Being Pleasantly Plump: Way to Live Longest with ALS?

Never mind what you’ve been hearing about cardiovascular health. Could one life-extending “treatment” for amyotrophic lateral sclerosis be a bucket of fries and a heaping piece of pie? In the online May issue of Muscle & Nerve, Harvard Medical School researchers report that a high body mass index (BMI), indicating mild obesity, was linked to survival. Those at the lowest or highest ends of the BMI spectrum fared worst.

“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by analyzing data and blood samples from three past studies (Cudkowicz et al., 2006; Cudkowicz et al., 2003; and one unpublished study from Massachusetts General Hospital).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

Comments

  1. In my opinion, this is a key paper in the field. The authors definitely confirm our previous results, and those of Albert Ludolph's group, that showed dyslipidemia was associated with increased survival. Here, they provide much deeper statistical analysis than we initially did, and show that body mass index (BMI), rather than cholesterol levels, is an independent prognostic factor in ALS. This study is very much in line with previous studies from Couratier and colleagues (see, e.g., Marin et al., 2011) showing that BMI is an important predictor of ALS patients’ survival. In my eyes, it is no surprise that adjusting for BMI in statistical analysis decreases the association level of cholesterol with survival: It is common sense that lipid levels are strongly associated with BMI.

    An important point of this study is that they first performed longitudinal analyses of blood lipids in ALS. The authors show that blood lipids manifest little change with time, suggesting that they do not represent a distal consequence of disease progression as suggested by other authors. The most original finding of this study is the U-shaped dose response curve between BMI and survival. They showed not only that lean patients have shortened survival, but also that morbidly obese patients also have such decreased survival. This suggests that risk factors associated with morbid obesity are also risk factors for shortened ALS survival. The authors suggest that cardiovascular risks might be such risk factors. I would rather suggest insulin resistance, which, from an energetic point of view, has the same consequences for the cell as does starvation (i.e., decreased nutrient entry).

    In all, this study strongly confirms that increasing BMI seems to represent a valid therapeutic strategy for ALS, to be tested in future clinical trials.

    References:

    Marin B, Desport JC, Kajeu P, Jesus P, Nicolaud B, Nicol M, Preux PM, Couratier P. Alteration of nutritional status at diagnosis is a prognostic factor for survival of amyotrophic lateral sclerosis patients. J Neurol Neurosurg Psychiatry. 2011 Jun;82(6):628-34. PubMed.

    View all comments by Luc Dupuis

  2. This may be congruent with a preliminary hypothesis based on my current research that a component of animal fat is neuroprotective, and that the myelin sheath is vulnerable in some individuals as consumption of animal fat decreases. As more individuals adopt a vegan lifestyle, we need to analyze whether the rate of certain psychiatric and neurological disorders, such as ALS, increases in this population.

    View all comments by J. Lucy Boyd

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References

Paper Citations

  1. Dupuis L, Pradat PF, Ludolph AC, Loeffler JP. Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol. 2011 Jan;10(1):75-82. PubMed.
  2. Dupuis L, Corcia P, Fergani A, Gonzalez de Aguilar JL, Bonnefont-Rousselot D, Bittar R, Seilhean D, Hauw JJ, Lacomblez L, Loeffler JP, Meininger V. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology. 2008 Mar 25;70(13):1004-9. PubMed.
  3. Chiò A, Calvo A, Ilardi A, Cavallo E, Moglia C, Mutani R, Palmo A, Galletti R, Marinou K, Papetti L, Mora G. Lower serum lipid levels are related to respiratory impairment in patients with ALS. Neurology. 2009 Nov 17;73(20):1681-5. PubMed.
  4. Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, Drachman DB. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol. 2006 Jul;60(1):22-31. PubMed.
  5. Cudkowicz ME, Shefner JM, Schoenfeld DA, Brown RH, Johnson H, Qureshi M, Jacobs M, Rothstein JD, Appel SH, Pascuzzi RM, Heiman-Patterson TD, Donofrio PD, David WS, Russell JA, Tandan R, Pioro EP, Felice KJ, Rosenfeld J, Mandler RN, Sachs GM, Bradley WG, Raynor EM, Baquis GD, Belsh JM, Novella S, Goldstein J, Hulihan J, . A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology. 2003 Aug 26;61(4):456-64. PubMed.

External Citations

  1. Phase 2 clinical trial

Further Reading

Papers

  1. Mattson MP, Kapogiannis D, Greig NH. Tweaking energy metabolism to prevent and treat neurological disorders. Clin Pharmacol Ther. 2010 Oct;88(4):437-9. PubMed.
  2. Jawaid A, Murthy SB, Wilson AM, Qureshi SU, Amro MJ, Wheaton M, Simpson E, Harati Y, Strutt AM, York MK, Schulz PE. A decrease in body mass index is associated with faster progression of motor symptoms and shorter survival in ALS. Amyotroph Lateral Scler. 2010 Dec;11(6):542-8. PubMed.
  3. Pradat PF, Bruneteau G, Gordon PH, Dupuis L, Bonnefont-Rousselot D, Simon D, Salachas F, Corcia P, Frochot V, Lacorte JM, Jardel C, Coussieu C, Le Forestier N, Lacomblez L, Loeffler JP, Meininger V. Impaired glucose tolerance in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010;11(1-2):166-71. PubMed.
  4. Fergani A, Oudart H, Gonzalez de Aguilar JL, Fricker B, René F, Hocquette JF, Meininger V, Dupuis L, Loeffler JP. Increased peripheral lipid clearance in an animal model of amyotrophic lateral sclerosis. J Lipid Res. 2007 Jul;48(7):1571-80. PubMed.
  5. Desport JC, Torny F, Lacoste M, Preux PM, Couratier P. Hypermetabolism in ALS: correlations with clinical and paraclinical parameters. Neurodegener Dis. 2005;2(3-4):202-7. PubMed.
  6. Dorst J, Kühnlein P, Hendrich C, Kassubek J, Sperfeld AD, Ludolph AC. Patients with elevated triglyceride and cholesterol serum levels have a prolonged survival in amyotrophic lateral sclerosis. J Neurol. 2011 Apr;258(4):613-7. PubMed.

Primary Papers

  1. 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 Jul;44(1):20-4. PubMed.

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