Early Screening for the Parkinson Variant of Multiple System Atrophy: A 6-Item Score.

BACKGROUND: A 4-item score based on ≥2 features out of orthostatic hypotension, overactive bladder, urinary retention and postural instability was previously shown to early distinguish the Parkinson-variant of multiple system atrophy (MSA-P) from Parkinson's disease (PD) with 78% sensitivity and 86% specificity. OBJECTIVES: To replicate and improve the 4-item MSA-P score. METHODS: We retrospectively studied 161 patients with early parkinsonism [ie, ≤2 years disease duration or no postural instability, aged 64 (57; 68) years, 44% females] and a diagnosis of clinically established MSA-P (n = 38) or PD (n = 123) after ≥24 months follow-up. RESULTS: The 4-item MSA-P score had a 92% sensitivity and 78% specificity for a final MSA-P diagnosis. By including dopaminergic responsiveness and postural deformities into a 6-item score (range: 0-6), reaching ≥3 points at early disease identified MSA-P patients with 89% sensitivity and 98% specificity. CONCLUSIONS: The 6-item MSA-P score is a cost-effective tool to pinpoint individuals with early-stage MSA-P.

Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial.

BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.

Subthalamic nucleus physiology is correlated with deep brain stimulation motor and non-motor outcomes.

Subthalamic nucleus deep brain stimulation is commonly indicated for symptomatic relief of idiopathic Parkinson's disease. Despite the known improvement in motor scores, affective, cognitive, voice and speech functions might deteriorate following this procedure. Recent studies have correlated motor outcomes with intraoperative microelectrode recordings. However, there are no microelectrode recording-based tools with predictive values relating to long-term outcomes of integrative motor and non-motor symptoms. We conducted a retrospective analysis of the outcomes of patients with idiopathic Parkinson's disease who had subthalamic nucleus deep brain stimulation at Tel Aviv Sourasky Medical Centre (Tel Aviv, Israel) during 2015-2016. Forty-eight patients (19 women, 29 men; mean age, 58 ± 8 years) who were implanted with a subthalamic nucleus deep brain stimulation device underwent pre- and postsurgical assessments of motor, neuropsychological, voice and speech symptoms. Significant improvements in all motor symptoms (except axial signs) and levodopa equivalent daily dose were noted in all patients. Mild improvements were observed in more posterior-related neuropsychological functions (verbal memory, visual memory and organization) while mild deterioration was observed in frontal functions (personality changes, executive functioning and verbal fluency). The concomitant decline in speech intelligibility was mild and only partial, probably in accordance with the neuropsychological verbal fluency results. Acoustic characteristics were the least affected and remained within normal values. Dimensionality reduction of motor, neuropsychological and voice scores rendered six principal components that reflect the main clinical aspects: the tremor-dominant versus the rigidity-bradykinesia-dominant motor symptoms, frontal versus posterior neuropsychological deficits and acoustic characteristics versus speech intelligibility abnormalities. Microelectrode recordings of subthalamic nucleus spiking activity were analysed off-line and correlated with the original scores and with the principal component results. Based on 198 microelectrode recording trajectories, we suggest an intraoperative subthalamic nucleus deep brain stimulation score, which is a simple sum of three microelectrode recording properties: normalized neuronal activity, the subthalamic nucleus width and the relative proportion of the subthalamic nucleus dorsolateral oscillatory region. A threshold subthalamic nucleus deep brain stimulation score >2.5 (preferentially composed of normalized root mean square >1.5, subthalamic nucleus width >3 mm and a dorsolateral oscillatory region/subthalamic nucleus width ratio >1/3) predicts better motor and non-motor long-term outcomes. The algorithm presented here optimizes intraoperative decision-making of deep brain stimulation contact localization based on microelectrode recording with the aim of improving long-term (>1 year) motor, neuropsychological and voice symptoms.

Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.

Myasthenia gravis patients exhibiting an eyelid myotonia-like phenomenon.

We report here a retrospective case series of 3 MG patients suffering from difficulty opening eyes that appeared together with a diagnosis of MG. All are male patients with late-onset MG who are seropositive for anti-acetylcholine receptor antibodies. The phenomenon was characterized by difficulty opening the eyes after forced closure or reflex eye closure, improving with the ice pack test and with repeated forced eye closure but worsening with pyridostigmine treatment. We provide a detailed clinical, serological, imaging and electrophysiological examination of these patients. Electromyography evaluation did not show spontaneous muscle activity or myotonia at rest in the orbital part of the orbicularis oculi muscle. However, there was sustained muscle activity lasting several seconds in the pre-tarsal and pre-septal parts of this muscle. Videos of those reported symptoms were produced and provided. We discuss the possible neurological pathophysiology of this disorder and suggest to name this rare ocular disorder "myotonia-like disorder of the pre-tarsal and pre-septal parts of the orbicularis oculi". This study expands our knowledge of this rare clinical feature of MG and highlights the need for increased awareness of it and further investigation of this ocular manifestation.

A single-center real-life study on the use of medical cannabis in patients with dystonia.

Background: While cannabis-based medicine is being commonly used in patients with movement disorders, there is a scarcity of publications regarding the effect of cannabis on dystonia. We aimed to describe medical cannabis use in patients with dystonia and related pain. Methods: We employed a structured interview to obtain data on the cannabis treatment regimen, perception of effectiveness and side effect profile. Eligible participants were patients diagnosed with dystonia from the movement disorders unit at the Tel-Aviv Medical Center who had used licensed medical cannabis between January 2019 and January 2021. Results: Twenty-three subjects were interviewed (11 women, mean age 52.7). The most common way of administration was smoking (n = 11). Following an average of 2.5 ± 2.9 years of use, those with widespread dystonia (generalized, hemi and multifocal, n = 11) self-reported on a numeric rating scale an average 63% (range 0%-100%) reduction in symptoms of dystonia, while those with more focal dystonia patterns reported a significantly lower treatment effect of 32%. Participants reported a positive impact in related pain and quality of life, with an average rating of 3.8 out of 5 (SD = 1.2, median = 4) and 3.6 out of 5 (SD = 1.15, median = 4), respectively. Most common side effects were dry mouth (65%), sedation (43%), dizziness (39%) and psychiatric disorders (26%). Three patients (13%) discontinued therapy. Conclusion: A subset of dystonia patients who use medical cannabis under clinical observation reported significant subjective improvement during 30 months of use in average. Further prospective randomized controlled trials are required to examine the effectiveness of cannabis in dystonia.

Healthcare utilization, costs, and epidemiology of Huntington's disease in Israel.

Introduction: Data on Huntington's disease (HD) epidemiology, treatment patterns, and economic burden in Israel are scarce. Methods: Annual prevalence and incidence of HD (ICD-9-CM 333.4) were assessed in the Israel-based Maccabi Healthcare Services (MHS) database 2016-2018. Adherence (medication possession rate [MPR], proportion of disease covered) were assessed for adult people with HD (PwHD) 2013-2018. Healthcare resources utilization (HCRU) and costs related to inpatient and outpatient visits and all medications in 2018 were assessed for PwHD, who were randomly matched to MHS members without HD (1:3) by birth-year and sex. Results: Overall, 164 patients had at least one HD diagnosis. Annual prevalence and incidence were 4.45 and 0.24/100,000, respectively. A total of 67.0% of adult patients (n = 106) were taking tetrabenazine (median MPR and proportion of disease covered, 74.3% and 30.2%, respectively), 65.1% benzodiazepines (75.8% and 32.3%), and 11.3% amantadine (79.2% and 6.0%). Over a 1-year follow-up, PwHD (n = 81) had significantly more neurologist, psychiatrist, physiotherapist, and speech therapist visits (P < 0.05 for each) and more hospitalization days (P < 0.0001) compared with matched controls (n = 243). Total healthcare and medication costs per patient (US dollars) were significantly higher for PwHD than controls ($7,343 vs. $3,625; P < 0.001). Discussion/Conclusion: PwHD have greater annual HCRU and medical costs than MHS members without HD in Israel. Among those who have taken medications, adherence was lower than 80% (both MPR and proportion of disease covered), which may translate into suboptimal symptom relief and quality of life.

Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Variants in the GBA1 gene, which encodes lysosomal acid glucocerebrosidase, are among the most common genetic risk factors for Parkinson's disease and are associated with faster disease progression. The mechanisms involved are unresolved but might include accumulation of glucosylceramide. Venglustat is a brain-penetrant glucosylceramide synthase inhibitor that, in previous studies, reduced amounts of the glycosphingolipid. We aimed to assess the safety, efficacy, and target engagement of venglustat in people with early-stage Parkinson's disease carrying pathogenic GBA1 variants. METHODS: MOVES-PD part 2 was a randomised, double-blinded, placebo-controlled phase 2 study done at 52 centres (academic sites, specialty clinics, and general neurology centres) in 16 countries. Eligible adults aged 18-80 years with Parkinson's disease (Hoehn and Yahr stage ≤2) and one or more GBA1 variants were randomly assigned using an interactive voice-response system (1:1) to 52 weeks of treatment with oral venglustat (15 mg/day) or matching placebo. Investigators, site personnel, participants, and their caregivers were masked to treatment allocation. The primary outcome measure was the change from baseline to 52 weeks in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III combined score (a higher score indicates greater impairment), and it was analysed in a modified intention-to-treat population (ie, all randomly assigned participants with a baseline and at least one post-baseline measurement during the treatment period). This study was registered with ClinicalTrials.gov (NCT02906020) and is closed to recruitment. FINDINGS: Between Dec 15, 2016, and May 27, 2021, 221 participants were randomly assigned to venglustat (n=110) or placebo (n=111). The least squares mean change in MDS-UPDRS parts II and III combined score was 7·29 (SE 1·36) for venglustat (n=96) and 4·71 (SE 1·27) for placebo (n=105); the absolute difference between groups was 2·58 (95% CI -1·10 to 6·27; p=0·17). The most common treatment-emergent adverse events (TEAEs) were constipation and nausea (both were reported by 23 [21%] of 110 participants in the venglustat group and eight [7%] of 111 participants in the placebo group). Serious TEAEs were reported for 12 (11%) participants in each group. There was one death in the venglustat group owing to an unrelated cardiopulmonary arrest and there were no deaths in the placebo group. INTERPRETATION: In people with GBA1-associated Parkinson's disease in our study, venglustat had a satisfactory safety profile but showed no beneficial treatment effect compared with placebo. These findings indicate that glucosylceramide synthase inhibition with venglustat might not be a viable therapeutic approach for GBA1-associated Parkinson's disease. FUNDING: Sanofi.

Licensed Medical Cannabis Use in Gilles de la Tourette Syndrome: A Retrospective Long-term Follow-Up.

Background: Medical cannabis (MC) is widely used in clinical practice to treat Gilles de la Tourette syndrome (GTS). However, legislation, multiple modes of administration, and inconsistent plant preparations have limited trials to assess its benefits and long-term safety. For the past decade, licensed MC has been authorized in Israel for use in resistant GTS. We aimed to describe subjects' satisfaction, consumption habits, and THC dose increment during long-term usage. Materials and Methods: A retrospective longitudinal data collection (up to 9 years) on cannabis use habits and structured questionnaires evaluating disease characteristics and MC influence from GTS subjects being treated in the Movement Disorders Unit of the Tel-Aviv Medical Center, Israel. Results: Twenty-five patients (84% male) participated in the study. The mean duration of MC use was 4.0±2.3 years (range 0.5-10). The majority of patients (96%) consumed MC primarily, but not exclusively, through inhalation methods such as smoking or vaporizing dried inflorescence. A linear increase was observed in mean monthly THC dose (p<0.0001) with an average increase of 0.6-0.7 g/year. MC led to a subjectively reported reduction in tics (75% average reduction) and symptoms associated with common comorbidities of GTS. MC was generally well tolerated, although most participants (88%) reported experiencing side effects. Conclusions: A subset of GTS subjects who use MC long term under clinical observation may subjectively improve control of symptoms. Subject-led dose increase can indicate emerging tolerance. Large randomized controlled and observational long-term trials are required to confirm these observations.

Novel variants in genes related to vesicle-mediated-transport modify Parkinson's disease risk.

OBJECTIVES: VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD. METHODS: 77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n = 1200) and stratified manner (LRRK2-G2019S-PD patients (n = 145), GBA-PD patients (n = 235), and non-carriers of these mutations (NC, n = 787)). RESULTS: Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios = 2.71, 5.32, 3.26. and 2.19 with p = 0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR = 3.69, p = 0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR = 5.45, p = 0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR = 2.48 and 2.06, with p = 0.022 and 0.0163, respectively). CONCLUSIONS: Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression.

Variants in PSMB9 and FGR differentially affect Parkinson's disease risk in GBA and LRRK2 mutation carriers.

INTRODUCTION: Recent studies found an association between Parkinson's disease (PD) and alterations in the innate immune system. However, whether the involvement of this system in two of the known genetic forms of PD, GBA-PD and LRRK2-PD, and in patients who do not carry these mutations is different, is yet to be determined. We aimed to test if genetic variations in the innate immune genes are differentially associated with PD in these subgroups. METHODS: Innate immune genes were identified and classified into sub-lists according to Reactome pathways. Whole-genome-sequencing (WGS) was performed on 201 unrelated Ashkenazi-Jewish (AJ) PD patients including 104 GBA-PD, 32 LRRK2-PD, and 65 non-carriers-PD (NC-PD). To identify genes with different burden between these subgroups of PD, gene-based Sequence kernel association optimal unified test (SKAT-O) analysis was performed on innate immune pathways. Candidate variants within the significant genes were further genotyped in a cohort of 1200 unrelated, consecutively recruited, AJ-PD patients, and to evaluate their association with PD-risk their allele frequencies were compared to AJ-non-neuro cases in gnomAD database, in a stratified and un-stratified manner. RESULTS: SKAT-O analysis showed significantly different burden for PSMB9 (GBA-PD versus NC-PD) and FGR (GBA-PD versus LRRK2-PD). Two candidate variants in PSMB9 showed an association with GBA-PD-risk and NC-PD-risk while one FGR variant showed an association with LRRK2-PD-risk. CONCLUSION: Our data supports differential involvement of innate immunity risk alleles in PD and emphasizes the differences between the GBA- and LRRK2-PD subgroups.

Progressive supranuclear palsy's economical burden: the use and costs of healthcare resources in a large health provider in Israel.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative movement disorder with no disease modifying therapy currently available. Data on the costs associated with PSP are scarce. This study aims to assess the direct medical expenditure of patients with PSP (PwPSP) throughout disease course. METHODS: This retrospective cohort study is based on the data of a large state-mandated health provider in Israel. We identified PwPSP who were initially diagnosed between 2000 and 2017. Each PwPSP was randomly matched to three health-plan members without PSP by birth-year, sex, and socioeconomic status. Healthcare resources' utilization and related costs were assessed. RESULTS: We identified 88 eligible PwPSP and 264 people in the reference group; mean age at diagnosis was 72.6 years (SD = 8.4) and 53.4% were female. The annual direct costs of PwPSP have risen over time, reaching US$ 21,637 in the fifth year and US$ 36,693 in the tenth year of follow-up vs US$ 8910 in the year prior diagnosis. Compared to people without PSP, PwPSP had substantially higher medical expenditure during the years prior- and post-index date. CONCLUSION: The present study demonstrates higher economic burden, which increases with time, in PwPSP as compared to those without.

Multidisciplinary Intensive Rehabilitation Program for People with Parkinson's Disease: Gaps between the Clinic and Real-World Mobility.

Intensive rehabilitation programs improve motor and non-motor symptoms in people with Parkinson's disease (PD), however, it is not known whether transfer to daily-living walking occurs. The effects of multidisciplinary-intensive-outpatient rehabilitation (MIOR) on gait and balance in the clinic and on everyday walking were examined. Forty-six (46) people with PD were evaluated before and after the intensive program. A 3D accelerometer placed on the lower back measured daily-living walking during the week before and after the intervention. Participants were also stratified into "responders" and "non-responders" based on daily-living-step-counts. After the intervention, gait and balance significantly improved, e.g., MiniBest scores (p < 0.001), dual-task gait speed increased (p = 0.016) and 6-minute walk distance increased (p < 0.001). Many improvements persisted after 3 months. In contrast, daily-living number of steps and gait quality features did not change in response to the intervention (p > 0.1). Only among the "responders", a significant increase in daily-living number of steps was found (p < 0.001). These findings demonstrate that in people with PD improvements in the clinic do not necessarily carry over to daily-living walking. In a select group of people with PD, it is possible to ameliorate daily-living walking quality, potentially also reducing fall risk. Nevertheless, we speculate that self-management in people with PD is relatively poor; therefore, to maintain health and everyday walking abilities, actions such as long-term engaging in physical activity and preserving mobility may be needed.

Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: long-term results from COSMOS.

BACKGROUND: While immediate benefits of levodopa-carbidopa intestinal gel (LCIG) are evident in patients with Parkinson's disease (PD), long-term LCIG effects require further study. OBJECTIVES: We explored long-term LCIG on motor symptoms, nonmotor symptoms (NMS), and LCIG treatment settings in patients with advanced PD (APD). METHODS: Data were obtained (medical records and patient visit) from COSMOS, a multinational, retrospective, cross-sectional post-marketing observational study in patients with APD. Patients were stratified into 5 groups based on LCIG treatment duration at the patient visit, from 1-2 to > 5 years LCIG. Between-group differences were assessed for changes from baseline in LCIG settings, motor symptoms, NMS, add-on medications, and safety. RESULTS: Out of 387 patients, the number of patients per LCIG group was: > 1- ≤ 2 years LCIG (n = 156); > 2- ≤ 3 years LCIG (n = 80); > 3- ≤ 4 years LCIG (n = 61); > 4- ≤ 5 years LCIG (n = 30); > 5 years LCIG (n = 60). Baseline values were similar; data reported are changes from the baseline. There were reductions in "off" time, dyskinesia duration, and severity across LCIG groups. Prevalence, severity, and frequency of many individual motor symptoms and some NMS were reduced amongst all LCIG groups, with few differences between groups. Doses for LCIG, LEDD and LEDD for add-on medications were similar across groups both at LCIG initiation and patient visit. Adverse events were similar across all LCIG groups and consistent with the established safety profile of LCIG. CONCLUSIONS: LCIG may provide sustained, long-term symptom control, while potentially avoiding increases in add-on medication dosages. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03362879. Number and date: P16-831, November 30, 2017.

Evaluation of Parkinson's disease early diagnosis using single-channel EEG features and auditory cognitive assessment.

Background: Parkinson's disease (PD) often presents with subtle early signs, making diagnosis difficult. F-DOPA PET imaging provides a reliable measure of dopaminergic function and is a primary tool for early PD diagnosis. This study aims to evaluate the ability of machine-learning (ML) extracted EEG features to predict F-DOPA results and distinguish between PD and non-PD patients. These features, extracted using a single-channel EEG during an auditory cognitive assessment, include EEG feature A0 associated with cognitive load in healthy subjects, and EEG feature L1 associated with cognitive task differentiation. Methods: Participants in this study are comprised of cognitively healthy patients who had undergone an F-DOPA PET scan as a part of their standard care (n = 32), and cognitively healthy controls (n = 20). EEG data collected using the Neurosteer system during an auditory cognitive task, was decomposed using wavelet-packet analysis and machine learning methods for feature extraction. These features were used in a connectivity analysis that was applied in a similar manner to fMRI connectivity. A preliminary model that relies on the features and their connectivity was used to predict initially unrevealed F-DOPA test results. Then, generalized linear mixed models (LMM) were used to discern between PD and non-PD subjects based on EEG variables. Results: The prediction model correctly classified patients with unrevealed scores as positive F-DOPA. EEG feature A0 and the Delta band revealed distinct activity patterns separating between study groups, with controls displaying higher activity than PD patients. In controls, EEG feature L1 showed variations between resting state and high-cognitive load, an effect lacking in PD patients. Conclusion: Our findings exhibit the potential of single-channel EEG technology in combination with an auditory cognitive assessment to distinguish positive from negative F-DOPA PET scores. This approach shows promise for early PD diagnosis. Additional studies are needed to further verify the utility of this tool as a potential biomarker for PD.

MAPT Locus in Parkinson's Disease Patients of Ashkenazi Origin: A Stratified Analysis.

Introduction: MAPT locus is associated with Parkinson's disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods: LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results: The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2-G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes (MAPT and SPPL2C); structural deletions and segmental duplication (KANSL1); and variants affecting gene expression and intron excision ratio in brain tissues (LRRC37A/2). Conclusions: Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy.

Management of advanced Parkinson's disease in Israel: Clinicians viewpoint and action items.

Parkinson's disease (PD) is taking a staggering toll on healthcare systems worldwide, with the bulk of the expenditures invested in the late stages of the disease. Considering the rising life expectancy and the increasing prevalence of PD across the globe, a clear understanding of the early signs and treatment options available for advanced PD (APD), will facilitate tailoring management programs and support services. This task is complicated by the lack of both global consensus in defining APD and standardized care guidelines. This perspective prepared by a panel of movement disorder specialists, proposes to extend and optimize currently accepted PD coding to better reflect the diverse disease manifestations, with emphasis on non-motor features. The panel seeks to promote timely diagnosis by adjustment of evaluation tools for use by community neurologists and suggests modification of eligibility criteria for advanced therapy. Moreover, it advocates multidisciplinary assessments of APD patients to drive personalized, patient-centered and holistic management. Overall, earlier and more targeted intervention is expected to markedly improve patient quality of life.

Epidemiology of Progressive Supranuclear Palsy: Real World Data from the Second Largest Health Plan in Israel.

Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative movement disorder and no disease modifying therapy (DMT) is currently available. This study aims to assess the epidemiology of PSP in Israel and to describe its clinical features. This retrospective analysis identified patients with PSP between 2000 and 2018 over the age of 40 years at first diagnosis (index date). We identified 209 patients with ≥1 diagnosis of PSP. Of those, 88 patients satisfied the inclusion criteria with a mean age at diagnosis of 72 years (SD = 8) and 53% were female. The 2018 prevalence and incidence rates were 5.3 and 1 per 100,000 persons, respectively. Median survival time was 4.9 years (95% CI 3.6-6.1) and median time from initial symptom to diagnosis was 4.2 years. The most common misdiagnoses were Parkinson's disease, cognitive disorder and depression. The present study demonstrates that the clinic-epidemiological features of PSP in Israel are similar to PSP worldwide. In light of PSP's rarity, investigation of PSP cohorts in different countries may create a proper platform for upcoming DMT trials.

Risk of Parkinson Disease Among Adults With vs Without Posttraumatic Stress Disorder.

Importance: Posttraumatic stress disorder (PTSD) in elderly men may be associated with increased risk of Parkinson disease (PD); thus, this group of patients needs to be monitored closely for timely, customized treatment. Objective: To evaluate the risk of PD in patients with PTSD compared with patients without PTSD. Design, Setting, and Participants: This population-based, retrospective, cohort study used data from Maccabi Health Care Services (MHS), the second largest health plan in Israel, spanning from 2000 to 2019. Participants included MHS members born before 1970 who received a diagnosis of PTSD in 2000 to 2015. Patients with PTSD who had PD before their first diagnosis were excluded. Data analysis was performed from February to June 2022. Exposures: Incident PTSD was denoted by at least 1 diagnosis (1) given by psychiatrists, psychologists, or neurologists; (2) hospital discharge diagnosis; or (3) registered as a chronic diagnosis (defined as such by the primary care physician). The index date was defined as first diagnosis for the patients with PTSD and for the corresponding patients without PTSD. Main Outcomes and Measures: PD incident cases up to 2019 were ascertained by idiopathic PD diagnosis (1) given by a neurologist, (2) extracted from a hospital discharge report, or (3) registered as a chronic diagnosis. Patients with PD-like syndromes documentation after the last mention of PD were excluded. Results: Of 8342 eligible patients, 8336 (99.9%) were matched to nonexposed patients in a 1:1 ratio by birth year and sex; 4303 patients (51.6%) were male, and the mean (SD) age at index was 55.8 (13.2) years. Patients with PTSD had a 1.48-fold (95% CI, 1.10-1.99) excess risk for PD, compared with patients without PTSD. An elevated risk of PD (hazard ratio, 1.95; 95% CI, 1.16-3.28) was recorded among men receiving a diagnosis of PTSD at age 72 years or older. Conclusions and Relevance: These findings suggest that elderly men who receive a diagnosis of PTSD are at an increased risk of PD. Further studies are needed to corroborate these findings and to further assess the association of stress with PD risk.