Unveiling Assessment Gaps in Parkinson's Disease Psychosis: A Scoping Review.

BACKGROUND: Parkinson's disease psychosis (PDP) is a multidimensional construct that is challenging to measure. Accurate assessment of PDP requires comprehensive and reliable clinical outcome assessment (COA) measures. OBJECTIVE: To identify PDP measurement gaps in available COAs currently used in clinical and research settings. METHODS: We conducted a scoping review using Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) guidelines. We implemented a three-step search strategy in international databases with keywords related to Parkinson's disease (PD), psychosis, and COA. We analyzed studies using COA to assess PDP, classifying their items according to domains and subdomains. RESULTS: From 5673 identified studies, we included 628 containing 432 PDP core items from 32 COAs. Among the 32 COAs, 19 were PD-specific, containing 266 items, constructed as clinician-reported outcomes (ClinRO) (148 items), patient-reported outcomes (PRO) (112 items), and observer-reported outcomes (ObsRO) (six items). Across all PD-specific COAs, regardless of structure, 89.4% of the items from 27 COAs focused primarily on assessing PDP symptoms' severity, and only 9.7% of items probed the impact of PDP on a person's daily functioning. CONCLUSIONS: Symptom-based domains are currently prioritized for measuring the severity of PDP, with limited coverage of the functional impact of PDP on patients' lives. Whereas the International Parkinson and Movement Disorder Society has traditionally developed a "Unified" COA that culls items from prior COAs to form a new one, a new COA will largely need newly developed items if the functional impact of PDP is prioritized. © 2024 International Parkinson and Movement Disorder Society.

Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.

The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Huntington's Disease: Latest Frontiers in Therapeutics.

PURPOSE OF REVIEW: Huntington's disease (HD) is an autosomal-dominant disorder caused by a pathological expansion of a trinucleotide repeat (CAG) on exon 1 of the huntingtin (HTT) gene. HD is characterized by the presence of chorea, alongside other hyperkinesia, parkinsonism and a combination of cognitive and behavioural features. Currently, there are no disease-modifying therapies (DMTs) for HD, and the only intervention(s) with approved indication target the treatment of chorea. This article reviews recent research on the clinical development of DMTs and newly developed tools that enhance clinical trial design towards a successful DMT in the future. RECENT FINDINGS: HD is living in an era of target-specific drug development with emphasis on the mechanisms related to mutant Huntingtin (HTT) protein. Examples include antisense oligonucleotides (ASO), splicing modifiers and microRNA molecules that aim to reduce the levels of mutant HTT protein. After initial negative results with ASO molecules Tominersen and WVE-120101/ WVE-120102, the therapeutic landscape continues to expand, with various trials currently under development to document proof-of-concept and safety/tolerability. Immune-targeted therapies have also been evaluated in early-phase clinical trials, with promising preliminary findings. The possibility of quantifying mHTT in CSF, along with the development of an integrated biological staging system in HD are important innovations applicable to clinical trial design that enhance the drug development process. Although a future in HD with DMTs remains a hope for those living with HD, care partners and care providers, the therapeutic landscape is promising, with various drug development programs underway following a targeted approach supported by disease-specific biomarkers and staging frameworks.

Using Movement Disorder Society Unified Parkinson's Disease Rating Scale Parts 2 and 3 Simultaneously: Combining the Patient Voice with Clinician Ratings.

BACKGROUND: Regulatory recommendations favor outcomes combining objective and patient input. The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the most commonly used scale in Parkinson's disease (PD), includes patient and investigator ratings in distinct parts, but original clinimetric analyses failed to confirm the validity of combining parts by simple summing. OBJECTIVES: The aim was to develop clinimetrically valid constructs for combining patient-reported Part 2 and investigator-rated Part 3 MDS-UPDRS scores. METHODS: Using 7888 MDS-UPDRS scores, we assessed construct validity of combined Part 2 and Part 3 items using exploratory factor analysis (EFA) and graded item response theory (IRT) with threshold criteria: comparative fit index ≥0.9 (EFA) and discrimination parameters ≥0.65 (IRT). RESULTS: The direct sum of Parts 2 + 3 failed to meet the threshold for a valid outcome of PD severity (comparative fit index, CFI = 0.855). However, a two-domain construct combining item scores for tremor and non-tremor domains from Parts 2 and 3 confirmed validity, meeting both EFA and IRT criteria as distinct but correlated indices of disease severity (CFI = 0.923; discrimination mean 2.197 ± 0.480 [tremor] and 1.737 ± 0.344 [non-tremor] domains). CONCLUSIONS: The sum of Parts 2 + 3 is not clinimetrically sound. However, considering tremor and non-tremor items of both Parts 2 and 3 as two outcomes results in a valid summary of PD motor severity that leverages simultaneous patient- and investigator-derived measures. This analytic application addresses regulatory prioritizations and retains the well-validated MDS-UPDRS items. In future interventional trials, we suggest that tremor and non-tremor components of PD motor severity from Parts 2 + 3 be monitored and analyzed to accurately detect objective changes that integrate the patient's voice. © 2023 International Parkinson and Movement Disorder Society.

It Is as It Was: MDS-UPDRS Part III Scores Cannot Be Combined with Other Parts to Give a Valid Sum.

BACKGROUND: Original clinimetric analyses by the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) developers did not confirm the validity of summing the scores of its parts. Recent studies used the summed score of Part III and other parts as efficacy outcomes. OBJECTIVE: The aim of this study was to establish whether summing scores of MDS-UPDRS parts can be recommended. METHODS: Using 7466 full MDS-UPDRS scores, we applied two-step factor analysis as in the original article to reassess the validity analysis with the threshold criterion set at comparative fit index ≥0.9. RESULTS: All comparative fit indexes of any combination including Part III were lower than 0.90. CONCLUSIONS: Summing Part III MDS-UPDRS scores with other parts is not clinimetrically sound. The MDS-UPDRS is a validated four-part scale with corresponding individual part scores and needs to be used within the limits originally presented. © 2022 International Parkinson and Movement Disorder Society.

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.

Economic burden of Huntington disease in Europe and the USA: Results from the Huntington's Disease Burden of Illness study.

BACKGROUND AND PURPOSE: The prevalence of Huntington disease (HD) has increased over time; however, there is a lack of up-to-date evidence documenting the economic burden of HD by disease stage. This study provides an estimate of the annual direct medical, nonmedical, and indirect costs associated with HD from participants in the Huntington's Disease Burden of Illness (HDBOI) study in five European countries and the USA. METHODS: The HDBOI is a retrospective, cross-sectional study. Data collection was conducted between September 2020 and May 2021. Participants were recruited by their HD-treating physicians and categorized as early stage (ES), mid stage (MS), or advanced stage (AS) HD. Data were collected via three questionnaires: a case report form, completed by physicians who collected health care resource use associated with HD to compute direct medical cost, and optional patient and caregiver questionnaires, which included information used to compute nondirect medical and indirect costs. Country-specific unit cost sources were used. RESULTS: HDBOI cost estimates were €12,663 (n = 2094) for direct medical costs, €2984 (n = 359) for nondirect medical costs, and €47,576 (n = 436) for indirect costs. Costs are higher in patients who are at later stages of disease; for example, direct medical costs estimates were €9220 (n = 846), €11,885 (n = 701), and €18,985 (n = 547) for ES, MS, and AS, respectively. Similar trends were observed for nondirect and indirect costs. Costs show large variations between patients and countries. CONCLUSIONS: Cost estimates from the HDBOI study show that people with HD and their caregivers bear a large economic burden that increases as disease progresses.

Genetic Testing in Clinical Movement Disorders: A Case-Based Review.

Genetics are fundamental to understanding the pathophysiology of neurological disease, including movement disorders. Genetic testing in clinical practice has changed dramatically over the last few decades. While the likelihood of establishing an etiological diagnosis is greater now with increased access to testing and more advanced technologies, clinicians face challenges when deciding whether to test, then selecting the appropriate test, and ultimately interpreting and sharing the results with patients and families. In this review, we use a case-based approach to cover core aspects of genetic testing for the neurologist, namely, genetic testing in Parkinson's disease, interpretation of inconclusive genetic test reports, and genetic testing for repeat expansion disorders using Huntington disease as a prototype.

Canadian Healthcare Access in Parkinson's Disease and COVID-19: A Cross-Sectional Survey.

BACKGROUND: Parkinson's disease (PD) is a common chronic neurodegenerative condition. As a result of the COVID-19 pandemic, healthcare provision faced challenges worldwide. We aimed to explore how the COVID-19 pandemic changed healthcare experiences for people living with Parkinson's disease (PwP) in Canada. METHODS: We conducted a national cross-sectional online survey about healthcare access for PwP in 2020. Participants (n = 298) were recruited through Parkinson Canada, the national patient association and its provincial partners, that advertised the study in a monthly newsletter. We used descriptive statistics and multivariate regression modelling to test associations of interest. A P < 0.05 was deemed statistically significant. RESULTS: During the COVID-19 pandemic, PwP reported greater difficulty obtaining PD-related healthcare services and lesser satisfaction with healthcare provision compared to pre-pandemic experiences. Dissatisfaction with care was associated with the presence of barriers to access services, a lack of confidence in accessing services remotely, pre-pandemic care dissatisfaction, and difficulty in obtaining care during the COVID-19 pandemic. Unmet care needs were associated with a lack of confidence in accessing services remotely, dissatisfaction with pre-pandemic care, difficulty obtaining pre-pandemic care, and communication challenges. CONCLUSION: Our results suggest that healthcare experiences for PwP significantly changed during the COVID-19 pandemic, with challenges in access to virtual care. Poorer pre-pandemic care experiences were amplified during the pandemic.

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.

Resolving Missing Data from the Movement Disorder Society Unified Parkinson's Disease Rating Scale: Implications for Telemedicine.

BACKGROUND: Telemedicine has become standard in clinical care and research during the coronavirus disease 2019 pandemic. Remote administration of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (Motor Examination) precludes ratings of all items, because Rigidity and Postural Stability (six scores) require in-person rating. OBJECTIVE: The objective of this study was to determine imputation accuracy for total-sum and item-specific MDS-UPDRS Motor Examination scores in remote administration. METHODS: We applied multivariate imputation by chained equations techniques in a cross-sectional dataset where patients had one MDS-UPDRS rating (International Translational Program, n = 8,588) and in a longitudinal dataset where patients had multiple ratings (Rush Program, n = 396). Successful imputation was stringently defined as (1) generalized Lin's concordance correlation coefficient >0.95, reflecting near-perfect agreement between total-sum score with complete data and surrogate score, calculated without patients' actual Rigidity and Postural Stability scores; and (2) perfect agreement for item-level scores for Rigidity and Postural Stability items. RESULTS: For total-sum score when Rigidity and Postural Stability scores were withdrawn, using one or multiple visits, multivariate imputation by chained equations imputation reached near-perfect agreement with the original total-sum score. However, at the item level, the degree of perfect agreement between the surrogate and actual Rigidity items and Postural Stability scores always fell below threshold. CONCLUSIONS: The MDS-UPDRS Part III total-sum score, a key clinical outcome in research and in clinical practice, can be accurately imputed without the Rigidity and Postural Stability items that cannot be rated by telemedicine. No formula, however, allows for specific item-level imputation. When Rigidity and Postural Stability item scores are of key clinical or research interest, patients with PD must be scored in person. © 2022 International Parkinson and Movement Disorder Society.

Small and Large Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia of Parkinson's Disease Patients.

BACKGROUND: Although previously thought to be asymptomatic, recent studies have suggested that magnetic resonance imaging-visible perivascular spaces (PVS) in the basal ganglia (BG-PVS) of patients with Parkinson's disease (PD) may be markers of motor disability and cognitive decline. In addition, a pathogenic and risk profile difference between small (≤3-mm diameter) and large (>3-mm diameter) PVS has been suggested. OBJECTIVE: The aim of this study was to examine associations between quantitative measures of large and small BG-PVS, global cognition, and motor/nonmotor features in a multicenter cohort of patients with PD. METHODS: We performed a cross-sectional study examining the association between large and small BG-PVS with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-IV and cognition (Montreal Cognitive Assessment) in 133 patients with PD enrolled in the Ontario Neurodegenerative Disease Research Initiative study. RESULTS: Patients with PD with small BG-PVS demonstrated an association with MDS-UPDRS Parts I (P = 0.008) and II (both P = 0.02), whereas patients with large BG-PVS demonstrated an association with MDS-UPDRS Parts III (P < 0.0001) and IV (P < 0.001). BG-PVS were not correlated with cognition. CONCLUSIONS: Small BG-PVS are associated with motor and nonmotor aspects of experiences in daily living, while large BG-PVS are associated with the motor symptoms and motor complications. © 2022 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.

Vitamins and Infusion of Levodopa-Carbidopa Intestinal Gel.

Levodopa-carbidopa intestinal gel infusion (LCIG) is an established therapy for advanced Parkinson disease (PD), resulting in a significant improvement of quality of life. With increased LCIG adoption worldwide, potential complications due to abnormal vitamin absorption or metabolism have been reported in these patients. Neurologists are unfamiliar with vitamins physiology and pathophysiological mechanisms in case of their deficiency. Unfortunately, clinical and laboratory guidelines related to vitamin monitoring and supplementation in the context of treatment with LCIG are not available. We herein summarize the current knowledge on three vitamins that are reduced with LCIG therapy reporting on their physiology, laboratory testing, and clinical impact of their deficiency/excess. In addition, we proposed an opinion-based recommendation for clinicians treating LCIG patients. Patients and caregivers should be informed about the risk of vitamin deficiency. Vitamin B12, homocysteine, and methylmalonic acid (MMA) should be tested before starting LCIG, six months after and once/year thereafter. Vitamin B6 and folate testing is not universally available but it should be considered if homocysteine is elevated but MMA and/or total vitamin B12 are normal. Prophylaxis of vitamin deficiency should be started as soon as LCIG is implemented, possibly even before. Dietary recommendations are enough in most patients although a subgroup of patients is at higher risk and should receive Vitamin B12 regularly and cycles of B6. Finally, once diagnosed a vitamin deficiency should be readily treated and accompanied by clinical and laboratory monitoring. Resistant cases should receive non-oral routes of administration and possibly discontinue LCIG, even temporarily.

Pilot Evaluation of a Pragmatic Network for Integrated Care and Self-Management in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder that challenges care provision. A multidisciplinary care model needs to be impactful, feasible, and viable economically for widespread utilization. Supportive evidence is lacking. OBJECTIVE: The objective of this study was to evaluate the implementation and impact of a pragmatic network for PD care, the Integrated Parkinson Care Network (IPCN). METHODS: A 6-month, pre-post design, single-center, phase 2 study for complex interventions for patients with newly diagnosed (<1 year) and advanced (diagnosis >8 years) PD was used to assess a patient-centered care model based on integrated care, self-management support, and technology-enabled care. We comprehensively assessed the implementation of care paths, change in selected health and care quality outcomes after the Integrated Parkinson Care Network program, and costs analyses. RESULTS: We recruited 100 participants in 6 months. Overall, the top care priorities were speech and communication (33.7%), anxiety and depression (31.6%), and mobility, balance, and falls (29.6%), and the most commonly (>45%) used resources were speech-language pathology, community seniors services, and physiotherapy. Care priorities were met successfully in 90.6% of the cases, and there was a positive change in the Parkinson's Disease Questionnaire-8 (2.7; 95% confidence interval, 0.4-5.0; statistically significant in the advanced group), the perception of support for chronic care (Patient Assessment of Chronic Illness Case score, 1.1; 95% confidence interval, 0.9-1.4), and self-management (5As score, 1.2; 95% confidence interval, 1.0-1.4). The total cost of the Integrated Parkinson Care Network was C$1367 per patient. CONCLUSIONS: A pragmatic development of a care delivery network based on integrated care and self-management support is promising for its feasibility, impact, and a sustainable cost. © 2020 International Parkinson and Movement Disorder Society.

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

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.

Are genetic and idiopathic forms of Parkinson's disease the same disease?

Genetic forms represent a small fraction of Parkinson's disease (PD) but their discovery has revolutionized research in the field, putting α-synuclein in the spotlight, and uncovering other key neuropathological mechanisms of the disease. The question of whether genetic and idiopathic PD (iPD) correspond to a same disease entity is not simply philosophical, has implications for the discovery of the biological background of PD and for the development of novel therapeutic strategies that may also be applicable to the larger iPD group. Here, we review the current landscape of what has been labeled genetic PD and critically discuss the rational for merging or separating genetic and idiopathic forms of PD as the same or different disease entities. We conclude by addressing the potential implications for future research.

Glycopyrrolate Improves Disability From Sialorrhea in Parkinson's Disease: A 12-Week Controlled Trial.

OBJECTIVE: The objective of this study was to assess the 12-week efficacy and safety of oral glycopyrrolate for moderate-to-severe sialorrhea in Parkinson's disease (PD). BACKGROUND: Chronic moderate-to-severe sialorrhea has a negative impact on quality of life in PD. There is no robust evidence for oral treatments for sialorrhea longer than 1 week. METHODS: This was a 12-week, double-blinded, placebo-controlled, parallel phase II study in patients with PD and Movement Disorder Society-Unified Parkinson's Disease Rating Scale item 2.2 > 2. The intervention was glycopyrrolate up to 4.5 mg/d; the primary outcome was sialorrhea related-disability (Radboud Oral Motor Inventory for Parkinson's Disease-Saliva). We used an intention-to-treat analysis. A P < 0.05 was deemed significant. RESULTS: We recruited 28 patients (age, 71.1 ± 6.9 years; PD duration, 11.4 ± 7.2 years; Radboud Oral Motor Inventory for Parkinson's Disease-Saliva, 22.4 ± 5.7). Glycopyrrolate was superior to placebo at 12 weeks in the Radboud Oral Motor Inventory for Parkinson's Disease-Saliva (between-group difference, 5.3; 95% confidence interval, 1.0-9.6). Dry mouth was the most common adverse event (glycopyrrolate, n = 6; placebo, n = 2). CONCLUSIONS: The results support the efficacy of glycopyrrolate to treat sialorrhea-related disability up to 12 weeks and contribute to addressing unmet nonmotor care needs in PD. © 2020 International Parkinson and Movement Disorder Society.

Synuclein Meeting 2019: where we are and where we need to go.

The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein Meeting is taking place in Ofir, a city in the outskirts of Porto, Portugal. The meeting is entitled 'Synuclein Meeting 2019: Where we are and where we need to go'. It has now been 22 years since the initial report of the genetic and pathological association between alpha-synuclein and Parkinson's disease (PD). The field has grown and matured, and major advances have been made. We are witnessing exciting times, with the first clinical trials being conducted that target synuclein, and bring the hope of novel therapies for patients with PD and their families. However, we still face many challenges and need to address fundamental questions for the field to progress to where we need to go: having biomarkers and effective therapies for PD and other synucleinopathies. In this context, we have designed the Synuclein Meeting 2019 with a different format. The program will include sessions in the format of a round-table discussion, to break away from the more rigid format of regular scientific meetings based on oral presentations. Our goal was to create opportunities for discussing the major questions in the field of synuclein and related human disorders, and challenge dogmatic ideas that require a critical revision in light of the most recent knowledge. In this issue, we assembled a series of comprehensive overviews of major topics, questions, and challenges in the field, that will be discussed in the meeting. We are confident that this special issue will be an instrumental reference for inspiring novel paths for future discoveries in the synuclein field and generate other discussions in the scientific community. This is the Preface for the Special Issue "Synuclein". Cover Image for this issue: doi: 10.1111/jnc.14520.

MDS evidence-based review of treatments for essential tremor.

BACKGROUND: Essential tremor is one of the most prevalent movement disorders. Many treatments for essential tremor have been reported in clinical practice, but it is uncertain which options have the most robust evidence. The International Parkinson and Movement Disorder Society commissioned a task force on tremor to review clinical studies of treatments for essential tremor. OBJECTIVES: To conduct an evidence-based review of current pharmacological and surgical treatments for essential tremor, using standardized criteria defined a priori by the International Parkinson and Movement Disorder Society. METHODS: We followed the recommendations of the International Parkinson and Movement Disorder Society Evidence Based Medicine Committee. RESULTS: Sixty-four studies of pharmacological and surgical interventions were included in the review. Propranolol and primidone were classified as clinically useful, similar to Topiramate, but only for doses higher than 200 mg/day. Alprazolam and botulinum toxin type A were classified as possibly useful. Unilateral Ventralis intermedius thalamic DBS, radiofrequency thalamotomy, and MRI-guided focused ultrasound thalamotomy were considered possibly useful. All the above recommendations were made for limb tremor in essential tremor. There was insufficient evidence for voice and head tremor as well as for the remaining interventions. CONCLUSION: Propranolol, primidone, and topiramate (>200 mg/day) are the pharmacological interventions in which the data reviewed robustly supported efficacy. Their safety profile and patient preference may guide the prioritization of these interventions in clinical practice. MRI-guided focused ultrasound thalamotomy was, for the first time, assessed and was considered to be possibly useful. There is a need to improve study design in essential tremor and overcome the limitation of small sample sizes, cross-over studies, short-term follow-up studies, and use of nonvalidated clinical scales. © 2019 International Parkinson and Movement Disorder Society.