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Dopaminergic replacement therapy remains the mainstay of symptomatic treatment for Parkinson's disease (PD), but many unmet needs and gaps remain. Device-based treatments or device-aided non-oral therapies are typically used in the advanced stages of PD, ranging from stereotactic deep brain stimulation to levodopa or apomorphine infusion therapies. But there are concerns associated with these late-stage therapies due to a number of procedural, hardware, or long-term treatment-related side effects of these treatments, and their limited nonmotor benefit in PD. Therefore, there is an urgent unmet need for low-risk adjuvants or standalone therapies which can address the range of burdensome motor and nonmotor symptoms that occur in PD. Recent studies suggest that non-invasive neurostimulation of the vestibular system may be able to address these gaps through the stimulation of the vestibular brainstem sensory network which extensively innervates brain regions, regulating both motor and a range of nonmotor functions. Therapeutic non-invasive vestibular stimulation is a relatively modern concept that may potentially improve a broad range of motor and nonmotor symptoms of PD, even at early stages of the disease. Here, we review previous studies supporting the therapeutic potential of vestibular stimulation for the treatment of PD and discuss ongoing clinical trials and potential areas for future investigations. [ABSTRACT FROM AUTHOR]

The 5-2-1 criteria was developed to facilitate the identification and referral of patients with Parkinson's Disease (PD) inadequately controlled by oral medications. The criterion was not developed to screen patients with PD for device-aided therapy eligibility. The robust design and validation of the 5-2-1 criteria minimizes over or inappropriate referrals, and supports physicians in the timely identification of patients with PD who may warrant further evaluation for treatment optimization. This response letter clarifies concerns raised by Moes et al. [ABSTRACT FROM AUTHOR]

Background: Foslevodopa/foscarbidopa is a subcutaneous infusion of levodopa/carbidopa prodrugs. Objectives: Assess correlations between sleep and efficacy from interim data of a phase 3 trial of foslevodopa/foscarbidopa (NCT03781167). Methods: Pearson correlations between sleep (Parkinson's Disease Sleep Scale‐2 [PDSS‐2]) and quality of life (QoL; Parkinson's Disease Questionnaire‐39), motor experiences of daily living (m‐EDL; Movement Disorder Society‐Unified Parkinson's Disease Scale Part II), and "Off"/"On" times were calculated for baseline and week 26 improvements. Regression analyses were adjusted for baseline PDSS‐2 score. Results: Baseline sleep correlated moderately with QoL (r = 0.44, P < 0.001) and weakly with m‐EDL (r = 0.28; P < 0.001). Sleep improvement weakly correlated with improved "Off" time (r = 0.37; P < 0.001) and QoL (r = 0.36; P < 0.001). Regression analyses demonstrated significant positive associations for improved sleep, "Off" time, QoL, and m‐EDL. Conclusions: Improved sleep with foslevodopa/foscarbidopa was associated with improved QoL and "Off" time. [ABSTRACT FROM AUTHOR]

This article explores the challenges faced by Parkinson's disease (PD) patients in low and middle-income countries, particularly in India, where access to continuous levodopa delivery is limited. The current device-aided therapies for continuous drug delivery (CDD) are expensive and not readily available in underserved countries. The article suggests a four-level approach to address this issue, including extending the duration of levodopa's effects, improving its absorption and transportation, considering alternative therapies like Mucuna pruriens, and reducing the cost of delivery systems. The authors also emphasize the importance of diversity in PD research and healthcare to address existing inequalities. [Extracted from the article]

Oral levodopa is the gold-standard therapy for treating Parkinson's disease (PD) but after a few years of treatment the therapeutic window narrows, and patients often experience various treatment-related complications. Patients in this advanced PD stage may benefit from alternative therapy, such as continuous intrajejunal delivery of levodopa-carbidopa intestinal gel (LCIG; or carbidopa-levodopa enteral suspension), continuous intrajejunal delivery of levodopa-carbidopa-entacapone intestinal gel, or continuous subcutaneous apomorphine infusion. Consideration and initiation of infusion therapies in advanced PD are suggested before the onset of major disability. The present review summarizes clinical evidence for infusion therapy in advanced PD management, discusses available screening tools for advanced PD, and provides considerations around optimal use of infusion therapy. [ABSTRACT FROM AUTHOR]

Background: Levodopa-carbidopa intestinal gel (LCIG) improves motor and non-motor symptoms in patients with advanced Parkinson's disease (aPD). Objective: To present the final 36-month efficacy and safety results from DUOGLOBE (DUOdopa/Duopa in Patients with Advanced Parkinson's Disease – a GLobal OBservational Study Evaluating Long-Term Effectiveness; NCT02611713). Methods: DUOGLOBE was an international, prospective, long-term, real-world, observational study of patients with aPD initiating LCIG in routine clinical care. The primary endpoint was change in patient-reported "Off" time to Month 36. Safety was assessed by monitoring serious adverse events (SAEs). Results: Significant improvements in "Off" time were maintained over 3 years (mean [SD]: –3.3 hours [3.7]; p < 0.001). There were significant improvements to Month 36 in total scores of the Unified Dyskinesia Rating Scale (–5.9 [23.7]; p = 0.044), Non-Motor Symptoms Scale (–14.3 [40.5]; p = 0.002), Parkinson's Disease Sleep Scale-2 (–5.8 [12.9]; p < 0.001), and Epworth Sleepiness Scale (–1.8 [6.0]; p = 0.008). Health-related quality of life and caregiver burden significantly improved through Months 24 and 30, respectively (Month 24, 8-item Parkinson's Disease Questionnaire Summary Index, –6.0 [22.5]; p = 0.006; Month 30, Modified Caregiver Strain Index, –2.3 [7.6]; p = 0.026). Safety was consistent with the well-established LCIG profile (SAEs: 54.9% of patients; discontinuations: 54.4%; discontinuations due to an adverse event: 27.2%). Of 106 study discontinuations, 32 patients (30.2%) continued LCIG outside the study. Conclusion: DUOGLOBE demonstrates real-world, long-term, reductions in motor and non-motor symptoms in patients with aPD treated with LCIG. [ABSTRACT FROM AUTHOR]

Many advances in understanding the pathophysiology of Parkinson disease (PD) have been based on research addressing its motor symptoms and phenotypes. Various data-driven clinical phenotyping studies supported by neuropathological and in vivo neuroimaging data suggest the existence of distinct non-motor endophenotypes of PD even at diagnosis, a concept further strengthened by the predominantly non-motor spectrum of symptoms in prodromal PD. Preclinical and clinical studies support early dysfunction of noradrenergic transmission in both the CNS and peripheral nervous system circuits in patients with PD that results in a specific cluster of non-motor symptoms, including rapid eye movement sleep behaviour disorder, pain, anxiety and dysautonomia (particularly orthostatic hypotension and urinary dysfunction). Cluster analyses of large independent cohorts of patients with PD and phenotype-focused studies have confirmed the existence of a noradrenergic subtype of PD, which had been previously postulated but not fully characterized. This Review discusses the translational work that unravelled the clinical and neuropathological processes underpinning the noradrenergic PD subtype. Although some overlap with other PD subtypes is inevitable as the disease progresses, recognition of noradrenergic PD as a distinct early disease subtype represents an important advance towards the delivery of personalized medicine for patients with PD. Some patients with Parkinson disease (PD) present with mostly non-motor symptoms. Here, Chaudhuri et al. discuss the evidence for CNS abnormalities in noradrenergic function in these individuals. Recognition of this noradrenergic subtype of PD might ultimately lead to subtype-specific treatments and personalized medicine. Key points: Parkinson disease (PD) is a phenotypically heterogeneous, multisystem condition that affects the CNS and peripheral nervous system as well as multiple neurotransmitters, rather than a single 'disease'. PD can present at diagnosis with motor-predominant and non-motor-predominant symptoms. Neuropathological studies, neuroimaging findings and data from animal models suggest that PD with specific non-motor-predominant symptoms is driven by noradrenergic dysfunction in the CNS and peripheral nervous system. Cluster analyses and clinical phenotyping studies confirm the association between PD with specific non-motor-predominant symptoms and noradrenergic dysfunction. The noradrenergic phenotype of PD includes key features of rapid eye movement sleep behaviour disorder and dysautonomia (including orthostatic hypotension and/or urinary dysfunction), pain and anxiety. Formal identification of the noradrenergic phenotype as a clinical subtype of PD would help to define its natural history and promote the development of subtype-specific personalized treatment. [ABSTRACT FROM AUTHOR]

Slow earthquakes in the form of tremors and low frequency earthquakes (low‐frequency earthquakes) occur along the south‐central range of Taiwan (Aguiar et al., 2017, https://doi.org/10.1002/2016gl072148; Chao et al., 2012, https://doi.org/10.1111/j.1365-246x.2011.05261.x; Tang et al., 2010, https://doi.org/10.1029/2010gl043918). This study detects discrete very low frequency earthquakes (VLFEs) using a grid‐search moment tensor inversion algorithm (Ghosh et al., 2015, https://doi.org/10.1002/2015gl063286; Hutchison & Ghosh, 2019, https://doi.org/10.1029/2018jb016138). By applying a matched filtered technique, we have created a robust VLFE catalog for 3 years. The two VLFEs closer to the tremor‐producing region show a temporal relationship, but the western VLFE is the most active among the three. Our VLFE catalog of high temporal resolution allows us to identify a significant increase in VLFE activities preceding earthquake swarms. An empirical comparison of the VLFE catalog with regional and local cataloged fast earthquakes reveals two such instances. We show that fluid migration from deeper to shallower crust explains this modulation of regular fast earthquakes by VLFEs. Plain Language Summary: Slow earthquakes are an important part of a broad spectrum of the earthquake behavior. Yet, their underlying physics and connection to rest of the earthquake spectrum remain enigmatic. Taiwan is an area with complex geology hosting slow earthquakes. Still, their characteristics and relationship to other regular earthquakes are poorly understood. Using three years of high‐quality seismic data, we have identified and located three discrete events known as very low‐frequency earthquakes occurring deeper than the typical seismogenic zone in the earth crust. Our analyses show that these events modulate regular earthquakes in its vicinity. This relationship between the slow and fast earthquakes may be a result of fluid transfer from the deep to the shallow crust. Key Points: Discovery of Discrete very low frequency earthquakes (VLFEs) in the Central range of TaiwanVLFEs modulate Fast earthquakes in the areaFluid flow in the fault system can explain this observation [ABSTRACT FROM AUTHOR]

Background: In advanced Parkinson's disease (PD), dyskinesias and non-motor symptoms such as sleep dysfunction can significantly impair quality of life, and high-quality management is an unmet need. Objective: To analyze changes in dyskinesia and non-motor symptoms (including sleep) among studies with levodopa-carbidopa intestinal gel (LCIG) in patients with advanced PD. Methods: A comprehensive literature review identified relevant studies examining LCIG efficacy. Outcomes of interest were dyskinesia (UDysRS, UPDRS IV item 32), overall non-motor symptoms (NMSS), mentation/behavior/mood (UPDRS I), and sleep/daytime sleepiness (PDSS-2, ESS). The pooled mean (95% confidence interval) change from baseline per outcome was estimated for each 3-month interval with sufficient data (i.e., reported by≥3 studies) up to 24 months using a random-effects model. Results: Seventeen open-label studies evaluating 1243 patients with advanced PD were included. All outcomes of interest with sufficient data for meta-analysis showed statistically significant improvement within 6 months of starting LCIG. There were statistically significant improvements in dyskinesia duration as measured by UPDRS IV item 32 at 6 months (–1.10 [–1.69, –0.51] h/day) and 12 months (–1.35 [–2.07, –0.62] h/day). There were statistically and clinically significant improvements in non-motor symptoms as measured by NMSS scores at 3 months (–28.71 [–40.26, –17.15] points). Significant reduction of NMSS burden was maintained through 24 months (–17.61 [–21.52, –13.70] points). UPDRS I scores significantly improved at 3 months (–0.39 [–0.55, –0.22] points). Clinically significant improvements in PDSS-2 and ESS scores were observed at 6 and 12 months in individual studies. Conclusion: Patients with advanced PD receiving LCIG showed significant sustained improvements in the burden of dyskinesia and non-motor symptoms up to 24 months after initiation. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative condition presenting with different clinical endophenotypes. The parkinsonian variant of PSP (PSP‐P) is characterised by early but fading responsiveness to high‐dose levodopa therapy; however, high‐dose oral therapy is often associated with intolerance due to dopaminergic side effects and so doses may have to be capped despite clinical benefits. Evidence from animal models and real‐life registries suggest far higher doses of levodopa can be tolerated if given in a continuous drug delivery (CDD) manner. We investigated tolerance and possible clinical benefits in patients with PSP‐P still responsive to levodopa after initiating CDD in the form of intrajejunal levodopa infusion (IJLI) therapy as part of a compassionate usage program (CU). Methods: This is an observational clinical data report from the IJLI implementation program undertaken in regional tertiary referral Parkinson's centres in India and at King's College Hospital London, Dubai as part of a CU. Four patients with PSP‐P receiving IJLI as a part of a CU underwent evaluations of liver and renal function, motor and nonmotor function, quality of life, sleep dysfunction, fatigue, anxiety and depression, and cognitive impairment at baseline and 6 and 12 months post‐IJLI initiation. Results: In total, three out of four patients successfully completed 12 months of treatment (6 months in one patient). All four patients showed good tolerability to IJLI even at higher doses (1400 and 1960 mg at 6 and 12 months, respectively) when compared to oral levodopa (812.5 ± 103 levodopa equivalent daily dose [LEDD]) and presented with overall persistent improvements in motor and nonmotor scores and quality‐of‐life scores at 6 and 12 months post‐IJLI. All patients showed improvement in estimated glomerular filtration rate (43.50 ml/min/1.73 m2 to 67.5 ml/min/1.73 m2 and 79.5 ml/min/1.73 m2 at 6 and 12 months, respectively). Conclusions: IJLI led to persistent beneficial effects on motor and some nonmotor aspects in patients with PSP‐P at up to 12 months after treatment with associated improvement in overall renal function. [ABSTRACT FROM AUTHOR]

The trajectory of the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) is variable and doses may need to be increased, but also tapered. The plan for dose adjustment is usually done as per drug information recommendations from the licensing bodies, but there are no clear guidelines with regards to the best practice regarding the tapering off schedule given sudden dose reductions of drugs such as dopamine agonists may have serious adverse consequences. A systematic literature search was, therefore, performed to derive recommendations and the data show that there are no controlled studies or evidence-based recommendations how to taper or discontinue PD medication in a systematic manner. Most of the data were available on the dopamine agonist withdrawal syndrome (DAWS) and we found only two instructions on how to reduce pramipexole and rotigotine published by the EMA. We suggest that based on the available data, levodopa, dopamine agonists (DA), and amantadine should not be discontinued abruptly. Abrupt or sudden reduction of DA or amantadine in particular can lead to severe life-threatening withdrawal symptoms. Tapering off levodopa, COMT inhibitors, and MAO-B inhibitors may worsen motor and non-motor symptoms. Based on our clinical experience, we have proposed how to reduce PD medication and this work will form the basis of a future Delphi panel to define the recommendations in a consensus. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease is a progressive neurodegenerative disease, which significantly impacts patients' quality of life and is associated with high treatment and direct healthcare costs. In England, levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of levodopa-responsive advanced Parkinson's disease with troublesome motor fluctuations when available combinations of medicinal products are unsatisfactory.Objective: We aimed to determine the cost effectiveness of LCIG compared to the standard of care for patients with advanced Parkinson's disease in England, using real-world data.Methods: A Markov model was adapted from previous published studies, using the perspective of the English National Health System and Personal and Social Services to evaluate the cost effectiveness of LCIG compared to standard of care in patients with advanced Parkinson's disease over a 20-year time horizon. The model comprised 25 health states, defined by a combination of the Hoehn and Yahr scale, and waking time spent in OFF-time. The base case considered an initial cohort of patients with an Hoehn and Yahr score of ≥ 3, and > 4 h OFF-time. Standard of care comprised standard oral therapies, and a proportion of patients were assumed to be treated with subcutaneous apomorphine infusion or injection in addition to oral therapies. Efficacy inputs were based on LCIG clinical trials where possible. Resource use and utility values were based on results of a large-scale observational study, and costs were derived from the latest published UK data, valued at 2017 prices. The EuroQol five-dimensions-3-level (EQ-5D-3L) instrument was used to measure utilities. Costs and quality-adjusted life-years were discounted at 3.5%. Both deterministic and probabilistic sensitivity analyses were conducted.Results: Total costs and quality-adjusted life-years gained for LCIG vs standard of care were £586,832 vs £554,022, and 2.82 vs 1.43, respectively. The incremental cost-effectiveness ratio for LCIG compared to standard of care was £23,649/quality-adjusted life-year. Results were sensitive to the healthcare resource utilisation based on real-world data, and long-term efficacy of LCIG.Conclusions: The base-case incremental cost-effectiveness ratio was estimated to be within the acceptable thresholds for cost effectiveness considered for England. [ABSTRACT FROM AUTHOR]

Background: Optimisation of dopaminergic therapy may alleviate fluctuation-related pain in Parkinson's disease (PD). Opicapone (OPC) is a third-generation, once-daily catechol-O-methyltransferase inhibitor shown to be generally well tolerated and efficacious in reducing OFF-time in two pivotal trials in patients with PD and end-of-dose motor fluctuations. The OpiCapone Effect on motor fluctuations and pAiN (OCEAN) trial aims to investigate the efficacy of OPC 50 mg in PD patients with end-of-dose motor fluctuations and associated pain, when administered as adjunctive therapy to existing treatment with levodopa/dopa decarboxylase inhibitor (DDCi).Methods: OCEAN is a Phase IV, international, multicentre, randomised, double-blind, placebo-controlled, parallel-group, interventional trial in PD patients with end-of-dose motor fluctuations and associated pain. It consists of a 1-week screening period, 24-week double-blind treatment period and 2-week follow-up period. Eligible patients will be randomised 1:1 to OPC 50 mg or placebo once daily while continuing current treatment with levodopa/DDCi and other chronic, stable anti-PD and/or analgesic treatments. The primary efficacy endpoint is change from baseline in Domain 3 (fluctuation-related pain) of the King's Parkinson's disease Pain Scale (KPPS). The key secondary efficacy endpoint is change from baseline in Domain B (anxiety) of the Movement Disorder Society-sponsored Non-Motor rating Scale (MDS-NMS). Additional secondary efficacy assessments include other domains and total scores of the KPPS and MDS-NMS, the Parkinson's Disease Questionnaire (PDQ-8), the MDS-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts III and IV, Clinical and Patient's Global Impressions of Change, and change in functional status via Hauser's diary. Safety assessments include the incidence of treatment-emergent adverse events. The study will be conducted in approximately 140 patients from 50 clinical sites in Germany, Italy, Portugal, Spain and the United Kingdom. Recruitment started in February 2021 and the last patient is expected to complete the study by late 2022.Discussion: The OCEAN trial will help determine whether the use of adjunctive OPC 50 mg treatment can improve fluctuation-associated pain in PD patients with end-of-dose motor fluctuations. The robust design of OCEAN will address the current lack of reliable evidence for dopaminergic-based therapy in the treatment of PD-associated pain.Trial Registration: EudraCT number 2020-001175-32 ; registered on 2020-08-07. [ABSTRACT FROM AUTHOR]

• Probiotics reduce markers of peripheral inflammation in PD. • Preclinical evidence suggests neuroprotective properties of probiotics in PD. • Probiotics activate the GLP-1 and PPAR-γ pathway in PD. • Future research should further explore the effects of probiotics on neuropsychiatric aspects of PD. There is increasing evidence highlighting the potential role of the gut-brain axis in the pathogenesis of Parkinson's disease (PD) and on the use of probiotics as a therapeutic strategy for this neurodegenerative disorder. While several studies have been published on the topic in recent years, there is still a lack of a comprehensive understanding of the effects of probiotics in PD and their possible underlying mechanisms. Through this systematic review, we collected a total of 17 articles, consisting of preclinical and clinical models of PD investigating the effect of probiotics on (1) energy metabolism, (2) inflammation and oxidative stress, (3) neurodegeneration, as well as (4) motor and (5) non-motor function. Articles were obtained from PubMed/Medline, Scopus, Web of Science and Embase databases. Findings from preclinical studies suggest that treatment with probiotics increases glucose metabolism (increased secretion of glucagon-like peptide-1), reduces peripheral and central inflammation (reduced interleukin-6 and tumor necrosis factor-α (TNF-α)), reduces peripheral and central oxidative stress (reduced peripheral superoxide anion levels and increased central antioxidant glutathione levels), decreases neurodegeneration (increased numbers of tyrosine hydroxylase dopaminergic neurons and levels of brain-derived neurotrophic factor), increases motor function (increased motor agility) and non-motor function (decreased memory deficits). Similarly, findings from clinical studies suggest that probiotics increase glucose metabolism (reduced insulin resistance), reduce peripheral inflammation (reduced peripheral TNF-α expression and C-reactive protein levels), and increase motor and non-motor function (decreased overall PD symptomatology and constipation); however, findings on oxidative stress were inconclusive across studies. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of probiotics on molecular and cellular mechanisms, as well as behavioural phenotypes, in either preclinical or clinical studies in PD. However, additional and more robust studies are still needed to confirm these outcomes, and should aim to focus more on bench-to-bedside approaches, in order to address the existing gaps between preclinical and clinical findings in this field. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Compared to other neurodegenerative diseases, Parkinson's disease (PD) is distinctive in terms of marked symptomatic variability and prognosis, as well as for the wide variety of symptomatic treatment options. Despite several decades of advances in medications and neurosurgical approaches, there remains an unmet need for symptomatic motor control. Better control of tremor, gait and balance, posture, dexterity, and communication skills are major challenges for better therapeutics of the PD movement disorder. Non-motor symptoms (NMS), which often precede motor impairments, add complexity to the burden of PD and its management. Recognized by James Parkinson MD two centuries ago, and despite 21st century neurological advances, a range of NMS plague the patient's journey, from prodromal to palliative stages. Characterizing the clinical phenotype of the entire non-motor profile of PD is challenging. Further research and understanding are needed for discovering biomarkers of certain NMS, such as dementia, fatigue, pain, sleep, and apathy. More work is needed to gather a robust evidence base for guiding treatment of troubling NMS, which exert a major impact on quality of life for people with PD and their caregivers. [ABSTRACT FROM AUTHOR]

Levodopa is the most effective drug for the treatment of Parkinson's disease, but its use as an oral medication is complicated by its erratic absorption, extensive metabolism and short plasma half-life. On long-term use and with disease progression, there is a high incidence of motor and non-motor complications, which remain a major clinical and research challenge. It is widely accepted that levodopa needs to be administered using formulations that result in good and consistent bioavailability and the physiologically relevant and continuous formation of dopamine in the brain to maximise its efficacy while avoiding and reversing 'wearing off' and dyskinesia. However, the physicochemical properties of levodopa along with its pharmacokinetic and pharmacodynamic profile make it difficult to deliver the drug in a manner that fulfils these criteria. In this review, we examine the problems associated with the administration of levodopa in Parkinson's disease and how the use of novel technologies and delivery devices is leading to a more consistent and sustained levodopa delivery with the aim of controlling motor function as well as non-motor symptoms. [ABSTRACT FROM AUTHOR]

Fine-motor impairment (FMI) is progressively expressed in early Parkinson's Disease (PD) patients and is now known to be evident in the immediate prodromal stage of the condition. The clinical techniques for detecting FMI may not be robust enough and here, we show that the subtle FMI of early PD patients can be effectively estimated from the analysis of natural smartphone touchscreen typing via deep learning networks, trained in stages of initialization and fine-tuning. In a validation dataset of 36,000 typing sessions from 39 subjects (17 healthy/22 PD patients with medically validated UPDRS Part III single-item scores), the proposed approach achieved values of area under the receiver operating characteristic curve (AUC) of 0.89 (95% confidence interval: 0.80–0.96) with sensitivity/specificity: 0.90/0.83. The derived estimations result in statistically significant ( p < 0.05 ) correlation of 0.66/0.73/0.58 with the clinical standard UPDRS Part III items 22/23/31, respectively. Further validation analysis on 9 de novo PD patients vs. 17 healthy controls classification resulted in AUC of 0.97 (0.93–1.00) with 0.93/0.90. For 253 remote study participants, with self-reported health status providing 252.000 typing sessions via a touchscreen typing data acquisition mobile app (iPrognosis), the proposed approach predicted 0.79 AUC (0.66–0.91) with 0.76/0.71. Remote and unobtrusive screening of subtle FMI via natural smartphone usage, may assist in consolidating early and accurate diagnosis of PD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The Movement Disorder Society-sponsored Nonmotor Rating Scale is an update of the existing Parkinson's disease Nonmotor Symptoms Scale modified to address some limitations in Nonmotor Symptoms Scale scoring, structure, and symptom coverage.Methods: PD patients were recruited from movement disorder centers in an international, multicenter study. The Movement Disorder Society Nonmotor Rating Scale, consisting of 13 domains plus a subscale for nonmotor fluctuations, was rater administered, along with the Nonmotor Symptoms Scale and other clinical assessments. Standard reliability and validity testing were conducted.Results: Four hundred and two PD patients were recruited (mean age ± standard deviation, 67.42 ± 9.96 years; mean age at PD onset ± standard deviation, 59.27 ± 10.67 years; median Hoehn and Yahr stage 2 (interquartile range 2-3). Data quality was satisfactory for all Movement Disorder Society Nonmotor Rating Scale domains except sexual (6.7% missing data). There were no floor or ceiling effects for the Movement Disorder Society Nonmotor Rating Scale and nonmotor fluctuations total score; domains had no ceiling effects, but some floor effects (13.5%-83.5%). The Movement Disorder Society Nonmotor Rating Scale and nonmotor fluctuations total score internal consistency were acceptable (average Cronbach's alpha, 0.66 and 0.84, respectively); interrater reliability was excellent (intraclass correlation coefficient, >0.95); for test-retest reliability, the intraclass correlation coefficient was 0.84 for the Movement Disorder Society Nonmotor Rating Scale and 0.70 for Movement Disorder Society nonmotor fluctuations total score, and precision was excellent for the Movement Disorder Society Nonmotor Rating Scale (standard error of measurement, 25.30) and fair for nonmotor fluctuations (standard error of measurement, 7.06). Correlations between Movement Disorder Society Nonmotor Rating Scale score and the corresponding Nonmotor Symptoms Scale and Movement Disorder Society UPDRS scores were high. There were no significant sex or age effects. The Movement Disorder Society Nonmotor Rating Scale score increased with increasing PD duration, disease severity, and PD medication dose (all P < 0.001).Conclusions: The Movement Disorder Society Nonmotor Rating Scale is a valid measure for measuring the burden of a wide range of Nonmotor Rating Scale scores, including nonmotor fluctuations, in PD patients. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective: To update evidence-based medicine recommendations for treating nonmotor symptoms in Parkinson's disease (PD).Background: The International Parkinson and Movement Disorder Society Evidence-Based Medicine Committee's recommendations for treatments of PD were first published in 2002, updated in 2011, and now updated again through December 31, 2016.Methods: Level I studies testing pharmacological, surgical, or nonpharmacological interventions for the treatment of nonmotor symptoms in PD were reviewed. Criteria for inclusion and quality scoring were as previously reported. The disorders covered were a range of neuropsychiatric symptoms, autonomic dysfunction, disorders of sleep and wakefulness, pain, fatigue, impaired olfaction, and ophthalmologic dysfunction. Clinical efficacy, implications for clinical practice, and safety conclusions are reported.Results: A total of 37 new studies qualified for review. There were no randomized controlled trials that met inclusion criteria for the treatment of anxiety disorders, rapid eye movement sleep behavior disorder, excessive sweating, impaired olfaction, or ophthalmologic dysfunction. We identified clinically useful or possibly useful interventions for the treatment of depression, apathy, impulse control and related disorders, dementia, psychosis, insomnia, daytime sleepiness, drooling, orthostatic hypotension, gastrointestinal dysfunction, urinary dysfunction, erectile dysfunction, fatigue, and pain. There were no clinically useful interventions identified to treat non-dementia-level cognitive impairment.Conclusions: The evidence base for treating a range of nonmotor symptoms in PD has grown substantially in recent years. However, treatment options overall remain limited given the high prevalence and adverse impact of these disorders, so the development and testing of new treatments for nonmotor symptoms in PD remains a top priority. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Ascending pathology affects pontine structures which may express premotor features of Parkinson disease, such as rapid eye movement (REM) sleep behavior disorder (RBD). Keywords: Dysautonomia; parkinson disease; Nonmotor; Nonmotor subtypes; Endophenotypes; Splanchnic; Personalized medicine EN Dysautonomia; parkinson disease Nonmotor Nonmotor subtypes Endophenotypes Splanchnic Personalized medicine 37 39 3 03/04/21 20210201 NES 210201 I congratulate I Clinical Autonomic Research i on its thirtieth anniversary. Autonomic function is an essential constituent of the newly developed holistic tools for bedside assessment of non-motor symptoms in Parkinson disease, such as the SCOPA-Autonomic and MDS-NMS scales, the latter being based on the Parkinson disease non-motor symptom scale (NMSS) [[3]]. The NMSS has been widely used worldwide for the global assessment of non-motor symptoms in epidemiological, clinical, and clinical trial-based research in Parkinson disease and has highlighted the important role of the autonomic domains ranging from gastrointestinal to cardiac in the clinical assessment of Parkinson disease. [Extracted from the article]

Purpose: The experience of working for people with Parkinson’s disease (PD) is known to vary substantially and affects the length of time in employment after diagnosis. This study aims at exploring the experience of working for people with PD and to create a model detailing the factors that influence their workplace success. Method: A qualitative grounded theoretical approach was used. Seventeen working people with PD were selected for individual interviews which were conducted sequentially. Data were analyzed in an iterative, inductive process of coding to identify common themes and to generate a model that explains the data. Results: Two core themes that influence workplace success for people with PD were identified. ‘Feeling in control of Parkinson’s’ describes the actions that they make to remain in control. ‘Being able to control Parkinson’s in the workplace’ describes external factors that they believe influence their ability to work successfully. Conclusions: The theoretical model demonstrates how a variety of factors interplay to influence workplace success for people with PD. PD is often poorly understood but the ability to explore and devise strategies for oneself and the flexibility to work around a fluctuating daily pattern were regularly identified as strategies that facilitated success. Implications for Rehabilitation: The experience of working for people with Parkinson’s is variable and is influenced by how in control the person with Parkinson’s feels and the strategies they use to manage challenges. There is a need for greater workplace education to enhance employers’ understanding of Parkinson’s to ensure better support for strategies or reasonable adjustments by employers. People with Parkinson’s are able to devise strategies to overcome some of their own specific workplace challenges including through technology but often, they prefer not to use disability aids. Daily fluctuations in Parkinson’s symptoms are an important factor influencing workplace success. [ABSTRACT FROM AUTHOR]

Despite enormous advances in our current understanding of PD since James Parkinson described the "shaking palsy" 200 years ago, l-dopa, in clinical use since the 1960s, remains the gold standard of treatment. Virtually every patient with PD requires varying doses of l-dopa to manage motor and some nonmotor symptoms and retain an acceptable quality of life. However, after a period of treatment with l-dopa, a number of problems emerge; the key ones are motor and nonmotor fluctuations, a range of dyskinesias, and a combination of both. Nonmotor complications can range from behavioral problems to sensory, autonomic, and cognitive issues. Even with a wealth of data, both in animal models and in vivo imaging that address the pathophysiology of l-dopa-related motor and nonmotor complications, the treatment remains challenging and is an unmet need. Although refinement in types of dopamine replacement therapy and delivery systems have improved the management of l-dopa-related complications, the search for the ideal treatment continues. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is not a single disease, and is characterized by a constellation of motor and non-motor symptoms (NMS) with a heterogeneity of pathology, genetic basis and clinical presentation. The clinical phenotypic presentations have been further developed to clinically identify non-motor subtypes or endophenotypes of PD based on specific central neurotransmitter dysfunctions and historical neuropathological data. The successful and complete modern management of PD also includes the care of several "vitals" of PD, consisting of (1) motor symptoms, (2) NMS, (3) vision and oral and gut health, (4) bone health and falls and (5) comorbidities, co-medications and impulse control disorders. Collectively, these domains are rarely assessed in clinics, as there is often a time constraint in busy settings. A recent international survey, assessing the recognition and use of the vitals, showed marked gaps in assessments. A dashboard based on international collaboration and the above-mentioned domains was recently published to help identify the key vitals that should not be overlooked in clinical practice. The vitals dashboard enriches and ensures PD care is complete at all levels, forming the basis of the stepped-care paradigm proposed in this article. [ABSTRACT FROM AUTHOR]

Emerging concepts suggest that a multitude of pathology ranging from misfolding of alpha-synuclein to neuroinflammation, mitochondrial dysfunction, and neurotransmitter driven alteration of brain neuronal networks lead to a syndrome that is commonly known as Parkinson's disease. The complex underlying pathology which may involve degeneration of non-dopaminergic pathways leads to the expression of a range of non-motor symptoms from the prodromal stage of Parkinson's to the palliative stage. Non-motor clinical subtypes, cognitive and non-cognitive, have now been proposed paving the way for possible subtype specific and non-motor treatments, a key unmet need currently. Natural history of these subtypes remains unclear and need to be defined. In addition to in vivo biomarkers which suggest variable involvement of the cholinergic and noradrenergic patterns of the Parkinson syndrome, abnormal alpha-synuclein accumulation have now been demonstrated in the gut, pancreas, heart, salivary glands, and skin suggesting that Parkinson's is a multi-organ disorder. The Parkinson's phenotype is thus not just a dopaminergic motor syndrome, but a dysfunctional multi-neurotransmitter pathway driven central and peripheral nervous system disorder that possibly ought to be considered a syndrome and not a disease. [ABSTRACT FROM AUTHOR]

Background and purpose Dopamine agonists in Parkinson's disease ( PD) are associated with impulse control disorders ( ICDs) and other compulsive behaviours (together called ICD behaviours). The frequency of ICD behaviours reported as adverse events ( AEs) in long-term studies of rotigotine transdermal patch in PD was evaluated. Methods This was a post hoc analysis of six open-label extension studies up to 6 years in duration. Analyses included patients treated with rotigotine for at least 6 months and administered the modified Minnesota Impulse Disorders Interview. ICD behaviours reported as AEs were identified and categorized. Results For 786 patients, the mean (± SD) exposure to rotigotine was 49.4 ± 17.6 months. 71 (9.0%) patients reported 106 ICD AEs cumulatively. Occurrence was similar across categories: 2.5% patients reported 'compulsive sexual behaviour', 2.3% 'buying disorder', 2.0% 'compulsive gambling', 1.7% 'compulsive eating' and 1.7% 'punding behaviour'. Examining at 6-month intervals, the incidence was relatively low during the first 30 months; it was higher over the next 30 months, peaking in the 54-60-month period. No ICD AEs were serious, and 97% were mild or moderate in intensity. Study discontinuation occurred in seven (9.9%) patients with ICD AEs; these then resolved in five patients. Dose reduction occurred for 23 AEs, with the majority (73.9%) resolving. Conclusions In this analysis of >750 patients with PD treated with rotigotine, the frequency of ICD behaviour AEs was 9.0%, with a specific incidence timeline observed. Active surveillance as duration of treatment increases may help early identification and management; once ICD behaviours are present rotigotine dose reduction may be considered. [ABSTRACT FROM AUTHOR]

Parkinson's disease is highly heterogeneous in early clinical features and later outcomes. This makes classifying subgroups of PD relevant to clinical research and practice, particularly if they are prognostically relevant. Subgroups have been defined both on the basis of motor and nonmotor features, and subgroups have been determined either empirically, based on clinical observation, or using data-driven analytic techniques. Previous studies have examined both the overall number and the nature of nonmotor symptoms and signs in tremor-dominant compared with non-tremor-dominant subtypes, and longitudinal studies identify nonmotor symptoms as important markers of prognosis and important defining features of PD subtypes. Autonomic features seem to preferentially affect individuals with non-tremor-dominant PD subtype early in the disease. Later in the disease cognitive disturbance distinguishes this phenotype. Pathological and neuroimaging studies provide substantial evidence for fundamental biological differences between tremor-dominant and postural instability gait disorder/akinetic-rigid subtypes. Biomarker studies point toward non-tremor-dominant PD as representing more advanced and diffuse neurodegeneration than tremor-dominant PD, encompassing dopaminergic and nondopaminergic as well as synuclein and nonsynuclein (Abeta) pathologies. This aligns with clinical studies that find a higher burden of nonmotor symptoms in non-tremor-dominant PD. The mounting evidence for the relevance of nonmotor features in PD subtypes behooves us to begin to investigate the biological underpinnings of subtypes defined by both motor and nonmotor features. This may be challenging, as PD subtypes are unlikely to be distinct nonoverlapping entities but are more likely to represent typical phenotypes within a multidimensional spectrum resulting from variable contributions of a number of simultaneous pathological processes. © 2016 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Pain is a common non-motor symptom of Parkinson's disease. We investigated the analgesic efficacy of prolonged-release oxycodone-naloxone (OXN PR) in patients with Parkinson's disease and chronic, severe pain.Methods: We did this phase 2 study in 47 secondary care centres in the Czech Republic, Germany, Hungary, Poland, Romania, Spain, and the UK. We enrolled patients with Hoehn and Yahr Stage II-IV Parkinson's disease, at least one type of severe pain, and an average 24-h pain score of at least 6 (assessed on an 11-point rating scale from 0=no pain to 10=pain as bad as you can imagine). Participants were randomly assigned (1:1) with a validated automated system (block size four) to either oral OXN PR or placebo for 16 weeks (starting dose oxycodone 5 mg, naloxone 2·5 mg, twice daily). Patients and investigators were masked to treatment assignment. The primary endpoint was average 24-h pain score at 16 weeks in the full analysis population. This study is registered with EudraCT (2011-002901-31) and ClinicalTrials.gov (NCT01439100).Findings: We enrolled 202 patients; 93 were assigned to OXN PR and 109 to placebo; the full analysis population consisted of 88 patients versus 106 patients. Least squares mean average 24-h pain score at 16 weeks in the full analysis population was 5·0 (95% CI 4·5 to 5·5) in the OXN PR group versus 5·6 (5·1 to 6·0) in the placebo group (difference -0·6, 95% CI -1·3 to 0·0; p=0·058). Similar proportions of patients in each group had adverse events (60/92 [65%] vs 76/109 [70%]), treatment-related adverse events (52/92 [57%] vs 62/109 [57%]), and serious adverse events (5/92 [5%] vs 7/109 [6%]). Treatment-related nausea was more common in the OXN PR group than in the placebo group (16/92 [17%] vs 10/109 [9%]), as was treatment-related constipation (16/92 [17%] vs 6/109 [6%]).Interpretation: The primary endpoint, based on the full analysis population at week 16, was not significant. Nonetheless, the results of this study highlight the potential efficacy of OXN PR for patients with Parkinson's disease-related pain and might warrant further research on OXN PR in this setting.Funding: Mundipharma Research. [ABSTRACT FROM AUTHOR]

Pain is a key unmet need and a major aspect of non-motor symptoms of Parkinson's disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross-sectional, open, multicenter, one-point-in-time evaluation with retest study of the first PD-specific pain scale, the King's PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy-eight PD patients with otherwise unexplained pain (age [mean ± SD], 64.38 ± 11.38 y [range, 29-85]; 62.92% male; duration of disease, 5.40 ± 4.93 y) and 83 nonspousal non-PD controls, matched by age (64.25 ± 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median King's PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the King's PD Pain Scale, explaining 57% of the variance (Kaiser-Mayer-Olkin, 0.73; sphericity test). Cronbach's alpha was 0.78, item-total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the King's PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD-Motor, Non-Motor Symptoms Scale total score, and quality of life measures was high. The King's PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD. [ABSTRACT FROM AUTHOR]

Navigate PD was an educational program established to supplement existing guidelines and provide recommendations on the management of Parkinson's disease (PD) refractory to oral/transdermal therapies. It involved 103 experts from 13 countries overseen by an International Steering Committee (ISC) of 13 movement disorder specialists. The ISC identified 71 clinical questions important for device-aided management of PD. Fifty-six experts responded to a web-based survey, rating 15 questions as 'critically important;' these were refined to 10 questions by the ISC to be addressed through available evidence and expert opinion. Draft guidance was presented at international/national meetings and revised based on feedback. Key take-home points are: • Patients requiring levodopa >5 times daily who have severe, troublesome 'off' periods (>1-2 h/day) despite optimal oral/transdermal levodopa or non-levodopa-based therapies should be referred for specialist assessment even if disease duration is <4 years. • Cognitive decline related to non-motor fluctuations is an indication for device-aided therapies. If cognitive impairment is mild, use deep brain stimulation (DBS) with caution. For patients who have cognitive impairment or dementia, intrajejunal levodopa infusion is considered as both therapeutic and palliative in some countries. Falls are linked to cognitive decline and are likely to become more frequent with device-aided therapies. • Insufficient control of motor complications (or drug-resistant tremor in the case of DBS) are indications for device-aided therapies. Levodopa-carbidopa intestinal gel infusions or subcutaneous apomorphine pump may be considered for patients aged >70 years who have mild or moderate cognitive impairment, severe depression or other contraindications to DBS. [ABSTRACT FROM AUTHOR]

Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical practice. This document outlines best-practice recommendations for selecting appropriate candidates for apomorphine intermittent injection (the pen-injection formulation) or apomorphine continuous infusion (the pump formulation), for initiating patients onto therapy and for managing their ongoing treatment. Apomorphine is a suitable therapeutic option for PD patients who experience troublesome ‘off’ periods despite optimized treatment with oral PD medications. Due to its speed of onset, apomorphine injection is particularly suited to those patients requiring rapid, reliable relief of both unpredictable and predictable ‘off’ periods, those who require reliable and fast relief when anticipating an ‘off’, those with levodopa absorption or gastric emptying problems resulting in delayed or failed ‘on’, or for rapid relief of early morning dystonia or akinesia. Apomorphine infusion 1 is suited for patients whose ‘off’ periods can no longer be adequately controlled by standard oral PD treatment or for those in whom rescue doses of apomorphine injection are effective but either needed too frequently (more than 4–6 times per day), or are associated with increasing dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine infusion may be effective for the management of specific non-motor symptoms of PD associated with ‘off’ periods. Apomorphine infusion is less invasive than other non-oral treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain stimulation. [ABSTRACT FROM AUTHOR]

Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical practice. This document outlines best-practice recommendations for selecting appropriate candidates for apomorphine intermittent injection (the pen-injection formulation) or apomorphine continuous infusion (the pump formulation), for initiating patients onto therapy and for managing their ongoing treatment. Apomorphine is a suitable therapeutic option for PD patients who experience troublesome 'off' periods despite optimized treatment with oral PD medications. Due to its speed of onset, apomorphine injection is particularly suited to those patients requiring rapid, reliable relief of both unpredictable and predictable 'off' periods, those who require reliable and fast relief when anticipating an 'off', those with levodopa absorption or gastric emptying problems resulting in delayed or failed 'on', or for rapid relief of early morning dystonia or akinesia. Apomorphine infusion(1) is suited for patients whose 'off' periods can no longer be adequately controlled by standard oral PD treatment or for those in whom rescue doses of apomorphine injection are effective but either needed too frequently (more than 4-6 times per day), or are associated with increasing dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine infusion may be effective for the management of specific non-motor symptoms of PD associated with 'off' periods. Apomorphine infusion is less invasive than other non-oral treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain stimulation. [ABSTRACT FROM AUTHOR]

Background Non-motor symptoms (NMS) of Parkinson's disease (PD) affect virtually every patient, yet they are under-recognized and under-treated. The NMS Questionnaire (NMSQuest) is a validated 30-item self-assessment instrument useful for NMS screening in clinic. Objective Development of a straight forward grading classification of the burden of non-motor symptoms in PD based on the number of NMS as assessed by the NMS Questionnaire. Methods In an observational, cross-sectional, international study of 383 consecutive patients distribution of the declared NMS as per NMSQuest was analyzed according to previously published levels based on the Non-Motor Symptoms Scale and also the median and interquartile range (IR, percentiles 25 and 75) of the total NMSQuest scores. After post hoc checking, these values were proposed as cut-off points for estimating NMS burden based only on the accumulation of symptoms. Results Burden and number of NMS correlate closely (r ≥ 0.80). On the basis of this finding, five levels (0 = No NMS to 4 = Very severe) of NMSQuest grading were proposed after identification of their cut-offs by ordinal logistic regression and median and interquartile range distribution. These values coincided almost completely with those obtained by median and interquartile range in an independent sample. Concordance between this classification and HY staging was weak (weighted kappa = 0.30), but was substantial (weighted kappa = 0.68) with the Non-Motor Symptoms Scale grading. Conclusion Completion of NMSQuest and subsequent grading of the burden could allow the health care professional to approach the severity of NMS burden using the self completed NMSQuest in a primary care setting. [ABSTRACT FROM AUTHOR]

Background and purpose Although Parkinson's disease (PD) is characterized by typical motor manifestations, non-motor symptoms (NMS) are an outstanding part of the disease. At present, several specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part I - Non-Motor Aspects of Experiences of Daily Living (nM-EDL) compared with the Non-Motor Symptoms Scale (NMSS). Methods To this purpose, 434 consecutive patients with PD were included in an international, observational, cross-sectional study. The association between scores of both scales was determined by the Spearman rank correlation coefficient. Equations for transformation of total score of a scale to the other were constructed from weighted regression models and both, transformed and observed score, contrasted by means of the Lin's Concordance Correlation Coefficient ( LCCC) and Bland-Altman plot. Results As a whole, the prevalence of the NMS according to each scale was quite similar, and most of the correlations between their corresponding components were high ( rS > 0.60). The total score correlation of the MDS-UPDRS Part I with the NMSS was high ( rS = 0.81). Concerning the transformed scores, estimated scores only partially approach the observed ones (sharing about 60-64% of the variance) because residual variance increased with increasing magnitudes of the scores, i.e. the most severe patients (Bland-Altman plot; LCCC < 0.60 for severe patients). Conclusions (i) MDS-UPDRS Part I ( nM-EDL) and NMSS showed a strong convergent validity; (ii) however, transformed scores using the equations from weighted regression models showed that for patients with the most severe NMS they are not concordant. [ABSTRACT FROM AUTHOR]

We thus need further studies to provide active epidemiologic surveillance of neuropsychiatric symptoms and signs post-vaccination, to better ascertain the neuropsychiatric effects of COVID-19 vaccination. For example, there had been concerns in the past that hepatitis B vaccination may be associated with multiple sclerosis (MS) due to the possibility of immunological cross-reactivity between human myelin basic protein and the vaccine.5 It was subsequently found that whereas the hepatitis B vaccines did not increase the risk for multiple sclerosis, the act of vaccination could hasten and trigger the development of symptoms in patients with subclinical MS.5 Notably, symptoms of MS may masquerade as FND, with reports of patients with MS initially misdiagnosed with FND and patients with MS who have concomitant functional symptoms.4 It is thus prudent to perform a detailed evaluation of patients who present with what appears to be functional neurological symptoms, to avoid missing underlying or concomitant organic disorders. We thank Goss and colleagues for providing a timely discussion on the neurological complications of the coronavirus disease 2019 (COVID-19) vaccines.1 Besides common neurological symptoms like dizziness, headache, and paraesthesia,1 there have been recent concerns over individuals who reportedly developed abnormal movements after taking COVID-19 vaccines.2 Viral videos depicting these movements triggered fear and distrust of the vaccines, to the extent that neuropsychiatric experts have provided public affirmation that these symptoms were likely due to functional neurological disorders (FND).3 It is crucial to educate the public that psychogenic movements may develop as part of conversion, somatoform, or factitious disorders and to correct misleading information that may result in significant vaccine fear and hesitancy. [Extracted from the article]

Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson's disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the CNS, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries about alterations to the gut microbiota in Parkinson's disease and focus on current mechanistic insights into the microbiota-gut-brain axis in disease pathophysiology. Moreover, we discuss the interactions between the production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we draw attention to diet modification, the use of probiotics and prebiotics and faecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson's disease. [ABSTRACT FROM AUTHOR]

Abstract: Although Parkinson's disease (PD) has been classically defined as a motor disorder, a range of non-motor symptoms (NMS) including cognitive, mood, autonomic and sleep disturbances occur with the passage of time. Although it seems that the non-motor aspect of PD is a recent observation, classic authors (James Parkinson, Charcot, Gowers, Oppenheim and Wilson) had described many NMS including pain, fatigue, bladder dysfunction, cognitive decline and delusion. In this review we have collated the classic literature of NMS in PD. [Copyright &y& Elsevier]

Abstract: Non-motor symptoms (NMS) are now recognized to occur across all stages of Parkinson's disease (PD) and as a result there has been an increasing focus on their diagnosis, quantification and effective management. While in some subjects, NMS may be present before diagnosis, in advanced PD, NMS can contribute to hospitalization, severe disability and a shortened life expectancy. Strategies for continuous drug delivery have been reported to have a beneficial effect on NMS in PD and while the efficacy of apomorphine on motor function in PD has been confirmed in a number of studies, in addition to its possible anti-dyskinetic effect, a number of reports have also outlined the possible beneficial effect of apomorphine on NMS. This review sets out to examine the efficacy of apomorphine in non-motor aspects of PD, including its effect on neuropsychiatric and gastrointestinal symptoms, sleep (including restless legs syndrome), urinary dysfunction, pain and impulse control disorders. The analysis takes into consideration case reports, and open-label and comparative case–control studies published to date. Results of this review suggest that although data on the effect of apomorphine on NMS in PD patients are limited there is a strong suggestion of a beneficial effect that warrants further investigation in double-blind studies. [Copyright &y& Elsevier]

The complications of long-term levodopa therapy for Parkinson's disease (PD) include motor fluctuations, dyskinesias, and also nonmotor fluctuations-at least equally common, but less well appreciated-in autonomic, cognitive/psychiatric, and sensory symptoms. In seeking the pathophysiologic mechanisms, the leading hypothesis is that in the parkinsonian brain, intermittent, nonphysiological stimulation of striatal dopamine receptors destabilizes an already unstable system. Accordingly, a major goal of PD treatment in recent years has been the attainment of continuous dopaminergic stimulation (CDS)-or, less theoretically (and more clinically verifiable), continuous drug delivery (CDD). Improvements in the steadiness of the plasma profiles of various dopaminergic therapies may be a signal of progress. However, improvements in plasma profile do not necessarily translate into CDS, or even into CDD to the brain. Still, it is reassuring that clinical studies of approaches to CDD have generally been positive. Head-to-head comparative trials have often failed to uncover evidence favoring such approaches over an intermittent therapy. Nevertheless, the findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement. In vivo receptor binding studies may help to determine the degree of CDS that a dopaminergic therapy can confer. This may be a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy. Certainly, the complexities of optimal PD management, and the rationale for an underlying strategy such as CDS or CDD, have not yet been thoroughly elucidated. [ABSTRACT FROM AUTHOR]

Abstract: Background: Non-motor symptoms of Parkinson's disease (PD) represent major causes of morbidity. RECOVER, a randomized controlled trial of rotigotine transdermal system, was the first prospective controlled trial to use the Non-Motor Symptoms Scale (NMSS) as an exploratory outcome for assessment of treatment effects on non-motor symptoms in PD. Rotigotine improved NMSS total score compared with placebo, and the “Sleep/fatigue” and “Mood/apathy” domains. This post hoc analysis further characterizes the effects of rotigotine on sleep/fatigue and mood/apathy. Methods: Patients with PD and unsatisfactory early-morning motor impairment were randomized to transdermal patches of rotigotine (2–16 mg/24 h) or placebo. Treatment was titrated to optimal dose over 1–8 weeks, maintained for 4 weeks. The NMSS was assessed at baseline and end of treatment. Post hoc analyses are presented for individual items of the “Sleep/fatigue” and “Mood/apathy” domains. The interpretation of p-values is considered exploratory in nature. Results: Of 287 patients randomized, NMSS data were available for 267 patients (178 rotigotine, 89 placebo). Within the “Sleep/fatigue” domain there was a significant difference, in favor of rotigotine, in change from baseline score in 1 of 5 items: “fatigue (tiredness) or lack of energy” (ANCOVA, p < 0.0001). Within the “Mood/apathy” domain, there were significant differences in favor of rotigotine in 4 of 7 items: “lost interest in surroundings” (p < 0.0001), “lost interest in doing things” (p < 0.0001), “seems sad or depressed” (p < 0.01), and “difficulty experiencing pleasure” (p < 0.05). Conclusions: Rotigotine transdermal system may improve non-motor symptoms such as fatigue, symptoms of depression, anhedonia, and apathy in patients with PD; further prospective controlled studies are required to confirm this post hoc analysis. [Copyright &y& Elsevier]

Background: The 24-week, double-blind Efficacy and Safety Evaluation in PD-Adjunct (EASE-PD Adjunct) study randomized patients with advanced Parkinson's disease (PD) suboptimally controlled with levodopa to once-daily placebo or adjunctive ropinirole prolonged release (2-24 mg/day). We investigated the effect of ropinirole prolonged release on nocturnal symptoms in these patients. Methods: Total and grouped item PD Sleep Scale (PDSS) scores were analyzed post hoc in patients with baseline PDSS total scores ≤ 100 (troublesome nocturnal symptoms) and >100. Results: Baseline PDSS total score was ≤ 100 in 93 of 198 (47%) and 89 of 189 (47%) patients receiving ropinirole prolonged release and placebo, respectively; this subgroup displayed evidence at baseline of greater daily awake 'off' time, reduced night-time sleep and worse quality of life, than the PDSS >100 subgroup. Significant improvements with ropinirole prolonged release versus placebo in PDSS score from baseline to Week 24 last observation carried forward were observed for those with baseline PDSS ≤ 100 [adjusted mean treatment difference 9.0 (95% CI: 2.76, 15.33; P = 0.0051)], but not >100. The PDSS ≤ 100 subgroup demonstrated treatment benefits for PDSS groupings of motor symptoms on waking and global quality of sleep. Changes in daytime sleepiness were similar between treatment groups. The PDSS >100 subgroup demonstrated significant treatment benefit for global quality of sleep. The unadjusted odds ratio for a positive response with ropinirole prolonged release relative to placebo, for the PDSS ≤ 100 subgroup, was 2.90 (95% CI: 1.42, 5.95, P = 0.004). Conclusions: Once-daily ropinirole prolonged release improves nocturnal symptoms in patients with advanced PD not optimally controlled with levodopa who suffer troublesome nocturnal disturbance. [ABSTRACT FROM AUTHOR]