IMPORTANCE Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.OBJECTIVE To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.DESIGN, PARTICIPANTS, AND SETTING Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.INTERVENTIONS Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. MAIN OUTCOMES AND MEASURESThe primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. RESULTSBased on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine 11.1 [95% CI,] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, −0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).CONCLUSIONS AND RELEVANCE Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.

OBJECTIVE Chronic pain is a major distressing symptom of Parkinson's disease (PD) that is often undertreated. Subthalamic nucleus (STN) deep brain stimulation (DBS) delivers high-frequency stimulation (HFS) to patients with PD and has been effective in pain relief in a subset of these patients. However, up to 74% of patients develop new pain concerns while receiving STN DBS. Here the authors explore whether altering the frequency of STN DBS changes pain perception as measured through quantitative sensory testing (QST). METHODS Using QST, the authors measured thermal and mechanical detection and pain thresholds in 19 patients undergoing DBS via HFS, low-frequency stimulation (LFS), and off conditions in a randomized order. Testing was performed in the region of the body with the most pain and in the lower back in patients without chronic pain. RESULTS In the patients with chronic pain, LFS significantly reduced heat detection thresholds as compared with thresholds following HFS (p = 0.029) and in the off state (p = 0.010). Moreover, LFS resulted in increased detection thresholds for mechanical pressure (p = 0.020) and vibration (p = 0.040) compared with these thresholds following HFS. Neither LFS nor HFS led to changes in other mechanical thresholds. In patients without chronic pain, LFS significantly increased mechanical pain thresholds in response to the 40-g pinprick compared with thresholds following HFS (p = 0.032). CONCLUSIONS Recent literature has suggested that STN LFS can be useful in treating nonmotor symptoms of PD. Here the authors demonstrated that LFS modulates thermal and mechanical detection to a greater extent than HFS. Low-frequency stimulation is an innovative means of modulating chronic pain in PD patients receiving STN DBS. The authors suggest that STN LFS may be a future option to consider when treating Parkinson's patients in whom pain remains the predominant complaint.

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Background: At least 14% of Parkinson disease (PD) patients develop impulse control disorders (ICDs). The pathophysiology behind these behaviors and the impact of deep brain stimulation in a real-life setting remain unclear. Objectives: We prospectively examined the impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on ICDs in PD patients, as well as the relationship between impaired sensorimotor gaiting and impulsivity. Methods: Patients undergoing bilateral STN-DBS were assessed for ICDs preoperatively and 1-year postoperatively using a validated questionnaire (QUIP-RS). A subset of patients completed the Balloon Analogue Risk Task (BART) and auditory prepulse inhibition (PPI) testing. Results: Analysis revealed 12 patients had an improvement in score assessing ICDs (‘good responders'; p = 0.006) while 4 had a worse or stable score (‘poor responders'; p > 0.05). Good responders further exemplified a significant decrease in hypersexual behavior (p = 0.005) and binge eating (p = 0.01). Impaired PPI responses also significantly correlated with impulsivity in BART (r = -0.72, p = 0.044). Discussion: Following bilateral STN-DBS, 75% of our cohort had a reduction in ICDs, thus suggesting deep brain stimulation effectively manages ICDs in PD. The role of impaired PPI in predisposition to ICDs in PD warrants further investigation.

BACKGROUND Chronic pain occurs in 83% of Parkinson disease (PD) patients and deep brain stimulation (DBS) has shown to result in pain relief in a subset of patients, though the mechanism is unclear. OBJECTIVE To compare functional magnetic resonance imaging (MRI) data in PD patients with chronic pain without DBS, those whose pain was relieved (PR) with DBS and those whose pain was not relieved (PNR) with DBS. METHODS Functional MRI (fMRI) with blood oxygen level-dependent activation data was obtained in 15 patients in control, PR, and PNR patients. fMRI was obtained in the presence and absence of a mechanical stimuli with DBS ON and DBS OFF. Voxel-wise analysis using pain OFF data was used to determine which regions were altered during pain ON periods. RESULTS At the time of MRI, pain was scored a 5.4 ± 1.2 out of 10 in the control, 4.25 ± 1.18 in PNR, and 0.8 ± 0.67 in PR cohorts. Group analysis of control and PNR groups showed primary somatosensory (SI) deactivation, whereas PR patients showed thalamic deactivation and SI activation. DBS resulted in more decreased activity in PR than PNR (P < .05) and more activity in anterior cingulate cortex (ACC) in PNR patients (P < .05). CONCLUSION Patients in the control and PNR groups showed SI deactivation at baseline in contrast to the PR patients who showed SI activation. With DBS ON, the PR cohort had less activity in SI, whereas the PNR had more anterior cingulate cortex activity. We provide pilot data that patients whose pain responds to DBS may have a different fMRI signature than those who do not, and PR and PNR cohorts produced different brain responses when DBS is employed.