Long-Term Medication Profiles in Parkinson's Disease under Subthalamic Deep Brain Stimulation: A Controlled Study.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) reduces antiparkinsonian medications in Parkinson's disease (PD) compared with the preoperative state. Longitudinal and comparative studies on this effect are lacking. OBJECTIVE: To compare longitudinal trajectories of antiparkinsonian medication in STN-DBS treated patients to non-surgically treated control patients. METHODS: We collected retrospective information on antiparkinsonian medication from PD patients that underwent subthalamic DBS between 1999 and 2010 and control PD patients similar in age at onset and baseline, sex-distribution, and comorbidities. RESULTS: In 74 DBS patients levodopa-equivalent daily dose (LEDD) were reduced by 33.9-56.0% in relation to the preoperative baseline over the 14-year observational period. In 61 control patients LEDDs increased over approximately 10 years, causing a significant divergence between groups. The largest difference amongst single drug-classes was observed for dopamine agonists. CONCLUSION: In PD patients, chronic STN-DBS was associated with a lower LEDD compared with control patients over 14 years.

Sex-related differences in the clinical presentation of multiple system atrophy.

PURPOSE: To investigate sex-related differences in the clinical presentation of multiple system atrophy (MSA) through a literature review and an analysis of a retrospective cohort. METHODS: The PubMed database was searched for articles including sex-related information in MSA. In a retrospective Innsbruck cohort, we investigated the baseline to last available follow-up clinical-demographic differences between men and women with MSA in a univariate fashion, followed by multivariable binary regression analysis. RESULTS: The literature search yielded 46 publications with sex-related information in MSA. Most studies found comparable survival rates between the sexes, while some recent reports suggested a potential survival benefit for women, possibly due to initial motor onset and overall less severe autonomic failure compared to men. The retrospective Innsbruck MSA cohort comprised 56 female and 60 male individuals with a comparable median follow-up of 27 months. At baseline, female sex was independently associated with depression (odds ratio [OR] 4.7; p = 0.007) and male sex with severe orthostatic hypotension (OR 5.5; p = 0.016). In addition, at last follow-up, female sex was associated with the intake of central nervous system-active drugs (OR 4.1; p = 0.029), whereas male sex was associated with the presence of supine hypertension (OR 3.0; p = 0.020) and the intake of antihypertensive medications (OR 8.7; p = 0.001). Male sex was also associated with initiation of antihypertensive medications over the observation period (OR 12.4; p = 0.004). CONCLUSION: The available literature and findings of the present study indicate sex-related differences in the clinical presentation of MSA and its evolution over time, highlighting the importance of considering sex in symptom exploration, therapeutic decision-making, and future clinical trial design.

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.

Longitudinal brain changes in Parkinson's disease with severe olfactory deficit.

INTRODUCTION: Olfactory dysfunction and REM sleep behavior disorder (RBD) are associated with distinct cognitive trajectories in the course of Parkinson's disease (PD). The underlying neurobiology for this relationship remains unclear but may involve distinct patterns of neurodegeneration. This study aimed to examine longitudinal cortical atrophy and thinning in early-stage PD with severe olfactory deficit (anosmia) without and with concurrent probable RBD. METHODS: Longitudinal MRI data over four years of 134 de novo PD and 49 healthy controls (HC) from the Parkinson Progression Marker Initiative (PPMI) cohort were analyzed using a linear mixed-effects model. Patients were categorized into those with anosmia by the University of Pennsylvania Smell Identification Test (UPSIT) score ≤ 18 (AO+) and those without (UPSIT score > 18, AO-). The AO+ group was further subdivided into AO+ with probable RBD (AO+RBD+) and without (AO+RBD-) for subanalysis. RESULTS: Compared to subjects without baseline anosmia, the AO+ group exhibited greater longitudinal declines in both volume and thickness in the bilateral parahippocampal gyri and right transverse temporal gyrus. Patients with concurrent anosmia and RBD showed more extensive longitudinal declines in cortical volume and thickness, involving additional brain regions including the bilateral precuneus, left inferior temporal gyrus, right paracentral gyrus, and right precentral gyrus. CONCLUSIONS: The atrophy/thinning patterns in early-stage PD with severe olfactory dysfunction include regions that are critical for cognitive function and could provide a structural basis for previously reported associations between severe olfactory deficit and cognitive decline in PD. Concurrent RBD might enhance the dynamics of cortical changes.

Pharmacotherapy for Disease Modification in Early Parkinson's Disease: How Early Should We Be?

Slowing or halting progression continues to be a major unmet medical need in Parkinson's disease (PD). Numerous trials over the past decades have tested a broad range of interventions without ultimate success. There are many potential reasons for this failure and much debate has focused on the need to test 'disease-modifying' candidate drugs in the earliest stages of disease. While generally accepted as a rational approach, it is also associated with significant challenges around the selection of trial populations as well as trial outcomes and durations. From a health care perspective, intervening even earlier and before at-risk subjects have gone on to develop overt clinical disease is at the heart of preventive medicine. Recent attempts to develop a framework for a biological definition of PD are aiming to enable 'preclinical' and subtype-specific diagnostic approaches. The present review addresses past efforts towards disease-modification, including drug targets and reasons for failure, as well as novel targets that are currently being explored in disease-modification trials in early established PD. The new biological definitions of PD may offer new opportunities to intervene even earlier. We critically discuss the potential and challenges around planning 'disease-prevention' trials in subjects with biologically defined 'preclinical' or prodromal PD.

Long-term safety and efficacy of open-label nabilone on sleep and pain in Parkinson´s Disease.

The synthetic tetrahydrocannabinol-analog nabilone improved non-motor symptoms (NMS) in Parkinson's disease (PD) patients in a placebo-controlled, double-blind, parallel-group, randomized withdrawal trial with enriched enrollment (NMS-Nab-study). This was a single-center open-label extension study to assess the long-term safety and efficacy of nabilone for NMS in PD. To be eligible for this study, patients had to be treatment responders during the previous NMS-Nab-trial and complete its double-blind phase without experiencing a drug-related serious/severe/moderate adverse event (AE). Patients were re-introduced to nabilone during an up-titration phase until their overall NMS burden improved. Nabilone was continued for six months with clinic visits every 3 months. Evaluation of AEs was based on self-report and clinical assessment. Twenty-two patients participated in the NMS-Nab2-study (age-median 68.33 y, 52% females, disease duration-median 7.42 y). Nabilone was well tolerated with concentration difficulties as the most common treatment-related AE (possibly/not related n = 1 each). One in two drop-outs discontinued because of an AE for which a prohibited concomitant medication needed to be introduced (night-time sleep problems). Efficacy evaluation showed a significant and lasting improvement in NMS burden according to the CGI-I (79% at V3). Nabilone improved overall sleep (NMSS Domain-2: -8.26 points; 95%CI -13.82 to -2.71; p = 0.004; ES = -0.72), night-time sleep problems (MDS-UPDRS-1.7: -1.42 points; 95 CI -2.16 to -0.68; p = 0.002; ES = -0.92), and overall pain (KPPS Total Score: -8.00 points; 95%CI -15.05 to -0.95; p = 0.046; ES -0.55 and MDS-UPDRS-1.9: -0.74 points; 95%CI -1.21 to -0.26; p = 0.008; ES = -0.74). This study demonstrates continuous long-term safety and efficacy in PD patients responding early to nabilone without intolerable side effects.

A Blinded Evaluation of Brain Morphometry for Differential Diagnosis of Atypical Parkinsonism.

BACKGROUND: Advanced imaging techniques have been studied for differential diagnosis between PD, MSA, and PSP. OBJECTIVES: This study aims to validate the utility of individual voxel-based morphometry techniques for atypical parkinsonism in a blinded fashion. METHODS: Forty-eight healthy controls (HC) T1-WI were used to develop a referential dataset and fit a general linear model after segmentation into gray matter (GM) and white matter (WM) compartments. Segmented GM and WM with PD (n = 96), MSA (n = 18), and PSP (n = 20) were transformed into z-scores using the statistics of referential HC and individual voxel-based z-score maps were generated. An imaging diagnosis was assigned by two independent raters (trained and untrained) blinded to clinical information and final diagnosis. Furthermore, we developed an observer-independent index for ROI-based automated differentiation. RESULTS: The diagnostic performance using voxel-based z-score maps by rater 1 and rater 2 for MSA yielded sensitivities: 0.89, 0.94 (95% CI: 0.74-1.00, 0.84-1.00), specificities: 0.94, 0.80 (0.90-0.98, 0.73-0.87); for PSP, sensitivities: 0.85, 0.90 (0.69-1.00, 0.77-1.00), specificities: 0.98, 0.94 (0.96-1.00, 0.90-0.98). Interrater agreement was good for MSA (Cohen's kappa: 0.61), and excellent for PSP (0.84). Receiver operating characteristic analysis using the ROI-based new index showed an area under the curve (AUC): 0.89 (0.77-1.00) for MSA, and 0.99 (0.98-1.00) for PSP. CONCLUSIONS: These evaluations provide support for the utility of this imaging technique in the differential diagnosis of atypical parkinsonism demonstrating a remarkably high differentiation accuracy for PSP, suggesting potential use in clinical settings in the future.

A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria.

With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.

Cognitive dysfunction in de novo Parkinson disease: Remitting vs. progressive cognitive impairment.

INTRODUCTION: Parkinson's disease (PD) exhibits divergent cognitive trajectories; however, the factors contributing to these variations remain elusive. This study aimed to examine the clinical features of patients with different long-term cognitive trajectories in de novo PD over a five-year follow-up. METHODS: We analyzed 258 patients who completed every annual evaluation for five years. According to the Montreal Cognitive Assessment (MoCA) scores, we classified patients into three groups: cognitively normal (n = 118, CN), remitting MoCA decline (n = 74, RMD), and progressive MoCA decline (n = 66, PMD). RESULTS: The RMD group was associated with lower olfactory scores (Odds Ratio (OR) = 0.958, p = 0.040), whereas PMD was associated with higher depression scores (OR = 1.158, p = 0.045), probable RBD (OR = 3.169, p = 0.002), older age (OR = 1.132, p < 0.001) and lower educational attainment (OR = 0.828, p = 0.004). PMD had higher neurofilament light chain protein values than CN and RMD (p = 0.006, 0.015, respectively). Longitudinally, PMD showed a greater decline in all cognitive scores and hippocampus volumes (p = 0.004). Meanwhile, RMD exhibited intermediate cognitive and volumetric trajectories between CN and PMD and displayed worse score changes in memory tasks than CN. CONCLUSIONS: While PMD exhibited known risk factors for cognitive impairment, along with worse cognitive performance and hippocampal volume decline, RMD displayed baseline lower olfactory scores and intermediate cognitive and hippocampal volume decline between the two groups. These findings suggest individuals in RMD may still be at risk for cognitive deficits. However, further long-term follow-up data are needed to unravel the determinants and dynamics of cognitive functions.

Progressive Brain Atrophy in Multiple System Atrophy: A Longitudinal, Multicenter, Magnetic Resonance Imaging Study.

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.

Pain in Multiple System Atrophy a Systematic Review and Meta-Analysis.

Background: Individuals with multiple system atrophy (MSA) often complain about pain, nonetheless this remains a poorly investigated non-motor feature of MSA. Objectives: Here, we aimed at assessing the prevalence, characteristics, and risk factors for pain in individuals with MSA. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, we systematically screened the PubMED, Cochrane, and Web of Science databases for papers published in English until September 30, 2022, combining the following keywords: "pain," "multiple system atrophy," "MSA," "olivopontocerebellar atrophy," "OPCA," "striatonigral degeneration," "SND," "Shy Drager," and "atypical parkinsonism." Results: The search identified 700 records. Sixteen studies provided information on pain prevalence in cohorts of MSA individuals and were included in a qualitative assessment based on the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Thirteen studies (11 cross-sectional, two longitudinal) scored ≥14 points on QUADAS assessment and were included in a quantitative analysis, pooling data from 1236 MSA individuals. The resulting pooled prevalence of pain in MSA was 67% (95% confidence intervals [CI] = 57%-75%), and significantly higher in individuals with MSA of parkinsonian rather than cerebellar type (76% [95% CI = 63%-87%] vs. 45% [95% CI = 33%-57%], P = 0.001). Pain assessment tools and collected information were highly heterogeneous across studies. Two studies reported pain treatment strategies and found that only every second person with MSA complaining about pain had received targeted treatment. Conclusions: We found that pain is a frequent, but still under-recognized and undertreated feature of MSA. Further research is needed to improve pain detection and treatment in MSA.

Apomorphine Sublingual Film Compared with Subcutaneous Apomorphine for OFF Episodes in Parkinson's Disease: An Open-Label, Randomized, Crossover Study.

BACKGROUND: Apomorphine sublingual film (SL-APO) and subcutaneous apomorphine (SC-APO) have been used for the treatment of OFF episodes in Parkinson's disease (PD). No study has prospectively compared efficacy and safety of these formulations. OBJECTIVE: To compare SL-APO with SC-APO for treatment of OFF episodes in PD. METHODS: An open-label, randomized, crossover study assessed SL-APO versus SC-APO in patients with PD and OFF episodes (N = 113). Doses were optimized in randomly assigned order. SL-APO dose initiation (10 mg) occurred in clinic; further dose optimization (15-30 mg; 5-mg increments) occurred primarily at home. SC-APO dosing (2-6 mg; 1-mg increments) occurred entirely in clinic. After a 3-7-day washout, patients were randomized 1 : 1 to 4 weeks of treatment with their optimized dose of SL-APO or SC-APO, followed by washout and 4 weeks of crossover treatment. RESULTS: Propensity score matching applied on 159 patients (STN-DBS n = 75, MED n = 84) resulted in 40 patients in each treatment group. At 36-month follow-up, STN-DBS led to significantly better PDSS and PDQ-8 change scores, which were significantly correlated. We observed no significant effects for HADS and no significant correlations between change scores in PDSS, HADS, and LEDD. CONCLUSIONS: We report Class IIb evidence of beneficial effects of STN-DBS on quality of sleep at 36-month follow-up, which were associated with QoL improvement independent of depression and dopaminergic medication. Our study highlights the importance of sleep for assessments of DBS outcomes. RESULTS: No difference was observed between SL-APO and SC-APO for change from predose to 90 minutes postdose in Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score at week 4 (primary endpoint), assessed by a blinded rater (-13.6 vs. -13.8, respectively; p = NS). Overall, 72.2% of patients preferred SL-APO compared with SC-APO/no preference (p = 0.0002) per the Treatment Preference Questionnaire (secondary endpoint). Patients reported greater satisfaction with SL-APO compared with SC-APO, per mean scores of convenience (73.7 vs. 53.5) and global satisfaction (63.9 vs. 57.6) on the Treatment Satisfaction Questionnaire for Medication (other endpoint). The safety profiles of both treatments were generally comparable and were well-tolerated. CONCLUSIONS: Patients reported overall preference for and greater satisfaction with SL-APO over SC-APO.

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.

Comparison of different risk scores for Parkinson disease in a population-based 10-year study.

BACKGROUND AND PURPOSE: Different algorithms aiming to identify individuals at risk of Parkinson disease (PD) have been proposed. Comparative studies of these scores and their recent updates in the general elder population are needed. METHODS: We have previously applied the "basic" PREDICT-PD algorithm, designed for remote screening, and the original and updated Movement Disorder Society (MDS) criteria for prodromal PD to the longitudinal population-based Bruneck study cohort. We have now additionally employed the "enhanced" PREDICT-PD algorithm (which includes motor assessment, olfaction, probable rapid eye movement sleep behaviour disorder status, pesticide exposure, and diabetes as additional factors). Risk scores were calculated based on comprehensive baseline assessments (2005) in 574 subjects aged 55-94 years (290 females), and cases of incident PD were identified at 5-year (n = 11) and 10-year follow-up (n = 9). We analysed the association of the different log-transformed risk scores with incident PD at follow-up (calculated per 1-SD unit change). RESULTS: The enhanced PREDICT-PD algorithm was associated with incident PD over 10-years of follow-up, yielding higher odds for incident PD (odds ratio [OR] = 4.61, 95% confidence interval [CI] = 2.68-7.93, p < 0.001) compared with the basic PREDICT-PD score (OR = 2.38, 95% CI = 1.49-3.79, p < 0.001). The updated MDS prodromal criteria yielded a numerically higher OR of 7.13 (95% CI = 3.49-14.54, p < 0.001) in comparison with the original criteria as well as the enhanced PREDICT-PD algorithm, with overlapping 95% CIs. CONCLUSIONS: The enhanced PREDICT-PD algorithm was significantly associated with incident PD. The consistent performance of both the enhanced PREDICT-PD algorithm and the updated MDS prodromal criteria compared to their original versions supports their use in PD risk screening.

Catechol-O-methyltransferase inhibition with entacapone: Evidence from controlled clinical trials in Parkinson's disease.

Adjunct therapy with the catechol-O-methyltransferase inhibitor entacapone is a first-line approach to treat wearing-off type motor fluctuations in levodopa-treated Parkinson's disease (PD) patients. Five randomized placebo-controlled trials including a total of >1000 patients have established its efficacy, showing increases in ON time between 0.7 and 1.6 h, with corresponding OFF-time reductions. These and other trials also found improvements in ON motor function and quality of life. Additional trials have tested the efficacy of adjunct entacapone in patients either without or with early and mild motor fluctuations and also found enhanced motor control and improved activities of daily living function and quality of life, whereas the STRIDE-PD trial failed to show efficacy of early entacapone use in delaying the onset of dyskinesias. Adjunct entacapone enhances dopaminergic activity and may increase levodopa-induced adverse events like dyskinesias, which can usually be controlled by modest levodopa dose reductions. There is no formal requirement to monitor liver function during entacapone treatment. Entacapone can be a rare cause of lymphocytic colitis with severe diarrhoea and need for treatment discontinuation. In 2003, a triple-combination pill of levodopa, carbidopa, and entacapone (LCE) was first introduced onto the market, and since then proprietary LCE (Stalevo® ) is indicated on the basis of those trials for patients with idiopathic PD to (i) substitute for immediate-release carbidopa/levodopa and entacapone previously administered as individual products or (ii) replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients taking a total daily dose of levodopa of ≤600 mg and not experiencing dyskinesias experience signs and symptoms of end-of-dose wearing off.

Dorsolateral Nigral Hyperintensity on 1.5 T Versus 3 T Susceptibility-Weighted Magnetic Resonance Imaging in Neurodegenerative Parkinsonism.

Background: An absent dorsolateral nigral hyperintensity (DNH) is a common finding in patients with neurodegenerative parkinsonism at high or ultra-high field susceptibility-weighted magnetic resonance imaging (SWI). Objective: Despite increasing use of high field magnetic resonance imaging (MRI) in specialized centers, these scanners are still frequently unavailable in primary care or outpatient facilities and underdeveloped or emerging countries. Therefore, the aim of the present study was to evaluate the diagnostic utility of DNH assessment at 1.5 versus 3 T MRI to distinguish patients with neurodegenerative parkinsonism, including Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), from healthy controls (HC). Methods: Absence of DNH was assessed on visual inspection of anonymized 1.5 T and 3.0 T SWI scans in a case-control study including 86 patients with neurodegenerative parkinsonism and 33 healthy controls (HC). All study participants were consecutively recruited to undergo 1.5 and 3 T MRI. Results: Overall correct classification was 81.7% (95% CI, 72.6-88.4%) for 1.5 T and 95.7% (95% CI, 89.1-98.7%) for 3 T MRI in discriminating neurodegenerative parkinsonism from controls. However, while DNH was bilaterally present in all but one of the HC at 3 T MRI, it was rated as abnormal (at least unilateral absence) in 15 of 22 HC at 1.5 T MRI, resulting in a specificity of 31.8%. Conclusions: The results of the present study demonstrate an insufficient specificity of visual assessment of DNH at 1.5 T MRI for the diagnosis of neurodegenerative parkinsonism.