The symptoms of Parkinson’s disease are often visible to even a casual observer. The condition causes involuntary tremors, unsteady gait, muscle and joint stiffness, and wobbly balance. Less obvious is the disruption the disease can cause to the restorative power of sleep and, with it, the ability to make decisions necessary to perform everyday tasks.

The damaging connection between sleep disruption and cognitive decline in Parkinson’s disease patients – and how to treat it – is a subject of research for Dr. Amy Amara, professor in the Department of Neurology at the University of Colorado School of Medicine. Amara currently leads a study that investigates whether a planned exercise regimen can improve key stages of sleep in people with Parkinson’s disease and bolster their cognitive function.

The therapeutic power of exercise for people with Parkinson’s disease

Why exercise as the focus of the inquiry? For Amara and many other neurology specialists, the best way to treat a progressive movement disorder like Parkinson’s disease is to encourage patients to commit to movement.

“Unfortunately, we don’t have a medication yet that slows down the progression of Parkinson’s, but exercise seems to,” Amara said. She added that exercise can also reduce the risk of developing Parkinson’s disease in people who may be vulnerable to it. Regular movement also helps to improve non-motor symptoms that often accompany Parkinson’s disease, such as mood disorders and apathy, Amara said.

“So we are really encouraging our patients to participate in exercise, and this is just one way to do that – in a research study,” she said.

Work to explore the connection between Parkinson’s disease, sleep, and cognition

The trial builds on studies Amara previously co-authored that suggested exercise could have other important benefits for people with Parkinson’s disease. A February 2020 investigation concluded that exercise improved important measures of sleep. Those measures included time spent in slow-wave sleep, or deep sleep, a stage that is vital to rejuvenating the brain in all people, Amara said.

A subsequent study, published in 2021, showed that those individuals with Parkinson’s disease who increased their time in slow-wave sleep with exercise also improved their executive function – the mental skills that are essential to decision making, planning, carrying out tasks, and other staples of routine functioning.

The benefits of that finding would be substantial, Amara said.

“There is very good evidence that having cognitive dysfunction not only disrupts the quality of life for the person experiencing it but also for the family,” she said. The dysfunction makes it harder for caretakers of individuals with debilitating conditions like Parkinson’s disease to meet their loved one’s needs and increases the risk that they will no longer be able to care for them at home, Amara added.

The 2021 study raised a key question: why did only some patients who exercised improve their sleep and cognition? Amara’s new trial attempts to identify more precisely those who benefited.

Patients are randomized to two groups. One immediately receives 12 weeks of resistance exercise, such as weightlifting. A second, “delayed” group begins the training after 12 weeks have elapsed. For both groups, those whose slow-wave sleep improves will continue with the training. Those who do not show improvement will transition to aerobic endurance training. Participants will get sleep studies, MRIs, and cognitive tests to measure the results of the interventions.

“We are hoping that this evaluation of sleep will help us determine the best type of exercise for people with Parkinson’s,” Amara said.

Causes of sleep disruption in people with Parkinson’s disease

Why do sleep disruptions frequently accompany Parkinson’s disease? The reasons for the havoc are “multifactorial,” Amara said. The physical symptoms of Parkinson’s disease are an obvious culprit.

“The motor problems of Parkinson’s, like stiffness and slowness of movement, make it hard to turn over in bed,” she noted. The disease also can disrupt the body’s regulatory systems, causing frequent bathroom trips. Medications to treat symptoms may cause daytime sleepiness, making for a restless night. A condition called rapid eye movement sleep behavior disorder can lead to people acting out their dreams, sometimes with violent movements.

These problems lead to “sleep fragmentation” that contributes to daytime sleepiness, Amara said. But the issues can go well beyond nodding off or feeling foggy during normal waking hours, she added. The accumulation of short-term interruptions of sleep can interfere with the descent into slow-wave sleep. Those relatively brief periods of respite are havens that allow the brain to recharge and refresh.

Sleep impairment and cognitive decline

“Slow-wave sleep is important for consolidation of memories,” she said. It is also a key to “synaptic potentiation,” or strengthening of the nerve connections and transmissions in the brain that help us to remember things we’ve learned, complete tasks, and communicate effectively with others, Amara said.

“When you have disrupted sleep, it tends to lead to less of those deeper stages, so even if you have the same number of hours, you may not get the same quality of sleep. That can lead to disrupted cognition,” she said. “That has been well established in healthy adults and children too. But if you enhance certain stages of sleep – like slow-wave sleep – you can actually improve performance on memory and cognitive tests.”

Amara said the mechanisms that govern the connection between sleep quality and cognition are still being explored. One target: a process, glymphatic clearance, that removes harmful neurotoxins – waste materials – from the brain during sleep, Amara said. That activity occurs primarily during the slow-wave sleep stage, she added.

“Not having enough of that type of sleep makes toxins, like beta-amyloid, which is detrimental in Alzheimer’s disease, [build up],” Amara said. The problem can also prevent alpha-synuclein, a protein implicated in Parkinson’s disease, from being cleared from the brain, leading to nerve degeneration, Amara said.

“All of these things can build up to impair cognition and make it worse over time,” she said.

The mechanics of recruiting Parkinson’s disease patients for the study

Amara’s trial aims to improve understanding of these complex interactions of exercise, sleep, and cognition. As with any study, the effort relies first and foremost on gathering good data. The study requires sleep studies of patients before they begin the exercise training and after they complete it, as well as MRIs (if they are able to have them), and cognitive exams. The 12-week supervised exercise routines occur at the Clinical Translational and Research Center at UCHealth University of Colorado Hospital.

The second standard challenge for the study, patient recruitment, has a twist. Amara began the trial in 2021 while working at the University of Alabama at Birmingham, where she enrolled about 20 patients. Recruitment on the Anschutz Medical Campus, which had to begin from scratch, is still in the relatively early stages, with a half-dozen or so patients enrolled thus far, Amara said.

Professional research assistant Madison Sleyster, who works for Amara on administering the study, said that in addition to referrals from Amara’s and other neurology clinics, the study team plans to contact Parkinson’s disease support groups. During the summer, a Parkinson’s disease event sponsored by the Michael J. Fox Foundation also provided information about the study, Sleyster said, as did a campus research roadshow and a movement disorders conference in late October.

Sleyster said one unexpected challenge of meeting recruitment goals in relatively health-conscious Colorado has been finding patients who are “decently sedentary,” as she put it. With more individuals enrolled who haven’t exercised much, “we can see what our intervention with the exercise actually changes,” Sleyster said.

Maintaining smooth logistics to gather valid data

Sleyster and her colleague Aya Miften started their work on the study on the Anschutz campus the same day as Amara a year ago. They are responsible for much of the day-to-day work required for the study. Sleyster enrolls patients and handles the cognitive exams patients take at baseline and again after completing their exercise regimens. Miften conducts stress tests to make sure patients can handle the exercise routines before sending them to Sleyster for their cognitive testing.

Miften said patients randomized to the group that receives the exercise intervention immediately get a DEXA scan to measure their bone density, as well as tests of their knee, grip, and maximum weight strength. The resistance training, which occurs three times a week for 12 weeks, includes squats, step-ups and work with resistance bands and weights, Miften said.

Those patients that show an improvement in slow-wave sleep after completing the regimen resume the routine for another 12 weeks, Miften added. Those who do not demonstrate that improvement begins 12 weeks of aerobic endurance training, she added.

Sleyster and Miften both acknowledged that helping Amara get the study up and running on the Anschutz campus was a challenge. The work included not only gearing up patient recruitment but also learning how the departments of the School of Medicine work together and handling the transition of data from the previous study site to ensure the validity of the study results.

“The whole year has been a series of learning processes,” Sleyster said. “It’s a lot of problem-solving and trying to figure out things that might not be laid out for you.”

The two-way benefits of working with Parkinson’s disease patients

Miften said she’s been most gratified by the opportunity to work closely with individuals who are highly motivated to find ways to manage their Parkinson’s disease.

“That’s hands-down the best part of the exercise component, is seeing them so often,” Miften said. “I know so much about them. It’s exciting to see them get healthier and stronger over time. Regardless of what happens with the study, we know that exercise is beneficial.”

The study begins from that now well-established benefit that Miften cites. One big question that might follow in the future, Amara concluded, is how exercise might be adapted to the “highly heterogeneous group” of people with Parkinson’s disease: those who have different levels of physical ability, disease symptoms, and cognitive strengths and deficits.

“This current study might give us clues as to whether there are things that can predict what types of exercise [patients] might be most likely to improve with,” Amara said.

For more information about the study, contact [email protected].