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Background: Pain is a frequent yet poorly characterized symptom of multiple system atrophy (MSA). Understanding the factors influencing pain and its burden is crucial for improving the symptomatic treatment and quality of life of MSA individuals., Objective: This study aimed at assessing the prevalence, characteristics, and current treatment strategies for pain in MSA., Methods: A community-based, online survey was conducted from February to May 2023. Invitations were extended to MSA individuals and informal MSA caregivers through patient advocacies and social media., Results: We included 190 persons with MSA and 114 caregivers. Eighty-seven percent of MSA individuals reported pain, which was more prevalent among women (odds ratio [OR]: 6.38 [95% confidence interval, CI: 1.27-32.08], P = 0.025) and low-income groups (OR: 5.02 [95% CI: 1.32-19.08], P = 0.018). Neck and shoulders (58%), back (45%), and legs (45%) were mostly affected. In the neck and shoulders, pain was associated with MSA core features, like orthostatic intolerance (OR: 4.80 [95% CI: 1.92-12.02], P = 0.001) and antecollis (OR: 3.24 [95% CI: 1.54-6.82], P = 0.002). Seventy-six percent of individuals experiencing pain received treatment, mostly nonsteroidal anti-inflammatory drugs (47%), acetaminophen (39%), and opioids (28%). Only 53% of respondents reported at least partial satisfaction with their current pain management. Pain mostly impacted work, household activities, and hobbies of MSA individuals, and caregivers' social activities., Conclusions: Pain is more prevalent than previously reported in MSA and particularly affects women and low-income groups. Despite its frequency, pain management remains suboptimal, highlighting an urgent therapeutic need, likely entailing an optimized management of MSA core motor and non-motor features. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA)., Background: Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion., Methods: Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion., Results: Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively., Conclusions: Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

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., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

A robust body of evidence from randomized controlled trials has established the efficacy of deep brain stimulation (DBS) in reducing off time and dyskinesias in levodopa-treated patients with Parkinson's disease (PD). These effects go along with improvements in on period motor function, activities of daily living, and quality of life. In addition, subthalamic DBS is effective in controlling drug-refractory PD tremor. Here, we review the available data from long-term observational and controlled follow-up studies in DBS-treated patients to re-examine the persistence of motor and quality of life benefits and evaluate the effects on disease progression, major disability milestones, and survival. Although there is consistent evidence from observational follow-up studies in DBS-treated patients over 5-10 years and beyond showing sustained improvement of motor control, the long-term impact of DBS on overall progression of disability in PD is less clear. Whether DBS reduces or delays the development of later motor and non-motor disability milestones in comparison to best medical management strategies is difficult to answer by uncontrolled observational follow-up, but there are signals from controlled long-term observational studies suggesting that subthalamic DBS may delay some of the late-stage disability milestones including psychosis, falls, and institutionalization, and also slightly prolongs survival compared with matched medically managed patients. These observations could be attributable to the sustained improvements in motor function and reduction in medication-induced side effects, whereas there is no clinical evidence of direct effects of DBS on the underlying disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Multiple system atrophy (MSA) is a rare and aggressive neurodegenerative disease that typically leads to death 6 to 10 years after symptom onset. The rapid evolution renders it crucial to understand the general disease progression and factors affecting the disease course., Objectives: The aims of this study were to develop a novel disease-progression model to estimate a population-level MSA progression trajectory and predict patient-specific continuous disease stages describing the degree of progress into the disease., Methods: The disease-progression model estimated a population-level progression trajectory of subscales of the Unified MSA Rating Scale and the Unified Parkinson's Disease Rating Scale using patients in the European MSA natural history study. The predicted disease continuum was validated via multiple analyses based on reported anchor points, and the effect of MSA subtype on the rate of disease progression was evaluated., Results: The predicted disease continuum spanned approximately 6 years, with an estimated average duration of 51 months for a patient with global disability score 0 to reach the highest level of 4. The predicted continuous disease stages were shown to be correlated with time of symptom onset and predictive of survival time. MSA motor subtype was found to significantly affect disease progression, with MSA-parkinsonian (MSA-P) type patients having an accelerated rate of progression., Conclusions: The proposed modeling framework introduces a new method of analyzing and interpreting the progression of MSA. It can provide new insights and opportunities for investigating covariate effects on the rate of progression and provide well-founded predictions of patient-level future progressions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: The Unified Multiple System Atrophy Rating Scale (UMSARS) is a commonly used semiquantitative rating scale to assess symptoms and measure disease progression in multiple system atrophy (MSA). However, it is currently incompletely understood which UMSARS items are the most sensitive to change and most relevant to the patient., Objective: The objective of this study was to assess sensitivity to change and patient-centricity of single UMSARS items., Methods: Data were taken from the European Multiple System Atrophy Study Group Natural History Study and the Rasagiline for Multiple System Atrophy trial. Sensitivity of change of an item of the UMSARS was assessed by calculation of a sensitivity-to-change ratio using its mean slope of progression divided by the standard deviation of the slope when modeling its progression over time. Patient-centricity was assessed through correlation of UMSARS items with quality-of-life measures., Results: Progression rates above the mean in at least one of the two studies examined here were seen for seven items of UMSARS I and 11 items of UMSARS II. These items related to key motor functions such as swallowing, speech, handwriting, cutting food, hygiene, and dressing or walking, whereas items related to autonomic dysfunction were generally less sensitive to change in either data set. More UMSARS I items were identified as patient-centric compared with UMSARS II items, and items most strongly impacting patients' quality of life were those affecting verbal communication skills, personal hygiene, and walking., Conclusion: The present results illustrate the potential to optimize the UMSARS to enhance sensitivity to change and patient centricity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages., Objective: To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology., Methods: We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference., Results: The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow., Conclusions: This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA., Objective: In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA., Methods: We analyzed [ 11 C]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA., Results: We observed a conspicuous pattern of elevated regional [ 11 C]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns., Conclusions: We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Continuous, subcutaneous (SC) levodopa/carbidopa infusion with ND0612 is under development as a treatment for patients with Parkinson's disease (PD) and motor fluctuations., Objective: Evaluate 1-year safety data., Methods: BeyoND is an open-label study evaluating the long-term safety of two ND0612 dosing regimens., Results: Of the 214 enrolled patients (24-hour SC infusion: n = 90; 16-hour SC infusion: n = 124), 120 (56%) completed 12 months of treatment. Leading causes for study discontinuation were consent withdrawal (19.6%) and adverse events (17.3%). Rates of discontinuation were reduced from 49% to 29% after a protocol revision and retraining. Systemic safety was typical for PD patients treated with levodopa/carbidopa. Most patients experienced infusion site reactions, particularly nodules (30.8%) and hematoma (25.2%), which were judged mostly mild to moderate and led to discontinuation in only 10.3% of the participants., Conclusions: Subcutaneous levodopa/carbidopa continuous infusion with ND0612 is generally safe, with typical infusion site reactions for SC delivery as the main adverse event. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Levodopa is the most effective therapy for Parkinson's disease; however, chronic treatment is associated with the development of OFF episodes, in which there is a return of parkinsonian features following a dose of levodopa and prior to the onset of benefit from the subsequent dose. OFF episodes can be a major source of disability for PD patients and frequently result in depression, apathy and an unwillingness to participate in social activities. Most currently available medical and surgical therapies are designed to reduce total daily OFF time but do not provide a rapid and reliable "on-demand" therapy for individual OFF episodes. Indeed, responses to individual doses of levodopa during an acute OFF episode are unreliable, frequently leading to partial-ON, delayed-ON, or no-ON responses even at different times in the same patient. There are now 3 therapies that are available for the on-demand treatment of OFF episodes; subcutaneous injection of apomorphine, sublingual apomorphine film, and inhaled levodopa. The first has not enjoyed widespread use in the PD community, whereas the latter 2 therapies have only recently been approved. This review will consider the currently available on-demand therapies and their potential advantages and disadvantages. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: The pathophysiology of cervical dystonia is still unclear. Recent evidence points toward a network disorder affecting several brain areas. The objective of this study was to assess the saccadic inhibition as a marker of corticostriatal function in cervical dystonia., Methods: We recruited 31 cervical dystonia patients and 17 matched healthy controls. Subjects performed an overlap prosaccade, an antisaccade, and a countermanding task on an eye tracker to assess automatic visual response and response inhibition., Results: Cervical dystonia patients made more premature saccades (P = 0.041) in the overlap prosaccade task and more directional errors in the antisaccade task (P = 0.011) and had a higher rate of failed inhibition in the countermanding task (P = 0.001)., Conclusions: The results suggest altered saccadic inhibition in cervical dystonia, possibly as a consequence of dysfunctional corticostriatal networks. Further studies are warranted to confirm whether these abnormalities are affected by the available therapies and whether this type of impairment is found in other focal dystonias. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Manual region-of-interest analysis of putaminal and middle cerebellar peduncle diffusivity distinguishes patients with multiple system atrophy (MSA) and Parkinson's disease (PD) with high diagnostic accuracy. However, a recent meta-analysis found substantial between-study heterogeneity of diagnostic accuracy due to the lack of harmonized imaging protocols and standardized analyses pipelines., Objective: Evaluation of diagnostic accuracy of observer-independent analysis of microstructural integrity as measured by diffusion-tensor imaging in patients with MSA and PD., Methods: A total of 29 patients with MSA and 19 patients with PD (matched for age, gender, and disease duration) with 3 years of follow-up were investigated with diffusion-tensor imaging and T1-weighted magnetic resonance imaging. Automated localization of relevant brain regions was obtained, and mean diffusivity and fractional anisotropy values were averaged within the regions of interest. The classification was performed using a C5.0 hierachical decision tree algorithm., Results: Mean diffusivity of the middle cerebellar peduncle and cerebellar gray and white matter compartment as well as the putamen were significantly increased in patients with MSA and showed superior effect sizes compared to the volumetric analysis of these regions. A classifier model identified mean diffusivity of the middle cerebellar peduncle and putamen as the most predictive parameters. Cross-validation of the classification model yields a Cohen's κ and overall diagnostic accuracy of 0.823 and 0.914, respectively., Conclusion: Analysis of microstructural integrity within the middle cerebellar peduncle and putamen yielded a superior effect size compared to the volumetric measures, resulting in excellent diagnostic accuracy to discriminate patients with MSA from PD in the early to moderate disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disease with limited symptomatic treatment options. Aggregation of α-synuclein in oligodendrocytes is believed to be a central mechanism of the neurodegenerative process. PD01A and PD03A are 2 novel therapeutic vaccine candidates containing short peptides as antigenic moieties that are designed to induce a sustained antibody response, specifically targeting pathogenic assemblies of α-synuclein. The objectives of the current study were to evaluate primarily the safety and tolerability of PD01A and PD03A in patients with early MSA. Thirty patients (11 women) were randomized to receive 5 subcutaneous injections of either PD01A (n = 12), PD03A (n = 12), or placebo (n = 6) in this patient- and examiner-blinded, placebo-controlled, 52-week phase 1 clinical trial (ClinicalTrial.gov identifier: NCT02270489). Immunogenicity and clinical scores were assessed as secondary objectives. Twenty-nine patients reported a total of 595 treatment-emergent adverse events (mild or moderate, n = 555; severe, n = 40). Treatment-related adverse events included 190 injection-site reactions typically observed in vaccination trials with similar per-subject incidence in the treatment groups over time. Sustained IgG titers were observed in the PD01A-treated group, and 89% of treated patients developed a PD01-specific antibody response after receiving all injections. Induced antibodies displayed clear reactivity to the α-synuclein target epitope. Titers and antibody responder rate (58%) were lower in the PD03A-treated group. In conclusion, both PD01A and PD03A were safe and well tolerated. PD01A triggered a rapid and long-lasting antibody response that specifically targeted the α-synuclein epitope. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: The objective of this study was to assess the efficacy and safety of nabilone, a synthetic tetrahydrocannabinol analogue, as a treatment for non-motor symptoms (NMS) in Parkinson's disease (PD)., Methods: This was a phase II placebo-controlled, double-blind, parallel-group, enriched enrollment randomized withdrawal trial conducted at the Medical University Innsbruck. A random sample of 47 patients with PD with stable motor disease and disturbing NMS defined by a score of ≥4 points on the Movement Disorder Society - Unified PD Rating Scale-I (MDS-UPDRS-I) underwent open-label nabilone titration (0.25 mg once daily to 1 mg twice daily, phase I). Responders were randomized 1:1 to continue with nabilone or switch to placebo for 4 weeks (phase II). The primary efficacy criterion was the change of the MDS-UPDRS-I between randomization and week 4. Safety was analyzed in all patients who received at least one nabilone dose., Results: Between October 2017 and July 2019, 19 patients received either nabilone (median dose = 0.75 mg) or placebo. At week 4, mean change of the MDS-UPDRS-I was 2.63 (95% confidence interval [CI] 1.53 to 3.74, p = 0.002, effect size = 1.15) in the placebo versus 1.00 (95% CI -0.16 to 2.16, p = 0.280, effect size = 0.42) in the nabilone-group (difference: 1.63, 95% CI 0.09 to 3.18, p = 0.030, effect size = 0.66). Seventy-seven percent of patients had adverse events (AEs) during open-label titration, most of them were transient. In the double-blind phase, similar proportions of patients in each group had AEs (42% in the placebo group and 32% in the nabilone group). There were no serious AEs., Interpretation: Our results highlight the potential efficacy of nabilone for patients with PD with disturbing NMS, which appears to be driven by positive effects on anxious mood and night-time sleep problems., Trial Registry: ClinicalTrials.gov (NCT03769896) and EudraCT (2017-000192-86). ANN NEUROL 2020;88:712-722., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Identifying individuals at risk of developing Parkinson's disease (PD) is critical to define target populations for future neuroprotective trials., Objective: The objective of this study was to apply the PREDICT-PD algorithm of risk indicators for PD in a prospective community-based study (the Bruneck study), representative of the general elderly population., Methods: PREDICT-PD risk scores were calculated based on risk factor assessments obtained at baseline (2005, n = 574 participants). Cases of incident PD were identified at 5-year and 10-year follow-ups. Participants with PD or secondary parkinsonism at baseline were excluded (n = 35). We analyzed the association of log-transformed risk scores with the presence of well-established markers as surrogates for PD risk at baseline and with incident PD at follow-up., Results: A total of 20 participants with incident PD were identified during follow-up (11 after 5 years and 9 after 10 years). Baseline PREDICT-PD risk scores were associated with incident PD with odds ratios of 2.09 (95% confidence interval, 1.35-3.25; P = 0.001) after 5 years and of 1.95 (1.36-2.79; P < 0.001) after 10 years of follow-up per doubling of risk scores. In addition, higher PREDICT-PD scores were significantly correlated with established PD risk markers (olfactory dysfunction, signs of rapid eye movement sleep behavior disorder and motor deficits) and significantly associated with higher probability for prodromal PD according to the Movement Disorder Society research criteria at baseline., Conclusions: The PREDICT-PD score was associated with an increased risk for incident PD in our sample and may represent a useful first screening step in future algorithms aiming to identify cases of prodromal PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Introduction: The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown., Objective: The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches., Methods: Case-control RNA sequencing of 2 cerebellar regions was done for 64 samples. A phenome-wide association study (pheWAS) of the differentially expressed genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. Finally, a transcriptome-wide association study (TWAS) was done to identify novel risk genes for ET., Results: We identified several novel dysregulated genes, including CACNA1A and SHF. Pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. The ET GWGAS data found calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. The TWAS also found calcium and olfactory pathways enriched. The pheWAS identified that the underexpressed differentially expressed gene, SHF, is associated with a blood pressure medication (P = 9.3E-08), which is used to reduce tremor in ET patients. Treatment of cerebellar DAOY cells with the ET drug propranolol identified increases in SHF when treated, suggesting it may rescue the underexpression., Conclusion: We found that calcium-related pathways were enriched across the GWGAS, TWAS, and transcriptome. SHF was shown to have significantly decreased expression, and the pheWAS showed it was associated with blood pressure medication. The treatment of cells with propranolol showed that the drug restored levels of SHF. Overall, our findings highlight the power of integrating multiple different approaches to prioritize ET pathways and genes. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Objective: In right-handed patients with Parkinson's disease (PD) or isolated rapid eye movement sleep behavior disorder, dopamine transporter (DAT) [(123)I]β-carboxymethyoxy-3-β-(4-iodophenyl) tropane single photon emission computed tomography (SPECT) shows predominant nigrostriatal deficit in the left striatum. This suggests that in PD patients, the nigrostriatal system of the dominant hemisphere is more susceptible to disease-related dysfunction. To confirm this hypothesis, we investigated whether the nigrostriatal function is symmetric in healthy controls and in patients with PD., Methods: In 113 right-handed healthy controls and 279 right-handed early-PD patients, we examined the striatal dopaminergic terminals function in each hemisphere using DAT-SPECT., Results: In the controls, DAT-SPECT showed symmetric specific binding ratios in the putamen and caudate nucleus of each hemisphere. In patients with PD, the specific binding ratio was lower in the left than in the right putamen., Conclusions: Right-handed healthy controls have symmetric nigrostriatal dopaminergic function. The left hemispheric predominance of nigrostriatal deficit seen in right-handed premotor and manifest PD represents an early pathological feature of the disease. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Objective: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes., Methods: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth., Results: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes., Interpretation: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Background: The Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them., Methods: We retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations., Results: Comprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1., Conclusions: The proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: Manual width measurements of the middle cerebellar peduncle on MRI were shown to improve the accuracy of an imaging-guided diagnosis of multiple system atrophy (MSA). Recently, automated volume segmentation algorithms were able to reliably differentiate patients with Parkinson's disease (PD) and the parkinsonian variant of MSA. The objective of the current study was to integrate probabilistic information of the middle cerebellar peduncle into an existing MRI atlas for automated subcortical segmentation and to evaluate the diagnostic properties of the novel atlas for the differential diagnosis of MSA (parkinsonian and cerebellar variant) versus PD., Methods: Three Tesla MRI scans of 48 healthy individuals were used to establish an automated whole-brain segmentation procedure that includes the volumes of the putamen, cerebellar gray and white matter, and the middle cerebellar peduncles. Classification accuracy of segmented volumes were tested in early-stage MSA patients (18 MSA-parkinsonism, 13 MSA-cerebellar) and 19 PD patients using a C4.5 classifier., Results: Putaminal and infratentorial atrophy were present in 77.8% and 61.1% of MSA-parkinsonian patients, respectively. Four of 18 MSA-parkinsonian patients (22.2%) had infratentorial atrophy without evidence of putaminal atrophy. Infratentorial atrophy was present in all MSA-cerebellar patients, with concomitant putaminal atrophy in 46.2% of these cases. The diagnostic algorithm using putaminal and infratentorial volumetric information correctly classified all PD patients and 96.8% of MSA patients., Conclusions: The middle cerebellar peduncle was successfully integrated into a subcortical segmentation atlas, and its excellent diagnostic accuracy outperformed existing volumetric MRI processing strategies in differentiating MSA patients with variable atrophy patterns from PD patients. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease (PD). Although recent validation studies suggest high accuracy, one unmet need is for highly specific criteria for clinical trials in early/de novo PD., Objectives: The objective of this study was to generate and test a PD diagnostic criteria termed "clinically established early PD.", Methods: We modified the Movement Disorder Society criteria to increase specificity for early PD by removing all disease duration components and changing red flags to absolute exclusions. We then estimated the sensitivity/specificity of clinically established early PD criteria in patients with disease duration <5 years, selected from a 626-patient validation study., Results: After documentation of parkinsonism, 18 individual exclusion criteria are assessed that preclude the diagnosis of "clinically established early PD." Among 212 PD and 152 non-PD patients, the estimated specificity was 95.4%, with 69.8% sensitivity., Conclusions: We describe high-specificity criteria for de novo PD, which are freely available for use in clinical trials. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Catechol-O-methyl transferase inhibitors are currently used as first-line add-on therapy to levodopa for the treatment of end-of-dose motor fluctuations in Parkinson's disease patients, as they increase levodopa bioavailability. Several factors hamper the use of current available catechol-O-methyl transferase inhibitors, that is, the moderate efficacy and multiple dosing for entacapone and the risk of liver toxicity with tolcapone. Opicapone, a new long-acting, peripherally selective, once-daily catechol-O-methyl transferase inhibitor, was recently licensed in Europe. Two phase 3 double-blind clinical trials demonstrated opicapone efficacy in reducing OFF time by an average of about 60 minutes daily compared with placebo, without increasing ON time with troublesome dyskinesias. These effects were also maintained during a subsequent open-label extension consisting of 1-year follow-up. Opicapone showed a good safety profile. From June 2016, Opicapone received the approval for marketing authorization from the European Commission as adjunctive therapy to levodopa/DOPA decarboxylase inhibitors in patients with PD and end-of-dose motor fluctuations. We aimed to review the clinical pharmacological data of opicapone, summarize its clinical efficacy and safety issues, and discuss its potential role in the management of Parkinson's disease. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease. These criteria aimed to codify/reproduce the expert clinical diagnostic process and to help standardize diagnosis in research and clinical settings. Their accuracy compared with expert clinical diagnosis has not been tested. The objectives of this study were to validate the International Parkinson and Movement Disorder Society diagnostic criteria against a gold standard of expert clinical diagnosis, and to compare concordance/accuracy of the International Parkinson and Movement Disorder Society criteria to 1988 United Kingdom Brain Bank criteria., Methods: From 8 centers, we recruited 626 parkinsonism patients (434 PD, 192 non-PD). An expert neurologist diagnosed each patient as having PD or non-PD, regardless of International Parkinson and Movement Disorder Society criteria (gold standard, clinical diagnosis). Then a second neurologist evaluated the presence/absence of each individual item from the International Parkinson and Movement Disorder Society criteria. The overall accuracy/concordance rate, sensitivity, and specificity of the International Parkinson and Movement Disorder Society criteria compared with the expert gold standard were calculated., Results: Of 434 patients diagnosed with PD, 94.5% met the International Parkinson and Movement Disorder Society criteria for probable PD (5.5% false-negative rate). Of 192 non-PD patients, 88.5% were identified as non-PD by the criteria (11.5% false-positive rate). The overall accuracy for probable PD was 92.6%. In addition, 59.3% of PD patients and only 1.6% of non-PD patients met the International Parkinson and Movement Disorder Society criteria for clinically established PD. In comparison, United Kingdom Brain Bank criteria had lower sensitivity (89.2%, P = 0.008), specificity (79.2%, P = 0.018), and overall accuracy (86.4%, P < 0.001). Diagnostic accuracy did not differ according to age or sex. Specificity improved as disease duration increased., Conclusions: The International Parkinson and Movement Disorder Society criteria demonstrated high sensitivity and specificity compared with the gold standard, expert diagnosis, with sensitivity and specificity both higher than United Kingdom Brain Bank criteria. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

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

Objective: We aimed to identify prodromal Parkinson's disease (PD) and its predictive accuracy for incident PD in an unselected elderly population and to estimate the relevance of this approach for future neuroprotection trials., Methods: We applied the recently published Movement Disorders Society (MDS) research criteria for prodromal PD to participants of the prospective population-based Bruneck Study of the 2005 assessment (n = 574, ages 55-94 years). Cases of incident PD were identified at 3-year, 5-year, and 10-year follow-up visits. We calculated predictive accuracies of baseline prodromal PD status for incident cases, and, based on them, estimated sample sizes for neuroprotection trials with conversion to PD as the primary outcome., Results: Baseline status of probable prodromal PD (n = 12) had a specificity in predicting incident PD of 98.8% (95% confidence interval, 97.3%-99.5%), a sensitivity of 66.7% (29.6%-90.8%), and a positive predictive value of 40.0% (16.7%-68.8%) over 3 years. Specificity remained stable with increasing follow-up time, sensitivity decreased to 54.6% (28.0%-78.8%) over 5 years and to 35.0% (18.0%-56.8%) over 10 years, whereas positive predictive value rose to 60.0% (31.2%-83.3%) and 77.8% (44.3%-94.7%), respectively. Sample size estimates at 80% power in an intention-to-treat approach ranged from 108 to 540 patients with probable prodromal PD depending on trial duration (3-5 years) and effect size of the agent (30%-50%)., Conclusions: Our findings show that the MDS criteria for prodromal PD yield moderate to high predictive power for incident PD in a community-based setting and may thus be helpful to define target populations of future neuroprotection trials. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Background: Imaging markers that are sensitive to parkinsonism across multiple sites are critically needed for clinical trials. The objective of this study was to evaluate changes in the substantia nigra using single- and bi-tensor models of diffusion magnetic resonance imaging in PD, MSA, and PSP., Methods: The study cohort (n = 425) included 107 healthy controls and 184 PD, 63 MSA, and 71 PSP patients from 3 movement disorder centers. Bi-tensor free water, free-water-corrected fractional anisotropy, free-water-corrected mean diffusivity, single-tensor fractional anisotropy, and single-tensor mean diffusivity were computed for the anterior and posterior substantia nigra. Correlations were computed between diffusion MRI measures and clinical measures., Results: In the posterior substantia nigra, free water was greater for PSP than MSA and PD patients and controls. PD and MSA both had greater free water than controls. Free-water-corrected fractional anisotropy values were greater for PSP patents than for controls and PD patients. PSP and MSA patient single-tensor mean diffusivity values were greater than controls, and single-tensor fractional anisotropy values were lower for PSP patients than for healthy controls. The parkinsonism effect size for free water was 0.145 in the posterior substantia nigra and 0.072 for single-tensor mean diffusivity. The direction of correlations between single-tensor mean diffusivity and free-water values and clinical scores was similar at each site., Conclusions: Free-water values in the posterior substantia nigra provide a consistent pattern of findings across patients with PD, MSA, and PSP in a large cohort across 3 sites. Free water in the posterior substantia nigra relates to clinical measures of motor and cognitive symptoms in a large cohort of parkinsonism. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Objective: To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic rapid eye movement sleep behavior disorder (IRBD) patients at risk for short-term development of clinically defined synucleinopathy., Methods: Eighty-seven patients with polysomnography-confirmed IRBD underwent 123 I-FP-CIT DAT-SPECT. Results were compared to 20 matched controls without RBD who underwent DAT-SPECT. In patients, FP-CIT uptake was considered abnormal when values were two standard deviations below controls' mean uptake. After DAT-SPECT, patients were followed up during 5.7 ± 2.2 (range, 2.6-9.9) years., Results: Baseline DAT deficit was found in 51 (58.6%) patients. During follow-up, 25 (28.7%) subjects developed clinically defined synucleinopathy (Parkinson's disease in 11, dementia with Lewy bodies in 13, and multiple system atrophy in 1) with mean latency of 3.2 ± 1.9 years from imaging. Kaplan-Meier survival analysis showed increased risk of incident synucleinopathy in patients with abnormal DAT-SPECT than with normal DAT-SPECT (20% vs 6% at 3 years, 33% vs 18% at 5 years; log rank test, p = 0.006). Receiver operating characteristics curve revealed that reduction of FP-CIT uptake in putamen greater than 25% discriminated patients with DAT deficit who developed synucleinopathy from patients with DAT deficit that remained disease free after 3 years of follow-up. At 5-year follow-up, DAT-SPECT had 75% sensitivity, 51% specificity, 44% positive predictive value, 80% negative predictive value, and likelihood ratio 1.54 to predict synucleinopathy., Interpretation: DAT-SPECT identifies IRBD patients at short-term risk for synucleinopathy. Decreased FP-CIT putamen uptake greater than 25% predicts synucleinopathy after 3 years' follow-up. These observations may be useful to select candidates for disease modification trials in IRBD. Ann Neurol 2017;82:419-428., (© 2017 American Neurological Association.)

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Background: PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome., Objective: We aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP., Methods: We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds., Results: Defined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features., Conclusions: Here, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Background: Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation., Methods: Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases., Results: Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work., Conclusions: Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Background: Dorsolateral nigral hyperintensity on iron-sensitive magnetic resonance imaging (MRI) sequences seems to be a typical finding in Parkinson's disease (PD), but most studies have involved small samples and have had heterogeneous control populations., Objectives: The objective of this study was to perform a meta-analysis on dorsolateral nigral hyperintensity as an imaging marker for PD., Methods: The methods included a systematic literature search and a hierarchical summary receiver operating characteristics curve approach., Results: Of the 16 identified studies, 10 were suitable for analysis, including 364 PD and 231 control cases. The meta-analysis showed an overall sensitivity and specificity of the absence of dorsolateral nigral hyperintensity for PD versus controls of 97.7% and 94.6% (3 and 7 Tesla) and of 94.6% and 94.4% (3 Tesla only). Descriptive analysis among the 4 studies including patients with non-PD parkinsonism showed that dorsolateral nigral hyperintensity was absent in 89.4% of cases with atypical parkinsonian disorders (n = 74), but only in 21.7% of cases with non-neurodegenerative parkinsonism (n = 69). Moreover, in 2 of these studies, the absence of dorsolateral nigral hyperintensity predicted ipsilateral dopamine-transporter deficiency with 87.5% sensitivity and 83.6% specificity., Conclusions: Visual assessment of dorsolateral nigral hyperintensity on iron-sensitive MRI sequences provides excellent diagnostic accuracy for PD versus controls. Moreover, its loss appears to be a marker of nigral pathology and holds the potential for the differentiation of neurodegenerative from non-neurodegenerative parkinsonian disorders. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

Background: Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA., Objectives: The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia., Methods: This was a phase-3, multicenter, prospective, double-blind, randomized, active, and placebo-controlled study (N = 369). Patients with cervical dystonia were randomized (3:3:1) to abobotulinumtoxinA solution for injection 500 U, abobotulinumtoxinA 500 U, or placebo. Following the double-blind phase, patients received abobotulinumtoxinA solution for injection, open-label, for up to 4 cycles. The primary outcome was change from baseline at week 4 of the Toronto Western Spasmodic Torticollis Rating Scale total score. Secondary measures included change from baseline or cycle baseline in Toronto Western Spasmodic Torticollis Rating Scale scores., Results: At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P < .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events., Conclusions: Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Introduction: We provide the first characterization of the minimally clinically important difference on the Unified Multiple System Atrophy Rating Scale in patients with the parkinsonian variant of early MSA., Methods: Data from a randomized controlled trial of rasagiline were analyzed using clinical global impression as an anchor. Because too few patients improved with treatment, analyses were limited to defining scale cutoffs that discriminated between minimal worsening and no change., Results: Based on receiver operating characteristic curves, minimally clinically important differences were 1.5 points on the activities of daily living scale, 1.5 points on the motor scale, and 3.5 points on the total scale., Conclusions: Appreciation of the minimally clinically important difference is important when deciding if statistically significant effects should influence practice. For the Unified Multiple System Atrophy Rating Scale, further work is required to establish cutoffs for improvement, extend relevance to cerebellar-predominant disease, and characterize progression rates at different disease stages. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Background: Recently, the International Parkinson and Movement Disorder Society has defined research criteria for prodromal Parkinson's disease (PD), but to date their predictive value has not yet been tested in population-based cohorts., Methods: We retrospectively applied these criteria to the longitudinal Bruneck Study cohort aged 55-94 years using recorded data on all included risk and prodromal markers that are quick and easily assessable., Results: After excluding participants with idiopathic PD or secondary parkinsonism, prevalence of probable prodromal PD in the remaining 539 participants was 2.2% (95% confidence interval, 1.2%-3.9%). Of 488 participants followed up over 5 years, 11 developed incident PD. Sensitivity of "probable prodromal PD" status for incident PD was 54.6% (95% confidence interval, 28.0%-78.8%), specificity was 99.2% (97.8%-99.8%), positive predictive value was 60.0% (31.2%-83.3%), and negative predictive value was 99.0% (97.5%-99.6%)., Conclusions: Our findings suggest that the new research criteria for prodromal PD are a promising tool to identify cases of incident PD over 5 years, arguing for their usefulness in defining target populations for disease-prevention trials. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Introduction: The aim of this study was to evaluate odor identification testing as a quick, cheap, and reliable tool to identify PD., Methods: Odor identification with the 16-item Sniffin' Sticks test (SS-16) was assessed in a total of 646 PD patients and 606 controls from three European centers (A, B, and C), as well as 75 patients with atypical parkinsonism or essential tremor and in a prospective cohort of 24 patients with idiopathic rapid eye movement sleep behavior disorder (center A). Reduced odor sets most discriminative for PD were determined in a discovery cohort derived from a random split of PD patients and controls from center A using L1-regularized logistic regression. Diagnostic accuracy was assessed in the rest of the patients/controls as validation cohorts., Results: Olfactory performance was lower in PD patients compared with controls and non-PD patients in all cohorts (each P < 0.001). Both the full SS-16 and a subscore of the top eight discriminating odors (SS-8) were associated with an excellent discrimination of PD from controls (areas under the curve ≥0.90; sensitivities ≥83.3%; specificities ≥82.0%) and from non-PD patients (areas under the curve ≥0.91; sensitivities ≥84.1%; specificities ≥84.0%) in all cohorts. This remained unchanged when patients with >3 years of disease duration were excluded from analysis. All 8 incident PD cases among patients with idiopathic rapid eye movement sleep behavior disorder were predicted with the SS-16 and the SS-8 (sensitivity, 100%; positive predictive value, 61.5%)., Conclusions: Odor identification testing provides excellent diagnostic accuracy in the distinction of PD patients from controls and diagnostic mimics. A reduced set of eight odors could be used as a quick tool in the workup of patients presenting with parkinsonism and for PD risk indication. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Background: Two phase 2 randomized, double-blind studies were designed to evaluate efficacy and safety of immediate-release (study 1) and modified-release (study 2) mavoglurant formulations in PD l-dopa-induced dyskinesia., Methods: Patients were randomized to mavoglurant 100-mg or placebo (4:3) groups (study 1) and mavoglurant 200-mg, mavoglurant 150-mg, or placebo (2:1:1) groups (study 2). Primary outcome was antidyskinetic efficacy, as measured by change from baseline to week 12 in modified Abnormal Involuntary Movement Scale total score., Results: Differences in least-squares mean (standard error) change in modified Abnormal Involuntary Movement Scale total score in week 12 did not reach statistical significance in either study (study 1: mavoglurant 100 mg twice a day versus placebo, 1.7 [1.31]; study 2: mavoglurant 150 mg twice a day (-1.3 [1.16]) and 200 mg twice a day (-0.2 [1.03]) versus placebo). Adverse events incidence was higher with mavoglurant than with placebo., Conclusions: Both studies failed to meet the primary objective of demonstrating improvement of dyskinesia with mavoglurant treatment. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

We assessed loss of dorsolateral nigral hyperintensity (DNH) on high-field susceptibility-weighted imaging (SWI), a novel magnetic resonance imaging marker for Parkinson's disease (PD), in 15 subjects with idiopathic rapid eye movement sleep behavior disorder (iRBD) and compared findings to 42 healthy controls (HCs) and 104 PD patients. We found loss of DNH in at least two thirds of iRBD subjects, which approaches the rate observed in PD and is in contrast to findings in HCs. We propose that absence of DNH on high-field SWI could identify prodromal degenerative parkinsonism in iRBD. Ann Neurol 2016;79:1026-1030., (© 2016 American Neurological Association.)