Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson's disease.

Postoperative apathy is a frequent symptom in Parkinson's disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: (i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering; and (ii) direct effect of chronic stimulation of the subthalamic nucleus. The primary objective of our study was to describe preoperative and 1-year postoperative apathy in Parkinson's disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to identify factors associated with 1-year postoperative apathy considering: (i) preoperative clinical phenotype; (ii) dopaminergic drug management; and (iii) volume of tissue activated within the subthalamic nucleus and the surrounding structures. We investigated a prospective clinical cohort of 367 patients before and 1 year after chronic bilateral deep brain stimulation of the subthalamic nucleus. We assessed apathy using the Lille Apathy Rating Scale and carried out a systematic evaluation of motor, cognitive and behavioural signs. We modelled the volume of tissue activated in 161 patients using the Lead-DBS toolbox and analysed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited 1-year postoperative apathy: 67 (18.2%) with 'de novo apathy' and 27 (7.4%) with 'sustained apathy'. We observed disappearance of preoperative apathy in 22 (6.0%) patients, who were classified as having 'reversed apathy'. Lastly, 251 (68.4%) patients had neither preoperative nor postoperative apathy and were classified as having 'no apathy'. We identified preoperative apathy score [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.10, 1.22; P < 0.001], preoperative episodic memory free recall score (OR 0.93; 95% CI 0.88, 0.97; P = 0.003) and 1-year postoperative motor responsiveness (OR 0.98; 95% CI 0.96, 0.99; P = 0.009) as the main factors associated with postoperative apathy. We showed that neither dopaminergic dose reduction nor subthalamic stimulation were associated with postoperative apathy. Patients with 'sustained apathy' had poorer preoperative fronto-striatal cognitive status and a higher preoperative action initiation apathy subscore. In these patients, apathy score and cognitive status worsened postoperatively despite significantly lower reduction in dopamine agonists (P = 0.023), suggesting cognitive dopa-resistant apathy. Patients with 'reversed apathy' benefited from the psychostimulant effect of chronic stimulation of the limbic part of the left subthalamic nucleus (P = 0.043), suggesting motivational apathy. Our results highlight the need for careful preoperative assessment of motivational and cognitive components of apathy as well as executive functions in order to better prevent or manage postoperative apathy.

Differences in Survival across Monogenic Forms of Parkinson's Disease.

OBJECTIVE: Survival of patients with monogenic Parkinson's disease may depend on the causative genes associated with the disease. In this study, we compare survival of patients with Parkinson's disease according to the presence of SNCA, PRKN, LRRK2, or GBA mutations. METHODS: Data from the French Parkinson Disease Genetics national multicenter cohort study were used. Patients with sporadic and familial Parkinson's disease were recruited between 1990 and 2021. Patients were genotyped for the presence of mutations in the SNCA, PRKN, LRRK2, or GBA genes. Vital status was collected from the National death register for participants born in France. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariable Cox proportional hazards regression. RESULTS: Of the 2,037 patients with Parkinson's disease, 889 had died after a follow-up of up to 30 years. Patients with PRKN (n = 100, HR = 0.41; p = 0.001) and LRRK2 mutations (n = 51, HR = 0.49; p = 0.023) had longer survival than those without any mutation, whereas patients with SNCA (n = 20, HR = 9.88; p < 0.001) or GBA mutations (n = 173, HR = 1.33; p = 0.048) had shorter survival. INTERPRETATION: Survival differs across genetic forms of Parkinson's disease, with higher mortality for patients with SNCA or GBA mutations, and lower mortality for those with PRKN or LRRK2 mutations. Differences in severity and disease progression among monogenic forms of Parkinson's disease likely explain these findings, which has important consequences for genetic counselling and choice of end points for future clinical trials for targeted therapies. ANN NEUROL 2023;94:123-132.

A Comparison Between Early Presentation of Dementia with Lewy Bodies, Alzheimer's Disease, and Parkinson's Disease: Evidence from Routine Primary Care and UK Biobank Data.

OBJECTIVE: The purpose of this study was to simultaneously contrast prediagnostic clinical characteristics of individuals with a final diagnosis of dementia with Lewy Bodies (DLB), Parkinson's disease (PD), and Alzheimer's disease (AD) compared with controls without neurodegenerative disorders. METHODS: Using the longitudinal THIN database in the United Kingdom, we tested the association of each neurodegenerative disorder with a selected list of symptoms and broad families of treatments, and compared the associations between disorders to detect disease-specific effects. We replicated the main findings in the UK Biobank. RESULTS: We used data of 28,222 patients with PD, 20,214 with AD, 4,682 with DLB, and 20,214 healthy controls. All neurodegenerative disorders were significantly associated with the presence of multiple clinical characteristics before their diagnosis, including sleep disorders, falls, psychiatric symptoms, and autonomic dysfunctions. When comparing patients with DLB with patients with PD and patients with AD patients, falls, psychiatric symptoms, and autonomic dysfunction were all more strongly associated with DLB in the 5 years preceding the first neurodegenerative diagnosis. The use of statins was lower in patients who developed PD and higher in patients who developed DLB compared to patients with AD. In patients with PD, the use of statins was associated with the development of dementia in the 5 years following PD diagnosis. INTERPRETATION: Prediagnostic presentations of falls, psychiatric symptoms, and autonomic dysfunctions were more strongly associated with DLB than PD and AD. This study also suggests that although several associations with medications are similar in neurodegenerative disorders, statin usage is negatively associated with PD but positively with DLB and AD as well as development of dementia in PD. ANN NEUROL 2023;94:259-270.

ON/OFF non-motor evaluation: a new way to evaluate non-motor fluctuations in Parkinson's disease.

BACKGROUND: NMF are currently poorly evaluated in therapeutic decisions. A quantification of their severity would facilitate their integration. The objective of this study was to validate an autoquestionnaire evaluating the severity of non-motor fluctuations (NMF) in Parkinson's disease (PD). METHODS: Patients with PD were included in presurgical situation for deep brain stimulation of subthalamic nuclei. They participated in the PREDISTIM cohort (a study evaluating the predictive factors for therapeutic response of subthalamic stimulation in PD) in 17 centres in France. Our questionnaire, resulting from previous phases of development, included 11 non-motor symptoms (NMS). Their severity ranged from 0 to 10 and was assessed in OFF and then ON-Dopa to study their fluctuations. RESULTS: 310 patients were included, of whom 98.8% had NMS and 98.0% had NMF. Each NMS was significantly improved by L-Dopa (decrease in severity score ranging from 43.1% to 69.9%). Fatigue was the most frequent and most severe NMS. NMS were considered more bothersome than motor symptoms by 37.5% of patients in OFF-Dopa and 34.9% in ON-Dopa. CONCLUSIONS: This is the first questionnaire allowing a real-time quantification of the severity of NMS and their fluctuation with levodopa. It was able to confirm and measure the effect of L-dopa and show differences according to the patients and the NMS. It differs from other questionnaires by its measurement at a precise moment of the severity of the NMS, allowing its use during pretherapeutic assessments.Our questionnaire has been validated to measure the severity of NMF. It will be able to quantify the non-motor effect of anti-parkinsonian treatments and could facilitate the integration of NMF in therapeutic decisions.

Advantages and Challenges of Platform Trials for Disease Modifying Therapies in Parkinson's Disease.

Traditional drug development in Parkinson's disease (PD) faces significant challenges because of its protracted timeline and high costs. In response, innovative master protocols are emerging and designed to address multiple research questions within a single overarching protocol. These trials may offer advantages such as increased efficiency, agility in adding new treatment arms, and potential cost savings. However, they also present organizational, methodological, funding, regulatory, and sponsorship challenges. We review the potential of master protocols, focusing on platform trials, for disease modifying therapies in PD. These trials share a common control group and allow for the termination or addition of treatment arms during a trial with non-predetermined end. Specific issues exist for a platform trial in the PD field considering the heterogeneity of patients in terms of phenotype, genotype and staging, the confounding effects of symptomatic treatments, and the choice of outcome measures with no consensus on a non-clinical biomarker to serve as a surrogate and the slowness of PD progression. We illustrate these aspects using the examples of the main PD platform trials currently in development with each one targeting distinct goals, populations, and outcomes. Overall, platform trials hold promise in expediting the evaluation of potential therapies for PD. However, it remains to be proven whether these theoretical benefits will translate into increased production of high-quality trial data. Success also depends on the willingness of pharmaceutical companies to engage in such trials and whether this approach will ultimately hasten the identification and licensing of effective disease-modifying drugs. © 2024 International Parkinson and Movement Disorder Society.

Charting Disease Trajectories from Isolated REM Sleep Behavior Disorder to Parkinson's Disease.

BACKGROUND: Clinical presentation and progression dynamics are variable in patients with Parkinson's disease (PD). Disease course mapping is an innovative disease modelling technique that summarizes the range of possible disease trajectories and estimates dimensions related to onset, sequence, and speed of progression of disease markers. OBJECTIVE: To propose a disease course map for PD and investigate progression profiles in patients with or without rapid eye movement sleep behavioral disorders (RBD). METHODS: Data of 919 PD patients and 88 isolated RBD patients from three independent longitudinal cohorts were analyzed (follow-up duration = 5.1; 95% confidence interval, 1.1-8.1] years). Disease course map was estimated by using eight clinical markers (motor and non-motor symptoms) and four imaging markers (dopaminergic denervation). RESULTS: PD course map showed that the first changes occurred in the contralateral putamen 13 years before diagnosis, followed by changes in motor symptoms, dysautonomia, sleep-all before diagnosis-and finally cognitive decline at the time of diagnosis. The model showed earlier disease onset, earlier non-motor and later motor symptoms, more rapid progression of cognitive decline in PD patients with RBD than PD patients without RBD. This pattern was even more pronounced in patients with isolated RBD with early changes in sleep, followed by cognition and non-motor symptoms and later changes in motor symptoms. CONCLUSIONS: Our findings are consistent with the presence of distinct patterns of progression between patients with and without RBD. Understanding heterogeneity of PD progression is key to decipher the underlying pathophysiology and select homogeneous subgroups of patients for precision medicine. © 2023 International Parkinson and Movement Disorder Society.

Isolated REM Sleep without Atonia Is Not Equivalent to REM Sleep Behavior Disorder in Early-Stage Parkinson's Disease.

BACKGROUND: In early-stage Parkinson's disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) predicts poor cognitive and motor outcome. However, the baseline significance and disease evolution associated with isolated REM sleep without atonia (iRWA, ie, enhanced muscle tone during 8.7% of REM sleep, but no violent behavior) are not well understood. OBJECTIVES: The objective is to determine whether iRWA was a mild form of RBD and progressed similarly over time. METHODS: Participants with early PD (<4 years from medical diagnosis) were included from 2014 to 2021 in a longitudinal study. They underwent interviews and examinations in the motor, cognitive, autonomous, psychiatric, sensory, and sleep domains every year for 4 years along with a video polysomnography and magnetic resonance imaging examination of the locus coeruleus/subcoeruleus complex (LC/LsC) at baseline. The clinical characteristics were compared between groups with normal REM sleep, with iRWA and with RBD, at baseline and for 4 years. RESULTS: Among 159 PD participants, 25% had RBD, 25% had iRWA, and 50% had normal REM sleep. At baseline, the non-motor symptoms were less prevalent and the LC/LsC signal intensity was more intense in participants with iRWA than with RBD. Over 4 years, participants with normal REM sleep and with iRWA had a similar cognitive and motor trajectory, whereas participants with RBD had greater cognitive and motor decline. CONCLUSIONS: We demonstrated that iRWA is frequent in early PD, but is not a milder form of RBD. Both groups have distinct baseline characteristics and clinical trajectories. They should be distinguished in clinical routine and research protocols. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Management of Impulse Control and Related Disorders in Parkinson's Disease: An Expert Consensus.

BACKGROUND: Impulse-control and related behavioral disorders (ICBDs) significantly impact the lives of Parkinson's disease (PD) patients and caregivers, with lasting consequences if undiagnosed and untreated. While ICBD pathophysiology and risk factors are well-studied, a standardized severity definition and treatment evidence remain elusive. OBJECTIVE: This work aimed to establish international expert consensus on ICBD treatment strategies. To comprehensively address diverse treatment availabilities, experts from various continents were included. METHODS: From 2021 to 2023, global movement disorders specialists engaged in a Delphi process. A core expert group initiated surveys, involving a larger panel in three iterations, leading to refined severity definitions and treatment pathways. RESULTS: Experts achieved consensus on defining ICBD severity, emphasizing regular PD patient screenings for early detection. General treatment recommendations focused on continuous monitoring, collaboration with significant others, and seeking specialist advice for legal or financial challenges. For mild to severe ICBDs, gradual reduction in dopamine agonists was endorsed, followed by reductions in other PD medications. Second-line treatment strategies included diverse approaches like reversing the last medication change, cognitive behavior therapy, subthalamic nucleus deep brain stimulation, and specific medications like quetiapine, clozapine, and antidepressants. The panel reached consensus on distinct treatment pathways for punding and dopamine dysregulation syndrome, formulating therapy recommendations. Comprehensive discussions addressed management strategies for the exacerbation of either motor or non-motor symptoms following the proposed treatments. CONCLUSION: The consensus offers in-depth insights into ICBD management, presenting clear severity criteria and expert consensus treatment recommendations. The study highlights the critical need for further research to enhance ICBD management. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Contribution of MRI for the Early Diagnosis of Parkinsonism in Patients with Diagnostic Uncertainty.

BACKGROUND: International clinical criteria are the reference for the diagnosis of degenerative parkinsonism in clinical research, but they may lack sensitivity and specificity in the early stages. OBJECTIVES: To determine whether magnetic resonance imaging (MRI) analysis, through visual reading or machine-learning approaches, improves diagnostic accuracy compared with clinical diagnosis at an early stage in patients referred for suspected degenerative parkinsonism. MATERIALS: Patients with initial diagnostic uncertainty between Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multisystem atrophy (MSA), with brain MRI performed at the initial visit (V1) and available 2-year follow-up (V2), were included. We evaluated the accuracy of the diagnosis established based on: (1) the international clinical diagnostic criteria for PD, PSP, and MSA at V1 ("Clin1"); (2) MRI visual reading blinded to the clinical diagnosis ("MRI"); (3) both MRI visual reading and clinical criteria at V1 ("MRI and Clin1"), and (4) a machine-learning algorithm ("Algorithm"). The gold standard diagnosis was established by expert consensus after a 2-year follow-up. RESULTS: We recruited 113 patients (53 with PD, 31 with PSP, and 29 with MSA). Considering the whole population, compared with clinical criteria at the initial visit ("Clin1": balanced accuracy, 66.2%), MRI visual reading showed a diagnostic gain of 14.3% ("MRI": 80.5%; P = 0.01), increasing to 19.2% when combined with the clinical diagnosis at the initial visit ("MRI and Clin1": 85.4%; P < 0.0001). The algorithm achieved a diagnostic gain of 9.9% ("Algorithm": 76.1%; P = 0.08). CONCLUSION: Our study shows the use of MRI analysis, whether by visual reading or machine-learning methods, for early differentiation of parkinsonism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Double-Blind, Randomized, Placebo-Controlled Trial of Bumetanide in Parkinson's Disease.

BACKGROUND: Acting on the main target of dopaminergic cells, the striatal γ-aminobutyric acid (GABA)-ergic cells, might be a new way to treat persons with Parkinson's disease (PD). OBJECTIVE: The objective of this study was to assess the efficacy of bumetanide, an Na-K-Cl cotransporter (NKCC1) inhibitor, to improve motor symptoms in PD. METHODS: This was a 4-month double-blind, randomized, parallel-group, placebo-controlled trial of 1.75 to 3 mg/day bumetanide as an adjunct to levodopa in 44 participants with PD and motor fluctuations. RESULTS: Compared to the baseline, the mean change in OFF Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score after 4 months of treatment (primary endpoint) did not improve significantly compared with placebo. No changes between participants treated with bumetanide and those treated with placebo were observed for most other outcome measures. Despite no relevant safety signals, bumetanide was poorly tolerated. CONCLUSIONS: There was no evidence in this study that bumetanide has efficacy in improving motor symptoms of PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Oxycodone or Higher Dose of Levodopa for the Treatment of Parkinsonian Central Pain: OXYDOPA Trial.

BACKGROUND: Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. OBJECTIVES: We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP. METHODS: OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses. RESULTS: Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%). CONCLUSIONS: The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amantadine use in the French prospective NS-Park cohort.

OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Home-based exergaming to treat gait and balance disorders in patients with Parkinson's disease: A phase II randomized controlled trial.

BACKGROUND: Exergaming has been proposed to improve gait and balance disorders in Parkinson's disease (PD) patients. We aimed to assess the efficacy of a home-based, tailored, exergaming training system designed for PD patients with dopa-resistant gait and/or balance disorders in a controlled randomized trial. METHODS: We recruited PD patients with dopa-resistant gait and/or balance disorders. Patients were randomly assigned (1:1 ratio) to receive 18 training sessions at home by playing a tailored exergame with full-body movements using a motion capture system (Active group), or by playing the same game with the computer's keyboard (Control group). The primary endpoint was the between-group difference in the Stand-Walk-Sit Test (SWST) duration change after training. Secondary outcomes included parkinsonian clinical scales, gait recordings, and safety. RESULTS: Fifty PD patients were enrolled and randomized. After training, no significant difference in SWST change was found between groups (mean change SWST duration [SD] -3.71 [18.06] s after Active versus -0.71 [3.41] s after Control training, p = 0.61). Some 32% of patients in the Active and 8% in the Control group were considered responders to the training program (e.g., SWST duration change ≥2 s, p = 0.03). The clinical severity of gait and balance disorders also significantly decreased after Active training, with a between-group difference in favor of the Active training (p = 0.0082). Home-based training induced no serious adverse events. CONCLUSIONS: Home-based training using a tailored exergame can be performed safely by PD patients and could improve gait and balance disorders. Future research is needed to investigate the potential of exergaming.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

Association between the LRP1B and APOE loci and the development of Parkinson's disease dementia.

Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson's disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson's disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson's disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson's disease dementia [hazard ratio = 2.41 (1.94-3.00), P = 2.32 × 10-15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17-4.81), P = 7.07 × 10-09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21-3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson's disease dementia, with significantly reduced levels of amyloid ß42 (P = 0.0012) in Parkinson's disease dementia compared to Parkinson's disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson's disease dementia.

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability.

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C>A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.

Mitochondrial haplogroups and cognitive progression in Parkinson's disease.

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.