Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

The Care Needs of Patients With Cognitive Impairment in Late-Stage Parkinson's Disease.

BACKGROUND: Cognitive impairment is common in Parkinson's disease (PD), but care needs and resource use for those with significant cognitive impairment are not well established. METHODS: 675 participants with PD from the international Care of Late-Stage Parkinsonism (CLaSP) study were grouped into those without (n = 333, 49%) and with cognitive impairment (MMSE < 24/30 or diagnosis of dementia or Mild Cognitive Impairment; n = 342, 51%) and their clinical features, care needs and healthcare utilisation compared. The relationship between cognition and healthcare consultations was investigated through logistic regression. RESULTS: Cognitive impairment was associated with more motor and non-motor symptoms, less antiparkinsonian but higher rates of dementia and antipsychotic medication, worse subjective health status and greater caregiver burden. A considerable proportion did not have a pre-established cognitive diagnosis. Care needs were high across the whole sample but higher in the cognitive impairment group. Home care and care home use was higher in the cognitive impairment group. However, use of healthcare consultations was similar between the groups and significantly fewer participants with cognitive impairment had had recent PD Nurse consultations. Worse cognitive impairment was associated with lower frequency of recent PD nurse and multidisciplinary therapy consultation (physiotherapy, massage, occupational therapy, speech training and general nursing). CONCLUSIONS: Those with cognitive impairment have more severe PD, higher care needs and greater social care utilisation than those with normal cognition, yet use of health care services is similar or less. Cognitive impairment appears to be a barrier to PD nurse and multidisciplinary therapy consultations. This challenges current models of care: alternative models of care may be required to serve this population. PLAIN LANGUAGE SUMMARY: Parkinson's disease is a long-term progressive health condition. Over time, many people with Parkinson's develop problems with thinking and memory, called cognitive impairment. This can negatively impact the daily lives of the person with Parkinson's and their caregiver. It is also thought to be a barrier to accessing healthcare. How people with Parkinson's who have cognitive impairment use healthcare and detail of their care needs is not well known.We analysed data from a large sample of people with advanced Parkinson's from six European countries to investigate their symptoms, care needs and healthcare use. We compared those with cognitive impairment to (342 people) to those without cognitive impairment (333 people).We found that those with cognitive impairment had more severe Parkinson's across a range of symptoms compared to those without cognitive impairment. They also had more care needs, reported their health status to be worse, and their caregivers experienced greater strain from caring. Whilst use of other healthcare services was similar between the two groups, those with cognitive impairment were less likely to have recently seen a Parkinson's nurse than those without cognitive impairment. Further analysis showed an association between cognitive impairment and not having seen a Parkinson's nurse or therapist recently, taking psychiatric symptoms, functional disability and care home residence into account. Therapists included were physiotherapy, massage, occupational therapy, speech training and general nursing. These findings highlight unmet need. We suggest that healthcare should be more targeted to help this group of people, given their higher care needs.

Functional cognitive disorder affects reaction time, subjective mental effort and global metacognition.

We previously hypothesized that functional cognitive disorder is characterized by heightened subjective mental effort, exhausted attentional reserve and metacognitive failure. To test this hypothesis, we administered a Stroop colour-word task in which attentional demand was varied by task difficulty (congruent versus incongruent cues) and the presence of a secondary auditory stimulus (passive or active listening to an oddball-type paradigm). We measured subjective mental effort, objective performance (reaction times and accuracy), metacognition and EEG-based biomarkers of mental workload. We tested 19 functional cognitive disorder patients and 23 healthy controls. Patients reported higher levels of depression, anxiety, fatigue, pain, sleep disruption, dissociation and obsessiveness. They rated their memory as significantly poorer than healthy controls; however, accuracy did not differ between groups in any condition. In contrast to healthy controls, patients rated their performance as poorer on the congruent Stroop task with background noise compared to silent conditions. Functional cognitive disorder was consistently associated with slower reaction times but this was not exacerbated by increased attentional demand. Patients but not healthy controls reported greater mental workload in noisy conditions but EEG biomarkers were similar between groups, regardless of task difficulty. Functional cognitive disorder has significant syndromic overlap with mood disorders and chronic fatigue and pain. It is associated with global metacognitive failure whereas local (task-specific) metacognition is only selectively impaired. Patients were slower than healthy controls, which might contribute to the 'brain fog' reported in this condition. Although subjective mental effort was increased in noisy conditions, we found no evidence of attentional exhaustion in functional cognitive disorder. Our results indicate that functional cognitive disorder is a multisystem condition affecting reaction time, subjective mental effort and global metacognition.

Immune-related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta-analysis.

PURPOSE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, though uncertainty exists regarding their immune-related safety. The objective of this study was to assess the comparative safety profile (odds ratio) of ICIs and estimate the absolute rate of immune-related serious adverse events (irSAEs) in cancer patients undergoing treatment with ICIs. METHODS: We searched for randomized trials till February 2021, including all ICIs for all cancers. Primary outcome was overall irSAEs, and secondary outcomes were pneumonitis, colitis, hepatitis, hypophysitis, myocarditis, nephritis, and pancreatitis. We conducted Bayesian network meta-analyses, estimated absolute rates and ranked treatments according to the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 96 trials (52,811 participants, median age 62 years). Risk of bias was high in most trials. Most cancers were non-small cell lung cancer (28 trials) and melanoma (15 trials). The worst-ranked ICI was ipilimumab (SUCRA 14%; event rate 848/10,000 patients) while the best-ranked ICI was atezolizumab (SUCRA 82%; event rate 119/10,000 patients). CONCLUSION: Each ICI showed a unique safety profile, with certain events more frequently observed with specific ICIs, which should be considered when managing cancer patients.

Factors associated with self-rated health in people with late-stage parkinson's and cognitive impairment.

PURPOSE: To investigate the contributors to self-rated health in people with late-stage Parkinson's disease (PD) and cognitive impairment. METHODS: A secondary analysis of baseline data from the international Care of Late-Stage Parkinsonism (CLaSP) cohort study was conducted. Participants with PD and either dementia or mild cognitive impairment or MMSE < 24/30 in the absence of major depression were included if they had completed the EQ-5D-3L assessment (n = 277). Factors associated with self-rated health (EQ-5D-3L Index and Visual Analogue Scale) were investigated through multivariable linear regression. RESULTS: More severe PD (motor and non-motor) was associated with worse self-rated health. The EQ-5D-3L dimensions of Mobility, Self-Care and Usual Activities were almost universally affected; the latter two particularly severely. Being unable to perform usual activities or having moderate to extreme anxiety or depression were significantly associated with EQ-5D-3L Visual Analogue Scale, suggesting these are particularly valued. Worse motor impairment and function and the non-motor symptom domains of mood, perception, sexual function, and miscellaneous (e.g., pain) were associated with worse self-rated health, whereas greater burden of gastrointestinal symptoms was associated with better self-rated health in multivariate analysis. Better self-rated health was associated with recent PD nurse consultation, and higher doses of dopaminergic medication. CONCLUSION: Improvement of activities of daily living, mood and anxiety should be prioritised in clinical practice, with consideration of perception and sexual function in this population. Recent nurse consultations and higher antiparkinsonian doses are associated with better self-rated health, suggesting there is no room for a therapeutic nihilism in this population of people within a complex phase of PD.

The Lessebo Effect in Disease Modification Trials in Parkinson's Disease.

BACKGROUND: The impact of expectation of benefit on outcomes is well established in Parkinson's disease (PD). A reduction of a treatment effect due to a perceived placebo allocation (lessebo effect) in randomized controlled trials (RCTs) was documented for symptomatic treatments. OBJECTIVES: To evaluate the lessebo effect in disease modification RCTs (DMT) in PD. METHODS: Subject-level meta-analyses of active treatment arms of DMT (n = 1149 subjects): FS-1, FS-TOO (probability of placebo allocation/P(placebo) = 0.33) and DATATOP, PRECEPT, QE2 (P(placebo) = 0.25). We tested the association between P(placebo) and time to dopaminergic treatment initiation using a marginal Cox proportional hazards model. RESULTS: The adjusted hazard ratio (P(placebo) = 0.25 vs. 0.33) for initiation of dopaminergic treatment was 1.15 (95% CI: 0.92-1.43). CONCLUSIONS: We did not observe the lessebo effect in DMT. The necessary use of a placebo (and no active comparator) is a limitation. The prospective measurement of expectation of benefit could help to evaluate the many impacts of placebo use. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Defining the Riddle in Order to Solve It: There Is More Than One "Parkinson's Disease".

BACKGROUND: More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them. OBJECTIVE: This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for "defining the riddle" will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD. CONCLUSION: Accuracy in defining endophenotypes of "typical PD" across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort.

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High frequency of Depressive Disorders and Suicidal Phenomena in Late-Stage Parkinson´s Disease - A Cross-Sectional Study.

BACKGROUND: Depressive disorders (DD) are widely recognized as one of the most frequent neuropsychiatric disorders in Parkinson´s disease. Patients with late-stage Parkinson´s disease (LSPD) continue to be a neglected population, and little is known about DD frequency in LSPD. OBJECTIVES: To determine the frequency of DD in LSPD patients through a clinical diagnostic interview (CDI) and according to diagnostic DSM- 5 criteria. Secondary objectives were to determine the predictive ability of depressive scales to detect DD, to identify potential predictors of DD in LSPD and, to evaluate suicidal phenomena in LSPD. METHODS: A cross-sectional study including LSPD patients (≥7 years from symptom 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. Six depression scales were applied. RESULTS: 92 LSPD patients were included. 59.78% of LSPD patients had a current diagnosis of DD according to CDI, 38.04% patients had a diagnosis of major depressive disorder, and 21.72% non-major depressive disorder. Suicidal ideation was present in 36.96% of patients. All applied scales were able to detect depressive disorders. CONCLUSIONS: More than half of LSPD patients met DD diagnostic criteria and over one-third were diagnosed with major depressive disorder. Overall, the LSPD population seem to have a unique clinical phenotype regarding the frequency and features of DD, whose early identification and treatment could improve the quality of life of patients and caregivers.

The effect of catheter-based sham renal denervation in hypertension: systematic review and meta-analysis.

BACKGROUND: Renal denervation (RDN) has emerged in recent years as a possible treatment for hypertension. The first sham-controlled trial showed a small magnitude and non-significant in the blood pressure (BP) lowering effect, also due to a substantial decrease of BP in sham arm. Considering this, we aimed to quantify the magnitude of BP decrease within the sham arm of Randomized Controlled Trials (RCT) with RDN in patients with hypertension. METHODS: Electronic databases were searched since inception until January 2022 for randomized sham-controlled trials which assessed the efficacy in lowering BP of the sham intervention for catheter-based RDN in adult patients with hypertension. The outcomes were change in ambulatory/office systolic and diastolic BP. RESULTS: A total of 9 RCT were included in the analysis enrolling a total of 674 patients. Sham intervention showed a decrease in all evaluated outcomes. Office systolic BP had a reduction of -5.52 mmHg [95%CI -7.91, -3.13] and office diastolic BP of -2.13 mmHg [95%CI -3.08, -1.17]. Sham procedure for RDN also showed a reduction of -3.41 mmHg [95%CI -5.08, -1.75] in ambulatory systolic BP and - 2.44 mmHg [95%CI -3.31, -1.57] in ambulatory diastolic BP. CONCLUSION: Despite recent data indicating that RDN might be an effective treatment for patients with resistant hypertension when compared to a sham intervention, our results indicate that the sham intervention for RDN also has a significant effect on lowering Office and Ambulatory (24-h) Blood Pressure in adult patients with hypertension. This highlights that BP itself might be sensitive to placebo-like effect and also brings further difficulties in establishing the BP lowering efficacy of invasive interventions due to the magnitude of the sham effect.

Data monitoring committees in pediatric randomized controlled trials registered in ClinicalTrials.gov.

BACKGROUND: Data monitoring committees advise on clinical trial conduct through appraisal of emerging data to ensure participant safety and scientific integrity. While consideration of their use is recommended for trials performed with vulnerable populations, previous research has shown that data monitoring committees are reported infrequently in publications of pediatric randomized controlled trials. We aimed to assess the frequency of reported data monitoring committee adoption in ClinicalTrials.gov registry records and to examine the influence of key trial characteristics. METHODS: We conducted a cross-sectional data analysis of all randomized controlled trials performed exclusively in a pediatric population and registered in ClinicalTrials.gov between 2008 and 2021. We used the Access to Aggregate Content of ClinicalTrials.gov database to retrieve publicly available information on trial characteristics and data on safety results. Abstracted data included reported trial design and conduct parameters, population and intervention characteristics, reasons for prematurely halting, serious adverse events, and mortality outcomes. We performed descriptive analyses on the collected data and explored the influence of clinical, methodological, and operational trial characteristics on the reported adoption of data monitoring committees. RESULTS: We identified 13,928 pediatric randomized controlled trial records, of which 39.7% reported adopting a data monitoring committee, 49.0% reported not adopting a data monitoring committee, and 11.3% did not answer on this item. While the number of registered pediatric trials has been increasing since 2008, we found no clear time trend in the reported adoption of data monitoring committees. Data monitoring committees were more common in multicenter trials (50.6% vs 36.9% for single-center), multinational trials (60.2% vs 38.7% for single-country), National Institutes of Health-funded (60.3% vs 40.1% for industry-funded or 37.5% for other funders), and placebo-controlled (47.6% vs 37.5% for other types of control groups). Data monitoring committees were also more common among trials enrolling younger participants, trials employing blinding techniques, and larger trials. Data monitoring committees were more common in trials with at least one serious adverse event (52.6% vs 38.4% for those without) as well as for trials with reported deaths (70.3% vs 38.9% for trials without reported deaths). In all, 4.9% were listed as halted prematurely, most often due to low accrual rates. Trials with a data monitoring committee were more often halted for reasons related to scientific data than trials without a data monitoring committee (15.7% vs 7.3%). CONCLUSION: According to registry records, the use of data monitoring committees in pediatric randomized controlled trials was more frequent than previously reported in reviews of published trial reports. The use of data monitoring committees varied across key clinical and trial characteristics based on which their use is recommended. Data monitoring committees may still be underutilized in pediatric trials, and reporting of this item could be improved.

Atrial fibrillation risk on Parkinson's disease - a systematic review and meta-analysis.

The association of Parkinson's Disease (PD) with atrial fibrillation (AF) is not well established and previous studies' results were heterogeneous. This review aimed to evaluate if patients with PD are at increased risk of having AF. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science, were searched from inception May 2021. Two reviewers independently selected observational studies with data allowing to estimate the risk of atrial fibrillation in PD patients compared with no-PD controls. Pooled estimates Odds Ratio (OR) and 95% confidence intervals (CIs) were derived through meta-analysis. Heterogeneity was assessed using I2 test. The risk of bias of individual studies was evaluated using the ROBINS-I tool. The study protocol was registered at PROSPERO: CRD42020216572. Seven studies were included: five case-control studies and two cohort studies. Three of the studies included were a population-based study. No significant difference was detected between PD and controls regarding atrial fibrillation (OR 1.10, 95% CI 0.81 to 1.49). Early PD present a significant higher risk of AF (OR 1.55, 95% CI 1.00 to 2.40, I2 98%). The overall risk of bias was serious, with only two studies being considered as having moderate risk. The best evidence available do not support that there is an increased risk of AF in PD patients. Further studies are needed to better conclude if there is a relation between AF and PD.

Direct oral anticoagulants vs vitamin K antagonist on dementia risk in atrial fibrillation: systematic review with meta-analysis.

Oral anticoagulation significantly reduces the incidence of dementia in atrial fibrillation patients. However, this protective effect has not been compared between Direct Oral Anticoagulants (DOAC) and Vitamin K antagonists' anticoagulants (VKA). We conducted an electronic search for potentially eligible studies through the bibliographic databases MEDLINE, CENTRAL, ClinicalTrials.gov, EMBASE and Web of Science. The outcome of interest was dementia. Random-effects meta-analysis was performed. Nine observational studies were included and 1,175,609 atrial fibrillation patients were enrolled. DOAC therapy was associated with a significant reduction when compared with patients under VKA therapy (hazard ratio 0.89; 95% confidence interval 0.80-0.99). The grade of confidence of our results was very low due to the risk of bias. DOAC therapy is associated with a significant decrease in the risk of dementia when compared with VKA therapy. However, the low certainty of the evidence along with the paucityof clinical trials dedicated to answering this important question underscores a need for global clinical research initiatives.

A Modular In-Vehicle C-ITS Architecture for Sensor Data Collection, Vehicular Communications and Cloud Connectivity.

The growth of the automobile industry in recent decades and the overuse of personal vehicles have amplified problems directly related to road safety, such as the increase in traffic congestion and number of accidents, as well as the degradation of the quality of roads. At the same time, and with the contribution of climate change effects, dangerous weather events have become more common on road infrastructure. In this context, Cooperative Intelligent Transport Systems (C-ITS) and Internet of Things (IoT) solutions emerge to overcome the limitations of human and local sensory systems, through the collection and distribution of relevant data to Connected and Automated Vehicles (CAVs). In this paper, an intra- and inter-vehicle sensory data collection system is presented, starting with the acquisition of relevant data present on the Controller Area Network (CAN) bus, collected through the vehicle's On-Board-Diagnostics II (OBD-II) port, as well as on an on-board smartphone device and possibly other additional sensors. Short-range communication technologies, such as Bluetooth Low Energy (BLE), Wi-Fi, and ITS-G5, are employed in conjunction with long-range cellular networks for data dissemination and remote cloud monitoring. The results of the experimental tests allow the analysis of the road environment, as well as the notification in near real-time of adverse road conditions to drivers. The developed data collection system reveals itself as a potentially valuable tool for improving road safety and to iterate on the current Road Weather Models (RWMs).

Co-Designing Digital Technologies for Improving Clinical Care in People with Parkinson's Disease: What Did We Learn?

The healthcare model is shifting towards integrated care approaches. This new model requires patients to be more closely involved. The iCARE-PD project aims to address this need by developing a technology-enabled, home-based, and community-centered integrated care paradigm. A central part of this project is the codesign process of the model of care, exemplified by the active participation of patients in the design and iterative evaluation of three sensor-based technological solutions. We proposed a codesign methodology used for testing the usability and acceptability of these digital technologies and present initial results for one of them, MooVeo. Our results show the usefulness of this approach in testing the usability and acceptability as well as the opportunity to incorporate patients' feedback into the development. This initiative will hopefully help other groups incorporate a similar codesign approach and develop tools that are well adapted to patients' and care teams' needs.

Meaning in Life in Late-Stage Parkinson's Disease: Results from the Care of Late-Stage Parkinsonism Study (CLaSP) in Six European Countries.

The Care of Late-Stage Parkinsonism (CLaSP) study is a longitudinal, multicentre, prospective cohort study to assess the needs and provision of care for people with late-stage Parkinson's disease and their caregivers in six European countries. As a cross-sectional study within the CLaSP study, 509 people with Parkinson's disease completed the "Schedule-for-Meaning-in-Life-Evaluation" (SMiLE) questionnaire. We compared the results to those of a representative sample of healthy participants (n = 856). People with late-stage Parkinson's disease reported family, partnership and spirituality as the greatest areas of importance. Overall, they had lower SMiLE indices compared to healthy participants. People with late-stage Parkinson's disease rated the importance of core meaning in life areas (namely family, social relations and health) as significantly lower than the representative cohort and they also rated satisfaction as significantly lower in most areas. In conclusion, people with late-stage Parkinson's disease do have areas where they can find meaning, such as family, partnership and spirituality. However, they indicate a lack of fulfilment of their individual MiL, reflected by low satisfaction rates in the majority of meaning in life categories. The need for spiritual support for people with Parkinson's disease indicates the important role of chaplains to help people with Parkinson's disease maintain meaning in life.

Effect of Opicapone on Levodopa Pharmacokinetics in Patients with Fluctuating Parkinson's Disease.

BACKGROUND: Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with Parkinson's disease (PD) experiencing motor fluctuations. OBJECTIVES: To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens. METHODS: A total of 24 patients with PD and motor fluctuations were enrolled in an exploratory, open-label, modified cross-over trial. Participants first received levodopa/carbidopa 500/125 mg (five intakes) for 2 weeks and were then randomly assigned (1:1) to levodopa/carbidopa 400/100 mg given over either four or five daily intakes plus opicapone 50 mg for an additional 2 weeks. Levodopa 12-hour pharmacokinetics was the primary outcome (ie, excluding the effect of last/evening levodopa/carbidopa intake), with motor complications evaluated as secondary outcomes. RESULTS: Over 12-hour pharmacokinetics and compared with five-intake levodopa/carbidopa 500/125 mg without opicapone, maximal levodopa concentrations were similar or nonsignificantly higher on both levodopa/carbidopa 400/100 mg regimens plus opicapone. Despite a 100 mg lower total levodopa/carbidopa daily dose, adding opicapone 50 mg at least doubled the levodopa plasma half-life and minimal concentrations, with a significant ≈30% increase in total exposure. The levodopa fluctuation index was only significantly lower for the five intakes plus opicapone regimen (difference of -71.8%; P < 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time. CONCLUSIONS: Combining opicapone 50 mg with a 100 mg lower daily dose of levodopa provides higher levodopa bioavailability with avoidance of trough levels. Despite the lower levodopa dose, modifying the levodopa pharmacokinetic profile with opicapone was associated with decreased off time and increased on time. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

European Academy of Neurology/Movement Disorder Society-European Section Guideline on the Treatment of Parkinson's Disease: I. Invasive Therapies.

BACKGROUND AND PURPOSE: This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist should know the therapies and their place in the treatment pathway. METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging-guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered. RESULTS: Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended. CONCLUSIONS: Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

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.

European Academy of Neurology/Movement Disorder Society - European Section guideline on the treatment of Parkinson's disease: I. Invasive therapies.

BACKGROUND AND PURPOSE: This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist and general practitioners taking care of PD patients should know the therapies and their place in the treatment pathway. METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging-guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered. RESULTS: Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended. CONCLUSIONS: Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups.