Peripheral Inflammatory and Immune Landscape in Multiple System Atrophy: A Cross-Sectional Study.

BACKGROUND: Neuroinflammation might contribute to the pathogenesis of multiple systemic atrophy (MSA). However, specific alterations in the peripheral inflammatory and immune profiles of patients with MSA remain unclear. OBJECTIVES: To determine the peripheral inflammatory and immune profiles of patients with MSA and their potential value as biomarkers for facilitating clinical diagnosis and monitoring disease severity. METHODS: This cross-sectional study included 235, 240, and 235 patients with MSA, patients with Parkinson's disease (PD), and healthy controls (HCs), respectively. Inflammatory and immune parameters were measured in peripheral blood, differences between groups were assessed, and clusters were analyzed. Associations between the parameters and clinical characteristics of MSA were assessed using Spearman and partial correlation analyses. RESULTS: Significant differences were observed especially in monocytes, neutrophils-to-lymphocyte ratio (NLR) and neutrophils-to-lymphocyte ratio (MPV) between MSA patients and HCs (P < 0.01). Monocytes and uric acid (UA) levels were also significantly different between the MSA and PD patients (P < 0.05). The combination of NLR and MPV distinguished MSA-P patients from HCs (areas under the curve = 0.824). In addition, complement components C4 and C3 were significantly correlated with the Scale Outcomes in PD for Autonomic Symptoms and Wexner scale, whereas immunoglobulin G (IgG) was significantly correlated with scores of Unified Multiple System Atrophy Rating Scale (P < 0.05). CONCLUSIONS: In MSA patients, monocytes, NLR and MPV might serve as potential diagnostic biomarkers, whereas MLR, C3, C4, and IgG significantly correlate with disease severity. © 2023 International Parkinson and Movement Disorder Society.

No Correlation between Plasma GPNMB Levels and Multiple System Atrophy in Chinese Cohorts.

BACKGROUND: Glycoprotein nonmetastatic melanoma protein B (GPNMB) has been demonstrated to mediate pathogenicity in Parkinson's disease (PD) through interactions with α-synuclein, and plasma GPNMB tended to be a novel biomarker for PD. OBJECTIVE: The goal of this study was to investigate whether plasma GPNMB could act as a potential biomarker for the clinical diagnosis and severity monitoring of multiple system atrophy (MSA), another typical synucleinopathy. METHODS: Plasma GPNMB levels in patients with MSA, patients with PD, and healthy control subjects (HCs) were quantified using enzyme-linked immunosorbent assays. RESULTS: A total of 204 patients with MSA, 65 patients with PD, and 207 HCs were enrolled. The plasma GPNMB levels in patients with MSA were similar to those in HCs (P = 0.251) but were significantly lower than those in patients with PD (P = 0.003). Moreover, there was no significant correlation detected between the plasma GPNMB levels and disease severity scores of patients with MSA. CONCLUSIONS: No evidence was detected for the biomarker potential of plasma GPNMB in MSA. © 2023 International Parkinson and Movement Disorder Society.

Synaptic Loss in Spinocerebellar Ataxia Type 3 Revealed by SV2A Positron Emission Tomography.

BACKGROUND: Severe reduced synaptic density was observed in spinocerebellar ataxia (SCA) in postmortem neuropathology, but in vivo assessment of synaptic loss remains challenging. OBJECTIVE SPINOCEREBELLAR ATAXIA TYPE 3: The objective of this study was to assess in vivo synaptic loss and its clinical correlates in spinocerebellar ataxia type 3 (SCA3) patients by synaptic vesicle glycoprotein 2A (SV2A)-positron emission tomography (PET) imaging. METHODS: We recruited 74 SCA3 individuals including preataxic and ataxic stages and divided into two cohorts. All participants received SV2A-PET imaging using 18 F-SynVesT-1 for synaptic density assessment. Specifically, cohort 1 received standard PET procedure and quantified neurofilament light chain (NfL), and cohort 2 received simplified PET procedure for exploratory purpose. Bivariate correlation was performed between synaptic loss and clinical as well as genetic assessments. RESULTS: In cohort 1, significant reductions of synaptic density were observed in cerebellum and brainstem in SCA3 ataxia stage compared to preataxic stage and controls. Vermis was found significantly involved in preataxic stage compared to controls. Receiver operating characteristic (ROC) curves highlighted SV2A of vermis, pons, and medulla differentiating preataxic stage from ataxic stage, and SV2A combined with NfL improved the performance. Synaptic density was significantly negatively correlated with disease severity in cerebellum and brainstem (International Co-operative Ataxia Rating Scale: ρ ranging from -0.467 to -0.667, P ≤ 0.002; Scale of Assessment and Rating of Ataxia: ρ ranging from -0.465 to -0.586, P ≤ 0.002). SV2A reduction tendency of cerebellum and brainstem identified in cohort 1 was observed in cohort 2 with simplified PET procedure. CONCLUSIONS: We first identified in vivo synaptic loss was related to disease severity of SCA3, suggesting SV2A PET could be a promising clinical biomarker for disease progression of SCA3. © 2023 International Parkinson and Movement Disorder Society.

The characteristic and biomarker value of transcranial sonography in cerebellar ataxia.

OBJECTIVE: Transcranial sonography (TCS) is a noninvasive neuroimaging technique, visualizing deep brain structures and the ventricular system. Although widely employed in diagnosing various movement disorders, such as Parkinson's disease and dystonia, by detecting disease-specific abnormalities, the specific characteristics of the TCS in cerebellar ataxia remain inconclusive. We aimed to assess the potential value of TCS in patients with cerebellar ataxias for disease diagnosis and severity assessment. METHODS: TCS on patients with genetic and acquired cerebellar ataxia, including 94 with spinocerebellar ataxias (SCAs) containing 10 asymptomatic carriers, 95 with cerebellar subtype of multiple system atrophy (MSA-C), and 100 healthy controls (HC), was conducted. Assessments included third ventricle width, substantia nigra (SN) and lentiform nucleus (LN) echogenicity, along with comprehensive clinical evaluations and genetic testing. RESULTS: The study revealed significant TCS abnormalities in patients with cerebellar ataxia, such as enlarged third ventricle widths and elevated rates of hyperechogenic SN and LN. TCS showed high accuracy in distinguishing patients with SCA or MSA-C from HC, with an AUC of 0.870 and 0.931, respectively. TCS abnormalities aided in identifying asymptomatic SCA carriers, effectively differentiating them from HC, with an AUC of 0.725. Furthermore, third ventricle width was significantly correlated with SARA and ICARS scores in patients with SCA3 and SCOPA-AUT scores in patients with MSA-C. The SN area and SARA or ICARS scores in patients with SCA3 were also positively correlated. INTERPRETATION: Our findings illustrate remarkable TCS abnormalities in patients with cerebellar ataxia, serving as potential biomarkers for clinical diagnosis and progression assessment.

Diagnostic and prognostic performance of plasma neurofilament light chain in multiple system atrophy: a cross-sectional and longitudinal study.

BACKGROUND: The longitudinal dynamics of neurofilament light chain (NfL) in multiple system atrophy (MSA) were incompletely illuminated. This study aimed to explore whether the plasma NfL (pNfL) could serve as a potential biomarker of clinical diagnosis and disease progression for MSA. METHODS: We quantified pNfL concentrations in both a large cross-sectional cohort with 214 MSA individuals, 65 PD individuals, and 211 healthy controls (HC), and a longitudinal cohort of 84 MSA patients. Propensity score matching (PSM) was used to balance the age between the three groups. The pNfL levels between groups were compared using Kruskal-Wallis test. Linear mixed models were performed to explore the disease progression-associated factors in longitudinal MSA cohort. Random forest model as a complement to linear models was employed to quantify the importance of predictors. RESULTS: Before and after matching the age by PSM, the pNfL levels could reliably differentiate MSA from HC and PD groups, but only had mild potential to distinguish PD from HC. By combining linear and nonlinear models, we demonstrated that pNfL levels at baseline, rather than the change rate of pNfL, displayed potential prognostic value for progression of MSA. The combination of baseline pNfL levels and other modifiers, such as subtypes, Hoehn-Yahr stage at baseline, was first shown to improve the diagnosis accuracy. CONCLUSIONS: Our study contributed to a better understanding of longitudinal dynamics of pNfL in MSA, and validated the values of pNfL as a non-invasive sensitive biomarker for the diagnosis and progression. The combination of pNfL and other factors is recommended for better monitoring and prediction of MSA progression.

Coffin-Siris syndrome in two chinese patients with novel pathogenic variants of ARID1A and SMARCA4.

BACKGROUND: Coffin-Siris syndrome (CSS) is a rare congenital syndrome characterized by developmental delay, intellectual disability, microcephaly, coarse face and hypoplastic nail of the fifth digits. Heterozygous variants of different BAF complex-related genes were reported to cause CSS, including ARID1A and SMARCA4. So far, no CSS patients with ARID1A and SMARCA4 variants have been reported in China. OBJECTIVE: The aim of the current study was to identify the causes of two Chinese patients with congenital growth deficiency and intellectual disability. METHODS: Genomic DNA was extracted from the peripheral venous blood of patients and their family members. Genetic analysis included whole-exome and Sanger sequencing. Pathogenicity assessments of variants were performed according to the guideline of the American College of Medical Genetics and Genomics. The phenotypic characteristics of all CSS subtypes were summarized through literature review. RESULTS: We identified two Chinese CSS patients carrying novel variants of ARID1A and SMARCA4 respectively. The cases presented most core symptoms of CSS except for the digits involvement. Additionally, we performed a review of the phenotypic characteristics in CSS, highlighting phenotypic varieties and related potential causes. CONCLUSIONS: We reported the first Chinese CSS2 and CSS4 patients with novel variants of ARID1A and SMARCA4. Our study expanded the genetic and phenotypic spectrum of CSS, providing a comprehensive overview of genotype-phenotype correlations of CSS.

Serum vitamin levels in multiple system atrophy: A case-control study.

Aim: There is increasing evidence suggesting that vitamins may play important roles in the pathogenesis of multiple system atrophy (MSA). The purpose of this study was to detect the changes of serum vitamin levels and investigate their correlation with disease severity in MSA patients. Methods: In this cross-sectional study, 244 MSA patients, 200 Parkinson's disease (PD) patients and 244 age-gender matched healthy controls were recruited. Serum vitamin levels were measured, including vitamin A, B1, B2, B9 (folate), B12, C, D, and E. Relevant clinical scales were used to assess the disease severity of MSA patients. Results: Compared with the healthy controls, decreased serum folate levels and increased serum vitamin A and C levels were detected in MSA patients. Similar differences were also observed in the gender-based subgroup analysis. There were no differences detected between MSA and PD patients. In MSA patients, significant correlation was found between vitamin A, folate, or vitamin C and relevant clinical scales or laboratory findings. In addition, ROC analysis showed potential diagnostic value of the combination of vitamin A, folate, and vitamin C in distinguishing MSA patients from healthy controls. Conclusion: There were significant changes in the blood vitamin spectrums of MSA patients, suggesting that dysregulation of vitamins homeostasis might play an important role in the pathogenesis of MSA.