Daniel Corcos - US grants

DESCRIPTION (provided by applicant): Over the past decade a burgeoning literature suggests that exercise has a therapeutic benefit in both patients with Parkinson's disease (PD) and in animal models of PD, especially when animals exercise at high intensity. Although many studies have been conducted and conventional wisdom acknowledges the beneficial effects of exercise, there have been no studies of: 1) the benefits of exercise in PD patients who have not yet started dopamine replacement therapy (patients with de novo PD), and 2) the dose-response effects of "moderate" versus "vigorous" exercise to attenuate the progression of PD symptoms in patients with de novo PD. Accordingly, the long-range goal is to determine whether exercise should be first-line therapy for de novo PD. As the first step in accomplishing our long-term goal, we will conduct a multi-center, randomized, controlled, single-blinded study of two intensities of endurance exercise over six months;we will also have a control "no- exercise" group. The two levels of exercise are moderate (4 days/wk at 60%-65% HRmax) and vigorous (4 days/wk at 80%-85% HRmax). We are proposing three aims. Aim 1 is to find out if patients can exercise at the higher level of intensity. Aim 2 is to find out if either or both of the exercie intensities yield benefits consistent with meaningful clinical change in the Unified Parkinson's Disease Rating Scale (UPDRS) (non-futility). Aim 3 is to document key responses associated with clinical trials, such as adverse events and attrition. Upon the completion of this study we will be well-positioned to conduct a phase III clinical trial if the futility trial is successful. e currently envision 6 possible successful scenarios based on the results of this exploratory study. These scenarios clearly indicate what parameters will be tested in the phase III clinical trial. Th scenarios are based not only on the outcome of the futility trial (Aim 2) but also on %HRmax attained and average number of days exercised (Aim 1). All 3 components are critical in planning the next study investigating exercise in PD. We also recognize the possibility the trial will be declared futile, which will force us to reconsider the therapeutic value of exercise for PD PUBLIC HEALTH RELEVANCE: Individuals with Parkinson's disease (PD) suffer from a slow and steady increase in symptoms of the disease and a progressive decline in function. Substantial evidence over the last decade suggests that endurance exercise can reduce the symptoms of the disease. This proposed phase II randomized clinical trial is designed to determine parameters of exercise intensity that attenuate progression of symptoms of PD. Upon the completion of this study, we will have defined the needed parameters for a phase III clinical trial.

? DESCRIPTION (provided by applicant): High frequency deep brain stimulation of the subthalamic nucleus (STN DBS) dramatically ameliorates most but not all symptoms of Parkinson's disease. STN DBS exerts a powerful influence over two nuclei that regulate ocolumotor and skeletomotor control (substantia nigra pars reticulata and globus pallidus internus). As such, STN DBS should influence eye-hand coordination. There is also mounting evidence that STN DBS can impair performance of occulomotor and skeletomotor tasks that require using memory and use frontostriatal circuits, especially when bilateral STN DBS is used. As such the long-term objective of the application is the study of the positive and negative effects of STN DBS using tasks designed to probe neural circuits involved during visually and memory guided movements. We will pursue 4 specific aims. Aim 1 tests the hypothesis that bilateral STN DBS improves the performance of visually guided eye movements (Aim 1A) and visually guided hand movements (Aim 1B) more than unilateral STN DBS or being off STN DBS. In this aim, there are no memory requirements since targets for both eye and hand moments are always visible. We will also study the effects of STN DBS voltage level on visually guided eye-hand coordination by testing 2 fixed voltage settings. Fixed voltage settings will allow us to determine whether it is the magnitude of the voltage or bilateral stimulation itself tht causes any performance decrement. Aim 2 tests the hypothesis that unilateral STN DBS can improve selected measures of performance of memory-guided saccades (Aim 2A), and memory guided movements (Aim 2B) more than bilateral STN DBS or being off STN DBS. The idea is that bilateral STN DBS adversely affects dorsolateral prefrontal cortex and this interferes with both occulomotor and skeletomotor performance. We will again study the effects of STN DBS voltage level on memory-guided eye-hand coordination by testing 2 fixed voltages. Aim 3A tests the hypothesis that the surgical lesion itself causes improvements in eye and eye- hand coordination measures compared to while being off medication prior to the surgery. Prior to surgery, Aim 3B tests the hypothesis that medication will improve eye and eye-hand coordination measures compared to while being off medication. Aim 3C compares the optimal medical treatment state prior to surgery and the optimal surgical treatment state after surgery. Aim 3C tests the hypothesis that medication will improve selected memory guided eye and eye-hand coordination measures more than bilateral stimulation. Aim 4 tests the hypothesis that three years of chronic stimulation will improve movement speed but not coordination of eye-hand movements. The outcome of the studies will meet a critical need in clinical neurology and basic neurophysiology by assessing the extent to which unilateral STN DBS, bilateral STN DBS, and dopaminergic medication affects eye-hand coordination in PD in the short and long term.

Priming techniques to enhance use dependent plasticity have been examined in stroke rehabilitation research. Priming can upregulate ipsilesional cortex and/or down regulate contralesional cortex to improve effectiveness of subsequent therapy. Most priming techniques are costly and approved only for research. Here, we describe a priming technique that is cost-effective and has the potential to significantly change clinical practice. Bilateral motor priming (BMP) uses bilateral, symmetrical, rhythmic movement to ready the motor cortex for functional limb training. A rocker is used so that the less affected limb can drive the more affected one in symmetrical wrist flexion and extension. Active range of motion of the affected wrist is not necessary, and, thus, BMP can be used in severely impaired participants. Beneficial aspects of bilateral motor priming (compared to priming using rTMS and tDCS) include the fact that BMP is: 1) cost-effective; 2) available to a larger pool of individuals due to a paucity of safety concerns; (3) does not require a skilled operator; and (4) can be used the clinic. Previous studies comparing bilateral priming plus therapy found the priming and therapy combination to be more effective than therapy alone. However, previous BMP studies have not used dose matched designs. This project compares two groups of randomly assigned participants receiving task specific training (TST). Seventy-six participants will be randomized to receive either fifteen 2-hour sessions (30 hours) of BMP + TST or the same dose matched 30 hours of TST alone. Participants will attend sessions 3 times per week for 5 weeks with possible missed sessions scheduled at week 6. Outcome measures will be collected at pre-intervention, post-intervention, and follow-up (6 weeks post discharge). Aim 1 will determine the magnitude of change in upper limb impairment and function in chronic stroke survivors who have undergone 5 weeks of BMP+TST. The primary outcome measure is the Fugl-Meyer Test of Upper Extremity Function (FMUE). The secondary outcome is the Chedoke Arm and Hand Activity Index, an assessment of bimanual functional tasks. We expect both groups to improve on behavioral measures from pre-to post-intervention. However, the BMP+TST group is expected to have larger improvements than the TST alone group. We also expect these measures to persist at follow-up (6 weeks post cessation of treatment) in the BMP+TST group but not in TST alone. Aim 2 will determine the effects of bilateral priming on cortical mechanisms as measured by transcranial magnetic stimulation (TMS). We expect to find changes in TMS parameters that reflect a greater balance of hemispheric excitability in the BMP+TST group only. We further hypothesize that increases in hemispheric excitability will be associated with improvements in the FMUE. Currently, there is no clinically demonstrated long-term effective treatment for individuals with severe chronic upper limb hemiparesis. It is important to identify treatments for this underserved and under-investigated population.

PROJECT SUMMARY The goal of this application is two-fold. First, we will test and validate across two imaging sites a set of diagnostic and progression biomarkers we have recently published that differentiate and track disease progression in Parkinson's disease (PD), parkinsonian variant of multiple system atrophy (MSAp) and progressive supranuclear palsy (PSP). Second, we will use a set of novel imaging biomarkers to further understand the neurobiology of how each of these three diseases differ and progress over time. With respect to goal 1, over the past 5 years our group has led the efforts in magnetic resonance imaging (MRI) for the Parkinson's Disease Biomarker Program (PDBP) and has developed 2 innovative biomarkers for differentiating PD, MSAp, and PSP. Both free-water diffusion imaging and task-fMRI have uncovered clear patterns of degeneration and abnormal functional activation in the basal ganglia and cerebellum that can reliably differentiate PD, MSAp, and PSP. In longitudinal studies we found that free-water diffusion imaging and task- fMRI track progression of PD, MSAp, and PSP over one year with no changes in age and sex matched controls. Reproducible, reliable, objective and validated MRI-based progression markers are of great significance and would transform clinical trials in PD, MSAp, and PSP. With respect to goal 2, in addition to evaluating free-water and task-based fMRI using our standardized protocol across two imaging sites, we will also test new biomarkers that leverage advanced imaging pulse sequences using simultaneous multi-slice imaging for acquiring data faster and at a higher spatial resolution. Such technical advances provide a richer examination of the nigrostriatal, cortico-striatal, and cerebellar-thalamo-cortical anatomical tracts for disease differentiation, and for understanding how the disease spreads along disease-specific tracts over time. Leveraging simultaneous multi-slice imaging will facilitate multi-shell diffusion imaging models for examining free-water, neurite density and orientation dispersion, as well as task-fMRI connectivity for examining the functional connections across a network. At our two imaging sites, we will acquire data on 100 PD, 50 MSAp, 50 PSP, and 50 healthy age and sex matched controls. We will provide timely data sharing with the PDBP community. We have a very experienced team of experts in neurology and neuroimaging, and a long history of publishing together in high impact journals.

The study objective is to establish the efficacy of high-intensity endurance exercise as first-line therapy for recently diagnosed people with Parkinson's disease (PD). No medications are yet proven to slow the progression of the signs of PD and dopaminergic medications do not benefit all the signs of PD. As such, people with PD have no adequate treatment to slow down the progression of the motor or non-motor signs of the disease. The key question is whether there is an additional benefit of exercising at high-intensity, in terms of slowing the progression of the signs of the disease, beyond the well documented benefit of treadmill training on general parameters of fitness, gait and functional mobility. Preclinical data, experimental data on humans, and epidemiological data all have demonstrated benefits of endurance exercise on the motor and nonmotor signs and symptoms of the disease, although the best dose for slowing down their progression has not been identified. We recently completed a multicenter Phase II clinical trial, the SPARX study, using a futility design. We studied the feasibility of participants with PD performing moderate intensity (60-65% of their maximal heart rate (HRmax)) and high intensity endurance exercise (80-85% HRmax). Participants had not yet started dopaminergic medication. We demonstrated that: 1) participants will exercise at between 80-85% of HRmax for at least 6 months, 2) they will exercise for at least 3 days per week, 3) adverse events are low, and 4) exercising at 80- 85% HRmax slowed progression by 2.9 points on the motor section of the UPDRS when compared to the wait list usual care group and was not deemed futile. These 4 findings were deemed a priori to be the necessary results to proceed to a Phase III efficacy trial. We now propose to conduct a 12-month multi-center, randomized (two doses of intensity), evaluator-masked study of high intensity endurance exercise. The 2 doses of treadmill exercise are moderate intensity (4 days/wk for 30 minutes per session at 60- 65% HRmax) and high intensity (4 days/wk for 30 minutes per session at 80-85% HRmax). The study is designed to test 3 specific aims. First, to establish the efficacy of high-intensity endurance exercise to slow the progression of the signs of PD as measured by the change in the MDS-Unified Parkinson Disease Rating Scale (MDS-UPDRS Part III) score over 6 and 12 months. Second, to ascertain the effect of high dose endurance versus moderate dose endurance exercise on the progression of the signs of PD over 6 and 12 months as measured by: 1) distance covered in 6 minute walk, 2) an increased number of daily steps, 3) improved cognitive function, 4) increased VO2max, 5) improved quality of life, and 6) time to initiate dopaminergic medication and the quantity of medication. Third, to test the effects of high intensity endurance exercise on PD over 12 months on biomarkers of dopaminergic neuronal integrity and blood-derived biomarkers of inflammation, and neurotrophic factors. The study design will facilitate the translation of the study results into a meaningful clinical application of clear therapeutic value.