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[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.

The advanced modeling and estimation of overall system dynamics play a vital role in electric vehicles (EVs), as the selection of components in the powertrain and prediction of performance are the key market qualifiers. The state-space averaged model and small-signal transfer function model are useful for assessing long-term behavior in system-level analysis and for designing the controller parameters, respectively. Both models take less computation time but ignore the high-frequency switching dynamics. Therefore, these two models could be impractical for the development and testing of EV prototypes. On the other hand, the multi-domain model in available simulation tools gives in-depth information about the short-term behavior and loss analysis of power electronic devices in each subsystem, considering the switching dynamics in a long computation time. In this paper, a general mathematical framework for the dynamical analysis of complete EVs is presented using a unified, switched nonlinear model. This equation-based model runs faster than the available module-based simulation tools. Two other models, namely the time domain state-space averaged model and frequency domain small-signal transfer function model, are also developed from the switched nonlinear model for the analysis with less computation time. The design and performance of an EV with two different motors and its controllers are evaluated using the general mathematical framework.

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.

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.

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.

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: 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.

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.

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

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.

Aims: Guidelines recommend targeting non-high-density lipoprotein cholesterol to reduce cardiovascular risk. We assessed the impact of baseline triglycerides on non-high-density lipoprotein cholesterol goal attainment in 10 phase 3 trials with alirocumab versus control (n = 4983). Methods: Trials were grouped into four pools based on alirocumab dose (75-150 mg every 2 weeks), control (placebo/ezetimibe) and statin use. Baseline triglyceride quintiles were built within each pool. Non-high-density lipoprotein cholesterol goal attainment (very high risk: <100 mg/dl; moderate/high risk: <130 mg/dl), low-density lipoprotein cholesterol goal attainment (very high risk: <70 mg/dl; moderate/high risk: <100 mg/dl) and changes from baseline in lipid parameters were assessed at Week 24 among baseline triglyceride quintiles. Results: Higher baseline triglycerides were associated with a worse cardiovascular risk profile. Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol increased with higher triglycerides, but the magnitude in non-high-density lipoprotein cholesterol was three- to four-fold higher compared with the increase in low-density lipoprotein cholesterol. Non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol percentage reductions from baseline with alirocumab were similar regardless of baseline triglycerides. A greater proportion of alirocumab-treated patients attained non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol goals compared with placebo or ezetimibe. Unlike low-density lipoprotein cholesterol goal attainment, non-high-density lipoprotein cholesterol goal attainment significantly declined with increasing baseline triglycerides (p < 0.05 for trend tests). A single standard deviation increase in baseline log(triglycerides) was significantly associated with lower odds ratios of attaining non-high-density lipoprotein cholesterol goals in the different pools and treatment (alirocu

Parkinson's Disease (PD) is a slowly evolving neuro-logical disease that affects about 1% of the population above 60 years old, causing symptoms that are subtle at first, but whose intensity increases as the disease progresses. Automated detection of these symptoms could offer clues as to the early onset of the disease, thus improving the expected clinical outcomes of the patients via appropriately targeted interventions. This potential has led many researchers to develop methods that use widely available sensors to measure and quantify the presence of PD symptoms such as tremor, rigidity and braykinesia. However, most of these approaches operate under controlled settings, such as in lab or at home, thus limiting their applicability under free-living conditions. In this work, we present a method for automatically identifying tremorous episodes related to PD, based on IMU signals captured via a smartphone device. We propose a Multiple-Instance Learning approach, wherein a subject is represented as an unordered bag of accelerometer signal segments and a single, expert-provided, tremor annotation. Our method combines deep feature learning with a learnable pooling stage that is able to identify key instances within the subject bag, while still being trainable end-to-end. We validate our algorithm on a newly introduced dataset of 45 subjects, containing accelerometer signals collected entirely in-the-wild. The good classification performance obtained in the conducted experiments suggests that the proposed method can efficiently navigate the noisy environment of in-the-wild recordings.

Non-Newtonian flow from a wedge constitutes a fundamental problem in chemical engineering systems and is relevant to processing of polymers, coating systems, etc. Motivated by such applications, the homotopy analysis method (HAM) was employed to obtain semi-analytical solutions for thermal convection boundary layer flow of incompressible micropolar fluid from a two-dimensional body (wedge). Viscous dissipation and heat sink effects were included. The non-dimensional boundary value problem emerges as a system of nonlinear coupled ordinary differential equations, by virtue of suitable coordinate transformations. The so-called Falkner-Skan flow cases are elaborated. Validation of the HAM solutions was achieved with earlier simpler models, as well as with a Nakamura finite difference method for the general model. The micropolar model employed simulates certain polymeric solutions quite accurately, and features rotary motions of micro-elements. Primary and secondary shear stress, wall couple stress, Nusselt number, microrotation velocity, and temperature were computed for the effect of vortex viscosity parameter (micropolar rheological), Eckert number (viscous dissipation), Falkner-Skan (pressure gradient) parameter, micro-inertia density, and heat sink parameter. The special cases of Blasius and stagnation flow were also addressed. It was observed from the study that the temperature and thermal boundary layer thickness are both suppressed with increasing wedge parameter and wall heat sink effect, which is beneficial to temperature regulation in polymer coating dynamics. Further, strong reverse spin was generated in the microrotation with increasing vortex viscosity, which resulted in increase in angular momentum boundary layer thickness. Also, both primary and secondary skin friction components were reduced with increasing wedge parameter. Nusselt number was also enhanced substantially with greater wedge parameter. This work is licensed under a Creative Commons Attribut

Non-motor Parkinson's: The Hidden Face-Management and the Hidden Face of Related Disorders, Volume 134, the latest release in the International Review of Neurobiology series, is an up-to-date and comprehensive textbook addressing non-motor aspects of Parkinson's disease, a key unmet need. Specific chapters in this updated release include Therapeutics and NMS in PD, Non-motor effects of conventional and transdermal therapies in PD, Infusion therapy, CDD and NMS in PD, DBS and NMS in PD, TMS and implications for NMS in PD, Botulinum toxin therapy and NMS in PD, and Nutrition and NMS in PD, amongst others. Including practical tips for non-specialists and clinical algorithms, the book contains contributions from over 40 opinion leaders in the field of movement disorders. It provides practitioners and researchers with a laboratory, to bedside, to caregiver perspective. Presents a comprehensive textbook on the non motor aspects of Parkinson's disease Includes practical tips and clinical algorithms, and is the only textbook to bring a holistic approach Contains contributions from over 40 global opinion leaders in the field of movement disorders Provides special chapters on exercise, personalized medicine, osteoporosis, genetics, treatment aspects and nutrition

Non-motor Parkinson's: The Hidden Face, Volume 133, the first part of the latest volume in the International Review of Neurobiology series, is an up-to-date, comprehensive textbook addressing the non-motor aspects of Parkinson's disease, a key unmet need. Chapters in this new release include topics such as The hidden face of Parkinson's, JP and non-motor symptoms, Parkinson's: a complex non-motor disease, Neuropathology of NMS of PD, Neurophysiology and animal models related to NMS in PD, Epidemiology of NMS in PD (cohort studies), Genes and NMS in PD, NMS in genetic forms of PD, and Imaging the NMS in PD. Including practical tips for non-specialists and clinical algorithms, this book contains contributions from over 40 opinion leaders in the field of movement disorders, covering the topic from laboratory, to bedside, to caregiver. Presents a comprehensive textbook on the non motor aspects of Parkinson's disease Includes practical tips and clinical algorithms, and is the only textbook to bring a holistic approach Contains contributions from over 40 global opinion leaders in the field of movement disorders Provides special chapters on exercise, personalized medicine, osteoporosis, genetics, treatment aspects and nutrition

Background and purpose A composite instrument able to rapidly and reliably assess the most relevant motor and non-motor afflictions suffered by Parkinson’s disease (PD) patients in a real world clinic setting is an unmet need. The recently validated PD Composite Scale (PDCS) was designed to fulfil this gap as a quick, comprehensive PD assessment. The objective of this study was extensive evaluation of the PDCS’s clinimetric properties using a large international sample. Methods This was a cross-sectional study in which the PDCS, the Movement Disorder Society Unified Parkinson’s Disease Rating Scale and the Clinical Impression of Severity Index for PD were applied. Basic clinimetric attributes of the PDCS were analysed. Results In total, 776 PD patients were included. The PDCS total score showed negligible floor and ceiling effects. Three factors (54.5% of the variance) were identified: factor 1 included motor impairment, fluctuations and disability; factor 2, non-motor symptoms; and factor 3, tremor and complications of therapy. Cronbach’s alpha was from 0.66 to 0.79. Inter-rater reliability showed weighted kappa values from 0.79 to 0.98 for items and intraclass correlation coefficient values from 0.95 (Disability) to 0.99 (Motor and total score). The Bland-Altmann method, however, showed irregular concordance. PDCS standard error of measurement and convergent validity with equivalent constructs of other measures were satisfactory (>= 0.70). PDCS scores significantly differed by Hoehn and Yahr stage. Conclusion Overall, in line with previous findings, the PDCS is a feasible, acceptable, valid, reliable and precise instrument for quickly and comprehensively assessing PD patients.

Item does not contain fulltext, Parkinson's disease (PD) is the second commonest neurodegenerative disorder in the world with a rising prevalence. The pathophysiology is multifactorial but aggregation of misfolded alpha-synuclein is considered to be a key underpinning mechanism. Amyloid-beta (Abeta) and tau deposition are also comorbid associations and especially Abeta deposition is associated with cognitive decline in PD. Some existing evidence suggests that low cerebrospinal fluid (CSF) Abeta42 is predictive of future cognitive impairment in PD. Recent studies also show that CSF Abeta is associated with the postural instability and gait difficulties (PIGD) or the newly proposed cholinergic subtype of PD, a possible risk factor for cognitive decline in PD. The glial-lymphatic system, responsible for convective solute clearance driven by active fluid transport through aquaporin-4 water channels, may be implicated in brain amyloid deposition. A better understanding of the role of this system and more specifically the role of Abeta in PD symptomatology, could introduce new treatment and repurposing drug-based strategies. For instance, apomorphine infusion has been shown to promote the degradation of Abeta in rodent models. This is further supported in a post-mortem study in PD patients although clinical implications are unclear. In this review, we address the clinical implication of cerebral Abeta deposition in PD and elaborate on its metabolism, its role in cognition and motor function/gait, and finally assess the potential effect of apomorphine on Abeta deposition in PD.

Objective Real-life observational report of clinical efficacy of bilateral subthalamic stimulation (STN-DBS), apomorphine (APO), and intrajejunal levodopa infusion (IJLI) on quality of life, motor, and nonmotor symptoms (NMS) in Parkinson's disease (PD). Methods In this prospective, multicenter, international, real-life cohort observation study of 173 PD patients undergoing STN-DBS (n = 101), IJLI (n = 33), or APO (n = 39) were followed-up using PDQuestionnaire-8, NMSScale (NMSS), Unified PD Rating Scale (UPDRS)-III, UPDRS-IV, and levodopa equivalent daily dose (LEDD) before and 6 months after intervention. Outcome changes were analyzed with Wilcoxon signed-rank or paired t test when parametric tests were applicable. Multiple comparisons were corrected (multiple treatments/scales). Effect strengths were quantified with relative changes, effect size, and number needed to treat. Analyses were computed before and after propensity score matching, balancing demographic and clinical characteristics. Results In all groups, PDQuestionnaire-8, UPDRS-IV, and NMSS total scores improved significantly at follow-up. Levodopa equivalent daily dose was significantly reduced after STN-DBS. Explorative NMSS domain analyses resulted in distinct profiles: STN-DBS improved urinary/sexual functions, mood/cognition, sleep/fatigue, and the miscellaneous domain. IJLI improved the 3 latter domains and gastrointestinal symptoms. APO improved mood/cognition, perceptual problems/hallucinations, attention/memory, and the miscellaneous domain. Overall, STN-DBS and IJLI seemed favorable for NMSS total score, and APO favorable for neuropsychological/neuropsychiatric NMS and PDQuestionnaire-8 outcome. Conclusions This is the first comparison of quality of life, nonmotor. and motor outcomes in PD patients undergoing STN-DBS, IJLI, and APO in a real-life cohort. Distinct effect profiles were identified for each treatment option. Our results highlight the importance of holistic nonmotor and motor sympt

Streets and sidewalks are often read as mere targets of urban development schemes, rarely acknowledged for their importance to various forms of everyday life. Western notions of public space as designed green places of relief from urbanity, or as the imagined public plazas and agoras of civic discussions, are inadequate theoretical frames that cannot account for the sidewalk, the paan-shop, or the tea-stall, as sites of commensality, conviviality, and potential violence. Drawing on personal experience and a range of secondary literature an alternative way of thinking about the streets and re-imagining the national cultural space is proposed —less officious, less bureaucratic, less national—than has been allowed so far in considerations of good taste.

INTRODUCTION: This registry evaluated the 24-month safety and efficacy of levodopa-carbidopa intestinal gel (LCIG) treatment in advanced Parkinson's disease (PD) patients under routine clinical care. METHODS: Motor fluctuations, dyskinesia, non-motor symptoms, quality of life, and safety were evaluated. Observations were fully prospective for treatment-naïve patients (60% of patients) and partially retrospective for patients with ≤12 months of pre-treatment with LCIG (40% of patients). Hours of "On" and "Off" time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale part IV items 32 and 39. RESULTS: Overall, 375 patients were enrolled by 75 movement disorder centers in 18 countries and 258 patients completed the registry. At 24 months LCIG treatment led to significant reductions from baseline in "Off" time (hours/day) (mean ± SD = -4.1 ± 3.5, P < 0.001), "On" time with dyskinesia (hours/day) (-1.1 ± 4.8, P = 0.006), Non-Motor Symptom Scale total (-16.7 ± 43.2, P < 0.001) and individual domains scores, and Parkinson's Disease Questionnaire-8 item total score (-7.1 ± 21.0, P < 0.001). Adverse events deemed to have a possible/probable causal relationship to treatment drug/device were reported in 194 (54%) patients; the most frequently reported were decreased weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device issues (4.8%), and polyneuropathy (4.5%). CONCLUSIONS: LCIG treatment led to sustained improvements in motor fluctuations, non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal domains, as well as quality of life in advanced PD patients over 24 months. Safety events were consistent with the established safety profile of LCIG.

Parkinson's disease (PD) is now considered to be a multisystemic disorder consequent on multineuropeptide dysfunction including dopaminergic, serotonergic, cholinergic, and noradrenergic systems. This multipeptide dysfunction leads to expression of a range of non-motor symptoms now known to be integral to the concept of PD and preceding the diagnosis of motor PD. Some non-motor symptoms in PD may have a dopaminergic basis and in this review, we investigate the evidence for this based on imaging techniques using dopamine-based radioligands. To discuss non-motor symptoms we follow the classification as outlined by the validated PD non-motor symptoms scale.

A unique pilot project conducted in America's small and medium-sized cities shows that broad-based community coalitions can proactively integrate the newcomers who are increasingly transforming Main St., USA. In the first project of its kind, a consortium of leading organizations in three mid-sized metropolitan areas undertook inclusive community-building. The project's final report contains valuable findings for policymakers, funders and organizations collectively approaching the challenge of helping newcomers adapt to their new communities and local communities welcome newcomers.

Background: STN-DBS is well established to improve motor symptoms and quality of life in patients with PD. While non-motor symptoms are crucial for quality of life in these patients, only neuropsychiatric and neuropsychological symptoms have been systematically studied in a longitudinal design so far. However, these are only a part of the non-motor symptoms spectrum. Hypothesis: We hypothesized that STN-DBS is associated with a beneficial effect on a range of non-motor symptoms. Methods: In this multicenter, open, prospective, international study (EuroInf-study, UKCRN10084/ DRKS00006735) we investigated non-motor effects of STN-DBS in real-life use. We evaluated Nonmotor Symptom Scale, and Questionnaire, PD Questionnaire-8, Scales for Outcomes of PD motor examination and complications, and activities of daily living preoperatively and at 6 months follow-up in 60 consecutive patients (35 male, mean age: 61.6 +/- 7.8 years, mean disease duration: 10.4 +/- 4.2 years). Results: All outcomes improved significantly at 6 months follow-up (PD Questionaire-8, p = 0.006; activities of daily living, p = 0.012; all others, p < 0.001; Wilcoxon signed-rank, respectively paired t-test; Bonferroni-correction). Post-hoc analyses of Non-motor Symptom Scale domains showed a significant reduction of sleep/fatigue and miscellaneous domains (p = 0.001), perceptual problems/hallucinations (p = 0.036), and urinary (p = 0.018) scores. Effect sizes were moderate for Non-motor Symptom Scale, and motor complications, large for motor examination, and small for other outcomes.

Dysfunction of the gastrointestinal tract has now been recognized to affect all stages of Parkinson's disease (PD). The consequences lead to problems with absorption of oral medication, erratic treatment response, as well as silent aspiration, which is one of the key risk factors in developing pneumonia. The issue is further complicated by other gut abnormalities, such as small intestinal bacterial overgrowth (SIBO) and an altered gut microbiota, which occur in PD with variable frequency. Clinically, these gastrointestinal abnormalities might be associated with symptoms such as nausea, early-morning off, and frequent motor and non-motor fluctuations. Therefore, non-oral therapies that avoid the gastrointestinal system seem a rational option to overcome the problems of oral therapies in PD. Hence, several non-oral strategies have now been actively investigated and developed. The transdermal rotigotine patch, infusion therapies with apomorphine, intrajejunal levodopa, and the apomorphine pen strategy are currently in clinical use with a few others in development. In this review, we discuss and summarize the most recent developments in this field with a focus on non-oral dopaminergic strategies (excluding surgical interventions such as deep brain stimulation) in development or to be licensed for management of PD.

Filiació URV: SI, Aims: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. Methods and results: Early diagnosis ofHoFHand prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH.We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensiveACVDevaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta

Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinson's disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open-label, prospective, observational, 6-month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 +/- 10.6 years; disease duration: 14 +/- 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3-4) and 44 on IJLI (56.8% males, age 62.7 +/- 9.1 years; disease duration: 16.1 +/- 6.7 years; median H & Y stage 4; IQR, 3-4). Cohen's effect sizes (0.8 considered as large) were large with both therapies with respect to total motor, nonmotor, and quality-of-life scores. The Non-Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy-five percent on IJLI improved in their quality-of-life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open-label, nonrandomized, comparative study, we report that, in advanced Parkinson's patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality-of-life, and some NMS. Controlled, randomized studies are required. (c) 2014 International Parkinson and Movement Disorder Society

Background: Patients affected by progressive long-term neurological conditions might benefit from specialist palliative care involvement. However, little is known on how neurology and specialist palliative care services interact. This study aimed to map the current level of connections and integration between these services. Methods: The mapping exercise was conducted in eight centres with neurology and palliative care services in the United Kingdom. The data were provided by the respective neurology and specialist palliative care teams. Questions focused on: i) catchment and population served; ii) service provision and staffing; iii) integration and relationships. Results: Centres varied in size of catchment areas (39-5,840 square miles) and population served (142,000-3,500,000). Neurology and specialist palliative care were often not co-terminus. Service provisions for neurology and specialist palliative care were also varied. For example, neurology services varied in the number and type of provided clinics and palliative care services in the settings they work in. Integration was most developed in Motor Neuron Disease (MND), e.g., joint meetings were often held, followed by Parkinsonism (made up of Parkinson’s Disease (PD), Multiple-System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP), with integration being more developed for MSA and PSP) and least in Multiple Sclerosis (MS), e.g., most sites had no formal links. The number of neurology patients per annum receiving specialist palliative care reflected these differences in integration (range: 9–88 MND, 3–25 Parkinsonism, and 0–5 MS). Conclusions: This mapping exercise showed heterogeneity in service provision and integration between neurology and specialist palliative care services, which varied not only between sites but also between diseases. This highlights the need and opportunities for improved models of integration, which should be rigorously tested for effectiveness.

Background Fatigue is a common and disabling non-motor symptom (NMS) in Parkinson's disease (PD) patients. However, the effect of subthalamic nucleus (STN) deep brain stimulation (DBS) on fatigue has not been widely studied. Objective To determine the effect of STN DBS on fatigue in PD patients, measured by the Non-motor symptoms scale (NMSS). Methods Cross-sectional analysis of 50 patients with PD who underwent STN DBS at King's College Hospital and Salford Royal Hospital with fatigue scores (measured by question number 4 from domain 2 (sleep/fatigue) of the NMSS as the primary outcome measure. Secondary outcome measures included the PD Sleep Scale (PDSS), Scales for Outcome in PD (SCOPA)-motor examination, activities of daily living, motor complications, Hoehn and Yahr (HY) stage and changes in Levodopa Equivalent Daily Dose (LEDD). Results 50 patients with a mean follow-up period of 1.98 +/- 1.36 years were studied. Significant improvement in median fatigue scores (4.00 (0.75-9.00) to 1.00 (0.00-4.50); p = .001) was observed. In addition, improvements in question 5 (sleep maintenance and fragmentation; 8.00 (4.00-12.00) to 0.00 (0.00-4.00); p < .001) and in domain 2 total score (sleep/fatigue; 20.00 (8.75-27.25) to 6.00 (0.75-16.00); p < .001) were also significant, together with improvements in NMSS total score, SCOPA scores and HY stage (p <= .02). Moreover, LEDD but especially dopamine agonists LEDD was significantly reduced after DBS (310.00 (0.00-480.00) to 150.00 (0.00-300.00); p < .020). Conclusions Even though open label and not using a validated fatigue scale, this observational analysis suggest that fatigue improves significantly after STN DBS with persisting benefits at two years follow-up.

Non-motor symptoms (NMS) occur in patients with cervical dystonia (CD) but with variable frequencies and impact on health-related quality of life (HRQoL). To define non-motor and motor profiles and their respective impact on HRQoL in CD patients using the newly validated Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest). In an observational prospective multicentre case-control study, we enrolled 61 patients with CD and 61 age- and sex-matched healthy controls (HC) comparing demographic data, motor and non-motor symptoms and HRQoL measurements. 95% CD patients reported at least one NMS. Mean total NMS score was significantly higher in CD patients (5.62 +/- 3.33) than in HC (1.74 +/- 1.52; p < 0.001). Pain, insomnia and stigma were the most prevalent NMS and HRQoL was significantly impaired in CD patients compared to HC. There was strong correlation of NMS burden with HRQoL (CDQ-24: r = 0.72, EQ-5D: r = - 0.59; p < 0.001) in CD patients. Regression analysis between HRQoL and NMS suggested that emotional well-being (standardized beta = - 0.352) and pain (standardized beta = - 0.291) had a major impact on HRQoL while, in contrast motor severity had no significant impact in this model. Most NMS with the exception of pain, stigma and ADL did not correlate with motor severity. NMS are highly prevalent in CD patients and occur independent of age, sex, disease duration, duration of botulinum neurotoxin therapy and socio-economic status. Specific NMS such as emotional well-being and pain have a major impact on HRQoL and are more relevant than motor severity.

Non-motor symptoms (NMS) occur in patients with cervical dystonia (CD) but with variable frequencies and impact on health-related quality of life (HRQoL). To define non-motor and motor profiles and their respective impact on HRQoL in CD patients using the newly validated Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest). In an observational prospective multicentre case-control study, we enrolled 61 patients with CD and 61 age- and sex-matched healthy controls (HC) comparing demographic data, motor and non-motor symptoms and HRQoL measurements. 95% CD patients reported at least one NMS. Mean total NMS score was significantly higher in CD patients (5.62 +/- 3.33) than in HC (1.74 +/- 1.52; p < 0.001). Pain, insomnia and stigma were the most prevalent NMS and HRQoL was significantly impaired in CD patients compared to HC. There was strong correlation of NMS burden with HRQoL (CDQ-24: r = 0.72, EQ-5D: r = - 0.59; p < 0.001) in CD patients. Regression analysis between HRQoL and NMS suggested that emotional well-being (standardized beta = - 0.352) and pain (standardized beta = - 0.291) had a major impact on HRQoL while, in contrast motor severity had no significant impact in this model. Most NMS with the exception of pain, stigma and ADL did not correlate with motor severity. NMS are highly prevalent in CD patients and occur independent of age, sex, disease duration, duration of botulinum neurotoxin therapy and socio-economic status. Specific NMS such as emotional well-being and pain have a major impact on HRQoL and are more relevant than motor severity.

Background Fatigue is a common and disabling non-motor symptom (NMS) in Parkinson's disease (PD) patients. However, the effect of subthalamic nucleus (STN) deep brain stimulation (DBS) on fatigue has not been widely studied. Objective To determine the effect of STN DBS on fatigue in PD patients, measured by the Non-motor symptoms scale (NMSS). Methods Cross-sectional analysis of 50 patients with PD who underwent STN DBS at King's College Hospital and Salford Royal Hospital with fatigue scores (measured by question number 4 from domain 2 (sleep/fatigue) of the NMSS as the primary outcome measure. Secondary outcome measures included the PD Sleep Scale (PDSS), Scales for Outcome in PD (SCOPA)-motor examination, activities of daily living, motor complications, Hoehn and Yahr (HY) stage and changes in Levodopa Equivalent Daily Dose (LEDD). Results 50 patients with a mean follow-up period of 1.98 +/- 1.36 years were studied. Significant improvement in median fatigue scores (4.00 (0.75-9.00) to 1.00 (0.00-4.50); p = .001) was observed. In addition, improvements in question 5 (sleep maintenance and fragmentation; 8.00 (4.00-12.00) to 0.00 (0.00-4.00); p < .001) and in domain 2 total score (sleep/fatigue; 20.00 (8.75-27.25) to 6.00 (0.75-16.00); p < .001) were also significant, together with improvements in NMSS total score, SCOPA scores and HY stage (p <= .02). Moreover, LEDD but especially dopamine agonists LEDD was significantly reduced after DBS (310.00 (0.00-480.00) to 150.00 (0.00-300.00); p < .020). Conclusions Even though open label and not using a validated fatigue scale, this observational analysis suggest that fatigue improves significantly after STN DBS with persisting benefits at two years follow-up.