In medicine’s ongoing battle with disease, technology plays a major, ever-evolving role. Advances abound in the form of new drugs, medical devices and gene therapies. But a decidedly low-tech treatment strategy for at least one disease simply requires putting one foot in front of the other – literally.

The target is Parkinson’s disease, a progressive movement disorder that affects around 1 million people in the United States and 10 million worldwide. While there is no cure, there are drugs to treat the symptoms of Parkinson’s, including tremors, rigidity, and impairment of fine motor movements. But a growing body of evidence suggests that a powerful counter to this movement disorder may be, well, movement.

A new nationwide trial that includes the University of Colorado is putting that idea to the test. Study in Parkinson Disease of Exercise (SPARX3) is a randomized clinical trial investigating whether regular, moderate and high-intensity exercise can slow the progression of symptoms in patients in the early stages of Parkinson’s disease who have not yet begun drug treatment.

Groundwork previously laid

The study, which is underway at 29 sites in North America, builds on the findings of SPARX2. That trial concluded in 2016, with results published in 2018 in JAMA Neurology. SPARX2 was led at CU by Dr. Margaret Schenkman, then director of the Physical Therapy Program and a pioneering investigator in using physical therapy to treat Parkinson’s disease.

SPARX2 divided early-onset Parkinson’s disease patients into two groups that followed four-day-a-week, 30-minute treadmill exercise regimens. One group elevated their heart rate to 65% of the maximum, the other to 85% of the maximum. A control group did not engage in a formal exercise program for the six- month study duration.

The study demonstrated that the approach was both safe and feasible for the people in the two exercise groups. It also showed that those in the two groups showed slower advance of the disease than those who did not exercise, as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS).

A deeper look at possible benefits

The findings spurred SPARX3, a much larger study with greater geographical reach. This time, patients will be randomly assigned to two groups for 30 minutes of treadmill exercise, four days a week. The exercise heart rates for the groups will again be 65% and 85% of the maximum. The aims: further test the effectiveness of exercise in blunting the advance of the disease and which, if either, approach is more effective in doing so.

“We’re not suggesting that exercise will eliminate Parkinson’s disease,” said Dr. Cory Christiansen, assistant professor of Physical Medicine and Rehabilitation with the CU School of Medicine, “but the results of SPARX2 signaled that exercise can slow the rate of disease progression.”

Christiansen is principal investigator for SPARX3 at CU and part of a diverse investigative team (see box). He co-authored the JAMA Neurology article on the SPARX2 trial and counts Dr. Schenkman, who is now retired, as a mentor.

The much larger and farther-reaching SPARX3 trial will help to show if the study’s exercise approach is “generalizable to a broad population” with regional differences, Christiansen added.

“We might discover factors that differ between groups,” he said. For example, people in Colorado are generally very active compared to other states, he noted.

Careful patient selection and execution

Nationally, Northwestern University leads SPARX3, with a target enrollment of 370; at CU the goal is 24 patients, Christiansen said. Study coordinator Katherine Balfany said that to be included, patients must be:

• Between 40 and 80 years old
• Within the first three years of their diagnosis
• Not currently on Parkinson’s disease medications – or slated to be within the next six months
• Not enrolled in a structured exercise program, but healthy enough to meet the activity requirements of the study for 18 months.

The trial also requires a brain-imaging test called a DaT scan to confirm a diagnosis of Parkinson’s disease. The test involves injecting a radioactive tracer that attaches to a protein that transmits dopamine. Dopamine is the neurotransmitter, or chemical messenger, that plays an important role in movement. An imaging scan then reveals how much, or little, of the tracer laid down roots in the brain. A small amount of tracer is consistent with low dopamine levels, an indicator of Parkinson’s disease.

Balfany said those enrolled in the study will be fitted for heart monitors with a chest strap. During exercise, they will connect via Bluetooth to their smartphone, which will display their heart rate as they churn through their routine and “draw their attention to the percentage they should be targeting,” Balfany said.

Each study site, she added, will be able to view their enrollees’ data, in real time, on a secure, web-based platform to make sure that individuals are staying in the proper exercise intensity range. Participants will also meet twice a month with study team members on the University of Colorado Anschutz Medical Campus to make sure they are maintaining and meeting the study protocols, Balfany said.

Neurology incorporates exercise

These closely observed details and procedures are, of course, essential to meeting the standards of clinical research. But SPARX3 builds on a now well-entrenched view that exercise is both viable and desirable to help people with Parkinson’s disease manage their symptoms.

As Schenkman observed in 2018 after publication of the SPARX2 trial findings, “The study shows that neurologists can rest assured that it’s safe and feasible for their patients to exercise at a high intensity. That’s huge. We can get people started right away on exercise habits when that is easier to do.”

That comment squares with the views of Dr. Jeanne Feuerstein, a neurologist and movement disorders specialist who practices at the UCHealth Neurosciences Center – Anschutz Medical Campus. Feuerstein is study neurologist and site co-investigator for the SPARX3 trial.

“What I always say to my patients is I can give you medications that will make you function as well as you can, but the reason I’m doing it is so you can exercise,” Feuerstein said. “That’s the key for you to actually modify the progression of the disease.”

Feuerstein said when she began her career 15 years ago by shadowing neurologists in movement disorders clinics, exercise was seldom emphasized to Parkinson’s patients. By the time of her residency, however, that had changed.

“Exercise has been considered part of the standard of care for people with Parkinson’s disease for at least five years,” she said. “Because of that, we now have more emphasis on specific types of exercise.”

A possible boost for quality of life

While SPARX3 focuses primarily on motor improvements, Feuerstein noted that exercise helps with other Parkinson’s symptoms, including constipation; mood disorders, such as apathy, anxiety and depression; and sleep problems. Mitigating these symptoms can help to improve quality of life and encourage people to engage with others. All these factors work together to blunt the undeniable challenges of the disease.

“I say to patients, ‘We can think about this [diagnosis] as a time for you to take a look at your life and figure out new, healthy ways to live,’” Feuerstein said.

Christiansen added that SPARX3 could give both patients and providers a roadmap for doing that, with something as simple and accessible as walking.

“It’s easy to tell someone to exercise, but what kind of exercise? The study could offer clinicians the ability to be more precise in their prescription of exercise and the intensity,” he said. “And once you’re dialed in as a patient, you don’t really need to go to a physician to tell you to exercise. People will have the ability to be more in charge of their own health.”

More questions to contemplate

Christiansen emphasized that exercise is not a replacement for medications that effectively manage Parkinson’s disease, notably carbidopa-levodopa and dopamine agonists, which are a group of drugs that fire parts of the brain that are normally charged by dopamine. However, he added, exercise could help people safely avoid the side effects of these medications, at least temporarily.

“It would be impactful if we could possibly delay the onset of symptoms, and/or decrease the dose of medications,” Christiansen said.

He added that SPARX3 will also examine a host of potential secondary outcomes of regular exercise, including improvements in quality of life, cognition, walking, fitness, and quality of movement. Researchers will also scrutinize blood biomarkers that are indicators of inflammation and changes in the nervous system.

In fact, the SPARX3 trial launch only begins to answer many questions about the promising but emerging benefits of exercise for Parkinson’s disease patients, Christiansen said.

“We’re hopeful that both groups will show the benefits of exercise, but we don’t know if it will be one or the other or equal,” he said. He noted, for example, that “it’s not a good thing” if patients spend so much energy on their exercise regimen that they have little left over for activities in the community.

“We don’t know if more intense exercise is better,” he concluded.

For more information on the SPARX3 trial, contact study coordinator Katherine Balfany at [email protected] or 303.724.9101.