Methylphenidate for the Treatment of Gait Impairment in Parkinson's Disease

Objective/Rationale:
The objective of this study is to explore the effects of methylphenidate on the gait of patients with Parkinson’s disease who are experiencing shuffling and freezing. Methylphenidate is a drug that enhances dopamine and norepinephrine, two chemicals used by the brain. Freezing of gait is believed to result from norepinephrine deficiency due to degeneration of a region within the brainstem (locus coeruleus). Hence, dopamine replacement alone is unlikely to improve this debilitating problem whereas increase in noradrenergic stimulation may enhance the ability to walk.

Project Description:
Patients with freezing and shuffling will be randomly assigned to either of two groups: one group will receive methylphenidate and another will receive a placebo. For each group, the dose will be slowly increased over four weeks (titration phase), and maintained at the target dose for eight weeks thereafter (maintenance phase). Evaluations of gait and other motor and cognitive functions will take place at the end of the titration and maintenance phases. Then patients will undergo a three-week washout period during which no study drug is taken. After this period is completed, patients are given the opposite study intervention (e.g., placebo instead of methylphenidate or vice versa). The same four-week titration and eight-week maintenance phases and evaluations are repeated. The study will be carried in a double-blind manner, meaning that neither the patients nor the investigators will know the nature of the intervention (placebo or methylphenidate) at any point during the study.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The readily available, generally safe drug proposed for this study, currently FDA-approved for the unrelated attention-deficit hyperactivity disorder, has the potential to alter the management of gait impairment in Parkinson’s disease and the functional outlook of many patients and would be a major accomplishment in enhancing their quality of life. Furthermore, with the extensive measurements of gait and balance undertaken as part of the study, we expect the participants to acquire a better understanding of their walking difficulties and exercise preventative care to avoid complications related to gait impairment.

Anticipated Outcome:
We expect to increase our knowledge about the role of norepinephrine deficiency as a contributor of gait impairment in Parkinson’s disease. Most of the current treatment strategies based on replacement of dopamine have failed to enhance walking in patients with moderate to advanced disease. Non-dopaminergic systems have been discussed as potential targets to improve this critical aspect of daily function.