Altered Metabolism May Precede ALS

Megan Brooks

August 24, 2015

Patients who develop amyotrophic lateral sclerosis (ALS) have alterations in metabolism before symptoms appear, hint results of new study.

Using a case-control design, researchers found that presymptomatic patients with the neurodegenerative disease consumed more daily calories but had lower body mass index (BMI) than their peers without ALS.

"Multiple studies have shown that ALS patients, after symptom onset, have an increased resting energy expenditure. This study, however, provides evidence that also presymptomatic energy metabolism is altered, providing further insight into the pathophysiological process of ALS," Jan Veldink, MD, PhD, from the University Medical Centre Utrecht, told Medscape Medical News.

The study was published online August 17 in JAMA Neurology.

The cause of ALS remains poorly understood. A growing body of literature suggests that nutrients might influence pathways involved in the development of ALS, Dr Veldink and colleagues note in their paper.

They studied 674 patients with a new diagnosis of possible, probable, or definite ALS and 2093 age- and sex-matched controls without ALS. They used a 199-item food-frequency questionnaire to assess the relationship between premorbid dietary intake and the risk for sporadic ALS.

They found that presymptomatic total calorie intake was significantly higher in patients with ALS than controls (average, 2258 vs 2119 kcal/day; P < .01). Yet, presymptomatic BMI was significantly lower in patients with ALS than controls (25.7 vs 26.0; P = .02).

They also observed that higher premorbid intake of total fat, saturated fat, trans-fatty acids and cholesterol was associated with an increased risk for ALS, while higher intake of alcohol was associated with a decreased risk for ALS. These associations were independent of total energy intake, age, sex, BMI, education, smoking, and lifetime physical activity.

Risk for ALS by Premorbid Nutrient Consumption

Intake Odds Ratio (95% Confidence Interval) P Value
Total fat 1.14 (1.07 - 1.23) <.001
Saturated fat 1.43 (1.25 - 1.64 <.001
Trans-fatty acids 1.03 (1.01 - 1.05) <.001
Cholesterol 1.08 (1.05 - 1.12) <.001
Alcohol 0.91 (0.84 - 0.99) .03


"The combination of a positive association of high total energy intake, low premorbid BMI, and high fat intake, corrected for lifetime physical activity, supports a role for an altered energy metabolism before clinical onset of ALS," the authors write.

"The finding that a higher intake of fat is associated with an increased risk of developing ALS corroborates the observations in a prior population-based case-control study, and warrants further research on energy metabolism prior to clinical onset of ALS," Dr Veldink told Medscape Medical News.

In the current study, there were no significant associations between dietary intake and survival in ALS. However, as reported by Medscape Medical News, a pilot study published in The Lancet in 2014 did find a positive effect of hypercaloric enteral nutrition on survival in patients with ALS.

Considering this finding, "our observations further emphasize the importance of a future phase 3 trial to compare whether a high-carbohydrate, high-caloric diet is to be preferred to a high-fat, high-caloric diet in ALS," Dr Veldink said.

Some prior studies have linked a higher intake of polyunsaturated fatty acids (PUFAs) with reduced risk for ALS. The current study showed a trend toward a decreased risk for ALS with a higher intake of PUFAs (P = .10 for trend).

"The PUFAs have neuroprotective properties because they exert beneficial effects on excitotoxicity, inflammation, and oxidative stress," Dr Veldink and colleagues point out.

Other studies have also linked high intake of carotenoids with reduced ALS risk.

Active Research Area

Kathryn C. Fitzgerald, MSc, from Harvard School of Public Health, Boston, Massachusetts, has been involved in several studies looking at diet and ALS risk. "It's an active and interesting area of research," she noted in an interview with Medscape Medical News.

"Hypermetabolism has been associated with ALS. A lot of studies have pretty consistently found that a higher BMI or obesity is associated with a lower risk of ALS. Understanding when the metabolic changes happen is important; usually it happens before diagnosis," Dr Fitzgerald explained.

This new study, she noted, is "observational and we should be cautious in interpreting the results due to the study design. When the patients filled out the dietary questionnaire, they already had ALS so it's possible that this could influence how they respond to the questionnaire. The study provides motivation to do further research," Dr Fitzgerald said.

Lyell K. Jones Jr, MD, neurologist specializing in ALS at the Mayo Clinic in Rochester, Minnesota, who wasn't involved in the study, also advises caution in interpreting the results.

"The main finding from this study related to diet and BMI in patients with ALS is an association between a higher recalled rate of dietary fat intake, and lower presymptom BMI, in ALS patients compared to controls. It's important to note (1) the authors are describing fairly small effect sizes with each of these factors (for example, the odds ratio of higher presymptomatic fat intake in ALS patients was 1.1 compared to controls) and (2) the findings cannot lead to a conclusion that there is any causative relationship between these dietary differences and the risk of developing ALS," Dr Jones told Medscape Medical News.

"In other words," he continued, "these data should not lead patients to the conclusion they should alter their diet to reduce their risk of ALS."

"Like many studies," Dr Jones said, "these findings lead to further questions. The study participants with ALS were asked about dietary patterns around the time of onset of ALS. We know that as a progressive disease, ALS can result in systemic changes prior to the patient's awareness of symptoms.

"For example, in this study, the lower BMI at symptom onset could reflect a factor related to the cause of the disease, or simply changes in weight occurring after disease onset (but prior to symptom awareness). As the authors point out, a controlled prospective trial would need to be performed to eliminate potential bias related to postdisease onset changes," Dr Jones said.

The study had no commercial funding. Dr Veldink has received travel grants from Baxter. Dr Fitzgerald and Dr Jones have disclosed no relevant financial relationships.

JAMA Neurol. Published online August 17, 2015. Abstract


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