Prospective longitudinal study of plasticity control and complications in Parkinson's disease

Although the management of Parkinson’s disease (PD) has been significantly improved in the past decades, motor complications, e.g. wearing off, on-off phenomena and levodopa-induced dyskinesia (LID), inevitably occur after several years of treatment and become increasingly problematic in advanced PD. These complications are bothersome and may cause negative effect on the life quality. Moreover, some of the motor complications, e.g. LID, limit the treatment of PD. Although several related mechanisms and factors have been noticed in human and animal studies, the fundamental mechanisms of the development of motor complications have yet been clear so far. A longitudinal study is therefore demanded to clarify the occurrence and evolvement of motor complication as the disease progresses. However, due to the limitation of available animal models, a longitudinal study on animals may not correctly reflex the reality of the progress of PD and its complications. A prospective longitudinal study in PD patients is therefore required. The techniques in our laboratory based on transcranial magnetic stimulation (TMS) allow us to study the physiology of conscious human brain non-invasively. We recently developed novel protocols to study the control of plasticity in humans and successfully differentiate between PD patients with LID and those without LIDs. In addition, the improvement in diffusion imaging provides a better ability to look into microstructures of the brain that differentiates PD from healthy subjects. With the help of these novel techniques, we will be able to probe the physiological and structure changes in PD patients in different stages. We therefore design the present project to longitudinally study the progress of PD and the development of motor complications in PD patients. In addition, seeing the difficulty in quantifying dyskinesia, we will set up a quantitative dyskinesia measurement system to quantify dyskinesia. The system will provide objective severity of dyskinesia for correlating with other parameters in the study, and for the clinical use in the future. In this long-term follow-up study, we will also understand the clinical evolution and the effect of dopamine agonists on physiological conditions and clinical symptoms as PD progresses. In the current study, theta burst stimulation based on the technique of repetitive TMS will be applied for studying plasticity and its reversibility. MR imaging, including diffusion analysis, will be used for detecting changes in brain structures. Clinical scales, including Unified Parkinson’s Disease Rating Scale (UPDRS), Abnormal Involuntary Movement Scale (AIMS) and Daily OFF time (h/day), will be evaluated. All the assessments will be performed every 6 months. For the plasticity assessment, the patients have to come for 4 sessions, which are separated one week apart from each other, for a complete assessment every year. In between, follow-up assessments that include only two sessions will be tested. The patients will be asked to come for different doses of levodopa, while the dose adjustment is only required for the dose before the experiment. Healthy subjects will be tested only once for all the assessments. Two groups of patients, including early PD and moderate PD, will be recruited simultaneously. With the study design, we expect to study a ten year course of PD in a 5 year project. Through this study, we expect to understand the transformation of plasticity and microstructures in the brain from early to advanced PD. These results will provide novel information for understanding the physiological fundamental of the progress of PD and the underlying mechanism of motor complications, and provide biomarkers for early detecting or predicting the development of motor complications. Based on the markers, therapeutic strategy and personalized medicine can be developed for the prevention or early treatment of motor complications. On the other hand, a quantitative dyskinesia measurement system will be developed for research purpose and clinical use. The evolution of clinical symptoms and the effect of DAs in physiology and symptomatology will also be systemically reviewed. All of these will be helpful in improving the quality of life in advanced PD by eliminating possible motor complications.

Project ID:PG10401-0097
External Project ID:NHRI-EX104-10343NI