Publications by authors named "Joaquim J Ferreira"

268 Publications

Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study.

Mov Disord 2022 Jan 8. Epub 2022 Jan 8.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding.

Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR).

Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry).

Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029).

Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28902DOI Listing
January 2022

High frequency of psychosis in late-stage Parkinsońs disease.

Clin Park Relat Disord 2021 24;5:100119. Epub 2021 Nov 24.

CNS - Campus Neurológico, Torres Vedras, Portugal.

Background: Psychosis is a frequent non-motor symptom in Parkinson's disease (PD). Estimates of the frequency of Parkinsońs disease psychosis (PDP) vary widely. Knowledge about the frequency and phenomenology of psychosis in late-stage (LS) PD patients is limited.This study aimed to determine the frequency of psychosis in LSPD patients through clinical diagnostic interview (CDI) (gold standard), according to NINDS/NIMH diagnostic criteria for PDP. The secondary objectives were to characterize the phenomenology, to test selected instruments and assess their adequacy in comparison to CDI, and to assess the psychiatric comorbidities.

Methods: A cross-sectional study including LSPD patients (patients with ≥ 7 years from symptoms onset and Hoehn and Yahr scale score > 3 or a Schwab and England scale score < 50% in the ON condition) was conducted. Patients were subjected to psychiatric, neurological, and neuropsychological evaluations. Each patient was interviewed by a psychiatrist who performed a CDI.

Results: 92 LSPD patients were included. 55.4% experienced psychotic symptoms according to NINDS/NIMH diagnostic criteria for PDP. Hallucinations were present in 94.1% and delusions in 29.4% of the psychotic patients. Visual hallucinations were the most common (88.23%) psychotic symptom. 72.5% of LSPD patients with psychotic symptoms had at least one comorbid psychiatric diagnosis. Lower frequency of psychosis was found when the assessment was performed only through selected instruments rather than CDI.

Conclusions: A high frequency (55.4%) of psychotic symptoms and comorbid psychiatric (72.5%) diagnosis were found in LSPD patients. The use of CDI, in addition to structured scales may increase the sensitivity of detecting psychotic symptoms.
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http://dx.doi.org/10.1016/j.prdoa.2021.100119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8710406PMC
November 2021

Frequency of dementia in Parkinson's disease: A systematic review and meta-analysis.

J Neurol Sci 2022 Jan 3;432:120077. Epub 2021 Dec 3.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz 1649-028, Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Av. Prof. Egas Moniz 1649-028, Lisbon, Portugal; CNS - Campus Neurológico, Bairro St. António 2560-280, Torres Vedras, Portugal. Electronic address:

Background: There is a considerable variation in the reported frequency of dementia in Parkinson's disease (PDD). The aim of this study was to evaluate the frequency of PDD reported in published studies and to examine the different methodological, clinical, and demographic factors that may contribute to this variation.

Methods: We conducted a systematic review, searching EMBASE and MEDLINE databases for relevant articles on PDD frequency published before May 2019. A global estimation of PDD was calculated. Different subgroup analyses were performed for methodological, clinical, and demographic characteristics. Meta-regression was also conducted to identify any significant differences within the subgroups.

Results: We included 295 studies. The global pooled dementia frequency was 26.3%. These estimations varied according to methodological (14%-55%), clinical (18%-46%), and demographic (21%-43%) variables. The declared primary objective of the studies (to study PDD), the follow-up length (≥7 years), the age of the participants (≥75 years), Parkinson's disease (PD) duration (>10 years), and the Hoehn & Yahr (H&Y) stage (>3) were important factors affecting reported dementia frequency.

Conclusions: This systematic review found that approximately one-quarter of the PD patients were diagnosed with PDD. Dementia frequency varied according to methodological, clinical and demographic variables. We cannot examine PDD frequency without considering all these variables that have an impact on it.
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http://dx.doi.org/10.1016/j.jns.2021.120077DOI Listing
January 2022

A Computational Analysis in a Cohort of Parkinson's Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes.

Cancers (Basel) 2021 Nov 28;13(23). Epub 2021 Nov 28.

Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany.

Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson's disease (PD) and colorectal cancer (CRC). We used high-throughput data sets retrieved from whole blood of idiopathic PD (IPD) patients and time course data sets derived from an in vitro model of CRC including the wildtype and three core-clock knockout (KO) cell lines. Several gene expression alterations in IPD patients resembled the expression profiles in the core-clock KO cells. These include expression changes in , , , , and . Notably, our results pointed to alterations in the core-clock network in IPD patients when compared to healthy controls and revealed variations in the expression profile of PD-associated genes (e.g., and ) upon disruption of the core-clock genes. Our study characterizes changes at the transcriptomic level following circadian clock disruption on common cellular pathways associated with cancer and neurodegeneration (e.g., immune system, energy metabolism and RNA processing), and it points to a significant influence on the overall survival of colon cancer patients for several genes resulting from our analysis (e.g., , , ).
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http://dx.doi.org/10.3390/cancers13235978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657387PMC
November 2021

Potential drug-drug interactions in acute poisonings managed in the intensive care unit: Occurrence, risk factors and relationship to patient severity on admission.

Basic Clin Pharmacol Toxicol 2022 Feb 13;130(2):337-345. Epub 2021 Dec 13.

Department of Medical and Toxicological Critical Care, Lariboisière Hospital, APHP, Paris University, INSERM UMRS-1144, Paris, France.

Beyond the direct toxicity resulting from each drug in the poisoned patient, additional toxicities may result from drug-drug interactions (DDIs). We aimed to determine the frequency of potential DDIs in the poisoned patient and investigate whether DDIs are associated with severity. We conducted a 1-year cohort study in a toxicological ICU. DDIs were identified using an electronic interaction-checker tool. Among our 354 ICU poisoned patients, 134 (38%) presented at least one potential DDI between acute poisoning drugs and 180 (51%) at least one potential DDI between acute poisoning and long-term treatment drugs. Using multivariate analyses, previous suicide attempt was associated with the presence of potential DDIs between acute poisoning drugs in suicide attempt patients (P = 0.014). Chronic alcoholism (P = 0.005) and tobacco smoking (P = 0.022) were associated with the presence of potential DDIs between acute poisoning and long-term treatment drugs in recreational drug users. Presence of potential DDIs between acute poisoning and long-term treatment drugs was associated with catecholamine infusion (P = 0.022) in suicidal self-exposure patients. Presence of potential pharmacodynamic DDIs between acute poisoning and long-term treatment drugs was associated with aspiration pneumonia onset in recreational drug users (P = 0.03). ICU poisoned patients present a high rate of potential DDIs that may influence the outcome.
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http://dx.doi.org/10.1111/bcpt.13698DOI Listing
February 2022

Neuroimaging cerebrovascular biomarkers in Parkinson's disease.

Neuroradiol J 2021 Dec 6:19714009211059118. Epub 2021 Dec 6.

Avenida Professor Egas Moniz, Faculty of Medicine, 89237University of Lisbon, Lisbon, Portugal.

Background And Purpose: The cardiovascular risk in Parkinson's disease (PD) remains uncertain and controversial. Some studies suggest PD patients present an increased risk of cerebrovascular disease. We aimed to study the prevalence of neuroimaging cerebrovascular biomarkers in PD patients compared to controls, using an accurate and complete magnetic resonance (MR) imaging evaluation.

Material And Methods: Neuroimaging sub-study within a larger cross-sectional case-control study. An enriched subgroup of PD patients (≤10 years since diagnosis) with at least a moderate cardiovascular mortality risk based on a Systematic COronary Risk Evaluation (SCORE) was compared to community-based controls regarding neuroimaging biomarkers. Patients underwent a high-resolution T1-weighted MR imaging sequence at 3.0 T to visualize neuromelanin. A 3D SWI FFE, sagittal 3D T1-weighted, axial FLAIR and diffusion-weighted image sequences were obtained.

Results: The study included 47 patients, 24 with PD and 23 controls. PD patients presented a reduced area and signal intensity of the substantia nigra and locus coeruleus on neuromelanin-sensitive MR. The median SCORE was 5% in both groups. No significant differences regarding white matter hyperintensities (OR 4.84, 95% CI 0.50, 47.06), lacunes (OR 0.43, 95% CI 0.07, 2.63), microbleeds (OR 0.64, 95% CI 0.13, 3.26), or infarcts (0.95, 95% CI 0.12, 7.41) was found. The frequency of these neuroimaging biomarkers was very low in both groups.

Conclusion: The present study does not support an increased prevalence of neuroimaging cerebrovascular biomarkers in PD patients.
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http://dx.doi.org/10.1177/19714009211059118DOI Listing
December 2021

A MDS Evidence-Based Review on Treatments for Huntington's Disease.

Mov Disord 2021 Nov 29. Epub 2021 Nov 29.

Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal.

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments.

Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers.

Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention.

Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments.

Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28855DOI Listing
November 2021

Frequency and Characteristics of Psychosis in Parkinson's Disease: A Systematic Review and Meta-Analysis.

J Parkinsons Dis 2021 Nov 15. Epub 2021 Nov 15.

CNS - Campus Neurológico, Torres Vedras, Portugal.

Background: Psychotic symptoms are highly frequent in Parkinson's disease (PD) patients and are associated with poor prognosis. They include hallucinations, delusions, and minor psychotic phenomena, including sense of presence, passage hallucinations, and illusions.

Objective: To evaluate the frequency of psychosis in PD patients.

Methods: A systematic review and meta-analysis of clinical trials, prospective and retrospective cohort studies, case-control studies, and cross-sectional studies reporting the frequency of psychosis, hallucinations, and delusions in PD.

Results: Electronic database search wielded 3,536 articles, an additional 91 were identified through citation chaining. Of these, 163 were fully inspected, 57 removed, and 106 included as relevant for neuropsychiatric events frequency, with 32 meeting our inclusion criteria (psychosis and/or specific psychotic phenomena). The pooled frequency of psychosis was 20.7% (95% CI 14.5 to 28.6; I2 = 94%, 15 studies; combined n = 2919). None of the pre-defined meta-regressions or subgroup analyses were statistically significant or helped explain the statistical heterogeneity. The pooled frequency of any form of hallucination was 21.6% (95% CI 14.7 to 30.6; I2 = 95%; 18 studies; combined n = 3,161). Duration of PD at baseline and mean baseline Hoehn & Yahr stage helped explain the statistical heterogeneity in the meta-analysis of hallucinations.

Conclusion: Based on the available evidence, around a fifth of PD patients experience psychosis or hallucinations. The risk of developing hallucinations is likely moderated by the disease duration, Hoehn & Yahr stage, and the cognitive status.
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http://dx.doi.org/10.3233/JPD-212930DOI Listing
November 2021

The Added Benefit of Opicapone When Used Early in Parkinson's Disease Patients With Levodopa-Induced Motor Fluctuations: A Analysis of BIPARK-I and -II.

Front Neurol 2021 5;12:754016. Epub 2021 Nov 5.

BIAL - Portela & Ca, S.A., Coronado, Portugal.

Opicapone (OPC) was efficacious in reducing OFF-time in two pivotal trials in patients with Parkinson's disease (PD) and end-of-dose motor fluctuations (BIPARK-I and -II). analyses of these trials evaluated the efficacy of OPC following pre-defined segmentation of the wide spectrum of motor fluctuations in PD. Data from matching treatment arms in BIPARK-I and -II were combined for the placebo (PLC) and OPC 50-mg groups, and exploratory analyses were performed to investigate the efficacy of OPC 50 mg vs. PLC in subgroups of patients who were in "earlier" vs. "later" stages of both their disease course (e.g., duration of PD <6 years vs. ≥6 years) and levodopa treatment pathway (e.g., number of daily levodopa intakes <4 vs. ≥4). Efficacy variables included changes from baseline in absolute OFF-time and total ON-time. The Full Analysis Set included 517 patients (PLC, = 255; OPC 50 mg, = 262). OPC 50 mg was significantly more effective than PLC in reducing OFF-time and increasing ON-time in the majority of subgroup analyses ( < 0.05). Moreover, patients in "earlier" stages of both their disease course and levodopa treatment pathway experienced numerically greater efficacy when using OPC 50 mg, in comparison with those in "later" stages. OPC 50 mg was efficacious over the whole trajectory of motor fluctuation evolution in PD patients. There was also a signal for enhanced efficacy in patients who were earlier vs. later in their disease course and levodopa treatment pathway.
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http://dx.doi.org/10.3389/fneur.2021.754016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603564PMC
November 2021

Anticoagulation therapy in patients with post-operative atrial fibrillation: Systematic review with meta-analysis.

Vascul Pharmacol 2021 Oct 30;142:106929. Epub 2021 Oct 30.

Centro Cardiovascular da Universidade de Lisboa, CAML, Faculdade de Medicina da Universidade de Lisboa, Portugal; Cardiology Department, Hospital Santa Maria - Centro Hospitalar Universitário Lisboa Norte (CHULN), Lisbon, Portugal; Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Universidade de Lisboa, Lisbon, Portugal. Electronic address:

Background: Post-operative atrial fibrillation (POAF) is a relevant complication after surgery. Several studies have shown that POAF has important consequences for long-term morbidity and mortality, by increasing the risk of thromboembolic events. However, the use of oral anticoagulation (OAC) is not well established in this context.

Methods: We searched MEDLINE, CENTRAL, PsycInfo and Web of Science for clinical trials and observational studies evaluating anticoagulation vs. no anticoagulation in patients with POAF (after cardiac or non-cardiac surgery). Data were screened and extracted by two independent reviewers. We performed a random- effects model to estimate the pooled odds ratio (OR) with 95% Confidence Intervals (CI), and heterogeneity was evaluated by I statistics. The outcomes of interest were all-cause mortality, thromboembolic events, and bleeding events.

Results: Overall, 10 observational retrospective studies were included: 5 studies with 203,946 cardiac surgery POAF patients, and 5 studies with 29,566 patients with POAF after non-cardiac surgery. In cardiac surgery POAF, the OAC use was associated with lower risk of thromboembolic events (OR 0.68; 95%CI 0.47-0.96, I = 31%; 4 studies) and the bleeding risk was significantly increased (OR 4.30; 95%CI 3.69 to 5.02, 1 study). In non-cardiac surgery POAF, OAC did not significantly reduce the risk of thromboembolic events (OR 0.71, 95%CI 0.33-1.15; I = 79%; 5 studies) but was associated with increased risk of bleeding (OR 1.20, 95%CI 1.10-1.32, I = 0%; 3 studies). Mortality was not significantly reduced in both cardiac and non-cardiac surgery POAF.

Conclusion: Oral anticoagulation was associated with a lower risk of thromboembolic events in patients with POAF following cardiac surgery but not in non-cardiac surgery. Bleeding risk was increased in both settings. The confidence on pooled results is at most low, and further data, namely randomized controlled trials are necessary to derive robust conclusions.
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http://dx.doi.org/10.1016/j.vph.2021.106929DOI Listing
October 2021

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease.

J Parkinsons Dis 2021 Oct 7. Epub 2021 Oct 7.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation.

Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases.

Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017).

Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking.

Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
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http://dx.doi.org/10.3233/JPD-212851DOI Listing
October 2021

Drooling rating scales in Parkinson's disease: A systematic review.

Parkinsonism Relat Disord 2021 10 21;91:173-180. Epub 2021 Sep 21.

Laboratory of Clinical Pharmacology and Therapeutics Unit, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal; Alcoitão School of Health Sciences, Santa Casa da Misericórdia de Lisboa, Lisbon, Portugal. Electronic address:

Background: Drooling is a clinically relevant non-motor symptom of people with Parkinson's disease (PwP). Several drooling rating scales are available. Nevertheless, the compelling scientific evidence supporting their validity is limited. This study aims to evaluate clinical rating scales for drooling, assessing their characteristics, clinimetric properties, and clinical utility classification.

Methods: A systematic review was undertaken. Two reviewers performed independent literature searches using the CENTRAL®, CINAHL®, Embase®, MEDLINE®, SciElo®, and SPEECH BITE® databases. We used consensus-based standards for the selection of health measurement instruments (COSMIN) and the International Parkinson's disease and the Movement Disorders (MDS) criteria to evaluate the included rating scales.

Results: The following six rating scales were identified: Drooling Impact Scale (DIS), Sialorrhea Scoring Scale (SSS), Drooling Severity and Frequency Scale (DSFS), Drooling Rating Scale (DRS), Sialorrhea Clinical Scale for Parkinson Disease (SCS-PD), and the Radboud Oral Motor inventory for Parkinson's disease - Saliva (ROMP-saliva). The scales had heterogeneous characteristics: (i) not all were created/adapted for PwP; (ii) different dimensions associated with drooling are assessed; (iii) cross-cultural adaptations are limited to some languages. The clinimetric properties showed: (i) target population size limitations; (ii) incomplete reliability analysis; (iii) lack of robust validity; (iv) sensitivity to change not fully explored. Following the MDS criteria, only one tool was classified as "recommended", the ROMP-saliva.

Conclusions: This review provides information for an adequate selection of a drooling rating scale for clinical and/or research purposes. To date, ROMP-saliva is the only scale with substantial evidence of its clinimetric properties adequacy and data in PwP.
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http://dx.doi.org/10.1016/j.parkreldis.2021.09.012DOI Listing
October 2021

Redefining the strategy for the use of COMT inhibitors in Parkinson's disease: the role of opicapone.

Expert Rev Neurother 2021 Sep 15;21(9):1019-1033. Epub 2021 Sep 15.

Department of Research & Development, BIAL - Portela & Ca SA, Portugal.

Introduction: Levodopa remains the gold-standard Parkinson's disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery.

Areas Covered: Peripheral inhibition of dopa-decarboxylase has long been considered an essential component of levodopa treatment at every stage of illness. In contrast, only relatively recently have catechol-O-methyltransferase (COMT) inhibitors been utilized to block the other major pathway of degradation and optimize levodopa delivery to the brain. First and second-generation COMT inhibitors were deficient because of toxicity, sub-optimal pharmacokinetics or a short duration of effect. As such, they have only been employed once 'wearing-off' has developed. However, the third-generation COMT inhibitor, opicapone has overcome these difficulties and exhibits long-lasting enzyme inhibition without the toxicity observed with previous generations of COMT inhibitors. In clinical trials and real-world PD studies opicapone improves the levodopa plasma profile and results in a significant improvement in ON time in 'fluctuating' disease, but it has not yet been included in the algorithm for early treatment.

Expert Opinion: This review argues for a shift in the positioning of COMT inhibition with opicapone in the PD algorithm and lays out a pathway for proving its effectiveness in early disease.
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http://dx.doi.org/10.1080/14737175.2021.1968298DOI Listing
September 2021

Validation of quantitative gait analysis systems for Parkinson's disease for use in supervised and unsupervised environments.

BMC Neurol 2021 Aug 28;21(1):331. Epub 2021 Aug 28.

Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal.

Background: Gait impairments are among the most common and impactful symptoms of Parkinson's disease (PD). Recent technological advances aim to quantify these impairments using low-cost wearable systems for use in either supervised clinical consultations or long-term unsupervised monitoring of gait in ecological environments. However, very few of these wearable systems have been validated comparatively to a criterion of established validity.

Objective: We developed two movement analysis solutions (3D full-body kinematics based on inertial sensors, and a smartphone application) in which validity was assessed versus the optoelectronic criterion in a population of PD patients.

Methods: Nineteen subjects with PD (7 female) participated in the study (age: 62 ± 12.27 years; disease duration: 6.39 ± 3.70 years; HY: 2 ± 0.23). Each participant underwent a gait analysis whilst barefoot, at a self-selected speed, for a distance of 3 times 10 m in a straight line, assessed simultaneously with all three systems.

Results: Our results show excellent agreement between either solution and the optoelectronic criterion. Both systems differentiate between PD patients and healthy controls, and between PD patients in ON or OFF medication states (normal difference distributions pooled from published research in PD patients in ON and OFF states that included an age-matched healthy control group). Fair to high waveform similarity and mean absolute errors below the mean relative orientation accuracy of the equipment were found when comparing the angular kinematics between the full-body inertial sensor-based system and the optoelectronic criterion.

Conclusions: We conclude that the presented solutions produce accurate results and can capture clinically relevant parameters using commodity wearable sensors or a simple smartphone. This validation will hopefully enable the adoption of these systems for supervised and unsupervised gait analysis in clinical practice and clinical trials.
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http://dx.doi.org/10.1186/s12883-021-02354-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403450PMC
August 2021

(Dys)Prosody in Parkinson's Disease: Effects of Medication and Disease Duration on Intonation and Prosodic Phrasing.

Brain Sci 2021 Aug 20;11(8). Epub 2021 Aug 20.

Center of Linguistics, School of Arts and Humanities, University of Lisbon, 1600-214 Lisbon, Portugal.

The phonology of prosody has received little attention in studies of motor speech disorders. The present study investigates the phonology of intonation (nuclear contours) and speech chunking (prosodic phrasing) in Parkinson's disease (PD) as a function of medication intake and duration of the disease. Following methods of the prosodic and intonational phonology frameworks, we examined the ability of 30 PD patients to use intonation categories and prosodic phrasing structures in ways similar to 20 healthy controls to convey similar meanings. Speech data from PD patients were collected before and after a dopaminomimetic drug intake and were phonologically analyzed in relation to nuclear contours and intonational phrasing. Besides medication, disease duration and the presence of motor fluctuations were also factors included in the analyses. Overall, PD patients showed a decreased ability to use nuclear contours and prosodic phrasing. Medication improved intonation regardless of disease duration but did not help with dysprosodic phrasing. In turn, disease duration and motor fluctuations affected phrasing patterns but had no impact on intonation. Our study demonstrated that the phonology of prosody is impaired in PD, and prosodic categories and structures may be differently affected, with implications for the understanding of PD neurophysiology and therapy.
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http://dx.doi.org/10.3390/brainsci11081100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392525PMC
August 2021

Feasibility of a Mobile-Based System for Unsupervised Monitoring in Parkinson's Disease.

Sensors (Basel) 2021 Jul 21;21(15). Epub 2021 Jul 21.

Instituto de Medicina Molecular, 1649-028 Lisbon, Portugal.

Mobile health (mHealth) has emerged as a potential solution to providing valuable ecological information about the severity and burden of Parkinson's disease (PD) symptoms in real-life conditions. : The objective of our study was to explore the feasibility and usability of an mHealth system for continuous and objective real-life measures of patients' health and functional mobility, in unsupervised settings. : Patients with a clinical diagnosis of PD, who were able to walk unassisted, and had an Android smartphone were included. Patients were asked to answer a daily survey, to perform three weekly active tests, and to perform a monthly in-person clinical assessment. Feasibility and usability were explored as primary and secondary outcomes. An exploratory analysis was performed to investigate the correlation between data from the mKinetikos app and clinical assessments. : Seventeen participants (85%) completed the study. Sixteen participants (94.1%) showed a medium-to-high level of compliance with the mKinetikos system. A 6-point drop in the total score of the Post-Study System Usability Questionnaire was observed. : Our results support the feasibility of the mKinetikos system for continuous and objective real-life measures of a patient's health and functional mobility. The observed correlations of mKinetikos metrics with clinical data seem to suggest that this mHealth solution is a promising tool to support clinical decisions.
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http://dx.doi.org/10.3390/s21154972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347665PMC
July 2021

Risk of SARS-CoV-2 Infection and COVID-19 Severity Associated With Exposure to Nonsteroidal Anti-Inflammatory Drugs: Systematic Review and Meta-Analysis.

J Clin Pharmacol 2021 12 17;61(12):1521-1533. Epub 2021 Sep 17.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

Nonsteroidal anti-inflammatory drugs (NSAIDs) were thought to increase the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus entrance into cells. Hence, it was suggested in the media that NSAIDs could lead to a higher risk of infection and/or disease severity. To determine the existence or absence of this association, we aimed to systematically evaluate the risk of SARS-CoV-2 infection and mortality and the risk of severe coronavirus disease 2019 (COVID-19) associated with previous exposure to NSAIDs. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE were searched in February 2021 for controlled studies. The results were calculated through random-effect meta-analyses and reported in terms of odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity was assessed with I test. Eleven studies were included, comprising a total of 683 715 patients. NSAID exposure did not increase the risk of having a positive test for SARS-CoV-2 infection (OR, 0.97; 95%CI, 0.85-1.11, I = 24%; 5 studies). The exposure to NSAIDs did not increase the risk of severe/critical COVID-19 disease (OR, 0.92; 95%CI, 0.80-1.05; I = 0%; 5 studies) nor all-cause mortality among patients with COVID-19 (OR, 0.86; 95%CI, 0.75-0.99; I = 14%, 4 studies). Our data did not suggest that exposure to NSAIDs increases the risk of having SARS-CoV-2 infection or increases the severity of COVID-19 disease. Also, the fragility of the studies included precludes definite conclusions and highlights the need for further robust data.
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http://dx.doi.org/10.1002/jcph.1949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426976PMC
December 2021

Direct oral anticoagulants versus vitamin K antagonists in patients with antiphospholipid syndrome: systematic review and meta-analysis.

RMD Open 2021 07;7(2)

Laboratório de Farmacologia Clinica e Terapêutica, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

Background: Despite vitamin K antagonists (VKA) being the gold standard in the prevention of thromboembolic events in antiphospholipid syndrome (APS), non-vitamin K antagonists oral anticoagulants/direct oral anticoagulants (DOACs) have been used off-label.

Objective: We aimed to perform a systematic review comparing DOACs to VKA regarding prevention of thromboembolic events, occurrence of bleeding events and mortality in patients with APS.

Methods: An electronic database search was performed through MEDLINE, CENTRAL and Web of Science. After data extraction, we pooled the results using risk ratio (RR) and 95% CI. Heterogeneity was assessed using the I². The outcomes considered were all thromboembolic events as primary, and major bleeding, all bleeding events and mortality as secondary. Evidence confidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology.

Results: We included 7 studies and a total of 835 patients for analyses. Thromboembolic events were significantly increased in DOACs arm, compared with VKA-RR 1.69, 95% CI 1.09 to 2.62, I²-24%, n=719, 6 studies. In studies using exclusively rivaroxaban, which was the most representative drug in all included studies, the thromboembolic risk was increased threefold (RR 3.36, 95% CI 1.53 to 7.37). The risks of major bleeding, all bleeding events and mortality were not significantly different from control arm. The grade of certainty of our results is very low.

Conclusions: Current evidence suggests DOACs use, particularly rivaroxaban, among patients with APS, is less effective than VKA since it is associated with 69% increased risk of thromboembolic events.

Trial Registration Number: CRD42020216178.
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http://dx.doi.org/10.1136/rmdopen-2021-001678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276293PMC
July 2021

miR-335 Targets LRRK2 and Mitigates Inflammation in Parkinson's Disease.

Front Cell Dev Biol 2021 15;9:661461. Epub 2021 Jun 15.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

Parkinson's disease (PD) is mainly driven by dopaminergic neuronal degeneration in the accompanied by chronic neuroinflammation. Despite being mainly sporadic, approximately 10% of all cases are defined as heritable forms of PD, with mutations in the leucine-rich repeat kinase () gene being the most frequent known cause of familial PD. MicroRNAs (miRNAs or miRs), including miR-335, are frequently deregulated in neurodegenerative diseases, such as PD. Here, we aimed to dissect the protective role of miR-335 during inflammation and/or neurodegenerative events in experimental models of PD. Our results showed that miR-335 is significantly downregulated in different PD-mimicking conditions, including BV2 microglia cells stimulated with lipopolysaccharide (LPS) and/or overexpressing wild-type LRRK2. Importantly, these results were confirmed in serum of mice injected with 1-methyl-1-4-phenyl-1,2,3,6-tetrahydripyridine hydrochloride (MPTP), and further validated in patients with idiopathic PD (iPD) and those harboring mutations in (LRRK2-PD), thus corroborating potential clinical relevance. Mechanistically, miR-335 directly targeted LRRK2 mRNA. In the BV2 and N9 microglia cell lines, miR-335 strongly counteracted LPS-induced proinflammatory gene expression, and downregulated receptor interacting protein 1 (RIP1) and RIP3, two important players of necroptotic and inflammatory signaling pathways. Further, miR-335 inhibited LPS-mediated ERK1/2 activation. LRRK2-Wt-induced proinflammatory gene expression was also significantly reduced by miR-335 overexpression. Finally, in SH-SY5Y neuroblastoma cells, miR-335 decreased the expression of pro-inflammatory genes triggered by α-synuclein. In conclusion, we revealed novel roles for miR-335 in both microglia and neuronal cells that strongly halt the effects of classical inflammatory stimuli or LRRK2-Wt overexpression, thus attenuating chronic neuroinflammation.
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http://dx.doi.org/10.3389/fcell.2021.661461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239393PMC
June 2021

Moving towards Integrated and Personalized Care in Parkinson's Disease: A Framework Proposal for Training Parkinson Nurses.

J Pers Med 2021 Jun 30;11(7). Epub 2021 Jun 30.

Parkinson Disease and Movement Disorders Centre, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1Y 4E9, Canada.

Delivering healthcare to people living with Parkinson's disease (PD) may be challenging in face of differentiated care needs during a PD journey and a growing complexity. In this regard, integrative care models may foster flexible solutions on patients' care needs whereas Parkinson Nurses (PN) may be pivotal facilitators. However, at present hardly any training opportunities tailored to the care priorities of PD-patients are to be found for nurses. Following a conceptual approach, this article aims at setting a framework for training PN by reviewing existing literature on care priorities for PD. As a result, six prerequisites were formulated concerning a framework for training PN. The proposed training framework consist of three modules covering topics of PD: (i) comprehensive care, (ii) self-management support and (iii) health coaching. A fourth module on telemedicine may be added if applicable. The framework streamlines important theoretical concepts of professional PD management and may enable the development of novel, personalized care approaches.
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http://dx.doi.org/10.3390/jpm11070623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304750PMC
June 2021

Clinical Diagnostic Criteria Have a High Impact on the Frequency of Dementia in Late-Stage Parkinson's Disease.

Front Neurol 2021 20;12:652424. Epub 2021 May 20.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

Cognitive impairment is a potential late feature of Parkinson's disease (PD). However, studies in patients with late-stage PD are lacking due to the particular characteristics of this population. To evaluate the frequency of dementia in late-stage PD patients and to assess the impact of using different diagnostic criteria. We conducted a cross-sectional study to estimate the frequency of dementia in late-stage PD patients using the International Parkinson and Movement Disorders Society (MDS) (Level II) clinical diagnostic criteria as the primary outcome. We also applied other diagnostic criteria [MDS (Level I), DSM-IV, and DSM-5 criteria] to determine their applicability and impact on dementia frequency. 93 participants with a mean age of 75.8 years (SD 6.8) and 16.5 years (SD 7.5) of disease duration were included. 64.3% were classified as demented using the International Parkinson and Movement Disorders Society (MDS) (Level II) clinical diagnostic criteria. We observed a high discrepancy on the frequency of dementia depending on the criteria applied [6.2% with MDS (Level I), 58.8% with DSM-IV, and 72.0% with DSM-5 criteria]. We found a frequency of dementia below what was observed in similar populations. The particular characteristics of our sample may have contributed as protective factors for late-stage dementia. Dementia frequency varied depending on the criteria used mainly due to the presence of major depression.
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http://dx.doi.org/10.3389/fneur.2021.652424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172803PMC
May 2021

Tremor and Parkinsonism in Chromosomopathies - A Systematic Review.

Mov Disord 2021 09 31;36(9):2017-2025. Epub 2021 May 31.

Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

The landscape of genetic forms of Parkinson's diseases (PD) has grown exponentially in recent years. Today, around 10% of PD cases are estimated to be of genetic etiology. However, the link between parkinsonism or tremor and chromosome disorders, both numerical and structural, has been neglected. We reviewed the occurrence and characteristics of parkinsonism and tremor syndromes in patients with chromosomic disorders. We searched PubMed for articles published until December 2018, using the non-MESH terms "Chromosomopathy," "karyotype," "chromosome," "aneuploidy," "deletion," "inversion," "insertion," "duplication," and "Parkinson," "Parkinsonism," "Tremor," and "Parkinsonian disorder." We restricted the search to human studies and selected articles for further analysis after abstract review. Tremor syndromes in which patients had another possible clinical reason for syndromes were excluded, as well as tremor syndromes associated with point mutations, imprinting syndromes, and patients presenting with other hyperkinetic disorders. Fifty-four articles were reviewed. Aneuploidies of sex chromosomes were the most common chromosomopathy. These patients more commonly exhibited postural and kinetic tremor, often meeting the description of essential tremor. In structural chromosomopathies, the most frequent association was PD and 22q11.2 deletion syndrome, but we found case reports and case series of several additional deletion and duplication syndromes. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28663DOI Listing
September 2021

Does Parkinson's Disease Increase the Risk of Atrial Fibrillation? Insights From Electrocardiogram and Risk Scores From a Case-Control Study.

Front Neurol 2021 12;12:633900. Epub 2021 May 12.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

Previous studies suggested that Parkinson's Disease (PD) patients could have an increased risk of atrial fibrillation. However, data supporting this association is not robust. We aimed to compare the potential risk of atrial fibrillation associated with PD in an age and gender matched case-control study, comparing the p-wave indexes from electrocardiograms and clinical risk scores among groups. A cross-sectional case-control study was performed. All subjects included in the analysis were clinically evaluated and subjected to a 12-lead electrocardiogram. Two blinded independent raters measured the p-wave duration. Subjects were classified as having normal P-wave duration (<120 ms), partial IAB (P-wave duration ≥ 120 ms, positive in inferior leads), and advanced IAB (p-wave duration ≥ 120 ms with biphasic morphology in inferior leads). Atrial fibrillation risk scores (CHARGE-AF, HATCH, and HAVOC) were calculated. From 194 potential participants, three were excluded from the control group due to a previous diagnosis of atrial fibrillation. Comparing the PD patients ( = 97) with controls ( = 95), there were no statistically significant differences regarding the mean p-wave duration (121 ms vs. 122 ms, = 0.64) and proportion of advanced interatrial block (OR = 1.4, 95%CI = 0.37-5.80, = 0.58). All patients had a low or medium risk of developing atrial fibrillation based on the clinical scores. There were no differences between the PD patients and controls regarding the mean values of CHARGE-AF, HATCH, and HAVOC. Our results do not support the hypothesis that PD patients have an increased risk of atrial fibrillation based on the p-wave predictors and atrial fibrillation clinical scores.
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http://dx.doi.org/10.3389/fneur.2021.633900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149901PMC
May 2021

Cardiovascular and cerebrovascular risk markers in Parkinson's disease: Results from a case-control study.

Eur J Neurol 2021 08 16;28(8):2669-2679. Epub 2021 Jun 16.

Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.

Background: The relationship between Parkinson's disease (PD) and cardiovascular and cerebrovascular disease is not yet well established. Recent data suggest an increased risk of myocardial infarction and stroke in PD patients. Therefore, we designed a study to assess surrogate markers of cardiovascular and cerebrovascular risk in PD.

Methods: We conducted a case-control study comparing PD patients recruited from a Movement Disorders Unit with controls randomly invited from a primary healthcare center. All participants underwent a detailed clinical evaluation, including medical history, physical assessment, carotid ultrasound, blood and urine analysis, and 24-h ambulatory blood pressure monitoring. The primary outcome was the carotid intima-media thickness (CIMT).

Results: We included 102 participants in each study arm. No significant difference was found in the CIMT among groups (MD: 0.01, 95% CI: -0.02, 0.04). Carotid plaques were more frequent in PD patients (OR: 1.90, 95% CI: 1.02, 3.55), although the lipid profile was more favorable in this group (LDL MD: -18.75; 95% CI: -10.69, -26.81). Nocturnal systolic blood pressure was significantly higher in PD patients (MD: 4.37, 95% CI: 0.27, 8.47) and more than half of the PD patients were non-dippers or reverse dippers (OR: 1.83, 95% CI: 1.04, 3.20).

Conclusion: We did not find a difference in CIMT between PD and controls. A higher frequency of carotid plaques and abnormal dipper profile supports the hypothesis that PD patients are not protected from cardiovascular and cerebrovascular disease.
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http://dx.doi.org/10.1111/ene.14938DOI Listing
August 2021

The Parkinson's Real-World Impact Assessment (PRISM) Study: A European Survey of the Burden of Parkinson's Disease in Patients and their Carers.

J Parkinsons Dis 2021 ;11(3):1309-1323

Department of Clinical and Movement Neurosciences, National Hospital for Neurology and Neurosurgery, London, United Kingdom.

Background: A greater understanding of the everyday experiences of people with Parkinson's disease (PD) and their carers may help improve clinical practice.

Objective: The Parkinson's Real-world Impact assesSMent (PRISM) study evaluated medication use, health-related quality of life (HRQoL) and the use of healthcare resources by people with PD and their carers.

Methods: PRISM is an observational cross-sectional study, in which people with PD and their carers completed an online survey using structured questionnaires, including the Parkinson's Disease Quality of Life Questionnaire (PDQ-39), Non-Motor Symptoms Questionnaire (NMSQuest) and Zarit Burden Interview (ZBI).

Results: Data were collected from 861 people with PD (mean age, 65.0 years; mean disease duration, 7.7 years) and 256 carers from six European countries. People with PD reported a large number of different co-morbidities, non-motor symptoms (mean NMSQuest score, 12.8), and impaired HRQoL (median PDQ-39 summary score, 29.1). Forty-five percent of people with PD reported at least one impulse control behaviour. Treatment patterns varied considerably between different European countries. Levodopa was taken in the last 12 months by 85.9% of participants, and as monotherapy by 21.8%. Carers, who were mostly female (64.8%) and the partner/spouse of the person with PD (82.1%), reported mild to moderate burden (mean ZBI total score, 26.6).

Conclusions: The PRISM study sheds light on the lives of people with PD and those who care for them, re-emphasising the many challenges they face in everyday life. The study also provides insights into the current treatment of PD in Europe.
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http://dx.doi.org/10.3233/JPD-212611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461669PMC
January 2021

Clinical Utility of Opicapone in the Management of Parkinson's Disease: A Short Review on Emerging Data and Place in Therapy.

Degener Neurol Neuromuscul Dis 2021 11;11:29-40. Epub 2021 May 11.

CNS - Campus Neurológico, Torres Vedras, Portugal.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and levodopa (L-dopa) remains the most efficacious drug treatment for PD and a gold-standard for symptom control. Nonetheless, a significant majority of PD patients develop motor fluctuations over their disease course, with a significant impact on quality-of-life, meaning control of such complications translates into a fundamental clinical need. Catechol-O-methyl transferase (COMT) inhibitors (COMT-i) are used as first-line adjuvant therapy to L-dopa for end-of-dose (EoD) motor fluctuations, since they increase L-dopa availability in the brain by inhibiting its peripheral metabolism. Opicapone (OPC), a once-daily, long-acting COMT-i, is the most recent and potent of its class, having been licensed in Europe in 2016 as an add-on to preparations of L-dopa/DOPA decarboxylase inhibitors in PD patients with EoD motor fluctuations. More recently, it has also received approval in the USA and Japan in 2020. Two high-quality positive efficacy studies (double-blind Phase III clinical trials) established OPC efficacy with significant reduction in OFF time (average 60 minutes vs placebo), without concomitant increase of distressing dyskinesias during ON time. These beneficial effects were sustained in open-label extension studies, without unexpected safety issues or adverse events, with dyskinesia having been the most frequent complaint. OPC also avoids liver toxicity and gastrointestinal issues compared with previous COMT-i. In this review, we aimed to cover OPC's lifecycle (synthesis to commercialization), its clinical pharmacological data, safety, tolerability and pharmacovigilance evidence, and discuss its role in the management of motor fluctuations in PD as well as its emerging place in international recommendations.
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http://dx.doi.org/10.2147/DNND.S256722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123942PMC
May 2021

Factors Associated with Health-Related Quality of Life in Late-Stage Parkinson's Disease.

Mov Disord Clin Pract 2021 May 23;8(4):563-570. Epub 2021 Mar 23.

Queen Square Institute of Neurology University College London London UK.

Background: There is limited knowledge on health-related quality of life (HRQoL) in late-stage Parkinson's disease (PD).

Objective: To assess factors associated with HRQoL in patients with late-stage PD, with a focus on health care provision.

Methods: The Care of Late Stage Parkinsonism (CLaSP) project is the largest study on late-stage PD to date. The current study analyzed data of 401 patients from 6 European countries in whom HRQoL was assessed with the 8-item PD Questionnaire in patients without dementia. Factors potentially associated with HRQoL were assessed and examined in linear regression analyses.

Results: Better HRQoL was associated with living at home, greater independence in activities of daily living (Schwab and England Scale), less severe disease (Hoehn and Yahr stage), better motor function (Unified PD Rating Scale Part III), and lower non-motor symptoms burden (Non-Motor Symptoms Scale [NMSS]) across all NMSS domains. Having a PDspecialist as physician for PD, contact with a PDnurse, and no hospital admission during the past 3 months were associated with better HRQoL, but having seen a physiotherapist or occupational therapist was associated with worse HRQoL.

Conclusions: The results emphasize the importance of optimizing treatment for motor and multiple non-motor symptoms to improve HRQoL in patients with late-stage PD. PD-specific health care resources, particularly PDnurses, are likely important in addressing issues to improve HRQoL in this population. Worse HRQoL in those who had recently seen a physiotherapist or occupational therapist may reflect referral based on factors not measured in this study.
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http://dx.doi.org/10.1002/mdc3.13186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088114PMC
May 2021

Expectations of Benefit in a Trial of a Candidate Disease-Modifying Treatment for Parkinson Disease.

Mov Disord 2021 08 4;36(8):1964-1967. Epub 2021 May 4.

Harvard Medical School, Boston, Massachusetts, USA.

Background: Expectations of benefit have an important therapeutic impact. How well study participants understand the concept of slowing disease progression and how their expectations of benefit are shaped in related clinical trials is not well known.

Objective: We aimed to assess expectancy and treatment arm preference of participants in a disease-modification trial in Parkinson disease (PD).

Methods: Participant expectations and treatment preference were assessed before treatment randomization in the SURE-PD3 trial (NCT02642393).

Results: We included 297 PD patients (0.71 ± 0.67 years after diagnosis). Pre-randomization, 90% of participants expressed a preference for inosine (active treatment) allocation (n = 266/297), and 53% (n = 158) expected to be "somewhat" or "a lot better" in their symptoms over 2 years of treatment with inosine.

Conclusions: Participants of a disease-modification trial in PD had likely unrealistic expectations of benefit (ie, improvement in symptoms over years), which may affect clinical trial interpretation and calls for improved education in future disease-modification trials in PD. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28630DOI Listing
August 2021

Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients.

Parkinsonism Relat Disord 2021 06 28;87:25-31. Epub 2021 Apr 28.

ACADIA Pharmaceuticals Inc., San Diego, CA, USA.

Introduction: Pimavanserin, a selective 5-HT inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment.

Methods: This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit.

Results: Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.
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http://dx.doi.org/10.1016/j.parkreldis.2021.04.012DOI Listing
June 2021
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