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High Cholesterol Levels May Benefit ALS Patients, Study Suggests

ARTICLE IN BRIEF

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French investigators reported in a new study that ALS patients with considerably higher cholesterol ratios lived, on average, one year longer than patients with lower levels, when compared with normal controls.

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The findings of the current study about ALS and cholesterol, whose process is defined here, are counterintuitive, but worth exploring in future studies, several experts not involved with the study said.

Higher cholesterol levels may help prolong survival in patients with amyotrophic lateral sclerosis (ALS) by warding off malnutrition and muscle wasting, according to a new study by French researchers.

About two-thirds of ALS patients develop hypermetabolism, which leads to increased resting energy expenditure as a result of the disease, but the origin of this finding is unclear. On average, these patients also tend to have much higher blood levels of both good and bad cholesterol and triglycerides. Studies have also indicated that glucose metabolism is affected in ALS patients and in other neurodegenerative diseases.

In the new study, researchers at the Federation of Nervous System Diseases, Hospital de la Pitie-Salpetriere in Paris, discovered that ALS patients with considerably higher cholesterol ratios lived, on average, one year longer than patients with lower levels, when compared with normal controls. The findings, published in the April 8 print edition of Neurology, appeared online Feb. 13.

According to lead investigator Vincent Meininger, MD, professor of neurology, the findings suggest that in addition to abnormalities in nerves and muscles, some poorly understood metabolic changes also occur.

“It seems likely or possible that the relationship between metabolism and ALS and other neurodegenerative processes may not be as simple as has been suggested,” he told Neurology Today in an e-mail message.

STUDY METHODS, FINDINGS

Because blood lipids are the major source of energy for muscles, the investigators wanted to see whether triglycerides, cholesterol, and high-density lipoprotein (HDL) had any impact on progression and survival in 369 ALS patients and 286 healthy individuals. In addition, they performed postmortem examinations on liver samples from 59 additional ALS patients and 16 individuals with Parkinson disease (PD) to evaluate steatosis, or “fatty” liver.

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DR. VINCENT MEININGER: “Basically the findings are that more patients with ALS have an hyperlipidemic profile and survival is better when they have a high LDL/HDL ratio.”

They found that ALS patients had a twofold higher rate of hyperlipidemia — based on total cholesterol or low-density lipoprotein (LDL) — but that only elevated LDL/HDL ratios were associated with an increase in 12-month survival.

As expected, autopsies showed more advanced steatosis in the ALS patients with high cholesterol levels than among the deceased PD patients.

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Investigators measured steatosis, which occurs when large vacuoles of trigylceride fats accumulate in liver cells (pictured here), in ALS patients postmortem, and found they had a twofold higher rate of hyperlipidemia.

Hyperlipidemia, they concluded, is a prognostic factor for survival in ALS patients, a finding with implications for nutritional intervention. Of greater significance, however, is that the finding calls into question the use of lipid-lowering medications in these patients.

“Basically the findings are that more patients with ALS have an hyperlipidemic profile and survival is better when they have a high LDL/HDL ratio,” Dr. Meininger said.

The association between hyperlipidemia and neurodegenerating diseases is not new, he noted. “This has been described for other patients, those with Alzheimer disease (AD), particularly, he said, but the study is the first to document the potential benefits of higher circulating blood fats in ALS patients. And, he said, the new data raise a more intriguing issue — whether hyperlipidemia might be an intrinsic part of the ALS disease process or the body's natural response to it.

Dr. Meininger also observed that animal studies show that mice with defects in the antioxidant enzyme superoxide dismutase (SOD) live longer if fed a high-fat diet. Mice with SOD defects or lacking the gene for the enzyme experience accelerated age-related muscle mass loss, which may be a promising direction for future study.

STATINS AND ALS

In an accompanying letter to the editor, Mark R. Goldstein, MD, of Coral Gables, FL, noted that the findings are particularly interesting because one 2007 report in Drug Safety suggests that statin therapy might increase the risk of ALS or an ALS-like syndrome.

“This begs the question: Is hyperlipidemia protective or are statins harmful in ALS?” he asked. “Furthermore, other agents that lower cholesterol levels should also be avoided in these patients. Finally, raising the cholesterol levels of ALS patients by dietary means might be beneficial and should be investigated.”

Dr. Meininger agreed, noting that his team has been considering the possible worsening effect of statins in ALS patients for over a decade.

“We systematically stop [these drugs] in patients at first visit. In the study, all patients were free of statin medication, which strongly suggests that the protective effect of dyslipidemia is not due to a higher frequency of statin therapy in the low LDL/HDL group of patients.”

By reducing LDL-cholesterol, statins decrease nutrient availability to muscle, which might contribute to neuromuscular junction damage and motor neuron death as previously shown in an animal model of ALS, he pointed out. In addition, multiple pathways activated by statins might be deleterious in ALS patients.

MORE DATA NEEDED

Hiroshi Mitsumoto, MD, the Wesley J. Howe Professor of Neurology at Columbia University and medical director of the Eleanor and Lou Gehrig MDA/ALS Center at Columbia Presbyterian Medical Center in New York City, called the findings “provocative,” and said further investigation is urgently needed.

In a telephone interview with Neurology Today, he noted that metabolic abnormalities in ALS patients have been reported since the 1970s, but this is the first study to suggest that high cholesterol levels might be beneficial.

“Clearly something is going on at a systemic level apart from the neurological changes but we need more data before we make any decisions about what to advise patients who are currently taking cholesterol-lowering medication,” he said. “Many patients are taking these drugs, and other experts have said the drugs might be harmful for ALS patients, so we need to look into this immediately.”

He also noted that ALS is such a rapidly progressive disease that, if there are benefits from higher cholesterol, they might outweigh the much longer-term risks of cardiovascular disease.

“About half of all ALS patients die within two to three years of diagnosis. Therefore, when compared to the time it takes heart disease to become life-threatening, it seems to me that ALS patients benefit more from having higher blood fat levels. In the long run the overall death rate from heart disease is high, but it takes a much longer time,” he said.

Merit Cudkowicz, MD, associate professor of neurology at Harvard Medical School and co-director of the ALS Clinic at Massachusetts General Hospital, also emphasized the need for more study.

“I'm not surprised by the findings,” she told Neurology Today in a telephone interview. “In our clinical trials, ALS patients have high cholesterol levels, sometimes very high levels. The relationship to survival makes sense, but I think we have to be somewhat cautious about how we interpret this.”

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DR. HIROSHI MITSUMOTO: “Clearly something is going on at a systemic level apart from the neurological changes but we need more data before we make any decisions about what to advise patients who are currently taking cholesterol-lowering medication.”

She stressed that while the findings may be useful in predicting which patients will fare better, other factors remain unknown.

“We just don't know what else is going on — this is just one piece of information. It might be an inherent part of the disease process, but it seems to be more than that to me. For one thing, high cholesterol rates are present before ALS symptoms appear. Why? We don't know yet.” •

REFERENCES

Meininger V, Dupuis L, Corcia, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008;70:1004–1009.
Edwards IR, Star K, Kiuru A. Statins. Neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: an analysis of individual case safety reports from Vigibase. Drug Saf 2007;30:515–525.