Search

Background: Sarcopenia is characterized by a progressive loss of muscle mass, strength, and function resulting in adverse health outcomes. Current assessment strategies are bothersome and means to simplify the diagnosis are an unmet medical need in Parkinson’s disease (PD). Objective: To evaluate temporal muscle thickness (TMT) obtained on routine cranial MRI as a surrogate marker of sarcopenia in PD patients. Methods: We correlated TMT from axial non-contrast-enhanced T1-weighted sequences of MRI close (±12 months) to an outpatient visit including sarcopenia (EWGSOP1, EWGSOP2, SARC-F), frailty (Fried’s criteria, clinical frailty scale), and disease characteristics of Parkinson’s patients (Hoehn and Yahr-scale, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, quality of life with the Parkinson’s Disease Questionnaire-8) assessments. Results: Cranial MRI was available in 32 patients with a mean age of 73.56±5.14 years, mean disease duration of 11.46±5.66 years, and median Hoehn and Yahr stage of 2.5. The mean TMT was 7.49±2.76 (7.15) mm. Mean TMT was significantly associated with sarcopenia (EWGSOP2, p = 0.018; EWGSOP1, p = 0.023) and frailty status (physical phenotype; p = 0.045). Moreover, there were significant moderate to strong correlations between TMT measurement and appendicular skeletal muscle mass index (r: 0.437, p = 0.012), as well as handgrip strength (r: 0.561, p

Sleep disorders, daytime sleepiness, and autonomic dysfunction are commonly reported among patients with multiple system atrophy and Parkinson disease (PD). We aimed to assess sleep and autonomic function in these patients to evaluate the relationships between sleep disorders, excessive daytime sleepiness, and autonomic function.Twenty patients with multiple system atrophy (n = 7) and PD (n = 13) underwent clinical assessment including questionnaires for autonomic function and sleep. Cardiovascular autonomic function tests and 2-night video-polysomnography were followed by administration of the Multiple Sleep Latency Test. Rapid eye movement sleep without atonia was quantified in the chin, flexor digitorum superficialis, tibial anterior, and sternocleidomastoid muscles.Rapid eye movement sleep behavior disorder was associated with orthostatic hypotension (The relationship of autonomic dysfunction with rapid eye movement sleep without atonia in PD and multiple system atrophy is accounted for by shared brainstem neuropathology and likely identifies patients in a more advanced stage of disease. Excessive daytime sleepiness is found exclusively in PD and may be secondary to levodopa treatment and not related to α-synuclein disease.Eckhardt C, Fanciulli A, Högl B, et al. Analysis of sleep, daytime sleepiness, and autonomic function and multiple system atrophy and Parkinson disease: a prospective study.

The Global Multiple System Atrophy Registry (GLOMSAR) was established in 2013. It is an online patient-reported contact registry open and free that relies on self-reported diagnosis by the patient or caregiver.To report the demographics of patients enrolled in GLOMSAR and the results of an ancillary online symptom questionnaire.Patients enrolled in GLOMSAR were invited to complete a custom-designed online questionnaire about disease onset and symptom prevalence.At the time of writing, there were 1083 participants in GLOMSAR, of which 33% (365) completed the questionnaire. The onset and frequency of most symptoms was similar to those reported in the literature in physician-reported studies. Some were understudied or not typically associated with multiple system atrophy (MSA), including reduced female sexual sensation (55%), forgetfulness (60%), pseudobulbar affect (37%), olfactory changes (36%), and visual hallucinations (21%).Patient-reported studies and ancillary online questionnaires are valid, underused research tools useful to advance our knowledge on understudied MSA features and highlight the patients' voice.

The galvanic isolation of solid-state transformers (SSTs) is typically realized with a medium-frequency (MF) magnetic-core transformer (MCT). Previous demonstrations indicate that achieving highly power dense and lightweight MCTs imposes several challenges on the design because of stringent requirements related to insulation and cooling. This work investigates the achievable efficiency of an optimized 166kW / 7 kV air-core transformer (ACT), which is a core part of a DC Transformer (DCX), i.e., an unregulated DC-DC SST with a voltage scaling defined by the transformer turns ratio. The ACT features relatively low complexity of the construction, comparably high coupling values, and high efficiency. Modeling, optimization, and construction of the realized ACT are explained and guidelines regarding insulation, cooling, and shielding of the magnetic stray flux are discussed in detail. Furthermore, the prototype is experimentally validated to demonstrate its full functionality. In the investigated DCX, which is based on a series resonant converter (SRC) topology, the realized ACT is found to achieve a full-load efficiency of 99.5% and an unprecedented gravimetric power density of 16.5 kW/kg. With the use of 10 kV SiC MOSFETs, the complete DCX is estimated to reach an efficiency of 99% at 166kW output power.

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.

Background: Essential tremor (ET) and the tremor of Parkinson’s disease (PD) are the most common tremors encountered in clinical practice. Especially in early disease stages, discrimination between the tremors of ET and PD can be challenging. Objective: The aim of this study was to evaluate the diagnostic accuracy of transcranial sonography (TCS) of the substantia nigra echogenicity for differential diagnosis of PD versus ET. Methods: A systematic PubMed search identified 512 studies. Sensitivity and specificity of substantia nigra hyperechogenicity was estimated. Data synthesis was carried applying a random effects bivariate binomial model. To assess study quality and risk of bias, the QUADAS-2 tool was used. Results: Eighteen studies were suitable for analysis including 1,264 PD and 824 ET patients. The meta analysis showed a pooled sensitivity and specificity for TCS in the differential diagnosis of PD versus ET of 84.6% (95% CI, 79.4–88.6%) and 83.9% (95% CI, 78.4–88.2%), respectively. Furthermore, we found nearly similar results in sensitivity and specificity comparing TCS and DaTSCAN in a subgroup-analysis of three studies using both diagnostic tools including 107 patients with PD and 62 patients with ET. The QUADAS-2 toolbox revealed a high risk of bias regarding the methodological quality of patient selection. Conclusion: Substantia nigra hyperechogenicity yield high diagnostic accuracy for the discrimination of PD from ET. TCS is a low cost, widely available, non-invasive marker without radiation Therefore, a diagnostic algorithm based on presence or absence of substantia nigra hyperechogenicity is highly warranted.

Background: Differentiating progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) is clinically challenging. Objective: This study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP-P from PD and to validate its diagnostic performance in two large independent cohorts. Methods: We enrolled 676 participants: a training cohort (n=346; 43 PSP-P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n=330; 62 PSP-P, 171 PD, and 97 control subjects) from an international research group. We developed a new in-house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP-P from PD and control subjects in both cohorts using receiver operating characteristic curves. Results: The automated MRPI 2.0 showed excellent performance in differentiating patients with PSP-P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC]=0.93 [95% confidence interval, 0.89–0.98] and AUC=0.97 [0.93–1.00], respectively) and in the international testing cohort (PSP-P versus PD, AUC=0.92 [0.87–0.97]; PSP-P versus controls, AUC=0.94 [0.90–0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP-P and PD in the early stage of the diseases (AUC=0.91 [0.84–0.97]). A strong correlation (r=0.91, P < 0.001) was found between automated and manual MRPI 2.0 values. Conclusions: Our study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP-P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP-P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

Background Urological dysfunction in patients with multiple system atrophy (MSA) is one of the main manifestations of autonomic failure. Urodynamic examination is clinically relevant since underlying pathophysiology of lower urinary tract (LUT) dysfunction can be variable. Objective Evaluation of the pathophysiology of urological symptoms and exploration of differences in urodynamic patterns of LUT dysfunction between MSA‐P and MSA‐C. Methods Retrospective study of patients with possible and probable MSA who were referred for urodynamic studies between 2004 and 2019. Demographic data, medical history, physical examination and urodynamic studies assessing storage and voiding dysfunction were obtained. Results Seventy‐four patients were included in this study (MSA‐P 64.9% n = 48; median age 62.5 (IQR 56.8–70) years). Detrusor overactivity during filling phase was noted in 58.1% (n = 43) of the patients. In the voiding phase, detrusor sphincter dyssynergia and detrusor underactivity were observed in 24.6% (n = 17) and in 62.1% (n = 41) of the patients, respectively. A postmicturition residual volume of over 100 ml was present in 71.4% (n = 50) of the patients. Comparison of MSA subtypes showed weaker detrusor contractility in MSA‐P compared to MSA‐C [pdetQmax 26.2 vs. 34.4 cmH20, P = 0.04]. In 56.2% (n = 41) of patients pathophysiology of LUT dysfunction was deemed to be neurogenic and consistent with the diagnosis of MSA. In 35.6% (n = 26) urodynamic pattern suggested other urological co‐morbidities. Conclusion Urodynamic evaluation is an important tool to analyze the pattern of LUT dysfunction in MSA. Impaired detrusor contractility was seen more in MSA‐P which needs to be investigated in further studies.

Solid-state transformers (SSTs) are employing compact high-power medium-voltage (MV) medium-frequency transformers (MFTs) and enable the power transfer between galvanically isolated DC systems. Considering a typical SST isolation stage, i.e., a 166kW unregulated series-resonant DC-DC converter acting as a DC transformer (DCX) with equal input and output MV DC voltages of 7 kV (1:1-DCX), we derive component-level and system-level performance limits of air-cooled realizations with either an air-core transformer (ACT) or with a magnetic-core transformer (MCT). We describe the design of two fully rated MFT prototypes in detail and provide a comprehensive experimental characterization to validate the derived performance limits, including also the dielectric losses and the analysis of stray magnetic fields. The realized ACT and MCT prototypes achieve measured efficiencies of 99.5% and 99.7% at gravimetric power densities of 16.5 kW/kg and 6.7 kW/kg, respectively. Considering 10 kV SiC MOSFETs, calculated system-level efficiencies of the ACT-based and MCT-based 1:1-DCX result in 99.0% and 99.2% at the nominal operating point, with similar part-load efficiency characteristics. The paper concludes with an application-oriented qualitative evaluation of the two concepts. ISSN:2168-6777 ISSN:2168-6785

Introduction Microstructural integrity of the middle cerebellar peduncle (MCP) and the putamen captured by diffusion-tensor imaging (DTI) is differentially affected in the parkinsonian and cerebellar variants of multiple system atrophy (MSA-P, MSA-C) compared to Parkinson's disease (PD). The current study applied DTI and tractography in order to 1) characterize the distribution of DTI metrics along the tracts of the MCP and from the putamen in MSA variants, and 2) evaluate the usefulness of combining these measures for the differential diagnosis of MSA-P against PD in the clinical setting. Methods Twenty-nine MSA patients (MSA-C, n = 10; MSA-P, n = 19), with a mean disease duration of 2.8 ± 1.7 years, 19 PD patients, and 27 healthy controls (HC) were included in the study. Automatized tractography with a masking procedure was employed to isolate the MCP tracts. DTI measures along the tracts of the MCP and within the putamen were acquired and jointly used to classify MSA vs. PD, and MSA-P vs. PD. Putamen volume was additionally tested as classification feature in post hoc analyses. Results DTI measures within the MCP and putamen showed significant alterations in MSA variants compared to HC and PD. Classification accuracy for MSA vs. PD and MSA-P vs PD using diffusion measures was 91.7% and 89.5%, respectively. When replacing the putaminal DTI measure by a normalized measure of putamen volume classification accuracy improved to 95.8% and 94.7%, respectively. Conclusion Multimodal information from MCP tractography and putamen volume yields excellent diagnostic accuracy to discriminate between early-to-moderately advanced patients with MSA and PD.

An accurate and fast transient calorimetric ferrite core-loss measurement method is proposed in this article. In contrast to electrical measurements, the accuracy of the calorimetric approach is largely independent of the magnetic excitation and operating frequency. However, accurate values of the thermal capacitance and the temperature of the core under test (CUT) are required. Accurate measurement of the specific heat capacity of the core material can be achieved with a differential scanning calorimeter (DSC) or by using the CUT as a dc electric conductor and measuring its thermal response for known Joule heating. Accurate temperature measurements can be realized with NTC temperature sensors. A thorough uncertainty analysis of the presented method is conducted by identifying the impact of each source of uncertainty in the course of a sensitivity analysis. For the considered reference case (R 22.1/13.7/7.9 toroidal core with N49 ferrite material by EPCOS-TDK - 500 kHz/100 mT), the method achieves a total uncertainty with a worst-case value of less than 12% or, in case of a more realistic approach considering a Gaussian distribution of each source of uncertainty, a mean value of −4.3% with a 95% confidence interval of $\mathbf {\pm }$ 3.2%. The results are verified by means of finite element method (FEM) simulations and experiments. Furthermore, a step-by-step description of the workflow for preparing and conducting the experiments is provided. The proposed method is tested experimentally and compared to a state-of-the-art electrical loss measurement method for MnZn N87 and N49 ferrite cores of EPCOS-TDK. In addition, it is used to measure the loss-map of the NiZn ferrite material 67 from Fair-Rite for very high frequencies up to 50 MHz, which enables the computation of the material's Steinmetz parameters.

Purpose The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA. Methods Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations. Results The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others. Conclusions Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.

Introduction Quantitative MR planimetric measurements were reported to discriminate between progressive supranuclear palsy (PSP) and non-PSP parkinsonism, yet few data exist on the usefulness of these markers in early disease stages. Methods The pons-to-midbrain area ratio (P/M) and the Magnetic Resonance Parkinsonism Index (MRPI) as well as new indices, termed P/M2.0 and MRPI2.0, multiplying the former by a ratio of the third ventricle (3rdV) width/frontal horns (FH) width, were calculated on T1-weighted images in 84 patients with clinically unclassifiable neurodegenerative parkinsonism (CUP) at the time of imaging. Areas under the curve (AUCs) of these markers for predicting future PSP was determined. The final clinical diagnosis was made after at least 24 months of follow-up. Results Final diagnosis was Parkinson's disease in 55 patients, multiple system atrophy in 12 cases, and PSP in 17. At baseline imaging, patients with a final PSP diagnosis had significantly higher MRPI, P/M, MRPI2.0 and P/M2.0 values compared to the other groups. AUCs in discriminating between future PSP and non-PSP parkinsonism were 0.91 for both the P/M and the MRPI and 0.98 for the P/M2.0 and the MRPI2.0. Conclusions Brainstem-derived MR planimetric measures yield high diagnostic accuracy for separating PSP from non-PSP parkinsonism in early disease stages when clinical criteria are not yet fully met. Consistent with the underlying pathology in PSP, our study suggests that inclusion of 3rdV width makes P/M2.0 and MRPI2.0 more accurate in diagnosing early stage PSP patients than the P/M and MRPI.

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

Neural progenitors derived from iPSCs of patients with multiple system atrophy show changes in the mitochondrial morphology, relocation of α‐synuclein to the nucleus, and increased susceptibility to exogenous oxidative stress. The findings suggest early cellular dysfunction preceding α‐synuclein aggregate formation in this disorder., Aims Multiple system atrophy (MSA) is a fatal neurodegenerative disease that belongs to the family of α‐synucleinopathies. At post mortem examination, intracellular inclusions of misfolded α‐synuclein are found in neurons and oligodendrocytes and are considered to play a significant role in the pathogenesis. However, the early steps of the disease process are unknown and difficult to study in tissue derived from end‐stage disease. Methods Induced pluripotent stem cells (iPSCs) were generated from patients’ and control skin fibroblasts and differentiated into NCAM‐positive neural progenitor cells (NPCs). The mitochondrial morphology and function were assessed by immunocytochemistry and high resolution respirometry. The ability to cope with exogenous oxidative stress was tested by exposure to different doses of luperox. The expression of α‐synuclein was studied by immunocytochemistry. Results We identified increased tubulation of mitochondria with preserved respiration profile in MSA‐derived NPCs. Exposure of these cells to exogenous oxidative stress even at low doses, triggered an excessive generation of reactive oxygen species (ROS) and cleavage of caspase‐3. MSA‐derived NPCs did not present changed levels of SNCA gene expression nor intracellular aggregates of α‐synuclein. However, we identified disease‐related translocation of α‐synuclein to the nucleus. Conclusions Our results show early cellular dysfunction in MSA‐derived NPCs. We identified changes in the redox homeostasis which are functionally compensated at baseline but cause increased susceptibility to exogenous oxidative stress. In addition, nuclear translocation of α‐synuclein in MSA‐derived NPCs supports an early cellular stress response which may precede the neurodegenerative process in this disorder.

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

Objective Cognitive impairment in multiple system atrophy (MSA) is common, but remain poorly characterized. We evaluated cognitive and behavioral features in MSA patients and assessed between‐group differences for MSA subtypes and the effect of orthostatic hypotension (OH) on cognition. Methods This retrospective study included 54 patients with clinical diagnosis of possible and probable MSA referred to the Department of Neurology at Medical University of Innsbruck between 2000 and 2018. Neurological work‐up included comprehensive neuropsychological testing including Consortium to Establish a Registry for Alzheimer's Disease (CERAD‐plus) test battery, Frontal Assessment Battery (FAB), digit span test (DST), clock drawing task (CLOX1), and Hospital Anxiety and Depression Scale (HADS‐D). Results The mean MMSE score was 27.6 points. Overall, slight to moderate cognitive impairment was noted in up to 40% of patients, with predominant impairment of executive function and verbal memory. Patients with the cerebellar variant performed significantly worse than patients with the parkinsonian type (P

Objectives MR planimetry of brainstem structures can be helpful for the discrimination of Parkinsonian syndromes. It has been suggested that ageing might influence brainstem MR measurements assessed by MR planimetry, while effects of gender and total intracranial volume (TIV) have not been assessed so far. The aim of this study was to evaluate age, gender and TIV effects on brainstem MR planimetric measures. Methods Brainstem MR planimetric measures of diameters (midbrain, pons, middle and superior cerebellar peduncle) and areas (pons and midbrain), the derived ratios, and the magnetic resonance Parkinsonism index (MRPI) were assessed on 1.5-T MR images in a large cohort of 97 healthy controls and analysed for the influence of age, gender and TIV with univariate and multivariate linear models. Results Neither gender nor age effects on planimetric measurements were observed in the population relevant for the differential diagnosis of neurodegenerative Parkinsonism, aged 50 to 80 years, except for single area-derived measurements, with gender effects on pontine area (p = 0.013) and age effects on midbrain area (p = 0.037). Results were similar upon inclusion of the TIV in the analyses. Conclusions There is no need to correct for age, gender or TIV when using brainstem-derived MR planimetric measurements in the differential diagnosis of neurodegenerative Parkinsonism. Key Points • There were no gender effects on single or combined imaging measurements of the brainstem in the population aged 50 to 80 years, the age range relevant for the differential diagnosis of neurodegenerative Parkinsonism (except for pontine area). • There were no age effects on single or combined imaging measurements of the brainstem in the population aged 50 to 80 years, the age range relevant for the differential diagnosis of neurodegenerative Parkinsonism (except for midbrain area). • There is no need for age- or gender-specific cut-offs for the relevant age group.

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).

The Unified Multiple System Atrophy (MSA) Rating Scale was developed to provide a surrogate marker of disease severity and clinical progression in patients with MSA. It is comprised of four subscales: UMSARS-I (12 items) rates patient-reported functional disability; UMSARS-II (14 items) assesses motor impairment based on a clinical examination; UMSARS-III records blood pressure and heart rate in the supine and standing positions; and UMSARS-IV (1 item) rates chore-based disability. Strengths of the UMSARS include its wide acceptance in the field, the comprehensive coverage of motor symptoms and its clinimetric properties (including reliability and validity). However, with its increasing use, potential areas of improvement in the UMSARS have become apparent. To address these limitations, a task force, involving clinicians, researchers, patient groups, and industry representatives, has recently been endorsed by the International Parkinson’s Disease and Movement Disorders Society. The present viewpoint summarizes strengths and weaknesses of the UMSARS and suggests a roadmap to develop an improved MSA clinical outcome assessment.

Quasi-2-level (Q2L) operation of multi-level bridge-legs, especially of flying-capacitor converters (FCC), is an interesting option for realizing single-cell power conversion in applications whose system voltages exceed the ratings of available power semiconductors. To ensure equal voltage sharing among a Q2L-FCC’s switches, the voltages of a Q2L-FCC’s minimized flying capacitors (FCs) must always be balanced. Thus, we propose a concept for load-independent FC voltage balancing: For non-zero load current, we use a model predictive control (MPC) approach to identify the commutation sequence of the individual switches within a Q2L transition that minimizes the FC or cell voltage errors. In case of zero load current, we employ a novel MPC-based approach using cell multiple switching (CMS), i.e., the insertion of additional zero-current commutations within a Q2L transition, to exchange charge between the FCs via the charging currents of the switches’ parasitic capacitances. Experiments with a 5-level FCC half-bridge demonstrator confirm the validity of the derived models and verify the performance of the proposed load-independent balancing concept., Electronics, 10 (19), ISSN:2079-9292

A new universal front-end PFC rectifier topology of a battery charger for Electric Vehicles (EVs) is proposed, which allows fast charging at rated and/or full power level in case of 3-phase (Europe) as well as 1-phase (USA) mains supply. In this regard, a conventional 3-phase PFC rectifier would facilitate only one-third of the rated power in case of 1-phase operation. The new topology is based on a two-level six-switch (2LB6) 3-phase boost-type PFC rectifier, which is extended with a diode bridge-leg and additional windings of the Common-Mode (CM) chokes of the EMI filter. Besides this extension of the power circuit, the general design of the new converter is explained, and the generated Differential Mode (DM) and Common Mode (CM) EMI disturbances are investigated for 3-phase and 1-phase operation, resulting in guidelines for the EMI filter design. The EMI performance (CISPR 11 class-B QP) is experimentally verified for 1-phase and 3-phase operation at an output power of 4.5 kW, using a full-scale hardware prototype that implements the proposed extensions for a 2LB6 3-phase boost-type PFC rectifier and that is designed for output power levels of 22 kW and 19 kW in case of 3-phase and 1-phase operation, respectively. Compared to a conventional 2LB6 PFC rectifier, the volume of the extended system increases from 2.7 dm3 to 3.4 dm3, of which 0.5 dm3 is due to the additional dc-link capacitance for buffering the power pulsation with twice the mains frequency occurring for 1-phase operation., Electronics, 10 (17), ISSN:2079-9292

Purpose The aims of this study were to evaluate the diagnostic accuracy of the dual imaging method combining cardiac iodine-123-metaiodobenzylguanidine single-photon emission computed tomography combined with low-dose chest computed tomography compared to routine cardiac scintigraphy, and assess regional differences in tracer distribution and the relationships between imaging and autonomic function in Parkinson’s disease and multiple system atrophy. Methods A prospective study including 19 Parkinson’s disease and 12 multiple system atrophy patients was performed. Patients underwent clinical evaluation, iodine-123-metaiodobenzylguanidine single-photon emission computed tomography combined with chest computed tomography, planar scintigraphy, and cardiovascular autonomic function tests. Results Co-registration of single-photon emission computed tomography and chest computed tomography resulted in three groups with distinct patterns of tracer uptake: homogeneous, non-homogeneously reduced and absent. There was a significant difference in group allocation among patients with multiple system atrophy and Parkinson’s disease (p = 0.001). Most multiple system atrophy patients showed homogeneous uptake, and the majority of Parkinson’s disease patients showed absent cardiac tracer uptake. We identified a pattern of heterogeneous cardiac tracer uptake in both diseases with reductions in the apex and the lateral myocardial wall. Sympathetic dysfunction reflected by a missing blood pressure overshoot during Valsalva manoeuvre correlated with cardiac tracer distribution in Parkinson’s disease patients (p Conclusions The diagnostic accuracy of the dual imaging method and routine cardiac scintigraphy were similar. Anatomical tracer allocation provided by the dual imaging method of cardiac iodine-123-metaiodobenzylguanidine single-photon emission computed tomography and chest computed tomography identified a heterogeneous subgroup of Parkinson’s disease and multiple system atrophy patients with reduced cardiac tracer uptake in the apex and the lateral wall. Sympathetic dysfunction correlated with cardiac imaging in Parkinson’s disease patients.

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

Background The rate of clinical progression in patients with multiple system atrophy (MSA) varies between individuals and predictors for disease progression remain undefined. While the MSA-rasagiline study found no difference in the rates of clinical progression for patients treated with rasagiline versus placebo, it included a large, prospective magnetic resonance imaging (MRI) substudy that can provide new information on the underlying disease progression in patients with early MSA. Methods This post-hoc analysis compared the rate of clinical progression in patients with MSA-specific structural changes at baseline (MRI-positive group) versus the rate of progression in patients without evidence of such changes at baseline (MRI-negative group) using a repeated measures ANCOVA. Clinical progression was assessed using the Unified MSA Rating Scale (UMSARS) and Clinical Global Impression of Improvement (CGI-I). Results Twenty-eight patients with early MSA of the parkinsonian subtype (MRI-positive n = 13; MRI-negative n = 15) who had complete baseline and follow-up UMSARS data were included in this analysis. Patients in the MRI-positive group had faster clinical progression from baseline to the end of the 48-week study compared with those in the MR-negative group as assessed by the UMSARS total (p = 0.028) and UMSARS motor (p = 0.008) scales. At week 48, MRI-positive patients also had a significantly worse health status vs. MRI-negative patients (p = 0.015). Conclusions This is the first study to demonstrate that MSA-specific abnormalities on structural MRI might represent a variant of MSA-P that is associated with more rapid progression and an overall worse prognosis.

Objective: The aim of this pilot study was to investigate change of olfactory functions in Huntington’s disease (HD). Background: HD is a neurodegenerative disease characterized by motor, cognitive, and behavioral abnormalities. There are several studies reporting olfactory dysfunction in manifest and some studies in premanifest HD carriers, and a recent neuropathological study demonstrated HD-specific protein aggregation in the anterior olfactory nucleus in HD patients. In this study, we wanted to assess olfactory functions as a possible early nonmotor symptom of HD mutation carriers without disease-specific motor symptoms and HD patients. Methods: All participants had genetic confirmed HD and were prospectively recruited during their routine control in a specialized outpatient clinic of the Medical University of Innsbruck, Department of Neurology, Austria. Healthy controls (HCs) were caregivers from patients. They were only included if they were younger than 70 years, scored more than 24/30 points on the Mini Mental State Examination, and had no other disease compromising olfactory function. Furthermore, all participants were tested on the Sniffin’ sticks 16-items identification test. Results: We included 23 patients with manifest HD, 13 HD mutation carriers, and 19 HCs. Mutation carriers showed significant impaired odor identification compared to HCs (p < 0.001), as well as Huntington’s patients compared with both mutation carriers (p = 0.003) and HCs (p < 0.001). Conclusions: The results of this pilot study suggest that olfactory dysfunction may be an early nonmotor symptom of HD and could be a potential marker to assess disease progression.