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Qi Rui See,1,* Kausar Raheel,1,* Iain Duncan,1,* Nazanin Biabani,1,* Irene Di Giulio,2 Andrea Romigi,3 Veena Kumari,1,4 David O’Regan,1,2,5 Scott Cairney,6 Daniele Urso,7,8 K Ray Chaudhuri,8 Valentina Gnoni,1,7 Panagis Drakatos,1,2,5,* Ivana Rosenzweig1,5,* 1Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, U.K; 2School of Basic and Medical Biosciences, Faculty of Life Science and Medicine, King’s College London, London, U.K; 3IRCCS Neuromed Istituto Neurologico Mediterraneo Pozzilli (IS), Pozzilli, Italy; 4Centre for Cognitive Neuroscience, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, U.K; 5Sleep Disorders Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, U.K; 6Department of Psychology, University of York and York Biomedical Research Institute, University of York, York, U.K; 7Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari ‘Aldo Moro’, “Pia Fondazione Cardinale G. Panico”, Tricase, Lecce, Italy; 8Movement Disorders Unit, King’s College Hospital and Department of Clinical and Basic Neurosciences, Institute of Psychiatry, Psychology & Neuroscience and Parkinson Foundation Centre of Excellence, King’s College London, London, U.K*These authors contributed equally to this workCorrespondence: Ivana Rosenzweig, Sleep and Brain Plasticity Centre, Department of Neuroimaging, Box 089, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London, SE5 8AF, UK, Email ivana.1.rosenzweig@kcl.ac.ukBackground: Speech graph analysis (SGA) of dreams has recently shown promise as an objective and language-invariant diagnostic tool that can aid neuropsychiatric diagnosis. Whilst the notion that dreaming mentations reflect distinct physio

Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, 'delayed on' or 'no on' phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract.

[Background and objectives] It has been recently suggested that LRRK2 mutations are associated with a more benign clinical phenotype and a potentially more preserved cholinergic function in Parkinson's disease (PD). However, to our knowledge, no studies have tested whether the better clinical progression observed in LRRK2-PD patients is associated with more preserved volumes of a cholinergic brain area, the basal forebrain (BF). To address this hypothesis, here we compared BF volumes in LRRK2 carriers with and without PD with respect to idiopathic PD (iPD) patients and controls, and assessed whether they are associated with better clinical progression observed in LRRK2-PD compared to iPD., [Methods] Thirty-one symptomatic LRRK2-PD patients and 13 asymptomatic LRRK2 individuals were included from the Parkinson's Progression Markers Initiative. In addition, 31 patients with iPD and 13 healthy controls matched to the previous groups were also included. BF volumes were automatically extracted from baseline T1-weighted MRI scans using a stereotactic atlas of cholinergic nuclei. These volumes were then compared between groups and their relationship with longitudinal cognitive changes was evaluated using linear mixed effects models. Mediation analyses assessed whether BF volumes mediated differences in cognitive trajectories between groups., [Results] LRRK2-PD patients showed significantly higher BF volumes compared to iPD (P = 0.019) as did asymptomatic LRRK2 subjects compared to controls (P = 0.008). There were no other significant differences in cortical regions or subcortical volumes between these groups. BF volumes predicted longitudinal decline in several cognitive functions in iPD patients but not in LRRK2-PD, who did not show cognitive changes over a 4-year follow-up period. BF volumes were a significant mediator of the different cognitive trajectories between iPD and LRRK2-PD patients (95% CI 0.056–2.955)., [Discussion] Our findings suggest that mutations in LRRK2 are associated with increased BF volumes, potentially reflecting a compensatory hypercholinergic state that could prevent cognitive decline in LRRK2-PD patients.

We introduce a novel framework for optimization based on energy-conserving Hamiltonian dynamics in a strongly mixing (chaotic) regime and establish its key properties analytically and numerically. The prototype is a discretization of Born-Infeld dynamics, with a squared relativistic speed limit depending on the objective function. This class of frictionless, energy-conserving optimizers proceeds unobstructed until slowing naturally near the minimal loss, which dominates the phase space volume of the system. Building from studies of chaotic systems such as dynamical billiards, we formulate a specific algorithm with good performance on machine learning and PDE-solving tasks, including generalization. It cannot stop at a high local minimum, an advantage in non-convex loss functions, and proceeds faster than GD+momentum in shallow valleys.

Item does not contain fulltext, BACKGROUND: Postural Instability and Gait difficulties (PIGD) subtype has been associated with worse cognitive performance in Parkinson's disease (PD). OBJECTIVE: To investigate whether PIGD subtype classification or PIGD-related clinical features predict the development of cognitive decline in de novo PD patients. METHODS: Data from 422 PD patients with de novo PD were obtained from the PPMI database. At follow-up (up to 6 years), patients were categorized as having cognitive impairment or not. Multivariate Cox survival analysis was carried out including motor subtype and individual MDS-UPDRS items defining PIGD phenotype as predictors. Previously validated clinical predictors of cognitive impairment were included in the model as covariates. Occurrence of cognitive impairment at follow-up was used as the time-to-event and Kaplan-Meier curve was generated. RESULTS: At baseline, 76 patients were classified as PIGD, 299 tremor-dominant and 47 as indeterminate. Development of cognitive impairment was not associated with PIGD subtype (p = 0.252). When individual MDS-UPDRS items were interrogated in the model, postural instability proved to be an independent predictor of cognitive impairment (HR = 2.045; 95%CI: 1.068-3.918; p = 0.031), while gait difficulties were not associated with cognitive decline (p = 0.870). CONCLUSIONS: Our findings suggest that postural instability, as assessed by MDS-UPDRS III, may serve as a possible indicator of the risk of developing cognitive impairment in de novo PD patients rather than the PIGD phenotype.

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Background: It is believed that motor symptoms, including dyskinesia, and non-motor symptoms impact health-related quality of life (HRQoL) in patients with Parkinson's disease (PD), and that improvements in these metrics are correlated. Objective(s): Investigate the relationship between HRQoL and measures of PD severity and treatment efficacy, including motor and non-motor symptoms. Method(s): This was a planned investigation of an international, prospective, single-arm, post-marketing observational study of the long-term effectiveness of levodopa-carbidopa intestinal gel (LCIG) in patients with advanced PD. Pearson correlation coefficients (PCC) were calculated for baseline and change from baseline at 12 months between HRQoL and motor and non-motor symptoms. Result(s): A total of 195 patients were included. At baseline, HRQoL was moderately positively correlated with Activities of Daily Living (UPDRS II, PCC = 0.44), non-motor symptoms (0.48), and measures of sleep (0.50 and 0.40); all p < 0.001. After 12 months of treatment with LCIG, improvements in HRQoL were moderately positively correlated with improvement from baseline in non-motor symptoms (PCC = 0.42), sleep (0.54), and daytime sleepiness (0.40; all p < 0.001), and weakly correlated with improvement in dyskinesia signs and symptoms (PCC = 0.23; p = 0.011). Improvement in HRQoL was not correlated with improvements in OFF time or dyskinesia time. Conclusion(s): Both at baseline and for change from baseline at 12 months, HRQoL was correlated with baseline and change from baseline in dyskinesia, Activities of Daily Living, and non-motor symptoms, including sleep; but not with baseline or change in OFF time.Copyright © 2022 - The authors. Published by IOS Press.

Background and aims: Levodopa-carbidopa intestinal gel (LCIG) reduced burden of motor and non-motor symptoms in clinical trials of patients with advanced Parkinson's disease (PD). We evaluated long-term LCIG effectiveness and safety in a real-world setting. Method(s): DUOGLOBE (NCT02611713) was a 3-year, global, observational, prospective study. LCIG-naive patients treated in routine clinical practice were enrolled. The primary outcome was change in patient-reported "Off" time. Secondary outcomes included non-motor symptoms (NMSS), sleep and daytime sleepiness (PDSS-2 and ESS), and health-related quality of life (HRQoL; PDQ-8). Serious adverse events (SAEs) were also assessed. Final outcomes for month (M) 36 are presented here. Result(s): Of 195 patients, 89 completed the 3-year followup. Baseline characteristics indicated substantial disease burden (Table 1). Concomitant use of oral levodopa derivatives, monoamine oxidase B inhibitors and, most prominently, catechol-O-methyltransferase inhibitors decreased (Table 2); approximately one-third of patients were treated with LCIG monotherapy or in combination with oral levodopa. "Off" time significantly improved through M36 (M36, 3.3 hours/day; p<0.001). Significant improvements through M36 were sustained for NMSS total scores (p<0.01), NMSS subdomains of sleep/fatigue (p<0.01), gastrointestinal tract (p<0.001), and miscellaneous (p<0.001); PDSS-2 (p<0.001), and ESS (p<0.01) (Table 1). HRQoL significantly improved until M24 (p<0.01). While 25% of patients discontinued due to AEs, non-safety reasons accounted for half of discontinuations. Falls and (worsening of) PD were the most common SAEs (Table 3). Conclusion(s): These final, long-term DUOGLOBE results showed significant and sustained improvements in motor symptoms, non-motor symptoms, and HRQoL with LCIG treatment. Safety was consistent with the established LCIG safety profile (Table Presented).

Contains fulltext : 248856.pdf (Publisher’s version ) (Open Access), BACKGROUND: Postural Instability and Gait difficulties (PIGD) subtype has been associated with worse cognitive performance in Parkinson's disease (PD). OBJECTIVE: To investigate whether PIGD subtype classification or PIGD-related clinical features predict the development of cognitive decline in de novo PD patients. METHODS: Data from 422 PD patients with de novo PD were obtained from the PPMI database. At follow-up (up to 6 years), patients were categorized as having cognitive impairment or not. Multivariate Cox survival analysis was carried out including motor subtype and individual MDS-UPDRS items defining PIGD phenotype as predictors. Previously validated clinical predictors of cognitive impairment were included in the model as covariates. Occurrence of cognitive impairment at follow-up was used as the time-to-event and Kaplan-Meier curve was generated. RESULTS: At baseline, 76 patients were classified as PIGD, 299 tremor-dominant and 47 as indeterminate. Development of cognitive impairment was not associated with PIGD subtype (p = 0.252). When individual MDS-UPDRS items were interrogated in the model, postural instability proved to be an independent predictor of cognitive impairment (HR = 2.045; 95%CI: 1.068-3.918; p = 0.031), while gait difficulties were not associated with cognitive decline (p = 0.870). CONCLUSIONS: Our findings suggest that postural instability, as assessed by MDS-UPDRS III, may serve as a possible indicator of the risk of developing cognitive impairment in de novo PD patients rather than the PIGD phenotype.

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Item does not contain fulltext, BACKGROUND: Non-motor fluctuations (NMF) in people with Parkinson's disease (PwP) are clinically important yet understudied. OBJECTIVE: To study NMF in PwP using both the Movement Disorder Society Non-Motor Rating Scale (MDS-NMS) NMF subscale and wearable sensors. METHODS: We evaluated differences in overall burden of NMF and of specific NMF across disease durations: <2 years (n = 33), 2-5 years (n = 35), 5-10 years (n = 33), and > 10 years (n = 31). In addition, wearable triaxial sensor output was used as an exploratory outcome for early morning "off" periods. RESULTS: Significant between-group differences were observed for MDS-NMS NMF total scores (P < 0.001), and specifically for depression, anxiety, fatigue and cognition, with both NMF prevalence and burden increasing in those with longer disease duration. Whereas only 9.1% with a short disease duration had NMF (none of whom had dyskinesia), in PwP with a disease duration of >10 years this was 71.0% (P < 0.001). From a motor perspective, dyskinesia severity increased evenly with increasing disease duration, while NMF scores in affected individuals showed an initial increase with largest differences between 2-5 years disease duration (P < 0.001), with plateauing afterwards. Finally, we observed that the most common NMF symptoms in patients with sensor-confirmed early morning "off" periods were fluctuations in cognitive capabilities, restlessness, and excessive sweating. CONCLUSIONS: Non-motor fluctuations prevalence in PwP increases with disease duration, but in a pattern different from motor fluctuations. Moreover, NMF can occur in PwP without dyskinesia, and in those with NMF the severity of NMF increases most during years 2-5 after diagnosis.

Contains fulltext : 249307.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 287510.pdf (Publisher’s version ) (Open Access), BACKGROUND: Non-motor fluctuations (NMF) in people with Parkinson's disease (PwP) are clinically important yet understudied. OBJECTIVE: To study NMF in PwP using both the Movement Disorder Society Non-Motor Rating Scale (MDS-NMS) NMF subscale and wearable sensors. METHODS: We evaluated differences in overall burden of NMF and of specific NMF across disease durations: <2 years (n = 33), 2-5 years (n = 35), 5-10 years (n = 33), and > 10 years (n = 31). In addition, wearable triaxial sensor output was used as an exploratory outcome for early morning "off" periods. RESULTS: Significant between-group differences were observed for MDS-NMS NMF total scores (P < 0.001), and specifically for depression, anxiety, fatigue and cognition, with both NMF prevalence and burden increasing in those with longer disease duration. Whereas only 9.1% with a short disease duration had NMF (none of whom had dyskinesia), in PwP with a disease duration of >10 years this was 71.0% (P < 0.001). From a motor perspective, dyskinesia severity increased evenly with increasing disease duration, while NMF scores in affected individuals showed an initial increase with largest differences between 2-5 years disease duration (P < 0.001), with plateauing afterwards. Finally, we observed that the most common NMF symptoms in patients with sensor-confirmed early morning "off" periods were fluctuations in cognitive capabilities, restlessness, and excessive sweating. CONCLUSIONS: Non-motor fluctuations prevalence in PwP increases with disease duration, but in a pattern different from motor fluctuations. Moreover, NMF can occur in PwP without dyskinesia, and in those with NMF the severity of NMF increases most during years 2-5 after diagnosis.

Contains fulltext : 248856.pdf (Publisher’s version ) (Open Access), BACKGROUND: Postural Instability and Gait difficulties (PIGD) subtype has been associated with worse cognitive performance in Parkinson's disease (PD). OBJECTIVE: To investigate whether PIGD subtype classification or PIGD-related clinical features predict the development of cognitive decline in de novo PD patients. METHODS: Data from 422 PD patients with de novo PD were obtained from the PPMI database. At follow-up (up to 6 years), patients were categorized as having cognitive impairment or not. Multivariate Cox survival analysis was carried out including motor subtype and individual MDS-UPDRS items defining PIGD phenotype as predictors. Previously validated clinical predictors of cognitive impairment were included in the model as covariates. Occurrence of cognitive impairment at follow-up was used as the time-to-event and Kaplan-Meier curve was generated. RESULTS: At baseline, 76 patients were classified as PIGD, 299 tremor-dominant and 47 as indeterminate. Development of cognitive impairment was not associated with PIGD subtype (p = 0.252). When individual MDS-UPDRS items were interrogated in the model, postural instability proved to be an independent predictor of cognitive impairment (HR = 2.045; 95%CI: 1.068-3.918; p = 0.031), while gait difficulties were not associated with cognitive decline (p = 0.870). CONCLUSIONS: Our findings suggest that postural instability, as assessed by MDS-UPDRS III, may serve as a possible indicator of the risk of developing cognitive impairment in de novo PD patients rather than the PIGD phenotype.

Background Over 80% people with Parkinson's disease (PD; PwP) live with chronic pain. Objective Whether ethnic disparities in receipt of appropriate analgesia exist among PwP with chronic pain living in the United Kingdom (UK). Methods A retrospective datamining of an existing King's PD Pain Questionnaire validation study dataset enrolling 300 PwP. Results 69 PwP: 23 Black (57% female), 23 Asian (57% female) and 23 White (65% female) had similar pain burden on the King's PD Pain Scale. Significantly more White PwP (83%) received pain relief compared to Black (48%) and Asian (43%) PwP (p = 0.016). The difference was most evident for opioid analgesics (White 43% vs. Black 4% vs. Asian 4%, p <= 0.001). Conclusions Ethnic disparities in the analgesic use among PwP with chronic pain living in the UK are evident in this retrospective analysis, prompting large-scale studies and reinforcement of interventions to tackle the impact ethnicity might have on the successful analgesia.

Background: The satisfaction with life and, in particular, with treatment in Parkinson's disease (PD) is understudied. Objective: To explore a new 7-item rating tool assessing satisfaction with life and treatment (SLTS-7) in PD. Methods: In this cross-sectional, multi-center study, including patients screened for advanced therapies, psychometric characteristics of the SLTS-7 were analyzed. An exploratory factor analysis identified the underlying factorial structure of the SLTS-7. Results: 117 patients were included, and the data quality of the SLTS-7 was excellent (computable data 100%), and acceptability measures satisfied standard criteria. Besides the global assessment (item 1), the exploratory factor analysis produced item 2 (physical satisfaction) as an independent item and two factors among the remaining items: items 3-5 (psycho-social satisfaction), and items 6 and 7 (treatment satisfaction). Cronbach's alpha was 0.89, indicative of high internal consistency. The SLTS-7 total score correlated moderately with motor symptoms and weakly with non-motor symptoms total scores. SLTS-7 showed the highest correlations with the European Quality of Life with 5 items (EQ-5D) visual analog scale (0.43-0.58, p <0.01), indicating a moderate convergent validity. The SLTS-7 significantly increased with higher non-motor symptoms burden levels (p = 0.002). Conclusion: Life satisfaction in PD covers three specific aspects, namely physical, psycho-social, and treatment satisfaction. The new SLTS-7 is a valid, reliable, and easy-to-use tool to assess satisfaction with life and treatment in patients with PD screened for advanced therapies. Longitudinal studies analyzing the effect of advanced PD treatment on life and treatment satisfaction are warranted.

Previous studies have shown less access to deep brain stimulation (DBS) for Parkinson's disease (PD) in women compared to men raising concerns about a potential gender gap resulting from nonclinical factors or gender differences in clinical efficacy for postoperative quality of life (QoL), motor, and nonmotor symptoms (NMS) outcomes. This was a cross-sectional and a longitudinal, prospective, observational, controlled, quasi-experimental, international multicenter study. A total sample size of 505 consisted of 316 consecutively referred patients for DBS indication evaluation at the University Hospital Cologne (01/2015-09/2020) and 189 consecutively treated patients at DBS centers in the University Hospitals Cologne and Marburg, Salford's Royal Hospital Manchester, and King's College Hospital London. In the cross-sectional cohort, we examined gender proportions at referral, indication evaluations, and DBS surgery. In the longitudinal cohort, clinical assessments at preoperative baseline and 6-month follow-up after surgery included the PD Questionnaire-8, NMSScale, Scales for Outcomes in PD-motor scale, and levodopa-equivalent daily dose. Propensity score matching resulted in a pseudo-randomized sub-cohort balancing baseline demographic and clinical characteristics between women with PD and male controls. 316 patients were referred for DBS. 219 indication evaluations were positive (women n = 102, respectively n = 82). Women with PD were disproportionally underrepresented in referrals compared to the general PD population (relative risk [RR], 0.72; 95%CI, 0.56-0.91; P = 0.002), but more likely to be approved for DBS than men (RR, 1.17; 95%CI, 1.03-1.34; P = 0.029). Nonetheless, their total relative risk of undergoing DBS treatment was 0.74 (95%CI, 0.48-1.12) compared to men with PD. At baseline, women had longer disease duration and worse dyskinesia. Exploring QoL domains, women reported worse mobility and bodily discomfort. At follow-up, all main outcomes improved equ

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Growing evidence suggests that non-motor symptoms (NMS) in Parkinson's disease (PD) have differential progression patterns that have a different natural history from motor progression and may be geographically influenced. We conducted a cross-sectional analysis of 1607 PD patients of whom 1327 were from Europe, 208 from the Americas, and 72 from Asia. The primary objective was to assess baseline non-motor burden, defined by Non-Motor Symptoms Scale (NMSS) total scores. Other aims included identifying the factors predicting quality of life, differences in non-motor burden between drug-naive and non-drug-naive treated patients, and non-motor phenotypes across different geographical locations. Mean age was 65.9 +/- 10.8 years, mean disease duration 6.3 +/- 5.6 years, median Hoehn and Yahr stage was 2 (2-3), and 64.2% were male. In this cohort, mean NMSS scores were 46.7 +/- 37.2. Differences in non-motor burden and patterns differed significantly between drug-naive participants, those with a disease duration of less than five years, and those with a duration of five years or over (p <= 0.018). Significant differences were observed in geographical distribution (NMSS Europe: 46.4 +/- 36.3; Americas: 55.3 +/- 42.8; Asia: 26.6 +/- 25.1; p<0.001), with differences in sleep/fatigue, urinary, sexual, and miscellaneous domains (p0.020). The best predictor of quality of life was the mood/apathy domain (beta =0.308, p<0.001). This global study reveals that while non-motor symptoms are globally present with severe NMS burden impacting quality of life in PD, there appear to be differences depending on disease duration and geographical distribution.

Background The effects of subthalamic stimulation (subthalamic nucleus-deep brain stimulation, STN-DBS) on impulsive and compulsive behaviours (ICB) in Parkinson's disease (PD) are understudied. Objective To investigate clinical predictors of STN-DBS effects on ICB. Methods In this prospective, open-label, multicentre study in patients with PD undergoing bilateral STN-DBS, we assessed patients preoperatively and at 6-month follow-up postoperatively. Clinical scales included the Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS), PD Questionnaire-8, Non-Motor Symptom Scale (NMSS), Unified PD Rating Scale in addition to levodopa-equivalent daily dose total (LEDD-total) and dopamine agonists (LEDD-DA). Changes at follow-up were analysed with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We explored predictors of QUIP-RS changes using correlations and linear regressions. Finally, we dichotomised patients into 'QUIP-RS improvement or worsening' and analysed between-group differences. Results We included 55 patients aged 61.7 years +/- 8.4 with 9.8 years +/- 4.6 PD duration. QUIP-RS cut-offs and psychiatric assessments identified patients with preoperative ICB. In patients with ICB, QUIP-RS improved significantly. However, we observed considerable interindividual variability of clinically relevant QUIP-RS outcomes as 27.3% experienced worsening and 29.1% an improvement. In post hoc analyses, higher baseline QUIP-RS and lower baseline LEDD-DA were associated with greater QUIP-RS improvements. Additionally, the 'QUIP-RS worsening' group had more severe baseline impairment in the NMSS attention/memory domain. Conclusions Our results show favourable ICB outcomes in patients with higher preoperative ICB severity and lower preoperative DA doses, and worse outcomes in patients with more severe baseline attention/memory deficits. These findings emphasise the need for comprehensive non-motor and motor symptoms asse

Background: Sleep disturbances and neuropsychiatric symptoms are some of the most common nonmotor symptoms in Parkinson's disease (PD). The effect of subthalamic stimulation (STN-DBS) on these symptoms beyond a short-term follow-up is unclear. Objective: To examine 36-month effects of bilateral STN-DBS on quality of sleep, depression, anxiety, and quality of life (QoL) compared to standard-of-care medical therapy (MED) in PD. Methods: In this prospective, controlled, observational, propensity score matched, international multicenter study, we assessed sleep disturbances using the PDSleep Scale-1 (PDSS), QoL employing the PDQuestionnaire-8 (PDQ-8), motor disorder with the Scales for Outcomes in PD (SCOPA), anxiety and depression with the Hospital Anxiety and Depression Scale (HADS), and dopaminergic medication requirements (LEDD). Within-group longitudinal outcome changes were tested using Wilcoxon signed-rank and between-group longitudinal differences of change scores with Mann-Whitney U tests. Spearman correlations analyzed the relationships of outcome parameter changes at follow-up. Results: Propensity score matching applied on 159 patients (STN-DBS n = 75, MED n= 84) resulted in 40 patients in each treatment group. At 36-month follow-up, STN-DBS led to significantly better PDSS and PDQ-8 change scores, which were significantly correlated. We observed no significant effects for HADS and no significant correlations between change scores in PDSS, HADS, and LEDD. Conclusions: We report Class IIb evidence of beneficial effects of STN-DBS on quality of sleep at 36-month follow-up, which were associated with QoL improvement independent of depression and dopaminergic medication. Our study highlights the importance of sleep for assessments of DBS outcomes.

To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable QoL responders/non-responders. At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as QoL non-responders. Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as 'difficulties experiencing pleasure' and 'problems sustaining concentration'. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy.

Device-aided therapies, including levodopa-carbidopa intestinal gel infusion, apomorphine subcutaneous infusion, and deep brain stimulation, are available in many countries for the management of the advanced stage of Parkinson's disease (PD). Currently, selection of device-aided therapies is mainly focused on patients' motor profile while non-motor symptoms play a role limited to being regarded as possible exclusion criteria in the decision-making process for the delivery and sustenance of a successful treatment. Differential beneficial effects on specific non-motor symptoms of the currently available device-aided therapies for PD are emerging and these could hold relevant clinical implications. In this viewpoint, we suggest that specific non-motor symptoms could be used as an additional anchor to motor symptoms and not merely as exclusion criteria to deliver bespoke and patient-specific personalised therapy for advanced PD.

Background: Ethnic phenotypic differences in Parkinson's disease (PD) are important to understand the heterogeneity of PD and develop biomarkers and clinical trials. Objective: To investigate (i) whether there are non-motor symptoms (NMS)- and comorbidity-based phenotypic differences between Black, Asian and Minority Ethnic (BAME) and White PD patients and (ii) whether clinically available biomarkers may help differentiate and explain the differences between the groups. Methods: This is a multicentre (four sites, London), real-life, cross-sectional study including PD patients of BAME or White ethnicity. The primary outcome was a detailed NMS assessment; additional measurements included disease and motor stage, comorbidity, sociodemographic parameters and brain MRI imaging. Results: 271 PD patients (54 Asian, 71 Black, and 146 White) were included balanced for age, gender, and disease severity (HY). Black patients had a shorter disease duration compared to White and Asian populations. The SCOPA-Motor activities of daily living scores as well as the NMSS scores were significantly higher in both Black (total score and domain miscellaneous) and Asian (total score and domains sleep/fatigue, mood/apathy and perception/hallucinations) than White individuals. Both BAME populations had higher prevalence of arterial hypertension, and the Black population had a higher prevalence of diabetes mellitus. Brain MRI revealed a greater severity of white matter changes in Black compared to the White and Asian cohorts. Conclusion: These findings suggest differences in phenotype of PD in BAME populations with greater burden of NMS and motor disability and a higher rate of cardiovascular comorbidities.

To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable "QoL responders"/"non-responders". At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as "QoL non-responders". Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as 'difficulties experiencing pleasure' and 'problems sustaining concentration'. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy.

Contains fulltext : 233579.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 233579.pdf (Publisher’s version ) (Open Access)

Growing evidence suggests that non-motor symptoms (NMS) in Parkinson's disease (PD) have differential progression patterns that have a different natural history from motor progression and may be geographically influenced. We conducted a cross-sectional analysis of 1607 PD patients of whom 1327 were from Europe, 208 from the Americas, and 72 from Asia. The primary objective was to assess baseline non-motor burden, defined by Non-Motor Symptoms Scale (NMSS) total scores. Other aims included identifying the factors predicting quality of life, differences in non-motor burden between drug-naive and non-drug-naive treated patients, and non-motor phenotypes across different geographical locations. Mean age was 65.9 +/- 10.8 years, mean disease duration 6.3 +/- 5.6 years, median Hoehn and Yahr stage was 2 (2-3), and 64.2% were male. In this cohort, mean NMSS scores were 46.7 +/- 37.2. Differences in non-motor burden and patterns differed significantly between drug-naive participants, those with a disease duration of less than five years, and those with a duration of five years or over (p <= 0.018). Significant differences were observed in geographical distribution (NMSS Europe: 46.4 +/- 36.3; Americas: 55.3 +/- 42.8; Asia: 26.6 +/- 25.1; p<0.001), with differences in sleep/fatigue, urinary, sexual, and miscellaneous domains (p0.020). The best predictor of quality of life was the mood/apathy domain (beta =0.308, p<0.001). This global study reveals that while non-motor symptoms are globally present with severe NMS burden impacting quality of life in PD, there appear to be differences depending on disease duration and geographical distribution.

Device-aided therapies, including levodopa-carbidopa intestinal gel infusion, apomorphine subcutaneous infusion, and deep brain stimulation, are available in many countries for the management of the advanced stage of Parkinson's disease (PD). Currently, selection of device-aided therapies is mainly focused on patients' motor profile while non-motor symptoms play a role limited to being regarded as possible exclusion criteria in the decision-making process for the delivery and sustenance of a successful treatment. Differential beneficial effects on specific non-motor symptoms of the currently available device-aided therapies for PD are emerging and these could hold relevant clinical implications. In this viewpoint, we suggest that specific non-motor symptoms could be used as an additional anchor to motor symptoms and not merely as exclusion criteria to deliver bespoke and patient-specific personalised therapy for advanced PD.

Background The effects of subthalamic stimulation (subthalamic nucleus-deep brain stimulation, STN-DBS) on impulsive and compulsive behaviours (ICB) in Parkinson's disease (PD) are understudied. Objective To investigate clinical predictors of STN-DBS effects on ICB. Methods In this prospective, open-label, multicentre study in patients with PD undergoing bilateral STN-DBS, we assessed patients preoperatively and at 6-month follow-up postoperatively. Clinical scales included the Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS), PD Questionnaire-8, Non-Motor Symptom Scale (NMSS), Unified PD Rating Scale in addition to levodopa-equivalent daily dose total (LEDD-total) and dopamine agonists (LEDD-DA). Changes at follow-up were analysed with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We explored predictors of QUIP-RS changes using correlations and linear regressions. Finally, we dichotomised patients into 'QUIP-RS improvement or worsening' and analysed between-group differences. Results We included 55 patients aged 61.7 years +/- 8.4 with 9.8 years +/- 4.6 PD duration. QUIP-RS cut-offs and psychiatric assessments identified patients with preoperative ICB. In patients with ICB, QUIP-RS improved significantly. However, we observed considerable interindividual variability of clinically relevant QUIP-RS outcomes as 27.3% experienced worsening and 29.1% an improvement. In post hoc analyses, higher baseline QUIP-RS and lower baseline LEDD-DA were associated with greater QUIP-RS improvements. Additionally, the 'QUIP-RS worsening' group had more severe baseline impairment in the NMSS attention/memory domain. Conclusions Our results show favourable ICB outcomes in patients with higher preoperative ICB severity and lower preoperative DA doses, and worse outcomes in patients with more severe baseline attention/memory deficits. These findings emphasise the need for comprehensive non-motor and motor symptoms asse

To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable QoL responders/non-responders. At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as QoL non-responders. Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as 'difficulties experiencing pleasure' and 'problems sustaining concentration'. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy.

Background: Sleep disturbances and neuropsychiatric symptoms are some of the most common nonmotor symptoms in Parkinson's disease (PD). The effect of subthalamic stimulation (STN-DBS) on these symptoms beyond a short-term follow-up is unclear. Objective: To examine 36-month effects of bilateral STN-DBS on quality of sleep, depression, anxiety, and quality of life (QoL) compared to standard-of-care medical therapy (MED) in PD. Methods: In this prospective, controlled, observational, propensity score matched, international multicenter study, we assessed sleep disturbances using the PDSleep Scale-1 (PDSS), QoL employing the PDQuestionnaire-8 (PDQ-8), motor disorder with the Scales for Outcomes in PD (SCOPA), anxiety and depression with the Hospital Anxiety and Depression Scale (HADS), and dopaminergic medication requirements (LEDD). Within-group longitudinal outcome changes were tested using Wilcoxon signed-rank and between-group longitudinal differences of change scores with Mann-Whitney U tests. Spearman correlations analyzed the relationships of outcome parameter changes at follow-up. Results: Propensity score matching applied on 159 patients (STN-DBS n = 75, MED n= 84) resulted in 40 patients in each treatment group. At 36-month follow-up, STN-DBS led to significantly better PDSS and PDQ-8 change scores, which were significantly correlated. We observed no significant effects for HADS and no significant correlations between change scores in PDSS, HADS, and LEDD. Conclusions: We report Class IIb evidence of beneficial effects of STN-DBS on quality of sleep at 36-month follow-up, which were associated with QoL improvement independent of depression and dopaminergic medication. Our study highlights the importance of sleep for assessments of DBS outcomes.

Background: Ethnic phenotypic differences in Parkinson's disease (PD) are important to understand the heterogeneity of PD and develop biomarkers and clinical trials. Objective: To investigate (i) whether there are non-motor symptoms (NMS)- and comorbidity-based phenotypic differences between Black, Asian and Minority Ethnic (BAME) and White PD patients and (ii) whether clinically available biomarkers may help differentiate and explain the differences between the groups. Methods: This is a multicentre (four sites, London), real-life, cross-sectional study including PD patients of BAME or White ethnicity. The primary outcome was a detailed NMS assessment; additional measurements included disease and motor stage, comorbidity, sociodemographic parameters and brain MRI imaging. Results: 271 PD patients (54 Asian, 71 Black, and 146 White) were included balanced for age, gender, and disease severity (HY). Black patients had a shorter disease duration compared to White and Asian populations. The SCOPA-Motor activities of daily living scores as well as the NMSS scores were significantly higher in both Black (total score and domain miscellaneous) and Asian (total score and domains sleep/fatigue, mood/apathy and perception/hallucinations) than White individuals. Both BAME populations had higher prevalence of arterial hypertension, and the Black population had a higher prevalence of diabetes mellitus. Brain MRI revealed a greater severity of white matter changes in Black compared to the White and Asian cohorts. Conclusion: These findings suggest differences in phenotype of PD in BAME populations with greater burden of NMS and motor disability and a higher rate of cardiovascular comorbidities.

Objective: Using narrative review techniques, this paper evaluates the evidence for separable underlying patho-mechanisms of periodic limb movements (PLMs) to separable PLM motor patterns and phenotypes, in order to elucidate potential new treatment modalities. Background: Periodic limb movement disorder (PLMD) is estimated to occur in 5–8% of the paediatric population and 4–11% of the general adult population. Due to significant sleep fragmentation, PLMD can lead to functional impairment, including hyperactivity and delayed language development in children, and poor concentration and work performance in adults. Longitudinal data demonstrate that those with PLMD are at greater risk of depression and anxiety, and a 4-fold greater risk of developing dementia. PLMD has been extensively studied over the past two decades, and several key insights into the genetic, pathophysiological, and neural correlates have been proposed. Amongst these proposals is the concept of separable PLM phenotypes, proposed on the basis of nocturnal features such as the ratio of limb movements and distribution throughout the night. PLM phenotype and presentation, however, varies significantly depending on the scoring utilized and the nocturnal features examined, across age, and co-morbid clinical conditions. Furthermore, associations between these phenotypes with major neurologic and psychiatric disorders remain controversial. Methods: In order to elucidate potential divergent biological pathways that may help clarify important new treatment modalities, this paper utilizes narrative review and evaluates the evidence linking PLM motor patterns and phenotypes with hypothesised underlying patho-mechanisms. Distinctive, underlying patho-mechanisms include: a pure motor mechanism originating in the spinal cord, iron deficiency, dopamine system dysfunction, thalamic glutamatergic hyperactivity, and a more cortical-subcortical interplay. In support of the latter hypothesis, PLM rhyth

Objective: Using narrative review techniques, this paper evaluates the evidence for separable underlying patho-mechanisms of periodic limb movements (PLMs) to separable PLM motor patterns and phenotypes, in order to elucidate potential new treatment modalities. Background: Periodic limb movement disorder (PLMD) is estimated to occur in 5–8% of the paediatric population and 4–11% of the general adult population. Due to significant sleep fragmentation, PLMD can lead to functional impairment, including hyperactivity and delayed language development in children, and poor concentration and work performance in adults. Longitudinal data demonstrate that those with PLMD are at greater risk of depression and anxiety, and a 4-fold greater risk of developing dementia. PLMD has been extensively studied over the past two decades, and several key insights into the genetic, pathophysiological, and neural correlates have been proposed. Amongst these proposals is the concept of separable PLM phenotypes, proposed on the basis of nocturnal features such as the ratio of limb movements and distribution throughout the night. PLM phenotype and presentation, however, varies significantly depending on the scoring utilized and the nocturnal features examined, across age, and co-morbid clinical conditions. Furthermore, associations between these phenotypes with major neurologic and psychiatric disorders remain controversial. Methods: In order to elucidate potential divergent biological pathways that may help clarify important new treatment modalities, this paper utilizes narrative review and evaluates the evidence linking PLM motor patterns and phenotypes with hypothesised underlying patho-mechanisms. Distinctive, underlying patho-mechanisms include: a pure motor mechanism originating in the spinal cord, iron deficiency, dopamine system dysfunction, thalamic glutamatergic hyperactivity, and a more cortical-subcortical interplay. In support of the latter hypothesis, PLM rhyth

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Danielle Wasserman,1,2,* Dorothea Bindman,1,* Alexander D Nesbitt,1– 3 Diana Cash,4 Milan Milosevic,5 Paul T Francis,6 K Ray Chaudhuri,7 Guy D Leschziner,1,2 Luigi Ferini-Strambi,8 Clive Ballard,9 Amy Eccles,10 Ivana Rosenzweig1,2 1Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK; 2Sleep Disorders Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3Headache Group, Department of Clinical Neurosciences, King’s College Hospital NHS Foundation Trust, London, UK; 4BRAIN, Department of Neuroimaging, King’s College London, London, UK; 5School of Public Health “Andrija Stampar“, University of Zagreb School of Medicine, Zagreb, Croatia; 6Wolfson Centre for Age-Related Diseases, King’s College London, London, UK; 7Movement Disorders Unit, King’s College Hospital, Department of Clinical and Basic Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, Parkinson Foundation Centre of Excellence, King’s College London, London, UK; 8Sleep Disorders Center, Department of Clinical Neurosciences, Università Vita-Salute San Raffaele, Milan, Italy; 9Medical School, University of Exeter, Exeter, UK; 10Department of Nuclear Medicine, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK*These authors contributed equally to this workCorrespondence: Ivana RosenzweigSleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, Box 089, De Crespigny Park, London SE5 8AF, UKEmail ivana.1.rosenzweig@kcl.ac.ukIntroduction: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is increasingly recognised as an important precursor disease state of alpha-synucleinopathies. This parasomnia is characterized by a his

Aim: A Delphi expert consensus panel proposed that fulfilling >=1 of the a 5-2-1 criteria' (>=five-times daily oral levodopa use, >=two daily hours with a Off' symptoms or >=one daily hour with troublesome dyskinesia) suggests advanced Parkinson's disease (PD). Patients & methods: DUOdopa/Duopa in Patients with Advanced PD-a GLobal OBservational Study Evaluating Long-Term Effectiveness (DUOGLOBE)-is a single-arm, postmarketing, observational, long-term effectiveness study of levodopa-carbidopa intestinal gel (LCIG) for advanced PD. Result(s): This 6-month interim analysis (n = 139) affirms that most (98%) enrolled patients fulfill >=1 of the 5-2-1 criteria. These patients responded favorably to LCIG treatment. Safety was consistent with other LCIG studies. Conclusion(s): In advanced PD patients, the 5-2-1 criteria generally aligns with clinician assessment.Copyright © 2020 AbbVie Inc., employer of authors L Bergmann, P Kukreja, K Onuk, W Robieson.

Aim: A Delphi expert consensus panel proposed that fulfilling >=1 of the a 5-2-1 criteria' (>=five-times daily oral levodopa use, >=two daily hours with a Off' symptoms or >=one daily hour with troublesome dyskinesia) suggests advanced Parkinson's disease (PD). Patients & methods: DUOdopa/Duopa in Patients with Advanced PD-a GLobal OBservational Study Evaluating Long-Term Effectiveness (DUOGLOBE)-is a single-arm, postmarketing, observational, long-term effectiveness study of levodopa-carbidopa intestinal gel (LCIG) for advanced PD. Result(s): This 6-month interim analysis (n = 139) affirms that most (98%) enrolled patients fulfill >=1 of the 5-2-1 criteria. These patients responded favorably to LCIG treatment. Safety was consistent with other LCIG studies. Conclusion(s): In advanced PD patients, the 5-2-1 criteria generally aligns with clinician assessment.Copyright © 2020 AbbVie Inc., employer of authors L Bergmann, P Kukreja, K Onuk, W Robieson.

Combined catechol-O-methyl-transferase-inhibition and Levodopa-Carbidopa intestinal gel (LCIG) infusion has the potential to reduce LCIG daily dose and the costs of this therapy. In this retrospective analysis, we report on Parkinson's disease (PD) patients on LCIG with concomitant Opicapone. In 11 patients, the introduction of Opicapone led to LCIG daily dose being reduced by 24.8% (p = 0.05) without any significant worsening of dyskinesia. Three patients withdrew from Opicapone due to side effects or inefficacy. LCIG daily dose reduction could lead to cost savings of 142,820.63 pound/year in the United Kingdom while maintaining clinical care.

In older patients with Parkinson's disease (PD), the use of dopamine agonists (DA) has been limited due to uncertainties related to their tolerability in spite of potential gains with the advent of longer acting or transdermal therapies. Comparative real-life data addressing the tolerability of DA therapy across age ranges are currently sparse. This study addressed the tolerability (Shulman criteria, continued intake of DA therapy for at least 6 months) in PD patients across several European centres treated with long-acting and transdermal DA (Rotigotine skin patch, Ropinirole extended release, or Pramipexole prolonged release) as part of routine clinical care in younger and older PD patients. A medical record-based retrospective data capture and clinical interview-based follow-up survey of patients initiating or initiated on DA treatment (short and long acting) in a real-life setting. 425 cases were included [mean age 68.3 years (range 37-90), mean duration of disease 7.5 years (range 0-37), 31.5% older age (>= 75 years of age)]. Tolerability was above 90% irrespective of age, with no significant differences between younger and older patients. Based on our findings, we suggest that long-acting/transdermal DA are tolerated in non-demented older patients, as well as in younger patients, however, with lower daily dose in older patients.

Background Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and sleep symptoms in Parkinson's disease (PD). However, the long-term effects of STN-DBS on sleep and its relationship with QoL outcome are unclear. Methods In this prospective, observational, multicenter study including 73 PD patients undergoing bilateral STN-DBS, we examined PDSleep Scale (PDSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD-motor examination, -activities of daily living, and -complications (SCOPA-A, -B, -C), and levodopa-equivalent daily dose (LEDD) preoperatively, at 5 and 24 months follow-up. Longitudinal changes were analyzed with Friedman-tests or repeated-measures ANOVA, when parametric tests were applicable, and Bonferroni-correction for multiple comparisons. Post-hoc, visits were compared with Wilcoxon signed-rank/t-tests. The magnitude of clinical responses was investigated using effect size. Results Significant beneficial effects of STN-DBS were observed for PDSS, PDQ-8, SCOPA-A, -B, and -C. All outcomes improved significantly at 5 months with subsequent decrements in gains at 24 months follow-up which were significant for PDSS, PDQ-8, and SCOPA-B. Comparing baseline and 24 months follow-up, we observed significant improvements of PDSS (small effect), SCOPA-A (moderate effect), -C, and LEDD (large effects). PDSS and PDQ-8 improvements correlated significantly at 5 and 24 months follow-up. Conclusions In this multicenter study with a 24 months follow-up, we report significant sustained improvements after bilateral STN-DBS using a PD-specific sleep scale and a significant relationship between sleep and QoL improvements. This highlights the importance of sleep in holistic assessments of DBS outcomes.

Objective To examine 36-month effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on non-motor symptoms (NMS) compared with standard-of-care medical treatment (MED) in Parkinson's disease (PD). Methods Here we report the 36-month follow-up of a prospective, observational, controlled, international multicentre study of the NILS cohort. Assessments included NMSScale (NMSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). Propensity score matching resulted in a pseudo-randomised sub-cohort balancing baseline demographic and clinical characteristics between the STN-DBS and MED groups. Within-group longitudinal outcome changes were analysed using Wilcoxon signed-rank and between-group differences of change scores with Mann-Whitney U test. Strength of clinical responses was quantified with Cohen's effect size. In addition, bivariate correlations of change scores were explored. Results Propensity score matching applied on the cohort of 151 patients (STN-DBS n=67, MED n=84) resulted in a well-balanced sub-cohort including 38 patients per group. After 36 months, STN-DBS significantly improved NMSS, PDQ-8, SCOPA-motor examination and -complications and reduced LEDD. Significant between-group differences, all favouring STN-DBS, were found for NMSS, SCOPA-motor complications, LEDD (large effects), motor examination and PDQ-8 (moderate effects). Furthermore, significant differences were found for the sleep/fatigue, urinary (large effects) and miscellaneous NMSS domains (moderate effects). NMSS total and PDQ-8 change scores correlated significantly. Conclusions This study provides Class IIb evidence for beneficial effects of STN-DBS on NMS at 36-month follow-up which also correlated with quality of life improvements. This highlights the importance of NMS for DBS outcomes assessments.

Background: Subthalamic (STN) and pallidal (GPi) deep brain stimulation (DBS) improve quality of life, motor, and nonmotor symptoms (NMS) in advanced Parkinson's disease (PD). However, few studies have compared their nonmotor effects. Objective: To compare nonmotor effects of STN-DBS and GPi-DBS. Methods: In this prospective, observational, multicenter study including 60 PD patients undergoing bilateral STN-DBS (n = 40) or GPi-DBS (n = 20), we examined PDQuestionnaire (PDQ), NMSScale (NMSS), Unified PD Rating Scale-activities of daily living, -motor impairment, -complications (UPDRS-II, -III, -IV), Hoehn&Yahr, Schwab&England Scale, and levodopa-equivalent daily dose (LEDD) preoperatively and at 6-month follow-up. Intra-group changes at follow-up were analyzed with Wilcoxon signed-rank or paired t-test, if parametric tests were applicable, and corrected for multiple comparisons. Inter-group differences were explored with Mann-Whitney-U/unpaired t-tests. Analyses were performed before and after propensity score matching which balanced out demographic and preoperative clinical characteristics. Strength of clinical changes was assessed with effect size. Results: In both groups, PDQ UPDRS-II, -IV, Schwab&England Scale, and NMSS improved significantly at follow-up. STN-DBS was significantly better for LEDD reduction, GPi-DBS for UPDRS-IV. While NMSS total score outcomes were similar, explorative NMSS domain analyses revealed distinct profiles: Both targets improved sleep/fatigue and mood/cognition, but only STN-DBS the miscellaneous (pain/olfaction) and attention/memory and only GPi-DBS cardiovascular and sexual function domains. Conclusions: To our knowledge, this is the first study to report distinct patterns of beneficial nonmotor effects of STN-DBS and GPi-DBS in PD. This study highlights the importance of NMS assessments to tailor DBS target choices to patients' individual motor and nonmotor profiles. (C) 2020 The Author(s). Published by Elsevier Inc.

Combined catechol-O-methyl-transferase-inhibition and Levodopa-Carbidopa intestinal gel (LCIG) infusion has the potential to reduce LCIG daily dose and the costs of this therapy. In this retrospective analysis, we report on Parkinson's disease (PD) patients on LCIG with concomitant Opicapone. In 11 patients, the introduction of Opicapone led to LCIG daily dose being reduced by 24.8% (p = 0.05) without any significant worsening of dyskinesia. Three patients withdrew from Opicapone due to side effects or inefficacy. LCIG daily dose reduction could lead to cost savings of 142,820.63 pound/year in the United Kingdom while maintaining clinical care.