS. Future large-scale studies focusing on specific at-risk genotypes and physical activity should be conducted to confirm this finding. This will strengthen the evidence already surrounding strenuous physical activity as an environmental risk factor for ALS and allow advice to be given to at-risk family members. Increasing our understanding of the genetic–environmental interactions in the pathophysiology of ALS will allow for the possibility of developing preventative therapeutic approaches.

Introduction

Amyotrophic lateral sclerosis (ALS) is the most common subtype of motor neuron disease (MND), and the terms are often used interchangeably. It is a rapidly progressive and fatal disorder, with life expectancy commonly only 2–3 years from symptom onset.^[1,2] The upper and lower motor neurons (MNs) degenerate causing progressive failure of the neuromuscular system, affecting the function of the upper and lower limbs, as well as the bulbar and respiratory muscles. The burden of ALS globally has increased substantially from 1990–2016, with a current estimated life-time risk of approximately 1 in 300.^[3,4]

The aetiology of ALS is considered to be due to a combination of risk-genotypes that interact with environmental factors over time, accelerating the neurodegenerative cascade.^[5–8] As such, ALS is an archetypal complex disease. Heritability studies suggest that ~60% of ALS risk is genetically determined, and the remainder is environmental.^[6] Many of the genetic mutations linked to ALS, even those which are highly penetrant, are present for more than 50 years before disease onset. Indeed, the late age of onset of ALS points to a multistep process, in which genetic risk factors are penetrant only in the presence of additional environmental 'hits'.^[9] The most common mutation linked to ALS is an intronic G4C2-repeat expansion of C9ORF72, which affects ~10% of all ALS patients. The penetrance and severity of C9ORF72-ALS is markedly variable, which is consistent with interacting environmental factors.^[10,11] To date, the only confirmed epidemiological risk factors for ALS are male sex and increasing age, with onset most commonly between 60 and 75 years of age.^[12,13] Over the last decade, multiple reports have been released attempting to delineate the environmental risk factors predisposing to the development of ALS, however these have often been underpowered and have not led to significant advances in the field. The identification of a specific gene–environmental interaction could play an important role in disease prevention and a future personalized medicine approach. This review focuses on physical activity (PA) as a risk factor, and its interaction with the commonest known genetic risk factor, mutations in the C9orf72 gene, as a monogenic risk factor. There are currently no clear data on the link between polygenic genetic risk factors and PA as an exogenous environmental risk factor.

The role of PA in the aetiology of ALS has been debated over several decades. ALS has been commonly documented in high profile athletes. This group are reported to have a higher incidence and lower age of onset of ALS, leading to the hypothesis that strenuous, repetitive exercise may represent an environmental risk factor.^[14] However, various studies have failed to confirm a link between PA and ALS.^[15–19] These conflicting conclusions may be explained by small study numbers, selection bias, no specific focus on risk-genotypes and the use of non-validated methods for quantification of historical levels of PA exposure.^[20] The controversy surrounding this hypothesis also relates to the benefits that regular exercise provides, for example for the cardiovascular system, leading to a potential survival bias.^[21] Most athletes and physically active individuals clearly do not develop ALS and it could be argued that the benefits of physical exercise outweigh the small potential risk of the development of ALS. However, a deeper understanding of this potential genetic–environmental interaction would allow for more personalized, focused advice for patients and family members and potentially could lead to the development of preventative strategies.

Previous reviews focusing on PA and ALS concluded that there was insufficient evidence to make a definite conclusion on PA as a risk factor for ALS.^[20,22] The present review aims to evaluate the recent evidence emerging since 2009, to provide a more conclusive answer as to whether or not PA is a factor in aetiology of ALS. An outline of each study's main findings can be seen in Table 1 and Supplementary Table 1.

Table 1. A summary of the reports 2009–21, investigating whether PA is an environmental risk factor for ALS
Publications	Summary conclusion: positive association
Daneshvar et al.²³	Significantly higher incidence and mortality with ALS among NFL players than the US population. Also a direct link with increased length of NFL career.
Raymond et al.²⁴	Participants involved in vigorous PA ≥3 times per week more likely to develop ALS and at a younger age.
Gamez et al.²⁵	Mean age of onset of ALS was younger in Spanish professional/semi-professional football players by 23.7 years compared to the general European population.
Russell et al.²⁶	Neurodegenerative disease risk in soccer players was highest in defenders and players that had played for >15 years.
Julian et al.²⁷	MR evidence supported a relationship between genetic liability to frequent strenuous leisure-time exercise and ALS. Transcriptomic analysis showed that genes altered in response to acute exercise are enriched with known ALS risk genes. A positive relationship found between age of onset of G4C2-repeat expansion C9orf72-ALS and strenuous, leisure-time exercise.
Westeneng et al.²⁸	Daily energy intake at symptom onset in C9-positive group and C9-negative group higher versus controls. Concluded that exercise increases the risk of ALS.
Canosa et al.²⁹	¹⁸F-FDG-PET demonstrated that in a group of ALS patients expressing the same level of disability, hypermetabolism was found in the subgroup that did not exercise, suggesting that this hypermetabolic group could potentially adapt better to the neurodegenerative process.
Fang et al. ³⁰	Examining a large cohort of cross-country skiers, as a high endurance exercise, the authors reported that the fastest skiers had a 4-fold increased risk of developing ALS. Participants who had been involved in over four races compared to a single race were also at increased risk.
Harwood et al.³¹	The use of the HAPAQ questionnaire showed that the level of total PA throughout adulthood is significantly associated with the risk of developing ALS.
Pasquinelli et al.³²	ALS patients with Gly482Ser allelic variant in PGC1α show increased exercise-related oxidative stress. ALS participants had significantly increased advanced oxidation protein products, decreased ferric reducing ability and thiol groups in comparison to controls.
Lehman et al.³³	Neurodegenerative mortality from ALS and Alzheimer's disease was increased 4-fold in professional footballers' versus the general US population.
Turner et al.³⁴	The was concordance for side of onset and handedness in upper limb-onset ALS patients, implying a higher exercise demand can trigger the site of onset of ALS.
Summary conclusion: negative association
Korner et al.³⁵	In a cohort study, ALS patients did not report increased PA at leisure or occupation versus controls.
Venkataramni et al.¹⁹	There was no statistically significant difference in the risk of long-term all-cause mortality among career NFL players versus NFL replacement players who participated in the NFL during a three-game league-wide player strike in 1987.
Janssen et al.¹⁸	American varsity high-school football players had an increased risk of medically documented trauma, but did not have increased risk of neurodegenerative disease overall.
Savica et al.¹⁶	In high school football players, there was no increased risk of Alzheimer's dementia, Parkinson's disease or ALS.

Table 1. A summary of the reports 2009–21, investigating whether PA is an environmental risk factor for ALS

Publications

Summary conclusion: positive association

Daneshvar et al.²³

Significantly higher incidence and mortality with ALS among NFL players than the US population. Also a direct link with increased length of NFL career.

Raymond et al.²⁴

Participants involved in vigorous PA ≥3 times per week more likely to develop ALS and at a younger age.

Gamez et al.²⁵

Mean age of onset of ALS was younger in Spanish professional/semi-professional football players by 23.7 years compared to the general European population.

Russell et al.²⁶

Neurodegenerative disease risk in soccer players was highest in defenders and players that had played for >15 years.

Julian et al.²⁷

MR evidence supported a relationship between genetic liability to frequent strenuous leisure-time exercise and ALS. Transcriptomic analysis showed that genes altered in response to acute exercise are enriched with known ALS risk genes. A positive relationship found between age of onset of G4C2-repeat expansion C9orf72-ALS and strenuous, leisure-time exercise.

Westeneng et al.²⁸

Daily energy intake at symptom onset in C9-positive group and C9-negative group higher versus controls. Concluded that exercise increases the risk of ALS.

Canosa et al.²⁹

¹⁸F-FDG-PET demonstrated that in a group of ALS patients expressing the same level of disability, hypermetabolism was found in the subgroup that did not exercise, suggesting that this hypermetabolic group could potentially adapt better to the neurodegenerative process.

Fang et al. ³⁰

Examining a large cohort of cross-country skiers, as a high endurance exercise, the authors reported that the fastest skiers had a 4-fold increased risk of developing ALS. Participants who had been involved in over four races compared to a single race were also at increased risk.

Harwood et al.³¹

The use of the HAPAQ questionnaire showed that the level of total PA throughout adulthood is significantly associated with the risk of developing ALS.

Pasquinelli et al.³²

ALS patients with Gly482Ser allelic variant in PGC1α show increased exercise-related oxidative stress. ALS participants had significantly increased advanced oxidation protein products, decreased ferric reducing ability and thiol groups in comparison to controls.

Lehman et al.³³

Neurodegenerative mortality from ALS and Alzheimer's disease was increased 4-fold in professional footballers' versus the general US population.

Turner et al.³⁴

The was concordance for side of onset and handedness in upper limb-onset ALS patients, implying a higher exercise demand can trigger the site of onset of ALS.

Summary conclusion: negative association

Korner et al.³⁵

In a cohort study, ALS patients did not report increased PA at leisure or occupation versus controls.

Venkataramni et al.¹⁹

There was no statistically significant difference in the risk of long-term all-cause mortality among career NFL players versus NFL replacement players who participated in the NFL during a three-game league-wide player strike in 1987.

Janssen et al.¹⁸

American varsity high-school football players had an increased risk of medically documented trauma, but did not have increased risk of neurodegenerative disease overall.

Savica et al.¹⁶

In high school football players, there was no increased risk of Alzheimer's dementia, Parkinson's disease or ALS.

Physical Activity as an Exogenous Risk Factor for Amyotrophic Lateral Sclerosis

A Review of the Evidence

Abstract and Introduction

Abstract

Introduction

Physical Activity as an Exogenous Risk Factor for Amyotrophic Lateral Sclerosis

A Review of the Evidence

Abstract and Introduction

Abstract

Introduction

Tables

References

Authors and Disclosures

Authors and Disclosures

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