Vigorous Exercise: Could it Promote ALS in Women?

Exercise staves off heart disease, diabetes, dementia—but might strenuous workouts exacerbate some people’s risk for amyotrophic lateral sclerosis? Previous studies, done mostly in men, hinted as much, and a new paper, published January 19 in JAMA Neurology online, suggests the correlation holds true for older women as well. However, study first author Yvonne Eaglehouse of the University of Pittsburgh cautioned that this epidemiological study does not prove that vigorous workouts lead to ALS. She said the tremendous benefits of physical activity outweigh the possible increased risk for the rare neurodegenerative condition.

What’s in a name?

A new study suggests a link between Lou Gehrig’s disease and athletics.

ALS gained its eponym, Lou Gehrig’s disease, from the famous New York Yankees baseball player who was diagnosed with ALS on his 36th birthday. Scientists have reported unusually high rates of the disease in professional football and soccer players (see Sep 2012 news; Chiò et al., 2005). However, results from epidemiological studies thus far are mixed. Some reported that sports or other vigorous activity increased ALS risk, while others found no effect or even a decreased risk (for selected references, see Related Papers at bottom of this page). 

None of those studies focused on women, though. Some included only men, others studied mixed populations, in which an effect in men could possibly mask a different correlation or no effect in women. Differences such as hormone levels might alter the outcome in women, Eaglehouse suggested. To focus on women only, she, senior author Lewis Kuller, and colleagues mined data from the National Institutes of Health’s Women’s Health Initiative (WHI) study.

The WHI enrolled 161,809 women, all past menopause, who joined between the ages of 50 and 79. At the time of enrollment, each woman completed a questionnaire about her physical activity. Thirteen percent indicated that they engaged in vigorous exercise, such as jogging or playing tennis, at least three times per week. Eaglehouse and colleagues examined death certificate data for all WHI participants, of whom 165 had ALS.

A new study focuses on athletic activity and ALS risk in women.

When they compared exercise data for the women who died of ALS with those who did not, they found that women with ALS had exercised vigorously an average of 0.9 times per week, compared with 0.7 weekly sessions for those who died of other causes or were still alive. Similarly, women who died of ALS worked out an average of 40 total minutes per week, compared with half an hour for the others. 

The authors also estimated the risk for ALS based on exercise habits. The average person’s risk for the disease is quite low to begin with; just one or two out of 100,000 people will get it in a given year (Guidetti et al., 1996; Kondo in Leigh and Swash, 1995). In the WHSI, vigorous workouts of 40 minutes or longer, or three or more workouts per week, increased a woman’s odds of ALS by more than 50 percent. These numbers did not reach statistical significance, though there was a trend toward greater risk in the heavy exercisers, Eaglehouse said. She concluded, “There appears to be a possible direct relationship between strenuous physical activity and ALS mortality in postmenopausal women.” Milder exercise was not associated with ALS.

“This is an important study,” commented Ettore Beghi of the Mario Negri Institute in Milan, who did not participate in the work. Beghi praised the decision to use of a prospective cohort rather than collect ALS cases and assess their previous physical activity, which could introduce bias.

However, both Beghi and Eaglehouse emphasized caveats about the study. For one, Beghi said, the WHI cohort does not represent the general population. He pointed out that many of the women—about 40 percent—participated in a clinical trial as part of the overall WHI, which tested whether a low-fat diet, hormone replacement therapy, or vitamin D and calcium supplements could reduce risk for cancer, heart disease, or hip fractures (Women’s Health Initiative Study Group, 1998). For another, Eaglehouse added, only a small fraction of the people in the WHI study reported regular strenuous exercise, and only 0.1 percent of total study volunteers died of ALS. This reduced the power of the study to link the two characteristics. In addition, the maximum amount of exercise women could report on the questionnaire was simply listed as one hour or more, so the study did not incorporate data on those who worked out for multiple hours at a time. It will be important to find whether a study with a greater proportion of physically active women finds the same trend, she said.

Eaglehouse and Beghi also agreed that a more objective measure of activity would be preferable. The WHI relied on self-assessments, and defined “strenuous physical activities” as those that raise the heart rate and make one sweat. The study organizers did test those assessments in 63 of the women who wore activity trackers, and their true activity matched their questionnaire answers. Still, the self-assessments of the vast majority of study participants were not verified.

In addition, Beghi thought the WHI definition of “strenuous” included fairly mild exercise. He suggested the difference between a woman’s resting and active heart rates would provide a better measure, though he admitted such data would be difficult to collect.

Considering the JAMA Neurology study and the rest of the literature, what do the overall data amount to? “It seems that physical activity is more detrimental than protective in terms of ALS,” Beghi said. The conflicting results from different studies could be due to variations in study design or populations, he added. However, no study has offered the final word, and Eaglehouse agreed that more research is needed.

Beghi speculated that certain people with genetic risk factors for ALS, whose motor neurons are already struggling, might get the disease earlier if they engage in regular vigorous activity. He said he has observed that highly active people who get ALS tend to get diagnosed at a younger age than less-active folks with the disease. Scientists already have some ideas about how sports and workouts might hasten neurodegeneration. For one, being active keeps weight down, and multiple studies, including the WHI, indicate that thinner folks are more likely to develop ALS (see May 2011 news and Related Papers below). Weight in turn influences metabolism, which can go off-kilter in people with ALS (Ngo and Steyn, 2015). 

Another theory that could link neurodegeneration and physical activity involves oxidative stress. Exercise could ramp up production of reactive oxygen species, and people susceptible to ALS might be less able to deal with the onslaught; for example, their blood often contains less of the antioxidant uric acid than other people’s (see Jul 2009 news). In addition, the high activity of motor neurons during vigorous activity might result in the release of more of the neurotransmitter glutamate than cells can clear up, and glutamate can be toxic to motor neurons (see Apr 2010 news).—Amber Dance

Comments

    • User Profile Image Marcia Ratner
      Boston University Chobanian & Avedisian School of Medicine
    • Posted:

    If the body's defenses against oxidative stress are devoted to coping with that induced by strenuous exercise, these defenses may be less able to cope with the oxidative stress associated with an acute exposure to neurotoxicants found in the environment and workplace.

    It is becoming increasingly clear that factors implicated in developing disease per se can interact with environmental and lifestyle factors to influence the subclinical progression of neurodegenerative disease. Unfortunately, few epidemiological studies have looked at age at onset as an endpoint in subjects stratified by these environmental and lifestyle risk factors. Even fewer studies have looked at the interactions between age at onset, exposure to environmental factors, and genetic polymorphisms that encode for drug metabolizing enzymes such as glutathione-S-transferase. More work in this area is needed.

    View all comments by Marcia Ratner
    • User Profile Image Steve Barger
      University of Arkansas for Medical Sciences
    • Posted:

    There was a really small difference in the exercise levels reported to confer risk. And I take issue with the claim by the paper's authors, and the reporting in this Alzforum article, that patients and controls differed in the number of times per week they engaged in strenuous physical activity (PA). From the JAMA Neurology article: "There was an elevated percentage of deaths from ALS with increasing frequency of strenuous PA in the WHI, with percentage of death from ALS varying from 0.09% for 0 days per week to 0.16% for 4 days per week (P for trend = .06)." In fact, the negative data was not limited to strenuous PA; there was no significant difference in the number of times per week they engaged in any physical activity: "Age-adjusted ALS mortality rates varied from 7.4/100,000 person-years for women who reported no strenuous PA to 10.6/100,000 person-years for women who did strenuous PA on 3 or more days per week (P = .07)."

    Arbitrary as it may be, a p-value of 0.05 is the cut-off that convention dictates we consider significant. If it is not a significant difference, we cannot really be sure that it is a difference at all.

    Obviously, the well-proven benefits of exercise for general health dramatically outweigh the nonsignificant trend toward an increased risk reported by Eaglehouse et al

    View all comments by Steve Barger

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References

News Citations

  1. Dementia Four Times More Likely in Pro Football Players
  2. Being Pleasantly Plump: Way to Live Longest with ALS?
  3. Antioxidant AWOL in ALS, Precursor Fights Stroke
  4. Glutamate Gums Up Motor, Dopaminergic Neurons

Paper Citations

  1. Chiò A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain. 2005 Mar;128(Pt 3):472-6. Epub 2005 Jan 5 PubMed.
  2. Guidetti D, Bondavalli M, Sabadini R, Marcello N, Vinceti M, Cavalletti S, Marbini A, Gemignani F, Colombo A, Ferrari A, Vivoli G, Solimè F. Epidemiological survey of amyotrophic lateral sclerosis in the province of Reggio Emilia, Italy: influence of environmental exposure to lead. Neuroepidemiology. 1996;15(6):301-12. PubMed.
  3. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials. 1998 Feb;19(1):61-109. PubMed.
  4. Ngo ST, Steyn FJ. The interplay between metabolic homeostasis and neurodegeneration: insights into the neurometabolic nature of amyotrophic lateral sclerosis. Cell Regen (Lond). 2015;4(1):5. Epub 2015 Aug 27 PubMed.

External Citations

  1. Women’s Health Initiative
  2. Kondo in Leigh and Swash, 1995

Further Reading

Papers

  1. Hamidou B, Couratier P, Besançon C, Nicol M, Preux PM, Marin B. Epidemiological evidence that physical activity is not a risk factor for ALS. Eur J Epidemiol. 2014 Jul;29(7):459-75. Epub 2014 Jul 2 PubMed.
  2. Scarmeas N, Shih T, Stern Y, Ottman R, Rowland LP. Premorbid weight, body mass, and varsity athletics in ALS. Neurology. 2002 Sep 10;59(5):773-5. PubMed.
  3. Pupillo E, Messina P, Giussani G, Logroscino G, Zoccolella S, Chiò A, Calvo A, Corbo M, Lunetta C, Marin B, Mitchell D, Hardiman O, Rooney J, Stevic Z, Bandettini di Poggio M, Filosto M, Cotelli MS, Perini M, Riva N, Tremolizzo L, Vitelli E, Damiani D, Beghi E, EURALS Consortium. Physical activity and amyotrophic lateral sclerosis: a European population-based case-control study. Ann Neurol. 2014 May;75(5):708-16. Epub 2014 May 21 PubMed.
  4. Yu Y, Su FC, Callaghan BC, Goutman SA, Batterman SA, Feldman EL. Environmental risk factors and amyotrophic lateral sclerosis (ALS): a case-control study of ALS in Michigan. PLoS One. 2014;9(6):e101186. Epub 2014 Jun 30 PubMed.
  5. Harwood CA, McDermott CJ, Shaw PJ. Physical activity as an exogenous risk factor in motor neuron disease (MND): a review of the evidence. Amyotroph Lateral Scler. 2009 Aug;10(4):191-204. PubMed.
  6. Huisman MH, Seelen M, de Jong SW, Dorresteijn KR, van Doormaal PT, van der Kooi AJ, de Visser M, Schelhaas HJ, van den Berg LH, Veldink JH. Lifetime physical activity and the risk of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2013 Sep;84(9):976-81. Epub 2013 Feb 16 PubMed.
  7. Strickland D, Smith SA, Dolliff G, Goldman L, Roelofs RI. Physical activity, trauma, and ALS: a case-control study. Acta Neurol Scand. 1996 Jul;94(1):45-50. PubMed.
  8. Doyle P, Brown A, Beral V, Reeves G, Green J. Incidence of and risk factors for motor neurone disease in UK women: a prospective study. BMC Neurol. 2012 May 6;12:25. PubMed.
  9. Kioumourtzoglou MA, Rotem RS, Seals RM, Gredal O, Hansen J, Weisskopf MG. Diabetes Mellitus, Obesity, and Diagnosis of Amyotrophic Lateral Sclerosis: A Population-Based Study. JAMA Neurol. 2015 Aug;72(8):905-11. PubMed.
  10. Huisman MH, Seelen M, van Doormaal PT, de Jong SW, de Vries JH, van der Kooi AJ, de Visser M, Schelhaas HJ, van den Berg LH, Veldink JH. Effect of Presymptomatic Body Mass Index and Consumption of Fat and Alcohol on Amyotrophic Lateral Sclerosis. JAMA Neurol. 2015 Oct;72(10):1155-62. PubMed.

Primary Papers

  1. Eaglehouse YL, Talbott EO, Chang Y, Kuller LH. Participation in Physical Activity and Risk for Amyotrophic Lateral Sclerosis Mortality Among Postmenopausal Women. JAMA Neurol. 2016 Mar 1;73(3):329-36. PubMed.

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