Fat abnormalities offer new clue to Lou Gehrig's disease

<br>WASHINGTON (AP) _ Mark Mattson examined the spinal cords of victims of Lou Gehrig's disease and spotted something surprising _ abnormal buildup of fat-like substances in the very cells the deadly

Monday, September 16th 2002, 12:00 am

By: News On 6

WASHINGTON (AP) _ Mark Mattson examined the spinal cords of victims of Lou Gehrig's disease and spotted something surprising _ abnormal buildup of fat-like substances in the very cells the deadly disease targets.

Could somehow blocking that fatty buildup slow the inexorable paralysis of the disease? The National Institutes of Health neuroscientist is trying to find out, injecting mice genetically destined to get Lou Gehrig's with an experimental drug that appears to block the abnormal lipids.

It's a novel theory, and the drug is years away from being tested in people. But no one knows what causes Lou Gehrig's and several recent treatment attempts have failed _ so every new clue is welcome, and scientists are awaiting Mattson's results with both hope and caution.

``It really looks like a very interesting thing, but there've been false leads before,'' says Dr. Daniel Newman of Henry Ford Hospital in Detroit, who treats patients with Lou Gehrig's, formally known as amyotrophic lateral sclerosis or ALS.

But the theory already is generating speculation among patients about whether diet plays a role in ALS. Researchers recently found links between a high-fat diet and another neurologic disease, Alzheimer's. The NIH does plan to study whether eating certain fatty acids might affect ALS, but skeptical specialists are telling patients not to make drastic dietary changes yet.

``Patients are starting to jump to the conclusion that diet makes a difference. That's leaping to a conclusion,'' warns Lucie Bruijn, science director of the ALS Association.

Some 30,000 Americans have ALS, which results in a creeping paralysis as movement-controlling neurons, or nerve cells, in the spinal cord and brain are progressively destroyed. It typically strikes in the 50s, and patients often die within five years of the first symptoms, as paralysis leaves them unable to eat or breathe. The only treatment prolongs life about three months.

A small proportion of ALS is inherited, but what causes most cases is a mystery.

Lipids are building blocks of fat, and Mattson, neuroscience chief at NIH's National Institute on Aging, knew that the way people metabolize lipids changes with age. Also, changes in lipids inside cells play a role in cell death. So Mattson's lab examined lipid levels in ALS.

The scientists discovered that the spinal cords of ALS patients harbor significantly higher levels of several lipids than do healthy people's spinal cords. While cholesterol was somewhat elevated inside the cells, of greater concern were lipids called ceramides, the byproduct of a fat important in the normal insulation of nerve cells.

Studying autopsy tissue doesn't reveal when the abnormal fats appeared. So Mattson next studied mice genetically engineered to get ALS _ and found ceramide levels rose before the mice ever showed ALS symptoms.

That suggests ceramides play a crucial role in neuron degeneration. But what causes the buildup in the first place?

Mattson exposed mouse nerve cells to free radicals, chemicals produced during metabolism that are thought to damage cells. Free radicals have long been thought to play a role in ALS, and some ALS specialists advise taking antioxidant vitamins in hopes of curbing them. In Mattson's experiment, published in this month's Annals of Neurology, free radicals caused ceramides to rise inside those crucial nerve cells.

Finally, Mattson knew that cancer researchers were experimenting with a drug called ISP-1 that blocks production of the fat that in turn produces ceramides. He borrowed some, treated mouse nerve cells and then exposed them to free radicals _ and the drug-treated cells stayed healthy, with low lipid levels.

Now Mattson is giving ISP-1 to ALS-prone mice, to see if it delays paralysis.

Even if Mattson's theory is right, it's far too soon to know if diet could play any role in ALS. After all, millions of Americans have high cholesterol but relatively few get ALS, and no one knows what effect diet has on the ceramides that Mattson pinpointed as the worrisome lipid.

Indeed, doctors like Newman expect medications, not diet, to ultimately hold the key. For now, Newman advises patients just to eat the moderate-fat diet the government already recommends for a healthy heart and take antioxidants such as vitamin E as a precaution.