ARTICLE IN BRIEF
Michael Zigmond, PhD, offers an overview of research in mouse and monkey models of Parkinson's disease, showing the benefits of exercise. Other PD specialists highlight findings on the impact of exercises in clinical trials.
NEW ORLEANS—What if the most effective protection against neurodegenerative disease was a daily run around the neighborhood? It might be, according to a growing body of research pointing to the strong neuroprotective effects of daily exercise.
The case for this simple and powerful treatment in preventing or slowing Parkinson's disease (PD) was presented by Michael Zigmond, PhD, in a plenary session at the AAN annual meeting here in April. And a randomize clinical trial, the results of which were presented at the meeting, suggest that regular exercise can significantly delay symptomatic decline in PD.
“There has been a dramatic shift in the amount of physical activity in which we engage” since the evolution of modern humans, said Dr. Zigmond, professor of neurology at the University of Pittsburgh. Estimates are that our ancestors of 50,000 years ago walked or ran between 12 and 19 kilometers per day. But no longer: the modern American averages less than 300 meters per day, “roughly the distance from your house to your car to your office and back again.”
The health benefits of exercise are felt throughout the body, from reducing diabetes and hypertension to increasing strength. In the brain, “exercise is associated with less depression, faster stroke recovery, and fewer age-related falls, and there is increasing evidence it reduces the risk of Alzheimer's disease,” he said.
A list of the likely cellular consequences that lead to PD, he said, is the opposite of those brought about by exercise. PD is associated with reduced mitochondrial ATP production, while exercise increases it. PD is characterized by increased inflammation; exercise decreases it.
Therefore, he said, “exercise ought to be a useful way to combat Parkinson's disease,” and 20 years of clinical studies have supported that conclusion. “But these trials have generally been of short duration, with small patient numbers, and focused on symptoms, rather than underlying disease progression. We still don't know whether exercise is protective or restorative.” The unanswered question is, “Does it change the face of disease?”
CONSTRAINT/FORCED USE MODELS
One of the earliest demonstrations that exercise might change the face of PD emerged from a constraint/forced-use model in rats. When rats receive a unilateral injection into the striatum of the toxin 6-hydroxydopamine (6-OHDA), which selectively kills dopamine neurons, it causes a predictable contralateral motor impairment, leading the rat to favor use of the ipsilateral limb. To test the ability of exercise to protect dopamine neurons against injury, researchers first applied a cast to the limb that would eventually be spared, forcing the rat to use the limb that would eventually be targeted. After a week, 6-OHDA was injected. The rat showed virtually no contralateral limb impairment, and at the cellular level, the striatum on the injected side showed almost no dopaminergic cell loss.
While remarkable, the results have not been consistently replicable, Dr. Zigmond said, and practically speaking, offer no regimen that humans at risk for PD might benefit from. But running is practical, and indeed widely practiced, so he set out to study whether it too might protect against damage to the dopaminergic system.
For this study, monkeys at age 16 to 20 years, roughly comparable to 50 to 60 years in humans, were allowed to run on a treadmill for one hour, five days per week, for three months, at either 60 percent or 80 percent of their maximum cardiac output. They were then given the dopaminergic toxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) unilaterally into the right carotid artery. After one week, the degree of protection was assessed by PET imaging. As in the rats, exercise offered substantial protection against toxicity, with more exercise offering more protection. Their motor function was also improved, with “essentially no deficit” despite receiving a toxin that, in sedentary monkeys, induces severe loss of motor ability.
“We haven't completely protected them, but it's enough to reduce or obliterate the behavioral deficits,” Dr. Zigmond said. “We have moved these animals back above the clinical threshold” for impairment due to loss of dopamine neurons. There is even some evidence that exercise begun after toxin administration may help protect against cell loss. “People may not be motivated to run until after diagnosis, but you can almost surely retard the progression of disease” by beginning exercise even then, he said.
The protective mechanism or, more likely, mechanisms appear to involve production of neurotrophic factors, including GDNF (glial cell-derived neurotrophic factor). The same protection can be induced by injection of GDNF before 6-OHDA treatment, an effect that can be blocked by administering other molecules that disrupt the downstream signaling of GDNF.
“A sedentary lifestyle is probably neurotoxic,” Dr. Zigmond concluded. “If that's the case, then we need to figure out how to restore in patients the physical activity that we were evolved to engage in, and hopefully in that way prevent or retard Parkinson's disease.”
Commenting on Dr. Zigmond's lecture, Cynthia Comella, MD, professor of neurology at Rush University Medical Center in Chicago, noted that the ability of exercise to prevent symptomatic decline in PD has been largely anecdotal.
“We don't know the mechanism,” she said in an interview with Neurology Today, “but in my experience, patients benefit greatly from regular exercise.”
EXERCISE IN CLINICAL TRIALS
In a study led by Daniel Corcos, PhD, professor of kinesiology at the University of Illinois at Chicago, Dr. Comella and colleagues at several other institutions randomized 48 de novo PD patients, in Hoehn and Yahr stages 2 or 3, to one of two exercise regimens, either progressive resistance training or Fitness Counts, a nonprogressive exercise program adapted for PD. Patients exercised with a personal trainer for one hour, twice per week, for six months, and then continued on their own for an additional 18 months. “There has never been a trial of exercise in PD this long,” Dr. Comella said.
At six months, both groups had improved their off-medication scores on the Unified Parkinson's Disease Rating Scale compared with baseline by about 6 points, with no difference between them. By 24 months, however, progressive resistance emerged as the clearly superior treatment. While scores for those in the Fitness Counts group had returned to baseline, those in the progressive resistance group remained better off than baseline by 7 points, as judged by blinded raters. “Improved motor status over 24 months in a progressive neurodegenerative disease suggests that long-term progressive resistance could be considered an integral component of comprehensive disease management,” the authors concluded.
“There is a fair amount of epidemiological evidence to suggest that consistent exercise or early exercise is inversely associated with risk of Parkinson's disease,” according to Caroline Tanner, MD, PhD, director of clinical research at the Parkinson's Research Institute in Sunnyvale, CA. “That is consistent with all of the findings Dr. Zigmond reported from the laboratory.”
“The first things I tell my patients once they have been diagnosed is, ‘One of the biggest things you can do for yourself is beginning exercise. You have to get your heart rate going.’ I tell patients that there is evidence to suggest, although it's not definitively proved, that it may even slow progression of disease. I say we don't know for sure, but we do know it will help in the short term, and it may have long-term benefits.”
• Zigmond MJ, Cameron JL, Hoffer BJ, Smeyne RJ. Neurorestoration by physical exercise: moving forward. Parkinsonism Relat Disord 2012;18 Suppl 1:S147–50.
• El Ayadi A, Zigmond MJ. Low concentrations of methamphetamine can protect dopaminergic cells against a larger oxidative stress injury: mechanistic study. PLoS One 2011;6(10):e24722. E-pub 2011 Oct 12.
• Zigmond MJ, Cameron JL, Smith AD, et al. Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency. Parkinsonism Relat Disord 2009 Dec;15 Suppl 3:S42–45.
• Cohen AD, Tillerson JL, Zigmond MJ, et al. Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF. J Neurochem 2003;85(2):299–305.