“This study strongly confirms that increasing BMI seems to represent a valid therapeutic strategy for ALS,” wrote Luc Dupuis, of the University of Strasbourg in France, in an e-mail to ARF. Dupuis was not involved with the study. Senior study author Anne-Marie Wills is pursuing just that strategy in a clinical trial. Wills works at Massachusetts General Hospital in Boston.

In addition to the degeneration of motor neurons and associated symptoms, people with ALS commonly suffer from problems with their metabolism: They eat less, but expend more energy for simple actions such as breathing (reviewed in Dupuis et al., 2011). Scientists have attempted to correlate the metabolic marker cholesterol and disease prognosis, with conflicting results: One study found that a high ratio of low-density lipoproteins to high-density lipoproteins (LDL/HDL ratio) improved survival (Dupuis et al., 2008); another found no link between LDL/HDL ratio and survival (Chiò et al., 2009). In contrast, a high HDL/total cholesterol ratio is generally considered good for health.

The Harvard team, led by Wills and first author Sabrina Paganoni of the Spaulding Rehabilitation Hospital in Boston, Massachusetts, addressed the cholesterol question by analyzing data and blood samples from three past studies (Cudkowicz et al., 2006; Cudkowicz et al., 2003; and one unpublished study from Massachusetts General Hospital). In all, they correlated cholesterol levels and survival rates from 427 people with ALS. Unlike in some other studies, they carefully adjusted their data for BMI, lung capacity, and age. The result was that lipid levels did not predict survival.

Body mass, however, did. The researchers calculated the percent of mortality within the one- or two-year timeline of each study they used, and found that it produced a U-shaped curve when plotted against BMI. Those who were underweight—with a BMI of less than 18.5—fared the worst, with 44 percent of subjects having passed away by the studies’ end. From this low point, survival increased in a stepwise fashion up to a BMI of 30-35, which the World Health Organization characterizes as the first level of obesity. Only 6 percent of the people in this category died during the studies. From there on outward, survival decreased again, with 52 percent of people whose BMI exceeded 40 passing away.

What made the heavier people live longer? People in the obese category “have the buffer of some metabolic reserves,” Wills said. “Even if they lost weight during the study, at least they had [energy stores] to fall back on.” She suspects that the thinner people, in contrast, were forced to break down muscle for energy.

At the high end of the spectrum, Wills hypothesizes that the heaviest people were more likely to suffer cardiovascular disease that contributed to their demise. Dupuis offered another possibility. “I would suggest insulin resistance, which, from an energetic point of view, has the same consequences for the cell as starvation (i.e., decreased nutrient entry),” he wrote.

At this point, Wills noted, “We cannot say whether this is just an association or whether it is actually causative.” But based on these and other data, Wills would want for people with ALS to gain weight, not lose it, in the hopes of slowing progression. She commonly recommends that her patients eat whatever they desire, but finds that many—particularly women—resist the idea.

Wills is currently leading a Phase 2 clinical trial of high-fat and high-calorie diets in people with ALS. She is recruiting people who already use feeding tubes in order to precisely control their intake. Although such people are usually far along in their disease course—and thus may not reap much benefit—she hopes with this trial to prove the safety of the overeating approach.—Amber Dance.

Reference:
Paganoni S, Deng J, Jaffa M, Cudkowicz ME, Wills AM. Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle Nerve. 2011;March 31.Abstract