Abstract Multiple system atrophy (MSA) is a rare, adult-onset, progressive neurodegenerative disorder with major diagnostic challenges. Aiming for a better diagnostic accuracy particularly at early disease stages, novel Movement Disorder Society criteria for the diagnosis of MSA (MDS MSA criteria) have been recently developed. They introduce a neuropathologically established MSA category and three levels of clinical diagnostic certainty including clinically established MSA, clinically probable MSA, and the research category of possible prodromal MSA. The diagnosis of clinically established and clinically probable MSA is based on the presence of cardiovascular or urological autonomic failure, parkinsonism (poorly L-Dopa-responsive for the diagnosis of clinically established MSA), and cerebellar syndrome. These core clinical features need to be associated with supportive motor and non-motor features (MSA red flags) and absence of any exclusion criteria. Characteristic brain MRI markers are required for a diagnosis of clinically established MSA. A research category of possible prodromal MSA is devised to capture patients manifesting with autonomic failure or REM sleep behavior disorder and only mild motor signs at the earliest disease stage. There is a number of promising laboratory markers for MSA that may help increase the overall clinical diagnostic accuracy. In this review, we will discuss the core and supportive clinical features for a diagnosis of MSA in light of the new MDS MSA criteria, which laboratory tools may assist in the clinical diagnosis and which major differential diagnostic challenges should be borne in mind. 

/pdf/a-review-on-the-clinical-diagnosis-of-multiple-system-2wj05fut.pdf

A Review on the Clinical Diagnosis of Multiple System Atrophy.

Multiple system atrophy (MSA) is a rare and progressive neurodegenerative disorder characterized by motor and autonomic dysfunction. Accurate and early diagnosis of MSA is challenging due to its clinical similarity with other neurodegenerative disorders, such as Parkinson’s disease and atypical parkinsonian disorders. Currently, MSA diagnosis is based on clinical criteria drawing from the patient’s symptoms, lack of response to levodopa therapy, neuroimaging studies, and exclusion of other diseases. However, these methods have limitations in sensitivity and specificity. Recent advances in molecular biomarker research, such as α-synuclein protein amplification assays (RT-QuIC) and other biomarkers in cerebrospinal fluid and blood, have shown promise in improving the diagnosis of MSA. Additionally, these biomarkers could also serve as targets for developing disease-modifying therapies and monitoring treatment response. In this review, we provide an overview of the clinical syndrome of MSA and discuss the current diagnostic criteria, limitations of current diagnostic methods, and emerging molecular biomarkers that offer hope for improving the accuracy and early detection of MSA.

Diagnosing multiple system atrophy: current clinical guidance and emerging molecular biomarkers

Background Non-motor symptoms (NMS) are compulsory clinical features for the clinical diagnosis of multiple system atrophy (MSA), some of which precede motor symptoms onset. To date, few studies have systematically investigated NMS in MSA and the timing of presenting NMS as the disease progresses. Clinically, MSA is difficult to be differentiated from Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and the differences in NMS between MSA and PD/PSP remain unclear. The aim of this study was to compare the burden of NMS between MSA and PD/PSP and to delineate the timing of NMS presentation relative to the onset of motor symptoms in MSA. Methods A total of 61, 87, and 30 patients with MSA, PD, and PSP, respectively, were enrolled in this study. NMS was systematically assessed in all patients using the NMS scale (NMSS), and the onset of NMS relative to the onset of motor symptoms in MSA was investigated. Results MSA group had higher total NMSS scores (82.15 ± 46.10) than the PD (36.14 ± 30.78) and PSP (50.30 ± 55.05) groups (p < 0.001 overall). The number distribution pattern of the NMS was significantly different among the three parkinsonian disorders (p < 0.001 overall). In total, 85.2% of patients with MSA had more than 10 NMS, which was significantly higher than PD (28.7%) and PSP (33.3%). The frequency and scores of many NMSS subdomains and symptoms were higher in MSA than in PD and PSP (all p < 0.05). Multivariate logistic regression analysis revealed that patients with fainting, lack of motivation, swallowing, and loss of sexual interest could be attributed to MSA rather than PD or PSP, while patients with loss of concentration and forgetfulness were characteristic features of PD or PSP rather than MSA. REM-sleep behavior disorder (RBD), constipation, problems having sex, and loss of sexual interest preceded the motor symptoms onset of MSA by 2.81 ± 4.51, 1.54 ± 6.32, 1.35 ± 4.70, and 0.45 ± 3.61 years, respectively. Conclusion The NMS spectrum in MSA differs from that of PD and PSP. Patients with MSA have a higher NMS burden than patients with PD or PSP. RBD, constipation, problems having sex, and loss of sexual interest may become early diagnostic clinical markers of MSA.

Non-motor symptoms in multiple system atrophy: A comparative study with Parkinson's disease and progressive supranuclear palsy

<h2>Abstract</h2><h3>Background</h3> Minimum clinically important difference <b>(</b>MCID) is the smallest change in an outcome measure that is considered clinically meaningful. Using validated MCID thresholds for outcomes powers trials adequately to detect meaningful treatment effects, aids in their interpretation and guides development of new outcome measures. <h3>Objectives</h3> To provide a comprehensive summary of MCID thresholds of various symptom severity scales reported in movement disorder. <h3>Methods</h3> We conducted systematic review of the literature and included studies of one or more movement disorders, and reporting MCID scales. <h3>Results</h3> 2763 reports were screened. Final review included 32 studies. Risk of bias (RoB) assessment showed most studies were of good quality. Most commonly evaluated scale was Unified Parkinson's Disease Rating Scale (UPDRS) (11 out of 32). Four studies assessing MDS-UPDRS had assessed its different sub-parts, reporting a change of 2.64,3.05,3.25 and 0.9 points to detect clinically meaningful improvement and 2.45,2.51,4.63 and 0.8 points to detect clinically meaningful worsening, for the Part I, II, III and IV, respectively. For Parts II + III, I + II + III and I + II + III + IV, MCID thresholds reported for clinically meaningful improvement were 5.73, 4.9, 6.7 and 7.1 points respectively; while those for clinically meaningful worsening were 4.7, 4.2, 5.2 and 6.3 points, respectively. MCID thresholds reported for other scales included Abnormal Involuntary Movement Scale (AIMS), Toronto Western Spasmodic Torticollis Rating Scale (TWSRS), and Burke-Fahn-Marsden Dystonia Scale (BFMD). <h3>Conclusion</h3> This review summarizes all the MCID thresholds currently reported in Movement disorders research and provides a comprehensive resource for future trials, highlighting the need for standardized and validated MCID scales in movement disorder research. 

Bridging the gap between statistical significance and clinical relevance: A systematic review of minimum clinically important difference (MCID) thresholds of scales reported in movement disorders research

Abstract Parkinsonian disorders, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), present shared early motor symptoms but have distinct cellular and regional pathophysiology, making accurate premortem diagnosis challenging. Extracellular vesicles (EVs) provide a unique central nervous system (CNS) insight, as they contain cell-state-specific biomolecules and can cross the blood-brain barrier to the peripheral circulation. Measuring biomarkers in blood CNS-originating EVs, specifically neuronal and oligodendroglial EVs (nEVs and oEVs), has become a promising avenue for minimally invasive diagnostics. This meta-analysis aimed to evaluate the potential of blood-isolated nEVs and oEVs α-synuclein (α-syn) proteoforms in parkinsonian disorders. Thirteen studies were included, with a total of 1,565 PD, 206 MSA, 21 DLB, 172 PSP, 152 CBS patients, and 967 healthy controls (HCs). An inverse-variance random-effects model was used to quantify effect size (SMD), while QUADAS-2 assessed the risk of bias. Begg’s rank correlation and Egger’s regression tests evaluated publication bias. The findings suggest that a combination of nEVs and oEVs α-syn concentrations are higher in patients with PD compared to HCs (SMD = 0.21; p = 0.021). Interestingly, nEVs α-syn was lower in patients with PSP and CBS when compared to PD patients (SMD = -1.04; p = 0.0017) or HCs (SMD = -0.41, p &lt; 0.001). Contrary to existing literature, α-syn levels in oEVs did not effectively differ among PD, MSA, or HCs. Meta-regressions revealed that demographic and clinical factors were not significant predictors of nEVs or oEVs α-syn concentrations. These findings emphasize the need for adopting more rigorous, standardized procedures and independent validations across all laboratories studying biomarkers in CNS-originating EVs. Furthermore, there is a pressing need for improved biomarkers to better distinguish between parkinsonian disorders. 

/pdf/evaluation-of-a-synuclein-in-cns-originating-extracellular-2m545560.pdf

Evaluation of α-Synuclein in CNS-originating Extracellular Vesicles for Parkinsonian Disorders: A Systematic Review and Meta-analysis.

Florian Krismer, MD, PhD, Jose-Alberto Palma, MD, PhD, Giovanna Calandra-Buonaura, MD, PhD, Iva Stankovic, MD, PhD, Luca Vignatelli, MD, PhD, Anna-Karin Berger, PhD, Cristian Falup-Pecurariu, MD, Alexandra Foubert-Samier, MD, PhD, Günter Höglinger, MD, Horacio Kaufmann, MD, Larry Kellerman, PhD, Han-Joon Kim, MD, PhD, Thomas Klockgether, MD, Johannes Levin, MD, Pablo Martinez-Martin, MD, PhD, Tiago A. Mestre, MD, PhD, Maria Teresa Pellecchia, MD, PhD, Susan Perlman, MD, Irfan Qureshi, MD, Olivier Rascol, MD, PhD, Anette Schrag, MD, PhD, Klaus Seppi, MD, Huifang Shang, MD, Glenn T. Stebbins, PhD, Gregor K. Wenning, MD, PhD, Wolfgang Singer, MD, and Wassilios G. Meissner, MD, PhD*

/pdf/the-unified-multiple-system-atrophy-rating-scale-status-3x79srlz.pdf

The Unified Multiple System Atrophy Rating Scale: Status, Critique, and Recommendations

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The Unified Multiple System Atrophy Rating Scale: Status, Critique, and Recommendations