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While women with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) see a faster functional decline, men have shorter survival times, mostly due to more rapid weight loss and lung function worsening, a study shows.
The findings highlight the importance of considering sex-specific differences when studying the mechanisms leading to ALS and when designing individual  <a href="https://alsnewstoday.com/als-treatment/">treatment plans</a>. The study, “<a href="https://onlinelibrary.wiley.com/doi/10.1002/ana.26933">Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis</a>,” was published in Annals of Neurology.
ALS tends to develop earlier and is <a href="https://alsnewstoday.com/news/als-prevalence-united-states-nearly-2017/">more frequent in men</a> than women. Clinical features may differ too. For example, men are more likely to have flail arm, marked by progressive weakness and atrophy in the arms, as an initial <a href="https://alsnewstoday.com/symptoms-of-als/">symptom of ALS</a>. But women are more often diagnosed with <a href="https://alsnewstoday.com/forms-of-als/#Clinical_onset">bulbar-onset ALS</a>, which first affects the muscles in the head and neck.
Since age and where initial symptoms happen are both strongly associated with survival and the rate of disease progression, researchers at the University of Turin, Italy drew on data from the Piemonte and Valle d&#8217;Aosta Register for ALS (PARALS), which included those <a href="https://alsnewstoday.com/als-diagnosis/">diagnosed with ALS</a> between 2007 and 2019, to better understand how the interaction of sex with these two clinical factors could improve predicting the disease&#8217;s course and survival, and guide treatment.
Of 1,890 patients, more than half (55.2%) were men. On average, men developed ALS at 66.4 years old, while women had their first symptoms about a year later, with bulbar-onset ALS being <a href="https://alsnewstoday.com/news/age-sex-gene-mutations-strongly-influence-als-type-symptoms-study-finds/">more common</a> (41.2% vs. 25.9%). The median diagnostic delay was nine months for both sexes.
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<h3>ALS survival in men, women</h3>
A survival analysis showed men tended to live shorter lives than women, but the difference only became significant when evaluating limb-onset ALS, which is sometimes called spinal ALS, and bulbar-onset ALS separately. This difference persisted even after considering factors like genetic makeup, cognitive function, and age at onset.
At the time of their diagnosis, men had a lower percentage of forced vital capacity (FVC), meaning worse respiratory function than women. Men also lost more weight each month (about 0.15 kg), regardless of having limb-onset or bulbar-onset ALS.
The fact that this occurred despite women having more bulbar symptoms, which often cause <a href="https://alsnewstoday.com/symptoms-of-als/#Breathing_difficulties">trouble breathing</a> and eating, was &#8220;an apparently counterintuitive result,&#8221; wrote the researchers.
A “cause-and-effect” analysis showed the faster declines in respiratory function and weight were the strongest factors contributing to worse survival in men, accounting for about 66% of the sex differences.
&#8220;These findings elucidate that the shorter survival in male ALS patients stems from their faster decline in respiratory function and weight loss, although other factors are involved,&#8221; the researchers wrote.
When men and women were matched for a number of clinical and demographic variables, men continued to have a 19% higher risk of death than women. But this worse survival didn&#8217;t correspond to faster disability progression since women actually progressed faster on the ALS Functional Rating Scale-Revised (ALSFRS-R) scale, a measure of disease severity, by about 0.1 points a month.
This included a significantly faster progression in ALSFRS-R domains of fine motor function, gross motor function, and bulbar function. While there was no difference in the respiratory domain, it took women longer to start noninvasive ventilation to help with breathing.
These findings were confirmed in two additional groups of patients from the <a href="https://ncri1.partners.org/ProACT/Home/Index">Pooled Resource Open-Access ALS Clinical Trials</a> (PRO-ACT) database, which includes data from participants in previous ALS clinical trials, and the <a href="https://www.answerals.org">Answer ALS</a> database.
“The present study casts new light on the multifaceted nature of sex-related differences in ALS prognosis [outlook] and has a direct impact on clinical practice, guiding the management of ALS patients toward sex-personalized care, and improving the design and interpretation of clinical trials,” the researchers said.

ALS women live longer than men despite faster functional decline

Cigarette smoking, either currently or in the past, significantly increases the likelihood of developing <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), particularly for women, according to a pooled meta-analysis of 32 studies.
A risk of the neurodegenerative condition was higher in current smokers, and it increased in a non-linear manner with more intense smoking — meaning, it rose continuously up to a certain level of smoking, and then stabilized or decreased slightly with additional packs per year.
&#8220;One of our most pivotal findings was the dose-response analysis, revealing an inverted U-shaped curve,&#8221; Yun Hak Kim, a professor at Pusan National University in South Korea and the study&#8217;s senior author, said in a <a href="https://www.prnewswire.com/news-releases/pusan-national-university-researchers-decode-the-link-between-smoking-and-amyotrophic-lateral-sclerosis-risk-302047458.html">university news release</a>. 
&#8220;This curve highlights that the risk associated with smoking isn&#8217;t a linear progression. Instead, it peaks and then starts to decrease or plateau, suggesting that the risk of ALS is influenced by the intensity of smoking,&#8221; Kim added.
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<h3>Cigarette smoking is among reported ALS risk factors</h3>
The study, “<a href="https://www.tobaccoinduceddiseases.org/Association-of-smoking-with-amyotrophic-lateral-sclerosis-A-systematic-review-and,175731,0,2.html">Association of smoking with amyotrophic lateral sclerosis: A systematic review, and meta-analysis, including dose-response analysis</a>,” was published in the journal <a href="https://tobaccoinduceddiseases.biomedcentral.com/">Tobacco Induced Diseases</a>.
ALS is a neurodegenerative disorder that primarily affects the voluntary motor nervous system — the nerves responsible for controlling voluntary movements, such as walking, talking, and swallowing.
Cigarette smoking has been extensively studied as a potential environmental <a href="https://alsnewstoday.com/causes-of-als/">risk factor for ALS</a>. However, while some studies indicate <a href="https://alsnewstoday.com/als-and-smoking/">smoking increases ALS risk</a>, others find <a href="https://alsnewstoday.com/news/smoking-not-seen-to-increase-risk-of-als-uk-study/">no link between tobacco and ALS </a>whatsoever.
A need exists for “a more thorough comprehension of the potential causal link between smoking and ALS,” the scientists wrote.
When faced with conflicting outcomes from different studies, a meta-analysis — the combination of results from multiple separate studies to gain greater statistical power — can help in reaching an overall understanding of the evidence.
Researchers conducted such a meta-analysis on 32 studies, published by scientists worldwide between 1981 and 2022, that investigated a relationship between smoking and ALS.
Four were cohort studies, and 28 were case-controlled. The cohort studies examined the occurrence of ALS in smokers versus nonsmokers. Case-control studies measured the frequency and amount of smoking among those with (cases) and without (controls) ALS, matched by sex and age. Follow-up periods ranged from seven to 28 years.
<h3>25% higher risk for female smokers, after adjusting for age, education, etc.</h3>
After pooling data from all 32 studies, there was a statistically significant 14% increase in the likelihood of ALS among current and past smokers. When the comparison was adjusted for factors that may influence the results, including sex, age, education, and socioeconomic status, the likelihood was still higher, at 12%.
When past smokers were excluded from the calculations, the risk of ALS rose to 28% among current smokers, with and without statistical adjustments.
Looking at patients by sex, researchers found that women smokers faced a 20% increased chance of developing ALS and a 25% higher risk after adjustments. There was no significant relationship between smoking and ALS among men.
&#8220;We have identified a significant association between smoking and ALS in females, while no significant association was observed in males,&#8221; the scientists wrote. This sex difference, they added, might be due to men being &#8220;more exposed to other potential risk factors for ALS, such as pesticides or organic solvents, during their occupational activities.&#8221;
<h3>Being a heavy smoker, up to a certain point, further elevates risk</h3>
Five studies included information on dose-response — the number of cigarettes smoked and odds of ALS — as measured by pack-years. A pack-year describes how many cigarettes have been smoked in a lifetime, with a pack equal to 20 cigarettes. For example, 20 pack-years equals smoking one pack a day for 20 years or two packs a day for 10 years.
Data showed a significant increase in ALS risk with increasing pack-years, which appeared to peak at about 30 pack-years and then declined through 50 pack-years. The team noted that this result might have been influenced by the limited number of higher pack-year studies, with these results mostly attributed to one study.
“Our study showed that there is a positive relationship between smoking and the risk of ALS,” the researchers wrote.
The quality of the selected studies then was assessed with a scale that describes studies as &#8220;good,&#8221; &#8220;fair,&#8221; or &#8220;poor&#8221; based on the selection of study groups, how well these groups can be compared, and how smoking exposure or outcomes were determined.
Among the 28 case-control studies, eight were rated as &#8220;good&#8221; and 20 as &#8220;poor,&#8221; while among cohort studies, two were rated as &#8220;good&#8221; and the other two as &#8220;fair.&#8221; Researchers said the higher &#8220;poor&#8221; rating among case-control studies was because the “assessment of exposure was not based on medical records or blinded interviews, and the response rate was either not mentioned or inconsistent between case and control group.”
There were no signs of publication bias, which occurs when studies with positive findings are more likely to be published.
“Our study provides evidence of a positive relationship between smoking and the risk of ALS,” the team wrote. “To mitigate the risk of developing ALS, discontinuing smoking, which is a modifiable risk factor, may be crucial.”

Tag: women

ALS women live longer than men despite faster functional decline

Cigarette smoking tied to greater risk of ALS, especially for women