Search

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.

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.

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.

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.

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.

Differential diagnosis of parkinsonian syndromes is considered one of the most challenging in neurology. Quantitative MR planimetric measurements were reported to discriminate between progressive supranuclear palsy (PSP) and non-PSP-parkinsonism. Several studies have used midbrain to pons ratio (M/P) and the Magnetic Resonance Parkinsonism Index (MRPI) in distinguishing PSP patients from those with Parkinson's disease. The current meta-analysis aimed to compare the performance of these measures in discriminating PSP from multiple system atrophy (MSA). A systematic MEDLINE review identified 59 out of 2984 studies allowing a calculation of sensitivity and specificity using the MRPI or M/P. Meta-analyses of results were carried out using random effects modelling. To assess study quality and risk of bias, the QUADAS-2 tool was used. Eight studies were suitable for analysis. The meta‐analysis showed a pooled sensitivity and specificity for the MRPI of PSP versus MSA of 79.2% (95% CI 72.7–84.4%) and 91.2% (95% CI 79.5–96.5%), and 84.1% (95% CI 77.2–89.2%) and 89.2% (95% CI 81.8–93.8%), respectively, for the M/P. The QUADAS-2 toolbox revealed a high risk of bias regarding the methodological quality of patient selection and index test, as all patients were seen in a specialized outpatient department without avoiding case control design and no predefined threshold was given regarding MRPI or M/P cut-offs. Planimetric brainstem measurements, in special the MRPI and M/P, yield high diagnostic accuracy for the discrimination of PSP from MSA. However, there is an urgent need for well-designed, prospective validation studies to ameliorate the concerns regarding the risk of bias.

Background: Enlargement of the third ventricle has been reported in atypical parkinsonism. We investigated whether the measurement of third ventricle width could distinguish Parkinson's disease (PD) from progressive supranuclear palsy (PSP). Methods: We assessed a new MR T1-weighted measurement (third ventricle width/internal skull diameter) in a training cohort of 268 participants (98 PD, 73 PSP, 98 controls from our center) and in a testing cohort of 291 participants (82 de novo PD patients and 133 controls from the Parkinson's Progression Markers Initiative, 76 early-stage PSP from an international research group). PD diagnosis was confirmed after a 4-year follow-up. Diagnostic performance of the third ventricle/internal skull diameter was assessed using receiver operating characteristic curve with bootstrapping; the area under the curve of the training cohort was compared with the area under the curve of the testing cohort using the De Long test. Results: In both cohorts, third ventricle/internal skull diameter values did not differ between PD and controls but were significantly lower in PD than in PSP patients (P < 0.0001). In PD, third ventricle/internal skull diameter values did not change significantly between baseline and follow-up evaluation. Receiver operating characteristic analysis accurately differentiated PD from PSP in the training cohort (area under the curve, 0.94; 95% CI, 91.1-97.6; cutoff, 5.72) and in the testing cohort (area under the curve, 0.91; 95% CI, 87.0-97.0; cutoff,: 5.88), validating the generalizability of the results. Conclusion: Our study provides a new reliable and validated MRI measurement for the early differentiation of PD and PSP. The simplicity and generalizability of this biomarker make it suitable for routine clinical practice and for selection of patients in clinical trials worldwide. © 2020 International Parkinson and Movement Disorder Society.

Summary Background Development of valid, non-invasive biomarkers for parkinsonian syndromes is crucially needed. We aimed to assess whether non-invasive diffusion-weighted MRI can distinguish between parkinsonian syndromes using an automated imaging approach. Methods We did an international study at 17 MRI centres in Austria, Germany, and the USA. We used diffusion-weighted MRI from 1002 patients and the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) to develop and validate disease-specific machine learning comparisons using 60 template regions and tracts of interest in Montreal Neurological Institute space between Parkinson's disease and atypical parkinsonism (multiple system atrophy and progressive supranuclear palsy) and between multiple system atrophy and progressive supranuclear palsy. For each comparison, models were developed on a training and validation cohort and evaluated in an independent test cohort by quantifying the area under the curve (AUC) of receiving operating characteristic curves. The primary outcomes were free water and free-water-corrected fractional anisotropy across 60 different template regions. Findings In the test cohort for disease-specific comparisons, the diffusion-weighted MRI plus MDS-UPDRS III model (Parkinson's disease vs atypical parkinsonism had an AUC 0·962; multiple system atrophy vs progressive supranuclear palsy AUC 0·897) and diffusion-weighted MRI only model had high AUCs (Parkinson's disease vs atypical parkinsonism AUC 0·955; multiple system atrophy vs progressive supranuclear palsy AUC 0·926), whereas the MDS-UPDRS III only models had significantly lower AUCs (Parkinson's disease vs atypical parkinsonism 0·775; multiple system atrophy vs progressive supranuclear palsy 0·582). These results indicate that a non-invasive imaging approach is capable of differentiating forms of parkinsonism comparable to current gold standard methods. Interpretations This study provides an objective, validated, and generalisable imaging approach to distinguish different forms of parkinsonian syndromes using multisite diffusion-weighted MRI cohorts. The diffusion-weighted MRI method does not involve radioactive tracers, is completely automated, and can be collected in less than 12 min across 3T scanners worldwide. The use of this test could positively affect the clinical care of patients with Parkinson's disease and parkinsonism and reduce the number of misdiagnosed cases in clinical trials. Funding National Institutes of Health and Parkinson's Foundation.

Background In the current consensus diagnostic criteria, the diagnosis of probable multiple system atrophy (MSA) is based solely on clinical findings, whereas neuroimaging findings are listed as aid for the diagnosis of possible MSA. There are overlapping phenotypes between MSA-parkinsonian type and Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and between MSA-cerebellar type and sporadic adult-onset ataxia resulting in a significant diagnostic delay and misdiagnosis of MSA during life. Objectives In light of an ongoing effort to revise the current consensus criteria for MSA, the Movement Disorders Society Multiple System Atrophy Study Group performed a systematic review of original articles published before August 2019. Methods We included articles that studied at least 10 patients with MSA as well as participants with another disorder or control group for comparison purposes. MSA was defined by neuropathological confirmation, or as clinically probable, or clinically probable plus possible according to consensus diagnostic criteria. Results We discuss the pitfalls and benefits of each diagnostic test and provide specific recommendations on how to evaluate patients in whom MSA is suspected. Conclusions This systematic review of relevant studies indicates that imaging and autonomic function tests significantly contribute to increasing the accuracy of a diagnosis of MSA.

BACKGROUND: The Magnetic Resonance Parkinsonism Index is listed as one of the most reliable imaging morphometric markers for diagnosis of progressive supranuclear palsy (PSP). However, the use of this index in diagnostic workup has been limited until now by the low generalizability of published results because of small monocentric patient cohorts, the lack of data validation in independent patient series, and manual measurements used for index calculation. The objectives of this study were to investigate the generalizability of Magnetic Resonance Parkinsonism Index performance validating previously established cutoff values in a large international cohort of PSP patients subclassified into PSP-Richardson's syndrome and PSP-parkinsonism and to standardize the use of the automated Magnetic Resonance Parkinsonism Index by providing a web-based platform to obtain homogenous measures around the world. METHODS: In a retrospective international multicenter study, a total of 173 PSP patients and 483 non-PSP participants were enrolled. A web-based platform (https://mrpi.unicz.it) was used to calculate automated Magnetic Resonance Parkinsonism Index values. RESULTS: Magnetic Resonance Parkinsonism Index values showed optimal performance in differentiating PSP-Richardson's syndrome and PSP-parkinsonism patients from non-PSP participants (93.6% and 86.5% of accuracy, respectively). The Magnetic Resonance Parkinsonism Index was also able to differentiate PSP-Richardson's syndrome and PSP-parkinsonism patients in an early stage of the disease from non-PSP participants (90.1% and 85.9%, respectively). The web-based platform provided the automated Magnetic Resonance Parkinsonism Index calculation in 94% of cases. CONCLUSIONS: Our study provides the first evidence on the generalizability of automated Magnetic Resonance Parkinsonism Index measures in a large international cohort of PSP-Richardson's syndrome and PSP-parkinsonism patients. The web-based platform enables widespread applicability of the automated Magnetic Resonance Parkinsonism Index to different clinical and research settings. © 2020 International Parkinson and Movement Disorder Society.

Background Imaging markers that are sensitive to parkinsonism across multiple sites are critically needed for clinical trials. The objective of this study was to evaluate changes in the substantia nigra using single- and bi-tensor models of diffusion magnetic resonance imaging in PD, MSA, and PSP. Methods The study cohort (n = 425) included 107 healthy controls and 184 PD, 63 MSA, and 71 PSP patients from 3 movement disorder centers. Bi-tensor free water, free-water-corrected fractional anisotropy, free-water-corrected mean diffusivity, single-tensor fractional anisotropy, and single-tensor mean diffusivity were computed for the anterior and posterior substantia nigra. Correlations were computed between diffusion MRI measures and clinical measures. Results In the posterior substantia nigra, free water was greater for PSP than MSA and PD patients and controls. PD and MSA both had greater free water than controls. Free-water-corrected fractional anisotropy values were greater for PSP patents than for controls and PD patients. PSP and MSA patient single-tensor mean diffusivity values were greater than controls, and single-tensor fractional anisotropy values were lower for PSP patients than for healthy controls. The parkinsonism effect size for free water was 0.145 in the posterior substantia nigra and 0.072 for single-tensor mean diffusivity 072. The direction of correlations between single-tensor mean diffusivity and free-water values and clinical scores was similar at each site. Conclusions Free-water values in the posterior substantia nigra provide a consistent pattern of findings across patients with PD, MSA, and PSP in a large cohort across 3 sites. Free water in the posterior substantia nigra relates to clinical measures of motor and cognitive symptoms in a large cohort of parkinsonism. © 2017 International Parkinson and Movement Disorder Society

Background: Progressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes. Objective: To identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP. Methods: We performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort. Results: Of 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity. Conclusions: Our results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP.

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

The differential diagnosis of parkinsonian syndromes is considered one of the most challenging in neurology and error rates in the clinical diagnosis can be high even at specialized centres. Despite several limitations, magnetic resonance imaging (MRI) has undoubtedly enhanced the diagnostic accuracy in the differential diagnosis of neurodegenerative parkinsonism over the last three decades. This review aims to summarize research findings regarding the value of the different MRI techniques, including advanced sequences at high- and ultra-high-field MRI and modern image analysis algorithms, in the diagnostic work-up of Parkinson’s disease. This includes not only the exclusion of alternative diagnoses for Parkinson’s disease such as symptomatic parkinsonism and atypical parkinsonism, but also the diagnosis of early, new onset, and even prodromal Parkinson’s disease.

Multiple system atrophy (MSA) is a devastating and fatal neurodegenerative disorder. The clinical presentation of this disease is highly variable, with parkinsonism, cerebellar ataxia and autonomic failure being the most common - and often debilitating - symptoms. These symptoms progress rapidly, and patients die from MSA-related complications after 9 years of symptom duration on average. Unfortunately, the course of the disease cannot be improved by drug or surgical treatment. In addition, symptomatic treatment options are currently limited, and therapeutic benefits are often only transient. Thus, further interventional studies of candidate disease-modifying and symptomatic therapies are essential to improve patient care. In the past 15 years, the understanding of MSA-specific requirements in trial methodology has improved, resulting in a substantial increase in high-quality interventional studies. In this Review, we discuss MSA risk factors, clinical presentation and neuropathology, and we provide a hypothesis on key pathophysiological events, a summary of recent randomized controlled trials, and an overview of ongoing international collaborations.

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

Objective To determine the diagnostic utility of olfactory testing in patients with neurodegenerative parkinsonism. Methods The Sniffin' Sticks test battery for assessment of odor identification, discrimination, and threshold was applied to patients with Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) as well as healthy controls (HC). Two different cohorts were analyzed: A PD/healthy control that included PD patients and HC as well as a PD/diseased control cohort for which patients PD, MSA and PSP were recruited. The former cohort was exploited to calculate cut-off values that discriminate PD patients from HC with a sensitivity (sensitivity-weighted cut-off) or specificity (specificity-weighted cut-off) exceeding 95%, respectively. The PD/diseased controls cohort was used to determine the diagnostic accuracy using these cut-off values in discriminating patients with neurodegenerative parkinsonism. Results PD patients (n = 67) performed significantly worse in olfactory testing than HC (n = 41) and patients with MSA (n = 23) or PSP (n = 23). There was no significant difference in olfactory function between MSA and PSP patients. Diagnostic performance of the identification subscore was similar to the sum score of the Sniffin’ Sticks test (AUC identification test 0.94, AUC sum score 0.96), while threshold and discrimination subscores were inferior. In patients with parkinsonism, the specificity-weighted cut-off predicted a diagnosis of PD with a sensitivity and specificity of 76.6 and 87.0%, respectively. The discriminative value of this cut-off in separating PD from MSA was 76.7% (sensitivity) and 95.7% (specificity). The corresponding, prevalence-adjusted positive predictive value of olfactory testing exceeded 95%. Conclusions Our data suggest that assessment of olfactory function, particularly odor identification, can be useful to discriminate PD from atypical parkinsonian disorders, particularly MSA patients.

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder with a highly variable clinical presentation. Unfortunately, there exists no effective therapy that can improve the course of the disease and symptomatic treatment options remain limited. Although significant progress in research has improved our understanding of MSA, knowledge gaps still remain. Thus, a global network focusing on different research areas is required to face this fatal disease.

Background Microstructural white matter integrity captured by diffusion-tensor imaging (DTI) is significantly more affected in progressive supranuclear palsy-Richardson's syndrome (PSP-RS) compared to PSP-parkinsonism (PSP–P). Objectives To characterize the microstructural integrity of large fascicular bundles using standardized probabilistic tractography and combine it with previously established DTI- and volumetric measures of subcortical brain structures in order to evaluate its diagnostic properties for the differentiation of PSP- RS, PSP-P and Parkinson's disease (PD). Methods DTI metrics as well as volumes of subcortical brain regions, acquired by 3T MRI of patients with PSP-RS (n = 15), PSP-P (n = 13), and a mean disease duration of 2.7 ± 1.8 years, were quantified by probabilistic tractography as well as a validated infratentorial atlas and compared to PD (n = 18) and healthy controls (n = 20). Classification accuracy of MRI measures was tested by consecutive linear discriminant analyses. Results DTI metrics of the anterior thalamic radiation, the corticospinal tract, the superior longitudinal fasciculus, the bundles of the corpus callosum and cingulate, the dentatorubrothalamic tract as well as volumes of the dorsal midbrain, globus pallidus and thalamus were significantly altered in PSP-RS and to a lesser extent in PSP-P compared to PD and healthy controls. Linear discriminant analysis identified DTI metrics of the dentatorubrothalamic tract and the anterior thalamic radiation as well as the volume of the dorsal midbrain to classify correctly 91.3% of PSP-RS, PSP-P and PD patients. Conclusions Observer-independent investigations of microstructural integrity of major fiber bundles improved existing MRI processing strategies to differentiate PSP-P from PSP-RS and PD, in their early disease stages.

Multiple system atrophy (MSA) is a sporadic, adult-onset, relentlessly progressive neurodegenerative disorder, clinically characterized by various combinations of autonomic failure, parkinsonism and ataxia. The neuropathological hallmark of MSA are glial cytoplasmic inclusions consisting of misfolded α-synuclein. Selective atrophy and neuronal loss in striatonigral and olivopontocerebellar systems underlie the division into two main motor phenotypes of MSA-parkinsonian type and MSA-cerebellar type. Isolated autonomic failure and REM sleep behavior disorder are common premotor features of MSA. Beyond the core clinical symptoms, MSA manifests with a number of non-motor and motor features. Red flags highly specific for MSA may provide clues for a correct diagnosis, but in general the diagnostic accuracy of the second consensus criteria is suboptimal, particularly in early disease stages. In this chapter, the authors discuss the historical milestones, etiopathogenesis, neuropathological findings, clinical features, red flags, differential diagnosis, diagnostic criteria, imaging and other biomarkers, current treatment, unmet needs and future treatments for MSA.

Background and objectives Gait impairment and reduced mobility are disabling symptoms of multiple system atrophy. While physiotherapy is increasingly recognized as a valuable supplement to pharmacotherapy for patients with Parkinson's disease, data on the efficacy of physiotherapy for multiple system atrophy are lacking. This study aimed to explore the feasibility of two consecutive exercise-based interventions in patients with multiple system atrophy. Subjects and Methods We included 10 patients with the parkinsonian variant of multiple system atrophy and 10 patients with Parkinson's disease, matched for gender and Hoehn & Yahr stage (≤3). Interventions consisted of a five-day inpatient physiotherapy program followed by a five-week unsupervised home-based exercise program. Outcomes included instrumented gait analysis, patient questionnaires, clinical rating scales and physical tests. Patients were examined at baseline, after the first inpatient treatment and again after the home-based intervention. Additionally, a structured telephone interview was performed immediately after the second intervention period. Results Both patient groups exhibited a similar improvement of gait after the interventions, as measured by instrumented gait analysis. These effects reached their maximum level after inpatient physiotherapy and remained stable following the home-based exercise program. Patient questionnaires also showed improvements after the interventions, but motor clinical rating scales did not. Conclusion Our pilot results suggest that a short-term bout of physiotherapy is feasible, safe and improves gait performance in patients with multiple system atrophy. This highlights the potential of physiotherapy for this disabling condition where pharmacotherapy typically achieves poor effects. The present findings warrant a larger controlled study.

© 2019 International Parkinson and Movement Disorder Society, Multiple system atrophy (MSA) is an adult-onset progressive neurodegenerative disorder that manifests clinically with autonomic failure, parkinsonism, and ataxia in any combination. Oligodendroglial cytoplasmatic inclusions consisting of misfolded α-synuclein are a pathological hallmark of disease. The clinical diagnosis of MSA is typically delayed as a result of incomplete or nonspecific manifestations during early disease stages. Quinn first published diagnostic criteria for MSA in 1989. Since then, the first consensus criteria in 1998 and their revision in 2008 have been widely accepted as diagnostic guidelines for MSA.

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

Multiple system atrophy has recently attracted increased attention in basic and clinical research. Understanding of key pathophysiological mechanismshas improved; and, in the past decade, the first clinical trials aiming at diseasemodification were conducted. However, there is still no established interventional therapy available. In this review, the authors summarize recent advances, discuss bottlenecks and possible pitfalls of previous interventional studies, and suggest future research avenues.

Atypical parkinson disorders (APD) are rapidly progressive neurodegenerative diseases with a variable clinical presentation that may even mimic Parkinson's disease. Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are commonly summarized under this umbrella term. Significant developments in research have expanded knowledge and have broadened available symptomatic treatments, particularly for the treatment of neurogenic orthostatic hypotension. Nonetheless, symptomatic support still remains limited in all of these disorders. Currently, there exists no effective treatment to delay disease progression and disease-modifying trials have failed to provide coherent and convincing results. Recent trials of rasagiline (in MSA), rifampicin (in MSA), tideglusib (in PSP) and davunetide (in PSP) reported negative results. Nevertheless, large cohorts of patients were recruited for interventional studies in the last few years which improved our understanding of trial methodology in APDs immensely. In addition, remarkable progress in basic research has been reported recently and will provide a solid foundation for future therapeutic trials. In this review, we will summarize published randomized, placebo-controlled clinical trials (RCTs) in APDs. Additionally, the design of ongoing and unpublished interventions will be presented.

Background: Sarcopenia and frailty are found in up to one-third of the general elderly population. Both are associated with major adverse health outcomes such as nursing home placement, disability, decreased quality of life, and death. Data on the frequency of both syndromes in Parkinson’s disease (PD), however, are very limited. Objective: We aimed to screen for sarcopenia and frailty in PD patients and to assess potential associations of both geriatric syndromes with demographic and clinical parameters as well as quality of life. Methods: In this observational, cross-sectional study, we included 104 PD patients from a tertiary center and 330 non-PD controls from a population-based cohort aged > 65 years. All groups were screened for sarcopenia using the SARC-F score and for frailty using the Clinical Frailty Scale of the Canadian Study of Health and Aging (CSHA CFS). Prevalence rates of sarcopenia and frailty were also assessed in 18 PD patients from a population-based cohort aged > 65 years. Moreover, PD patients from the tertiary center were evaluated for motor and non-motor symptoms, quality of life, and dependency. Results: The prevalence of sarcopenia was 55.8% (95% CI: 46.2–64.9%) in PD patients from the tertiary center and 8.2% (5.7–11.7%; p < 0.001) in non-PD controls. Frailty was detected in 35.6% (27.0–45.2%) and 5.2% (3.2–8.1%; p < 0.001). Prevalence rates for sarcopenia and frailty were 33.3% (16.1–56.4%; p = 0.004) and 22.2% (8.5–45.8%; p = 0.017) in the community-based PD sample. Both sarcopenia and frailty were significantly associated with longer disease duration, higher motor impairment, higher Hoehn and Yahr stages, decreased quality of life, higher frequency of falls, a higher non-motor symptom burden, institutionalization, and higher care levels in PD patients from a tertiary center compared to not affected PD patients (all p < 0.05). Conclusions: Both frailty and sarcopenia are more common in PD patients than in the general community and are associated with a more adverse course of the disease. Future studies should look into underlying risk factors for the occurrence of sarcopenia and frailty in PD patients and into adequate management to prevent and mitigate them.

Item does not contain fulltext OBJECTIVE: Differentiating Parkinson's disease (PD) from atypical parkinsonian disorders (APD) such as Multiple System Atrophy, parkinsonian type (MSA-p) or Progressive Supranuclear Palsy (PSP-RS) can be challenging. Early signs of postural Instability and gait disability (PIGD) are considered clues that may signal presence of APD. However, it remains unknown which PIGD test - or combination of tests - can best distinguish PD from APD. We evaluated the discriminative value of several widely-used PIGD tests, and aimed to develop a short PIGD evaluation that can discriminate parkinsonian disorders. METHODS: In this multicentre cohort study patients were recruited by 11 European MSA Study sites. Patients were diagnosed using standardized criteria. Postural instability and gait disability was evaluated using interviews and several clinical tests. RESULTS: Nineteen PD, 21 MSA-p and 25PSP-RS patients were recruited. PIGD was more common in APD compared to PD. There was no significant difference in axial symptoms between PSP-RS and MSA-p, except for self-reported falls (more frequent in PSP-RS patients). The test with the greatest discriminative power to distinguish APD from PD was the ability to perform tandem gait (AUC 0.83; 95% CI 71-94; p

Qualitative and quantitative structural magnetic resonance imaging offer objective measures of the underlying neurodegeneration in atypical parkinsonism. Regional changes in tissue volume, signal changes and increased deposition of iron as assessed with different structural MRI techniques are surrogate markers of underlying neurodegeneration and may reflect cell loss, microglial proliferation and astroglial activation. Structural MRI has been explored as a tool to enhance diagnostic accuracy in differentiating atypical parkinsonian disorders (APDs). Moreover, the longitudinal assessment of serial structural MRI-derived parameters offers the opportunity for robust inferences regarding the progression of APDs. This review summarizes recent research findings as (1) a diagnostic tool for APDs as well as (2) as a tool to assess longitudinal changes of serial MRI-derived parameters in the different APDs.

Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are relentlessly progressive neurodegenerative diseases leading to severe disability and ultimately death within less than 10 y. Despite increasing efforts in basic and clinical research, effective therapies for these atypical parkinsonian disorders are lacking. Although earlier small clinical studies in MSA and PSP mainly focused on symptomatic treatment, advances in the understanding of the molecular underpinnings of these diseases and in the search for biomarkers have paved the way for the first large and well-designed clinical trials aiming at disease modification. Targets of intervention in these trials have included α-synuclein inclusion pathology in the case of MSA and tau-related mechanisms in PSP. Since 2013, four large randomized, placebo-controlled, double-blind disease-modification trials have been completed and published, using rasagiline (MSA), rifampicin (MSA), tideglusib (PSP), or davunetide (PSP). All of these failed to demonstrate signal efficacy with regard to the primary outcome measures. In addition, two randomized, placebo-controlled, double-blind trials have studied the efficacy of droxidopa in the symptomatic treatment of neurogenic orthostatic hypotension, including patients with MSA, with positive results in one trial. This review summarizes the design and the outcomes of these and other smaller trials published since 2013 and attempts to highlight priority areas of future therapeutic research in MSA and PSP. © 2015 International Parkinson and Movement Disorder Society

Background Absence of a hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense pars compacta of the substantia nigra (referred to as dorsolateral nigral hyperintensity) on iron-sensitive high-field magnetic resonance imaging sequences seems to be a typical finding for patients with Parkinson's disease (PD). Objective This study was undertaken to evaluate the diagnostic value of the dorsolateral nigral hyperintensity in a cohort of patients with neurodegenerative parkinsonism including PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) as well as healthy controls using high-field susceptibility-weighted imaging (SWI) at 3.0 Tesla (T). Methods Absence of dorsolateral nigral hyperintensity was assessed on visual inspection of anonymized 3.0T SWI scans in a case-control study including 148 patients with neurodegenerative parkinsonism (PD: n = 104; MSA: n = 22; PSP: n = 22) and 42 healthy controls. Results Dorsolateral nigral hyperintensity was absent unilaterally in all patients with MSA or PSP, in 83 of 90 patients with PD, but only in one of the healthy controls resulting in an overall correct classification of 95.2% in discriminating neurodegenerative parkinsonism from controls in the per-protocol analysis. Overall correct classification was 93.2% in the intent-to-diagnose analysis, including also SWI scans with poor quality (12.1% of all scans) for nigral evaluation. Conclusion Visual assessment of dorsolateral nigral hyperintensity on high-field SWI scans may serve as a new simple diagnostic imaging marker for neurodegenerative parkinsonian disorders. © 2015 International Parkinson and Movement Disorder Society

Current consensus diagnostic criteria for multiple system atrophy (MSA) consider dementia a non-supporting feature, although cognitive impairment and even frank dementia are reported in clinical practice. Mini-Mental State Examination (MMSE) is a commonly used global cognitive scale, and in a previous study, we established an MSA-specific screening cut-off score

Background Putaminal diffusivity in brain magnetic resonance diffusion-weighted imaging (DWI) is increased in patients with the parkinsonian variant of multiple system atrophy (MSA-P) compared to Parkinson disease (PD) patients. Purpose We performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of DWI to distinguish MSA-P from PD. Methods Studies on DWI were identified through a systematic PubMed and Clarivate Analytics® Web of Science® Core Collection search. Papers were selected based on stringent inclusion criteria; minimum requirement was the inclusion of MSA-P and PD patients and documented true positive, true negative, false positive and false negative rates or overall sample size and reported sensitivity and specificity. Meta-analysis was performed using the hierarchical summary receiver operating characteristics curve approach. Results The database search yielded 1678 results of which 9 studies were deemed relevant. Diagnostic accuracy of putaminal diffusivity measurements were reported in all of these 9 studies, whereas results of other regions of interest were only reported irregularly. Therefore, a meta-analysis could only be performed for putaminal diffusivity measurements: 127 patients with MSA-P, 262 patients with PD and 70 healthy controls were included in the quantitative synthesis. The meta-analysis showed an overall sensitivity of 90% (95% confidence interval (CI): 76.7%-95.8%) and an overall specificity of 93% (95% CI: 80.0%-97.7%) to distinguish MSA-P from PD based on putaminal diffusivity. Conclusion Putaminal diffusivity yields high sensitivity and specificity to distinguish clinically diagnosed patients with MSA-P from PD. The confidence intervals indicate substantial variability. Further multicenter studies with harmonized protocols are warranted particularly in early disease stages when clinical diagnosis is less certain.

There is evidence that the α-synucleinopathies Parkinson's disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P) overlap at multiple levels. Both disorders are characterized by deposition of abnormally phosphorylated fibrillar α-synuclein within the central nervous system suggesting shared pathophysiological mechanisms. Despite the considerable clinical overlap in the early disease stages, MSA-P, in contrast to PD, is fatal and rapidly progressive. Moreover recent clinical studies have shown that surrogate markers of disease progression can be quantified easily and may reliably depict the rapid course of MSA. We therefore posit that, MSA-P may be exploited as a filter barrier in the development of disease-modifying therapeutic strategies targeting common pathophysiological mechanisms of α-synucleinopathies. This approach might reduce the number of negative phase III clinical trials, and, in turn, shift the available resources to earlier development stages, thereby increasing the number of candidate compounds validated., Highlights • α-synucleinopathies overlap at multiple levels. • α-synucleinopathies are characterized by an abnormal deposition of α-synuclein. • Validated surrogate markers in MSA reliably monitor disease progression. • MSA may serve as a template disease for other α-synucleinopathies.

Different neuroimaging modalities hold potential as surrogate markers of underlying neurodegeneration in multiple system atrophy (MSA) and may reflect cell loss, altered glucose metabolism, microglial proliferation, astroglial activation, and nigrostriatal denervation. Multiple studies have demonstrated that serial structural and functional imaging studies are capable of demonstrating neurodegeneration in MSA patients quantitatively, which allows sample size estimates based on rates of progression of these neuroimaging markers. This review summarizes recent research findings as a tool to assess longitudinal changes of serial neuroimaging-derived parameters in MSA.

BackgroundUnresponsiveness to dopaminergic therapies is a key feature in the diagnosis of multiple system atrophy (MSA) and a major unmet need in the treatment of MSA patients caused by combined striatonigral degeneration (SND). Transgenic, alpha-synuclein animal models do not recapitulate this lack of levodopa responsiveness. In order to preclinically study interventions including striatal cell grafts, models that feature SND are required. Most of the previous studies focused on extensive nigral and striatal lesions corresponding to advanced MSA-P/SND. The aim of the current study was to replicate mild stage MSA-P/SND with L-dopa failure.Methods and resultsTwo different striatal quinolinic acid (QA) lesions following a striatal 6-OHDA lesion replicating mild and severe MSA-P/SND, respectively, were investigated and compared to 6-OHDA lesioned animals. After the initial 6-OHDA lesion there was a significant improvement of motor performance after dopaminergic stimulation in the cylinder and stepping test (pConclusionOur novel L-dopa response data suggest that L-dopa failure can be induced by restricted lateral striatal lesions combined with dopaminergic denervation. We propose that this sequential striatal double-lesion model replicates a mild stage of MSA-P/SND and is suitable to address neuro-regenerative therapies aimed at restoring dopaminergic responsiveness.

Multiple system atrophy (MSA), a rapidly progressive neurodegenerative disorder with parkinsonism, cerebellar ataxia, and autonomic failure, has few effective therapies, so disease-modifying therapies remain a critical need. So far, randomized controlled trials (RCTs) testing a variety of drug candidates largely failed.1 The exception was a small-scale interventional RCT of sequential intra-arterial and IV administration of mesenchymal stem cells (MSC) in patients with cerebellar-type MSA2 that found a small reduction in the increase of severity rating scores (Unified MSA Rating Scale [UMSARS]) over 1 year, as compared to placebo.

Background Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder which causes early sustained disability and quality of life impairment. Recently, a self-reported questionnaire focusing on MSA-specific symptoms (Multiple System Atrophy Quality of Life questionnaire, MSA-QoL) was developed in the English language. This article reports the validation of the German translation of the MSA-QoL. Methods Translation of the MSA-QoL was implemented in a 3-tiered approach including a forward translation, a back translation and an independent review. For the validation study 38 consecutive patients with MSA according to the consensus criteria were recruited by the participating centers in a German-Austrian cohort. Data were analyzed using standard psychometric procedures. Results As determined by the independent review, the German translation of the MSA-QoL was classified as fully equivalent to the English version. The validation study confirmed good psychometric properties of the rating scale. Conclusion The German translation of the MSA-QoL was shown to be a reliable patient-reported rating scale to determine health-related quality of life in MSA patients.

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

Multiple system atrophy is a rapidly progressive neurodegenerative disorder with a markedly reduced life expectancy. Failure of symptomatic treatment raises an urgent need for disease-modifying strategies. We have investigated the neuroprotective potential of erythropoietin in (proteolipid protein)-α-synuclein transgenic mice exposed to 3-nitropropionic acid featuring multiple system atrophy-like pathology including oligodendroglial α-synuclein inclusions and selective neuronal degeneration. Mice were treated with erythropoietin starting before (early erythropoietin) and after (late erythropoietin) intoxication with 3-nitropropionic acid. Nonintoxicated animals receiving erythropoietin and intoxicated animals treated with saline served as control groups. Behavioral tests included pole test, open field activity, and motor behavior scale. Immunohistochemistry for tyrosine hydroxylase and dopamine and cyclic adenosine monophosphate-regulated phosphoprotein (DARPP-32) was analyzed stereologically. Animals receiving erythropoietin before and after 3-nitropropionic acid intoxication scored significantly lower on the motor behavior scale and they performed better in the pole test than controls with no significant difference between early and late erythropoietin administration. Similarly, rearing scores were worse in 3-nitropropionic acid-treated animals with no difference between the erythropoietin subgroups. Immunohistochemistry revealed significant attenuation of 3-nitropropionic acid-induced loss of tyrosine hydroxylase and DARPP-32 positive neurons in substantia nigra pars compacta and striatum, respectively, in both erythropoietin-treated groups without significant group difference in the substantia nigra. However, at striatal level, a significant difference between early and late erythropoietin administration was observed. In the combined (proteolipid protein)-α-synuclein 3-nitropropionic acid multiple system atrophy mouse model, erythropoietin appears to rescue dopaminergic and striatal gabaergic projection neurons. This effect is associated with improved motor function. Further studies are warranted to develop erythropoietin as a potential interventional therapy in multiple system atrophy. © 2011 Movement Disorder Society

Hepatic encephalopathy is a common complication of cirrhosis. The degree of neuro-psychiatric impairment is highly variable and its clinical staging subjective. We investigated whether eye movement response times—saccadic latencies—could serve as an indicator of encephalopathy. We studied the association between saccadic latency, liver function and paper- and pencil tests in 70 patients with cirrhosis and 31 patients after liver transplantation. The tests included the porto-systemic encephalopathy (PSE-) test, critical flicker frequency, MELD score and ammonia concentration. A normal range for saccades was established in 31 control subjects. Clinical and biochemical parameters of liver, blood, and kidney function were also determined. Median saccadic latencies were significantly longer in patients with liver cirrhosis when compared to patients after liver transplantation (244 ms vs. 278 ms p

Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results suggest that combining several CSF fluid biomarkers may be more successful than using single markers, at least for the diagnosis. Currently, the clinically most useful markers may comprise a combination of the light chain of neurofilament (which is consistently elevated in MSA compared to controls and Parkinson’s disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success.