ALS Research Roundup May 2008

by Margaret Wahl on Thu, 2008-05-01 17:00
Article Highlights:

Research Roundup updates as of April 2008

Does a high serum cholesterol level increase survival time in ALS?

A French research team that published its findings March 25 in Neurology has found that elevated levels of lipids (fatlike substances) in the blood, known to be risk factors for cardiovascular disease, actually may be a good thing in ALS.

High lipids more common in ALS group than non-ALS control group

First, Vincent Meininger at the Pitié-Salpêtrière Hospital in Paris, and colleagues, looked at lipid levels in 369 people with and 286 people without ALS.

They measured serum triglycerides, the most common form of fat in the bloodstream; cholesterol, a fatlike substance known to build up in arteries but also necessary for building cell membranes; lowdensity lipoproteins (LDL), which carry cholesterol from the liver to the rest of the body and are sometimes called “bad cholesterol”; and high-density lipoproteins (HDL), which carry cholesterol from the body’s tissues to the liver (for elimination) and are sometimes called “good cholesterol.”

The researchers found elevated total serum cholesterol levels in 24 percent of the ALS patients, compared with 11 percent of the non-ALS patients. They found elevated LDL levels in 49 percent of the ALS patients, compared with 20 percent of the control group.

ALS patients with high lipid levels survived longer

Medical records from 59 French ALS patients found having a high ratio of “bad” to “good” serum cholesterol levels was associated with living about a year longer.

They then looked at the records of 59 patients with ALS who died between 1983 and 2005 and divided them into two groups: those with low LDL/HDL ratios and those with high LDL/HDL ratios. What they found was surprising: Those with a low LDL (“bad cholesterol”) to HDL (“good cholesterol”) ratio lived an average of just over three years, while those with a high LDL/HDL ratio lived an average of just over four years.

The authors interpret their findings to mean that having an elevated ratio of LDLs to HDLs increased survival time in ALS by about a year, which suggests to them that the disease itself might be triggering a protective alteration in metabolism.

They say their findings “warn against the use of lipid-lowering drugs in this vulnerable population of patients” and that attention to adequate nutrition should be a priority in ALS care.

Study brings WHO report to mind

In an accompanying editorial, University of Pittsburgh epidemiologist Steven Albert reminds readers of a 2007 report from the World Health Organization that raises the possibility that the use of statin medications, such as atorvastatin (Lipitor), lovastatin (Mevacor) and others, which lower cholesterol levels, could increase the risk of developing ALS. (See "Research Roundup September 2007".)

Are high lipid levels the true cause of longer survival time?

Stan Appel, an MDA research grantee at Methodist Neurological Institute in Houston, where he directs the MDA/ALS Center, says the investigators are to be congratulated for their study, but it may be premature to conclude that increased LDL/HDL ratios are protective in ALS.

“Their report provides no data as to why either increased LDL, low HDL, or the increased ratio of LDL/HDL might be associated with prolonged survival,” Appel says.

“In fact, the challenge to the field is to confirm these results and then determine why the high LDL/HDL patients live longer. It may be premature to conclude, as they do in their title, that ‘Dyslipidemia [altered fat levels] is a Protective Factor in ALS.’

“A preferred title would have been ‘ALS Patients With Dyslipidemia Have Prolonged Survival,’” he says, a phrasing that doesn’t assume cause and effect but merely states an association.

“It’s also premature to warn ALS patients against the use of statins or related compounds — especially in patients with significant past cardiovascular disease, where statins are of proven therapeutic value,” Appel says.

Weighing the risks of lipid-lowering meds

These are preliminary findings, noted MDA Medical Director and Vice President of Research, Valerie Cwik.

“In the meantime, patients should not make any decisions about their diet or medications without first consulting their own physician.”

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ALS-causing flaws in TDP-43 gene found in two new studies

Genetic variations could make some people particularly vulnerable to poisoning from organophosphate compounds, such as those used in some pesticides.

More cases of ALS caused by mutations in the protein known as TDP-43 have been identified, this time in France and Quebec, Canada, by a team coordinated by MDA grantee Guy Rouleau at the University of Montreal; and in a European and a Chinese family by Gerard Schellenberg at Veterans Affairs Medical Center in Seattle, and colleagues.

Rouleau and colleagues, who published their findings online March 30 in Nature Genetics, screened 200 people with ALS and 185 without the disease. They found TDP-43 mutations in six people with sporadic (nonfamilial) ALS, and three in people with familial ALS; they found none in the unaffected control group.

Schellenberg and colleagues, who published their findings online April 5 in Lancet Neurology, screened 259 patients with ALS, frontotemporal dementia (a brain disease), or both, for TDP-43 gene variations. They found two variants that correlated with inherited ALS in two families. The variations were absent in an unaffected control group. These findings further support evidence that TDP-43 gene and protein abnormalities may cause ALS. (See Research Roundup, April 2008.)

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Researchers probe possible links between genes and exposures to toxins

New findings from researchers at Massachusetts General Hospital in Boston and the University of Washington-Seattle have unexpectedly contradicted earlier reports that suggested variations in an enzyme called PON1 (paraoxonase 1) might underlie susceptibility to illness, including ALS, from exposure to organophosphate-based pesticides and other potentially toxic substances. (See "Research Roundup April 2008" and “ALS and Vets,” MDA/ALS Newsmagazine March 2008.)

An elevated incidence of ALS in veterans of the Persian Gulf War has been observed, and a combination of PON1-related genetic susceptibility and exposures to pesticides and antinerve gas medications has been proposed as its cause.

However, when Anne-Marie Wills at Mass General, and colleagues, analyzed blood samples from 140 people with ALS and 153 without the disease, they were surprised to find there was no significant difference in the two groups in either the amount of PON1 enzyme or its ability to break down organophosphates, even though a particular variant of the PON1 gene and enzyme was more common in the ALS group than in the non-ALS group.

Robert Brown, director of the MDA/ALS Center at Mass General, and Merit Cudkowicz, a longtime MDA ALS research grantee, were on the study team, which published its findings in the March 18 issue of Neurology.

Elsewhere, a different research group has found mutations in another gene, one that also has connections to organophosphates, also causes a disease of the motor neurons (the nerve cells affected in ALS).

Shirley Rainier at the University of Michigan and her colleagues, who published their findings in the March issue of the American Journal of Human Genetics, identified mutations in the neuropathy target esterase (NTE) gene in two families with a form of motor neuron disease. The disorder resembled neurologic symptoms of chronic organophosphate poisoning.

Organophosphates are known to interfere with the NTE enzyme and/or cause it to take on toxic properties. None of the affected family members had knowingly been exposed to these chemicals, however.

“Each affected subject had two mutant NTE genes,” said John Fink, a neurology professor at the University of Michigan and senior investigator on the study. “In our patients, we think it is the NTE mutations alone that caused the motor neuron disease. We speculate, however, that individuals who have only one NTE gene mutation may be vulnerable to neurotoxic organophosphate compound exposures.”

Fink said one implication of the NTE findings is that together with PON1’s association with ALS, there is now further support for the theory that neurotoxic organophosphate compounds cause motor neuron disease in general and ALS in particular; and that genetic variations, such as in PON1 and NTE, could lower the threshold for organophosphate neurotoxicity.

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People with ALS sustain hope with variety of strategies

Robert Miller, director of the MDA/ALS Center at California Pacific Medical Center in San Francisco, was part of a group of researchers who recently surveyed 16 people with ALS to assess their ability to maintain hope in the face of a devastating illness. (Hope can be defined as the belief that one can find and use pathways to reach desired goals.)

The investigators, who published their findings in the May-June issue of the Journal of Palliative Medicine, found people used a variety of approaches to sustain hope. Among them were maintaining belief in a cure for the disease, relying on spiritual beliefs, adapting to changing capacities, living in the moment and “transcending the self,” which the researchers describe as placing less emphasis on external definitions of self and a greater sense of connection with one’s past and with future generations.

The 16 study participants (13 men and three women, with an average age of 54) were, for the most part, able to remain hopeful, and their level of hope was not correlated with their projected survival time or degree of physical disability.

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Margaret Wahl
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