Key Clue to Huntington’s Disease Found : Medicine: Discovery of a brain chemistry change in those afflicted with the degenerative illness may lead to development of the first therapies to treat it.

Scientists reported Monday that they have discovered a new biological defect associated with Huntington’s disease that they say might lead to the first therapies for this degenerative disorder that affects 25,000 Americans.

Recent studies have suggested that brain cells in Huntington’s patients have difficulties producing the high-energy chemicals that fuel brain activity.

Now, sophisticated studies of brain chemistry indicate that these difficulties in energy production lead to a buildup of a chemical called lactic acid, researchers from the Massachusetts General Hospital reported at a meeting of the Society for Neuroscience in Anaheim. The lactic acid buildup serves as a “red flag” indicating that the brain cells are using a metabolic pathway that will eventually lead to their destruction, said Dr. Walter Koroshetz, a neurologist at Mass General.

This discovery marks the first time that a biological abnormality linked to Huntington’s has been observed in the brains of living humans, Koroshetz said.

Koroshetz and his colleagues monitor the buildup of lactic acid in the brain with magnetic resonance imaging and have just begun using that buildup as a biological marker to test the efficacy of a variety of medications that may delay the progression of the disorder and thereby extend the patients’ lives.

In this way, they hope to gain an indication of a medication’s potential effectiveness in as little as six weeks, compared to the three years or longer that would be necessary if they were only monitoring visible symptoms of the disorder. This could allow them to quickly identify potentially effective treatments, but those treatments would then need to be tested in full-scale clinical trials that would require three years or longer. They have no results yet.

“This is a stellar finding,” said Dr. Nancy Wexler, a neurologist at Columbia University who is also president of the Hereditary Diseases Foundation. “It gives us an entryway into new therapeutics for Huntington’s. . . . It’s one of the most exciting stories I have heard in ages.”

Huntington’s disease is an inherited disorder caused by the death of cells in the areas of the brain responsible for movement, thought, perception and memory. It typically begins in patients 35 to 40 years old. The first signs are subtle impairments in coordination and movement. These progress to involuntary jerking movements of the body, limbs and facial muscles, accompanied by impaired reasoning and memory problems. No treatment exists and the disorder is ultimately fatal.

In addition to the 25,000 Americans who already have Huntington’s, another 125,000 are at risk of developing it.

Koroshetz and his colleagues used magnetic resonance imaging to study the brains of 24 Huntington’s victims. The imaging device was modified to detect lactic acid--a normal byproduct of anaerobic (oxygen-free) metabolism of sugars--in various regions of the brain. Anaerobic metabolism is used by muscles and brain cells to provide energy when the cells are stressed, such as by exercise, and cannot get enough energy through aerobic metabolism, in which oxygen is used to produce energy from sugars.

Lactic acid is not itself toxic, and its accumulation in the cells probably does them no harm, Koroshetz said, but its presence indicates the cells are not functioning properly. The excessive reliance on anaerobic metabolism, he said, leaves them unusually vulnerable to an early death.

In 23 of the 24 Huntington’s patients, the researchers observed unusually high levels of lactic acid in the cortex, the center for thought, perception and memory. Normal levels of lactic acid were observed, however, in the brains of healthy individuals and in individuals who had been genetically diagnosed to have Huntington’s, but who had not yet developed symptoms.

The Mass General team is now using the discovery to help test potential new therapies for Huntington’s in a group of “about 20 patients,” Koroshetz said. The medications tested represent a variety of compounds that the researchers think will stimulate the efficiency of aerobic metabolism in the brain cells and thereby reduce the stress that eventually leads to their death.

The patients are screened with magnetic resonance imaging to determine their lactic acid levels before receiving each drug. They are then rescreened six weeks later to determine if levels of lactic acid have declined.

The researchers would not disclose the identity of any of the compounds they are testing, however, because the compounds are widely available and they fear that Huntington’s patients would take them indiscriminately. Experts said, however, that they were testing vitamins and antioxidants, such as ascorbic acid, among other drugs. All the compounds being tested have previously been found to be safe in humans.