Effects of safinamide on pain in patients with fluctuating Parkinson's disease

Background: Non-motor symptoms (NMS) are integral to Parkinson's Disease (PD) and management remains a challenge. Safinamide is a novel molecule in relation to addressing NMS due to its multifocal mechanism of action with both dopaminergic and non-dopaminergic properties. Objective: To investigate the efficacy of safinamide on NMS and its burden in PD patients with motor fluctuations after 6 months of treatment. Methods: This observational, multicenter, open-label, pilot study assessed a wide range of NMS using the following rating scales, NMSS (non-motor symptom scale), KPPS (King's PD pain scale), HADS (hospital anxiety and depression scale), PDQ-8 (Parkinson's disease quality of life questionnaire), and PDSS-2 (Parkinson's disease sleep scale), EuroQol-5D 3 level version (EQ-5D-3L), CGI-I (clinical global impression of improvement), and PGI-C (patient global impression of change). Motor examination using UPDRS part III (Unified Parkinson's disease rating scale, motor examination), UPDRS IV (complications of therapy) and Hoehn and Yahr staging were also obtained. Results: 27 patients were included in the analysis and were evaluated at baseline and ≥ 6 months after safinamide treatment. 26 patients had a daily maintenance dose of 100 mg and 1 patient a daily dose of 50 mg. Significant improvements in UPDRS IV, KPPS item 5 (region-specific "off" dystonia), KPPS domain 3 (items 4-6, fluctuation related pain) and KPPS total score were observed after treatment with safinamide, while maintaining stable dopaminergic medication. No statistically significant differences were found in NMSS, HADS, PDSS-2, EQ-5D-3L, and PDQ-8 after treatment. Conclusions: Our results suggest that safinamide may have a beneficial effect on pain, a key unmet need in fluctuating PD patients.The study was funded by Zambon SpA with an unconditional research grant. In addition, the study was funded by MultiPark, the strategic research area for neuroscience at Lund University; the Swedish Parkinson Foundation; the Swedish Parkinson Academy and the Faculty of Medicine at Lund University.I was not given any grant numbers or any other details. The funds were used to finance the study personell and the logistic needs of the study.S

The real-life effect of catechol-O-methyltransferase inhibition on non-motor symptoms in levodopa-treated Parkinson's disease: opicapone versus entacapone

Objective: To evaluate the long-term, real-life effects on non-motor symptoms (NMS) of opicapone compared to entacapone in levodopa-treated people with Parkinson's disease (PwP). Methods: A retrospective data analysis, with pre- and post-opicapone initiation data of 17 PwP with motor fluctuations compared to a comparable group of 18 PwP introduced on entacapone. The primary outcome was changes in the NMS Scale (NMSS) total score after 1-year follow-up. Secondary outcomes included changes in the NMSS domains, and Parkinson's Disease Sleep Scale (PDSS) total and item scores after the same time span. Results: Groups were comparable for baseline demographics and Parkinson's-related features (p ≥ 0.314) as well as duration of follow-up (1.33 ± 0.66 years for PwP on opicapone and 1.23 ± 0.49 years for those on entacapone; p = 0.858). PwP who were introduced on opicapone showed no changes in NMSS and PDSS total scores after 1 year (p = 0.605 and p = 0.507, respectively), whereas PwP who were introduced on entacapone showed significant worsening of NMSS and PDSS total scores at follow-up (p = 0.005 and p = 0.001, respectively). In neither group changes in individual NMSS domains from baseline to follow-up were observed (p ≥ 0.288 for entacapone and p ≥ 0.816 for opicapone, respectively). In PwP on entacapone significant worsening was seen in the distressing dreams, hallucinations, and limb numbness items of the PDSS (p ≤ 0.05). Conclusions: Introduction of opicapone in real-life PwP with motor fluctuations seems to stabilise NMS burden and aspects of sleep dysfunction, in contrast to entacapone where there was a worsening of NMS burden and PDSS scores over 1 year follow-up.The views expressed are those of the authors and not necessarily those of the NHS, NIHR or Department of Health. The authors acknowledge the support of the International Parkinson and Movement Disorder Society Non-Motor Parkinson’s disease Study Group, the NIHR London South Clinical Research Network, the NIHR Biomedical Research Centre, and the clinical research team at the Parkinson’s Foundation centre of excellence at King’s College Hospital and King’s College London. This article represents independent collaborative research part funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.S

ANO3 as a Cause of Early‐Onset Chorea Combined with Dystonia: Illustration of Phenotypic Evolution

Here, we signpost a case of a childhood-onset chorea-dominant phenotype later evolved into a dystonia-dominant phenotype during adulthood, in a subject carrying a missense pathogenic variant (c.1528 G > A; p.Glu510Lys)1 in the anoctamin 3 protein-coding gene (ANO3, DYT24, OMIM 610110).

Exploring hyperhidrosis and related thermoregulatory symptoms as a possible clinical identifier for the dysautonomic subtype of Parkinson’s disease

ObjectiveTo identify associated (non-)motor profiles of Parkinson’s disease (PD) patients with hyperhidrosis as a dominant problem.MethodsThis is a cross-sectional, exploratory, analysis of participants enrolled in the Non-motor Longitudinal International Study (NILS; UKCRN No: 10084) at the Parkinson’s Centre at King’s College Hospital (London, UK). Hyperhidrosis scores (yes/no) on question 28 of the Non-Motor Symptom Questionnaire were used to classify patients with normal sweat function (n = 172) and excessive sweating (n = 56) (Analysis 1; n = 228). NMS scale (NMSS) question 30 scores were used to stratify participants based on hyperhidrosis severity (Analysis 2; n = 352) using an arbitrary severity grading: absent score 0 (n = 267), mild 1–4 (n = 49), moderate 5–8 (n = 17), and severe 9–12 (n = 19). NMS burden, as well as PD sleep scale (PDSS) scores were then analysed along with other correlates.ResultsNo differences were observed in baseline demographics between groups in either analysis. Patients with hyperhidrosis exhibited significantly higher total NMSS burden compared to those without (p p p ConclusionsChronic hyperhidrosis appears to be associated with a dysautonomia dominant subtype in PD patients, which is also associated with sleep disorders and a higher rate of dyskinesia (fluctuation-related hyperhidrosis). These data should prompt the concept of hyperhidrosis being used as a simple clinical screening tool to identify PD patients with autonomic symptoms.</div

Influence of probiotic bacteria on gut microbiota composition and gut wall function in an in-vitro model in patients with Parkinson's disease

We report here the potential role of a 4-strain probiotic suspension for use with patients with Parkinson's disease (PD). Stool samples from a group of three patients with diagnosed PD were used to create microbiotas in an in-vitro gut model. The effects of dosing with an oral probiotic suspension (Symprove) on bacterial composition and metabolic activity in the microbiotas was evaluated over 48 h and compared with healthy controls. Additionally, the effect of probiotic dosing on epithelial tight-junction integrity, production of inflammatory markers and wound healing were evaluated in cell culture models. In general, the relative proportions of the main bacterial phyla in the microbiotas of PD patients differed from those of healthy subjects, with levels of Firmicutes raised and levels of Bacteroidetes reduced. Dosing with probiotic resulted in a change in bacterial composition in the microbiotas over a 48 h period. Several other indicators of gut health changed upon dosing with the probiotic; production of short chain fatty acids (SCFAs) and lactate was stimulated, levels of anti-inflammatory cytokines (IL-6, IL-10) increased and levels of pro-inflammatory cytokines and chemokines (MCP-1 and IL-8) decreased. Tight junction integrity was seen to improve with probiotic dosing and wound healing was seen to occur faster than a control. The data suggest that if development and/or progression of PD is influenced by gut microbiota dysbiosis then supplementation of the diet with a properly formulated probiotic may be a useful adjunct to standard treatment in clinic

COVID-19 and possible links with Parkinson\u27s disease and parkinsonism: from bench to bedside

This Viewpoint discusses insights from basic science and clinical perspectives on coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection in the brain, with a particular focus on Parkinson\u27s disease. Major points include that neuropathology studies have not answered the central issue of whether the virus enters central nervous system neurons, astrocytes or microglia, and the brain vascular cell types that express virus have not yet been identified. Currently, there is no clear evidence for human neuronal or astrocyte expression of angiotensin-converting enzyme 2 (ACE2), the major receptor for viral entry, but ACE2 expression may be activated by inflammation, and a comparison of healthy and infected brains is important. In contrast to the 1918 influenza pandemic and avian flu, reports of encephalopathy in COVID-19 have been slow to emerge, and there are so far no documented reports of parkinsonism apart from a single case report. We recommend consensus guidelines for the clinical treatment of Parkinson\u27s patients with COVID-19. While a role for the virus in causing or exacerbating Parkinson\u27s disease appears unlikely at this time, aggravation of specific motor and non-motor symptoms has been reported, and it will be important to monitor subjects after recovery, particularly for those with persisting hyposmia

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Personalised Advanced Therapies in Parkinson’s Disease: The Role of Non-Motor Symptoms Profile

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

Gastrointestinal dysfunction in Parkinson’s disease:gut microbiota, inflammation and endophenotypes

BackgroundGastrointestinal dysfunction (GID) and gut dysbiosis are increasingly considered as an integral aspect of Parkinson's disease (PD), spanning across all stages of the condition, from prodromal to advanced PD. The hypothesis at the basis of this PhD project is that GID and other motor and non-motor symptoms (NMS) of PD could be driven by gut dysbiosis and, as such, could be partly addressed by gut-modulating interventions, such as probiotics. Probiotics are, in fact, already regarded as a useful therapeutic option for the treatment of constipation in PD.Objectives1. To review the available literature on GID, gastrointestinal barriers to levodopa transport and absorption, gut dysbiosis, gut-brain axis, and use of probiotics in PD;2. To investigate whether constipation – considered within the range of NMS as a clinical manifestation of GID and an established risk factor for PD development - is also a biomarker of disease progression;3. To investigate whether intake of a four-strain probiotic (SymproveTM) in patients with PD and constipation leads to:- Improvements of motor parameters;- improvement of NMS other than constipation;- improvements of quality of life;by potentially inducing changes in the gut microbiota composition, reducing levels of intestinal and systemic inflammation and/or improving levodopa pharmacokinetics.MethodsThe above-mentioned objectives were achieved by using the following approaches:1. A narrative review on GID, gastrointestinal barriers to levodopa transport and absorption (incorporated publication), gut dysbiosis, gut-brain axis, and a systematic review on preclinical and clinical evidence on the use of probiotics in PD (incorporated publication);2. A longitudinal analysis with a focus on data on constipation (as a marker of GID) and cognitive impairment (as a marker of disease progression) collected from 196 de novo patients with PD followed in the world largest non-motor-focused longitudinal cohort study, the National Institute for Health Research portfolio-adopted Non-motor International Longitudinal Study (NILS) led by Professor K. Ray Chaudhuri and coordinated by Ms A. Rizos from King's College Hospital and King's College London, United Kingdom. For external validity, the NILS results were further investigated in an additional and independent cohort of 423 de novo patients with PD patients from the Parkinson’s Progression Markers Initiative (PPMI) database (incorporated publication);3. A three-month, randomised, double-blind, placebo-controlled, multicentre study evaluating the effect of SymproveTM versus placebo on gut microbiota composition, motor as well as NMS, markers of systemic inflammation, and levodopa pharmacokinetics in patients with PD and constipation (the SymPD study). This is one of the first studies of this nature with a wide range of motor and non-motor outcomes assessed.Results1. A published narrative review indicated that GID is a common and troublesome aspect of PD with possible implications on levodopa pharmacokinetics and the development of motor and non-motor fluctuations. Recent clinical and preclinical evidence has also supported the role of the gut microbiota and gut-brain axis in the pathogenesis of PD; this has set the basis for the use of gut microbiota-modulating interventions, such as probiotics, in PD. A published systematic review suggested that despite the encouraging preclinical data, translational research has resulted in level I evidence for the use of probiotics to treat constipation only in PD without clinical evidence for their beneficial effect on other symptoms of PD.2. Early presence of constipation is associated with faster development of cognitive impairment in two multicentre and independent cohorts of patients with de novo PD, suggesting a shared pathophysiological background. Constipation is a candidate biomarker for disease progression in PD.3. Results from the SymPD study showed that 12-week intake of the four-strain probiotic SymproveTM was effective to beneficially enrich the gut microbiome and reduce ‘time-to-ON’ as well as total NMS burden (driven by improvements of constipation and fatigue) in patients with PD and constipation.ConclusionsProbiotics represent a useful gut microbiota-modulating intervention for the symptomatic treatment of motor and non-motor aspects of PD. Ongoing and future research will clarify the mechanisms underpinning the observed clinical benefits and whether probiotics may also serve as a therapy for PD subtypes dominated by GID dysfunction.<br/