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The pathophysiology of Parkinson’s disease (PD) tremor remains incompletely understood and there is a lack of clinical trials specifically addressing its pharmacological treatment. Levodopa is the most efficacious drug for most patients and should be used as primary approach to control troublesome tremor. While the efficacy of oral dopamine agonists on PD tremor has been demonstrated in controlled trials, there is no evidence of greater antitremor efficacy compared to levodopa. The magnitude of the antitremor effect of anticholinergics is generally lower than that of levodopa. Due to their adverse effects, anticholinergics have a limited role in selected young and cognitively intact patients. Propranolol may improve resting and action tremor and may be considered as an adjunct in patients with insufficient tremor response to levodopa and this also applies to clozapine, despite its unfavorable adverse effect profile. Treating motor fluctuations with MAO-B and COMT inhibitors, dopamine agonists, amantadine, or on-demand treatments such as subcutaneous or sublingual apomorphine and inhaled levodopa as well as with continuous infusions of levodopa or apomorphine will improve off period tremor episodes. For patients with drug-refractory PD tremor despite levodopa optimization deep brain stimulation and focused ultrasound are first-line considerations. Surgery can also be highly effective for the treatment medication-refractory tremor in selected patients without motor fluctuations. The present review highlights the clinical essentials of parkinsonian tremor, critically examines available trial data on the effects of medication and surgical approaches and provides guidance for the choice of treatments to control PD tremor in clinical practice.

Multiple system atrophy is a rapidly progressive and fatal neurodegenerative disorder. While numerous preclinical studies suggested efficacy of potentially disease modifying agents, none of those were proven to be effective in large-scale clinical trials. Three major strategies are currently pursued in preclinical and clinical studies attempting to slow down disease progression. These target α-synuclein, neuroinflammation, and restoration of neurotrophic support. This review provides a comprehensive overview on ongoing preclinical and clinical developments of disease modifying therapies. Furthermore, we will focus on potential shortcomings of previous studies that can be avoided to improve data quality in future studies of this rare disease.

Levodopa remains the cornerstone treatment for Parkinson's disease (PD) but its use is associated with the development of 'wearing-off' fluctuations and other motor and non-motor complications over time. Adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/dopa decarboxylase (DDC) inhibitor therapy reduces fluctuations in the profile of plasma levodopa levels following oral dosing, and can therefore be beneficial for the management of motor complications. The objective of the EPSILON study is to investigate the efficacy of opicapone (OPC; a third-generation, once-daily COMT inhibitor) in enhancing the clinical benefit of levodopa in patients in earlier stages of PD, without end-of-dose motor fluctuations.EPSILON is a phase III, double-blind, randomised, placebo-controlled and parallel-group study, designed to evaluate the efficacy and safety of OPC as add-on to levodopa/DDC inhibitor therapy in patients with early PD who do not exhibit signs of motor complications. Eligible patients will be randomised (1:1) to receive OPC 50 mg or placebo, in addition to their existing levodopa/DDC inhibitor therapy, over a 24-week, double-blind treatment period, after which they will have the option of entering an additional 1-year, open-label extension period, during which all patients will receive OPC 50 mg.The primary efficacy endpoints are change in Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III total score from baseline to the end of the double-blind period (double-blind phase) and change in MDS-UPDRS Part IV total score from open-label baseline to the end of the open-label period (open-label phase). Secondary outcomes during the double-blind phase will include other measures of PD symptoms, including quality of life, non-motor symptoms, and development of motor fluctuations. Safety assessments will include evaluation of treatment-emergent adverse events, laboratory safety parameters, suicidality and impulse control disorders.European Union Drug Regulating Authorities Clinical Trials Database (number 2020-005011-52).

With the growing hope that disease-modifying treatments could target the molecular basis of neurodegenerative diseases even before the onset of symptoms, there is mounting pressure to define disease entities based on pathophysiology rather than on clinical syndromes. The Alzheimer’s disease research community has recently transitioned from diagnostic criteria based on an amnestic syndrome to a purely biomarker-based disease definition, relying on the demonstration of amyloid-beta pathology, tau pathology, and neurodegeneration. In contrast, current diagnostic criteria for Parkinson’s disease still rely on the presence of the well-described clinical syndrome of parkinsonism, with the addition of characteristic motor- and non-motor signs and symptoms. However, there is now unequivocal evidence that Parkinson’s disease starts years before the onset of parkinsonism. Furthermore, neuropathologically defined Lewy body disease is clinically heterogeneous, combining a range of motor, non-motor, dopaminergic and non-dopaminergic features. Finally, clinically defined Parkinson’s disease has diverse underlying etiologies most, but not all, associated with α-synuclein positive Lewy pathology. In light of recent scientific advances, we propose a biologically based definition for the diagnosis of Parkinson's disease, initially to be used for research purposes. The criteria use a three-component ‘G-S-N’ system. The first is documentation of defined gene variants (‘G’), which cause or strongly predispose to PD as the most upstream component. The second is α-synuclein pathology (‘S’), currently defined as pathological α-synuclein deposition in tissue or positive α-synuclein seeding assays. The third is evidence of underlying neurodegeneration (‘N’), currently defined by specific neuroimaging procedures. The associated clinical syndrome (‘C’) is defined by a single high-specificity feature or multiple lower-specificity features. Initiating this transition will enable the field to fuel both basic and clinical research and move closer to the precision medicine required to develop clinically meaningful disease-modifying therapies. We acknowledge current limitations, ethical implications, and the need for prospective validation of this approach.

BackgroundParkinson’s Disease (PD) has been associated with a distinct odour, strongest in sebum-rich areas. Thermal Desorption – Gas Chromatography – Mass Spectrometry (TD-GC-MS) has revealed volatile signatures that distinguish individuals with Parkinson’s Disease (PD) from healthy controls. Here, we applied the same method, including subjects with isolated REM sleep behaviour disorder (iRBD) to examine the volatiles in sebum and compare this with that found in PD subjects and control participants. Participants with iRBD have a high likelihood for conversion to overt clinical synucleinopathies like PD, Dementia with Lewy Bodies (DLB) or (less commonly) Multiple System Atrophy (MSA).MethodsSubjects with clinically established PD (n=16) or iRBD (n=9) as well as healthy controls (n=9) were included. Following methods established in our laboratory, sebum was sampled from each participant using cotton gauze and the headspace from these swabs, analysed directly with TD-GC-MS1,2. Univariate and multivariate analysis was employed to probe the differences between volatile metabolites found for each phenotype. Putative identifications were assigned using spectral matching against the Golm metabolome and NIST spectral databases.FindingsWe can completely classify each phenotype using the sampled volatilome from which we built models with logistic regression analysis. The classification between PD and control improved on previously published work, from 85% to 100%. Putatively annotated molecules include alkanes, aldehydes, fatty acid methyl esters (FAMEs), and three metabolites namely purine, tropinone and oleamide. Investigation of highly ranked features revealed 18 features that showed intermediate expression in samples from iRBD participants.InterpretationTD-GC-MS can differentiate volatile metabolite signatures from sebum between PD, RDB and control samples. More than 70% of the identifiable metabolites that permit this discrimination were putatively annotated as hydrocarbons and fatty acid methyl esters (FAMEs). Our prior work indicates that these components arise from larger lipid molecules that decompose during the experiment2. Features putatively annotated as tropinone, oleamide and purine, have previously been linked with neuroprotection, sleep induction and antioxidation, respectively, are significantly different between the three groups of participants, along with FAMEs and hydrocarbons.FundingWe thank Michael J Fox Foundation (grant ref:12921) and Parkinson’s UK (grant ref: K-1504) for funding this study and Community of Analytical and Measurement Sciences (CAMS) for supporting DT’s research position. This work was supported by the BBSRC (award BB/L015048/1) for instrumentation used in this work and by a DTA to CW-D (project ref. 2113640). We also thank our recruitment centres for their enthusiasm and rigor during the recruitment process. We are very grateful to all the participants who took part in this study as well as PIs and nurses at the recruiting centres.

Despite levodopa's superior efficacy in reducing the motor symptoms of Parkinson's disease (PD), its risk to induce motor complications requires consideration of the pros and cons of initiating treatment with levodopa-sparing strategies. The current drive toward early levodopa monotherapy is primarily driven by safety and tolerability concerns with dopamine agonists and only mild efficacy of other available approaches. Recently, P2B001, a novel once-daily combination of low-dose, extended-release formulations of pramipexole and rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this drug evaluation, we review the preclinical and current clinical data for P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.Parkinson’s disease is the fastest growing neurologic disorder across the globe. Once diagnosed, it is now generally agreed that there is no clinical rationale to postpone symptomatic treatment in people who develop Parkinson’s-related disability. There are three main treatment options available for use in early Parkinson’s disease: levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Of these, there is a current push toward using levodopa as the main first-line therapy. This is primarily because of the significant safety and tolerability concerns with dopamine agonists and only mild efficacy of MAO-B inhibitors. Recently, P2B001, a novel drug formulation combining once-daily, extended-release, low dosages of the dopamine agonist pramipexole and the MAO-B inhibitor rasagiline (0.6 mg and 0.75 mg respectively), has entered clinical development. In this article, the authors review the preclinical and current clinical data on P2B001 and its components. The P2B001 combination has the potential to provide greater efficacy than either pramipexole or rasagiline alone and a better tolerability profile compared to higher dosage dopamine agonist monotherapy, while maintaining the advantage of lower motor complication risk than levodopa.

Background Ophthalmological disorders are common and frequently disabling for people with Parkinson’s disease (PD). However, details on the prevalence, severity and impact of ophthalmological disorders thus far lacking. We aimed to identify PD patients with undetected ophthalmological disorders in a large cross-sectional, observational study. Methods We previously delivered a screening questionnaire to detect ophthalmological symptoms (Visual impairment in PD questionnaire; VIPD-Q) to 848 patients. Here, we report on a subgroup of 102 patients who received complete ophthalmological assessment aimed at identifying clinically relevant ophthalmological diseases, which were classified as either vison-threatening or not. Impact on daily life functioning was measured using the visual functioning-25 questionnaire (VFQ-25) and fall frequency. Results Almost all patients (92%) had one or more clinically relevant ophthalmological disorders. Of those, 77% had a potentially vision-threatening disease, while 34% had a potentially treatable ophthalmological disease which impacted on quality of life. The most prevalent ophthalmological disorders were dry eyes (86%), ocular misalignment (50%) and convergence insufficiency (41%). We found a weak but significant association between clinically relevant ophthalmological diseases and both fall frequency (R2 = 0.15, p = 0.037) and VFQ-25 score (R2 = 0.15, p = 0.02). The VIPD-Q could not correctly identify patients with relevant ophthalmological disorders. Conclusions Surprisingly, in our study sample, many participants manifested previously undetected ophthalmological diseases, most of which threatened vision, impacted on daily life functioning and were amenable to treatment. Screening for these ophthalmological disorders using a questionnaire asking about symptoms seems insufficient. Instead, episodic ophthalmological assessments should be considered for PD patients, aiming to identify vision-threatening yet treatable diseases. Trial registration Dutch Trial Registration, NL7421.

© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way., Introduction: There is currently a resurgence of levodopa as the initial treatment of choice for most patients with Parkinson's disease, albeit at lower doses than previously used. The addition of adjuvant treatments (including MAO-B inhibitors, COMT inhibitors and dopamine agonists) is an established strategy to reduce motor complications that develop with sustained levodopa therapy. Areas covered: In this narrative review, the authors discuss the evidence underpinning current levodopa optimization strategies, during early disease and once motor complications occur. To support the discussion, the authors performed a broad PubMed search with the terms 'levodopa/L-dopa/L-Dopa, and Parkinson's disease,' restricted to clinical trials. There is now a wealth of evidence that improving levodopa delivery to the brain improves outcomes and we discuss how agents can be combined earlier in the course of disease to leverage the full potential of this strategy. Expert opinion: Levodopa remains the cornerstone of antiparkinsonian therapy. Several promising advances in formulation have been made and include novel extended-release oral drugs as well as non-oral delivery systems. However, evidence has long suggested that anti-parkinsonian medications may be better used in combination earlier in the disease, and consequently patients will benefit from low doses of several agents rather than ever larger levodopa doses., This paper was supported by BIAL, who procured medical writing support but had no other influence on the content of the paper. No author received any remuneration for the preparation of this article.

Background: Recurrent falls represent a major source of serious adverse health outcomes in the general older population. Gait impairment has been linked to recurrent falls, but there are only limited long-term data on this association. Objectives: The objective of the study was to investigate the association of gait disorders (GDs) and gait tests with future falls in an existing longitudinal population-based cohort. Method: The study was performed in participants of the Bruneck Study cohort 2010 aged 60–97 years, with prospective 5-year follow-up. At baseline, participants underwent a clinical gait assessment (to determine neurological and non-neurological GDs according to an established classification) and were also evaluated by quantitative and semiquantitative gait tests (Hauser Index, Tinetti balance and gait test, and gait speed). Logistic regression analysis adjusted for age and sex was used to determine the relationship of baseline variables with incident recurrent falls at 5-year follow-up. Results: Of 328 included participants, 22 (6.7%) reported recurrent falls at follow-up. Baseline presence of GDs was associated with recurrent falls at follow-up (odds ratio [OR] 4.2; 95% confidence interval [CI] 1.6–11.1; p = 0.004), and this effect was largely driven by neurological GDs (OR 5.5; 95% CI 1.7–17.4; p = 0.004). All 3 simple gait tests were predictive for incident falls (Hauser Index, p = 0.002; Tinetti test, p = 0.006; and gait speed, p < 0.001). Conclusions: Clinical assessment of GDs and gait tests both had independent significant predictive value for recurrent falls over a 5-year follow-up period. This highlights the potential of such assessments for early fall risk screening and timely implementation of fall-preventive measures.

Summary The efficacy of amantadine in the symptomatic treatment of patients with Parkinson's disease, discovered serendipitously more than 50 years ago, has stood the test of time and the drug is still commonly used by neurologists today. Its pharmacological actions are unique in combining dopaminergic and glutamatergic properties, which account for its dual effect on parkinsonian signs and symptoms and levodopa-induced dyskinesias. Furthermore, amantadine has additional and less well-defined pharmacological effects, including on anticholinergic and serotonergic activity. Evidence from randomised controlled trials over the past 5 years has confirmed the efficacy of amantadine to treat levodopa-induced dyskinesias in patients with Parkinson's disease, and clinical studies have also provided support for its potential to reduce motor fluctuations. Other uses of amantadine, such as in the treatment of drug-induced parkinsonism, atypical parkinsonism, Huntington's disease, or tardive dyskinesia, lack a strong evidence base. Future trials should examine its role in the management of motor and non-motor symptoms in patients with early Parkinson's disease and those with other movement disorders.

Background: Early identification of Parkinson’s disease (PD) patients at risk for becoming functionally dependent is important for patient counseling. Several models describing the relationship between predictors and outcome have been reported, however, most of these require computer software for practical use. Objective: Here we report the development of a risk nomogram allowing an approximate graphical computation of the risk of becoming functionally dependent in early PD. Methods: We analyzed data form the Parkinson’s Progression Markers Initiative cohort of newly diagnosed PD patients from baseline through the first 5 years of follow-up. Functional dependence was defined as a score

This work describes the objectives, design, and preliminary participant characteristics of PPMI Online, a longitudinal, online study involving people with and without Parkinson’s disease (PD). PPMI Online is one of several programs in PPMI and seeks to describe the lived experiences of people with and without PD, identify participants eligible for PPMI Remote and PPMI Clinic, and complement data derived from study activities in other PPMI programs. PPMI Online has launched in the U.S. and enrolled over 20,000 participants, with future expansion to other countries and languages planned.

This work describes the use of PPMI Online as a broad-based and cost-effective method to identify people at risk of developing PD through a staged screening process. This process begins with questionnaires focused on symptoms relevant to the prodromal stages of PD, then invites eligible participants to complete a DATScan and, if still eligible, participate further in PPMI Clinic. This poster describes preliminary characteristics of participants at various stages of this pipeline.

BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). RESULTS: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. CONCLUSIONS: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).

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.To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens.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.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 lt; 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time.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.

Multiple system atrophy is considered a sporadic disease, but neuropathologically confirmed cases with a family history of parkinsonism have been occasionally described. Here we report a North-Bavarian (colloquially, Lion’s tail region) six-generation pedigree, including neuropathologically confirmed multiple system atrophy and Parkinson’s disease with dementia. Between 2012 and 2020, we examined all living and consenting family members of age and calculated the risk of prodromal Parkinson’s disease in those without overt parkinsonism. The index case and one paternal cousin with Parkinson’s disease with dementia died at follow-up and underwent neuropathological examination. Genetic analysis was performed in both and another family member with Parkinson’s disease. The index case was a female patient with cerebellar variant multiple system atrophy and a positive maternal and paternal family history for Parkinson’s disease and dementia in multiple generations. The families of the index case and her spouse were genealogically related, and one of the spouse's siblings met the criteria for possible prodromal Parkinson’s disease. Neuropathological examination confirmed multiple system atrophy in the index case and advanced Lewy body disease, as well as tau pathology in her cousin. A comprehensive analysis of genes known to cause hereditary forms of parkinsonism or multiple system atrophy lookalikes was unremarkable in the index case and the other two affected family members. Here, we report an extensive European pedigree with multiple system atrophy and Parkinson`s disease suggesting a complex underlying α-synucleinopathy as confirmed on neuropathological examination. The exclusion of known genetic causes of parkinsonism or multiple system atrophy lookalikes suggests that variants in additional, still unknown genes, linked to α-synucleinopathy lesions underlie such neurodegenerative clustering.

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.

Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.

Iron accumulation in subcortical brain nuclei has been shown to be differentially increased in atypical parkinsonian disorders. It is unclear whether the patterns of iron accumulation are consistent between variants of progressive supranuclear palsy (PSP) and their diagnostic utility in early to moderately advanced stages of the diseases.Brain iron content (RSignificant group differences in RIron accumulation in subcortical brain nuclei has distinct correlated patterns in PSP-P and PSP-RS, which could be reflecting different pathophysiological mechanisms. Increased iron content in these nuclei appears to be a predictor for atypical parkinsonian disorders such as PSP and MSA. Further studies are required to reproduce this finding and elucidate the evolution of these patterns over the course of the disease.

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.The objective of this study was to assess sensitivity to change and patient-centricity of single UMSARS items.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.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.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.

BackgroundThe 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.ObjectiveTo develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology.MethodsWe 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.ResultsThe 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.ConclusionsThis 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.

The synthetic tetrahydrocannabinol analogue nabilone improved overall non-motor symptom (NMS) burden in Parkinson's disease (PD) patients in comparison to placebo.To characterize the effects of nabilone on different sleep outcomes in PD patients.We performed a post-hoc analysis of the controlled, double-blind, enriched enrollment randomized withdrawal NMS-Nab study to assess the effects of nabilone on sleep outcomes in study participants who reported clinically-relevant sleep problems (MDS-UPDRS-1.7 ≥ 2 points).After open-label nabilone administration, 77.4% reported no relevant sleep problem. In the withdrawal phase of the trial, the MDS-UPDRS-1.7. and the NMS-Scale Domain 2 (i.e., Sleep/Fatigue) significantly worsened only in PD patients in the placebo group, which was mostly driven by a significant worsening of insomnia (question 5 of the NMS-Scale Domain 2).This post-hoc analysis of the NMS-Nab trial suggests that nabilone has beneficial effects on sleep outcomes in PD patients experiencing sleep problems at baseline.The original trial was registered with ClinicalTrials.gov (NCT03769896, https://clinicaltrials.gov/ct2/show/NCT03769896) and EudraCT (2017-000192-86).

Multiple system atrophy (MSA) is a rare neurodegenerative disease that is characterized by neuronal loss and gliosis in multiple areas of the central nervous system including striatonigral, olivopontocerebellar and central autonomic structures. Oligodendroglial cytoplasmic inclusions containing misfolded and aggregated α-synuclein are the histopathological hallmark of MSA. A firm clinical diagnosis requires the presence of autonomic dysfunction in combination with parkinsonism that responds poorly to levodopa and/or cerebellar ataxia. Clinical diagnostic accuracy is suboptimal in early disease because of phenotypic overlaps with Parkinson disease or other types of degenerative parkinsonism as well as with other cerebellar disorders. The symptomatic management of MSA requires a complex multimodal approach to compensate for autonomic failure, alleviate parkinsonism and cerebellar ataxia and associated disabilities. None of the available treatments significantly slows the aggressive course of MSA. Despite several failed trials in the past, a robust pipeline of putative disease-modifying agents, along with progress towards early diagnosis and the development of sensitive diagnostic and progression biomarkers for MSA, offer new hope for patients.

Ophthalmological disorders are common and frequently disabling for people with Parkinson's disease (PD). However, details on the prevalence, severity and impact of ophthalmological disorders thus far lacking. We aimed to identify PD patients with undetected ophthalmological disorders in a large cross-sectional, observational study.We previously delivered a screening questionnaire to detect ophthalmological symptoms (Visual impairment in PD questionnaire; VIPD-Q) to 848 patients. Here, we report on a subgroup of 102 patients who received complete ophthalmological assessment aimed at identifying clinically relevant ophthalmological diseases, which were classified as either vison-threatening or not. Impact on daily life functioning was measured using the visual functioning-25 questionnaire (VFQ-25) and fall frequency.Almost all patients (92%) had one or more clinically relevant ophthalmological disorders. Of those, 77% had a potentially vision-threatening disease, while 34% had a potentially treatable ophthalmological disease which impacted on quality of life. The most prevalent ophthalmological disorders were dry eyes (86%), ocular misalignment (50%) and convergence insufficiency (41%). We found a weak but significant association between clinically relevant ophthalmological diseases and both fall frequency (RSurprisingly, in our study sample, many participants manifested previously undetected ophthalmological diseases, most of which threatened vision, impacted on daily life functioning and were amenable to treatment. Screening for these ophthalmological disorders using a questionnaire asking about symptoms seems insufficient. Instead, episodic ophthalmological assessments should be considered for PD patients, aiming to identify vision-threatening yet treatable diseases.Dutch Trial Registration, NL7421.