For years, scientists have sought ways to better treat or slow the progression of Huntington's disease (HD). HD is an inherited neurological disorder that causes involuntary movements (chorea), cognitive decline, and psychiatric problems such as depression, irritability, anger, and psychosis. The disease progresses slowly over 20 years or more.

HD is passed on from parent to child through a mutation in the huntingtin gene. It is an autosomal dominant disease, which means that just one mutated gene from a parent will cause the condition. Typically, a person with HD carries one mutated gene and one normal one, so his or her children have a 50 percent chance of inheriting the mutated gene and subsequently developing the disease.

While research has not yet uncovered a cure for HD, there have been inroads in treatments that alleviate some of the disease's symptoms, and scientists continue to focus on strategies to slow or stop the progression of the disease before symptoms actually begin.

Recently, scientists have become interested in studying creatine, an enzyme naturally produced in the liver and kidney that helps provide energy to cells, as a possible therapy for HD. Damage from HD makes certain cells very inefficient, which forces the body to consume enormous amounts of energy. HD patients can require up to 7,000 calories a day just to maintain a normal weight. Some researchers believe that supplementing the body's natural supply of creatine might boost energy efficiency in cells affected by HD.

In earlier experiments, mice that were genetically altered to carry the huntingtin gene and given a daily creatine supplement showed less shrinkage in areas of the brain (atrophy), as well as improved motor and cognitive function. Subsequent small trials involving humans proved disappointing, however—participants experienced no benefits from taking 5 grams of creatine daily.

A Unique Study Design

Still, a team of scientists from Harvard and its affiliated teaching hospitals recruited 64 participants for the Creatine Safety and Tolerability in Premanifest HD (PRECREST) trial to see whether higher doses of creatine would be safe and well-tolerated in humans. Some participants had a 50 percent risk of inheriting the disease but had not yet been tested for the HD gene, while others already knew they possessed the HD gene, meaning they would develop the disease at some point.

Most patients with HD are diagnosed only after symptoms appear, and by this time much of the brain damage has already occurred. By opening up the trial to people who were pre-symptomatic, the researchers hoped to examine what occurs in the earliest pre-symptomatic, or prodromal, stages of the disease.

The researchers felt that including people who didn't know or didn't want to know their genetic status was important because it widened the pool of available trial participants. Typically, few people—only about 5 percent of at-risk people in the United States—opt to be tested for the mutated gene. But the PRECREST scientists attracted participants by promising that they would not be told the results of the genetic test, but would still have the opportunity to take part in a study that could potentially benefit them. The participants were guaranteed that their HD status could not be uncovered accidentally or deliberately.

The researchers then screened all participants for the mutated gene and determined that 47 of them had the HD gene and 17 did not. The smaller group became the healthy control group for the study. As promised, the researchers did not disclose the results of the genetic test to those who didn't want to know.

In addition to determining whether a higher dose of creatine—30 grams daily—could be safe and well-tolerated in these participants, the researchers also wanted to evaluate potential biological markers for disease progression in pre-symptomatic people, including cognitive, blood, and brain imaging tests.

"We have no good predictors of [disease] onset," says study author H. Diana Rosas, MD, director of the Center for Neuroimaging of Aging and Neurodegenerative Disease at Massachusetts General Hospital and a member of the American Academy of Neurology (AAN). "However, we know the brain atrophies in HD, and that this is already happening before patients are symptomatic."

For six months, the study participants were randomly assigned to take either 15 grams of creatine twice daily or a sham therapy—a placebo or sugar pill. Neither the study participants nor the researchers knew who received the placebo and who received the drug.

Throughout the study period, the researchers administered blood tests, cognitive and memory function tests, and brain scans using magnetic resonance imaging (MRI) to measure brain volume in all the participants.

What the Researchers Learned

The study, published in March 2014 in the AAN journal Neurology, found that two-thirds of the participants were able to tolerate the highest creatine dose of 30 grams, and more than three-quarters tolerated 15 grams or more. Mild gastrointestinal discomfort was the most common adverse side effect, but taking creatine with food or probiotics often alleviated or reduced this discomfort.

MRI scans showed that the participants with pre-symptomatic HD already had as much as 10 percent thinning in some brain regions compared with healthy controls. At six months, the rate of thinning in certain brain areas was slower in pre-symptomatic subjects taking creatine than in those taking the placebo, but there were no significant changes at 18 months. The healthy participants showed no significant change in brain volume throughout the study, regardless of whether they took the placebo or creatine.

The trial also found that using MRI to measure brain volume was the best of several potential tools for measuring disease progression in the pre-symptomatic phase of HD. Other biomarkers, such as blood tests and cognitive, motor, and memory function tests, all proved too insensitive or inappropriate for measuring disease progression.

Importantly, the findings suggest that MRI may be a useful tool for measuring progression in future trials, according to the study authors. Currently, the U.S. Food and Drug Administration only accepts the Huntington Total Functional Capacity Score as a measurement of disease progression in clinical trials. This scale is used to rate the functional abilities of an HD patient in five areas of life: work, finances, domestic chores, daily activities, and the need for care at home.

"The results of PRECREST show that high doses of creatine are relatively safe and well-tolerated," says Dr. Rosas. But, she cautions, the study was not designed to test whether creatine is effective in slowing disease progression. Nor does it prove that creatine slows brain atrophy over the long term. "It is possible that slowing brain atrophy will not result in direct clinical benefits for patients, or that the positive effects of creatine may be temporary and become ineffective over time," she says.

She also stresses that patients should not try over-the-counter high-dose creatine supplements. The creatine used in the trial was a purer form of the enzyme, free of the contaminants and additives found in over-the-counter products. Store-bought supplements are not regulated, and thus purity and quality vary from product to product.

Still, the PRECREST study underscores the value of these kinds of clinical trials, says Anne Killoran, MD, an assistant professor of neurology at the West Virginia University Department of Medicine and director of the West Virginia University Movement Disorders Clinic, who was not involved with the study.

"We want to know when the disease starts, and today, it's a fuzzy line," Dr. Killoran says. "We have always diagnosed people based on physical symptoms, even though they may already show cognitive and psychiatric symptoms. In the future, that may change once we find [predictive markers of disease progression] like the MRI tools used in the study." But this will only be useful if researchers can find an effective treatment, she adds.

The Harvard researchers are actively recruiting participants for a larger study to test the efficacy of high-dose creatine—40 grams daily—in HD patients. To participate in the trial or to receive more information, visit the Huntington Study Group's CREST-E web page.

Huntington's Disease By the Numbers

• 1986 The year a genetic test for HD became available.
• 50% The likelihood of inheriting the mutated HD gene if a parent carries it.
• 5% The average percentage of people in the United States who are at risk of inheriting the mutated HD gene who choose to take the genetic test before symptoms appear.
• 30,000–40,000 The estimated number of people diagnosed with HD in the U.S.
• 15–20 The average number of years adult HD patients live after physical symptoms become noticeable.
• 10–15 The average number of years patients whose physical symptoms appear before the age of 20 live.

For More Information:

• National Institute of Neurological Disorders and Stroke HD Information Page
• Clinical trials currently recruiting HD patients at ClinicalTrial.gov
• Neurology Now articles about HD