Search

Purpose of Review: Sleep disturbances are amongst most frequent non-motor symptoms of Parkinson's Disease (PD), and they are similarly frequently reported in other alpha-syncleinopathies, such as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). More recently, the orexin system has been implicated in control of arousal based on salient environmental set points, and its dysregulation in sleep issues in alpha-synucleinopathies suggested by the findings from the translational animal models. However, its role in the patients with alpha-synucleinopathies remains unclear. We thus set to systematically review, and to critically assess, contemporary evidence on the association of the orexinergic system and sleep disturbances in alpha-synucleinopathies. In this systematic review, studies investigating orexin and sleep in alpha-synucleinopathies (Rapid Eye Movement (REM) Behaviour Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) were identified using electronic database searches of PubMed, Web of Science and PsychINFO using MeSH terms, keywords, and title words such as "Alpha-synucleinopathies" AND "Orexin" AND "Sleep Disturbances"., Recent Findings: 17 studies were included in this systemic review, of which 2 studies on RBD, 10 on PD, 4 on DLB, and 1 on MSA patients. Taken together, RBD and PD studies suggest a potential adaptive increase in orexin levels in early stages of the neurodegenerative process, with reduced levels more often reported for later, more advanced stages of illness. To date, no differences in orexin levels were demonstrated between MSA patients and healthy controls. There is a dearth of studies on the role of orexin levels in alpha-synucleinopathies. Moreover, significant methodologic limitations in the current body of work, including use of non-standardised research protocols and lack of prospective, multi-centre studies, disallow for any finite conclusion in regards to underlying pathomechanisms. Nonetheless, a picture of a complex, multifaceted relationship between the dysregulation of the orexinergic pathway and sleep disturbances in alpha-synucleinopathies is emerging. Hence, future studies disentangling orexinergic pathomechanisms of alpha-syncleinopathies are urgently needed to obtain a more comprehensive account of the role of orexinergic pathway in alpha-synucleinopathies. Pharmacological manipulations of orexins may have multiple therapeutic applications in treatment strategies, disease diagnosis, and might be effective for treating both motor and non-motor symptoms., (© 2024. The Author(s).)

Introduction: Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a rare autoimmune encephalitis that can mimic progressive supranuclear palsy or corticobasal syndrome. Moreover, anti-IgLON5 disease can present with symptoms characteristic of multiple system atrophy (MSA), such as cerebellar ataxia and autonomic dysfunction. However, the clinical features of anti-IgLON5 disease resembling MSA have not been well established., Methods: We enrolled 35 patients with suspected MSA for whom anti-IgLON5 antibody tests were requested. We evaluated immunoglobulin G (IgG) against IgLON5 using cell-based assays. We also summarized the clinical characteristics of patients who were positive for anti-IgLON5 antibodies., Results: We identified serum and cerebrospinal fluid anti-IgLON5 antibodies in three patients. These patients had many clinical features characteristic of MSA, including parkinsonism, cerebellar ataxia, severe orthostatic hypotension, acute respiratory failure, sleep parasomnia, vocal cord paralysis, and pyramidal tract signs. Clinical features atypical for MSA were myorhythmia, horizontal eye movement restriction, fasciculations, and painful muscle cramps., Conclusion: Anti-IgLON5 disease may be an important differential diagnosis of MSA. A comprehensive physical examination, including assessments of eye movement, lower motor neuron signs, and atypical involuntary movements, is important to avoid misdiagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Early and precise diagnosis of α-synucleinopathies is challenging but critical. In this study, we developed a molecular beacon-based assay to evaluate microRNA-containing extracellular vesicles (EVs) in plasma. We recruited 1203 participants including healthy controls (HCs) and patients with isolated REM sleep behavior disorder (iRBD), α-synucleinopathies, or non-α-synucleinopathies from eight centers across China. Plasma miR-44438-containing EV levels were significantly increased in α-synucleinopathies, including those in the prodromal stage (e.g., iRBD), compared to both non-α-synucleinopathy patients and HCs. However, there are no significant differences between Parkinson's disease (PD) and multiple system atrophy. The miR-44438-containing EV levels negatively correlated with age and the Hoehn and Yahr stage of PD patients, suggesting a potential association with disease progression. Furthermore, a longitudinal analysis over 16.3 months demonstrated a significant decline in miR-44438-containing EV levels in patients with PD. These results highlight the potential of plasma miR-44438-containing EV as a biomarker for early detection and progress monitoring of α-synucleinopathies.

Purpose: There is a critical need for reliable diagnostic biomarkers as well as surrogate markers of disease progression in multiple system atrophy (MSA). Neurofilament light chain (NfL) has been reported to potentially meet those needs. We therefore sought to explore the value of NfL in plasma (NfL-p) in contrast to cerebrospinal fluid (NfL-c) as a diagnostic marker of MSA, and to assess NfL-p and NfL-c as markers of clinical disease progression., Methods: Well-characterized patients with early MSA (n = 32), Parkinson's disease (PD; n = 21), and matched controls (CON; n = 15) were enrolled in a prospective, longitudinal study of synucleinopathies with serial annual evaluations. NfL was measured using a high-sensitivity immunoassay, and findings were assessed by disease category and relationship with clinical measures of disease progression., Results: Measurements of NfL-c were highly reproducible across immunoassay platforms (Pearson, r = 0.99), while correlation between NfL-c and -p was only moderate (r = 0.66). NfL was significantly higher in MSA compared with CON and PD; the separation was essentially perfect for NfL-c, but there was overlap, particularly with PD, for NfL-p. While clinical measures of disease severity progressively increased over time, NfL-c and -p remained at stable elevated levels within subjects across serial measurements. Neither change in NfL nor baseline NfL were significantly associated with changes in clinical markers of disease severity., Conclusions: These findings confirm NfL-c as a faithful diagnostic marker of MSA, while NfL-p showed less robust diagnostic value. The significant NfL elevation in MSA was found to be remarkably stable over time and was not predictive of clinical disease progression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain's biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies., (© 2021. The Author(s).)

[Figure: see text].

Introduction: Ubiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown., Methods: Using competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients., Results: Repertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels., Conclusions: Differences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The aim of this trial was to investigate the safety, tolerability, and capability of serum uric acid (UA) elevation of inosine 5'-monophosphate (IMP) in multiple system atrophy (MSA). The IMPROVE-MSA trial was a randomized, double-blind, placebo-controlled trial in patients with MSA with no history of hyperuricemia-related disorders. The participants were assigned to placebo (n = 25) or IMP (n = 30) in a 1 to 1 ratio, and then followed up for 24 weeks. The primary end points included safety, tolerability, and alteration of the serum UA level during the follow-up period. The secondary end points were changes in scores of the unified MSA rating scale (UMSARS) and the Mini-Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The total number of adverse events (AEs) and serious AEs was comparable between the active and placebo groups. Serum UA level (mg/dL) was significantly increased from baseline (active vs. placebo, 4.57 vs. 4.58; P = 0.98) to study end point (6.96 vs. 4.43; P < 0.001) in the active group compared with the placebo group (time × group interaction; P < 0.001). The change in UMSARS scores did not differ between the active and placebo groups. However, the active group showed better alterations in MoCA scores with nominal significance (P < 0.001) and tendency for better alterations in MMSE scores (P = 0.09) than the placebo group. Our data demonstrated that IMP treatment was generally safe and well-tolerated in patients with MSA. A further trial with a long-term follow-up is required to examine whether UA elevation will slow clinical progression in early MSA., (© 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

To identify biomarkers for multiple system atrophy-cerebellar type (MSA-C), we used flow cytometry to measure surface marker expression of peripheral blood monocytes from patients with MSA-C or hereditary spinocerebellar degeneration (hSCD) and from healthy controls (HCs). The percentage of intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs and showed significant positive correlations with disease duration and unified MSA rating scale scores. The percentage of CD62L + intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs. Early decrease of peripheral blood intermediate monocytes is characteristic of MSA-C and is a biomarker., (Copyright © 2020 Elsevier B.V. All rights reserved.)

MicroRNAs are reportedly involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease and multiple system atrophy. We previously identified 7 differentially expressed microRNAs in Parkinson's disease patients and control sera (miR-30c, miR-31, miR-141, miR-146b-5p, miR-181c, miR-214, and miR-193a-3p). To investigate the expression levels of the 7 serum microRNAs in Parkinson's disease and multiple system atrophy, 23 early Parkinson's disease patients (who did not take any anti- Parkinson's disease drugs), 23 multiple system atrophy patients, and 24 normal controls were recruited at outpatient visits in this study. The expression levels of the 7 microRNAs in serum were detected using quantitative real-time polymerase chain reaction. A receiver operating characteristic curve was used to evaluate whether microRNAs can differentially diagnose Parkinson's disease and multiple system atrophy. Clinical scales were used to analyze the correlations between serum microRNAs and clinical features. The results indicated that miR-214 could distinguish Parkinson's disease from the controls, and another 3 microRNAs could differentiate multiple system atrophy from the controls (miR-141, miR-193a-3p, and miR-30c). The expression of miR-31, miR-141, miR-181c, miR-193a-3p, and miR-214 were lower in multiple system atrophy than in Parkinson's disease (all P < 0.05). Combinations of microRNAs accurately discriminated Parkinson's disease from multiple system atrophy (area under the receiver operating characteristic curve = 0.951). For the correlation analysis, negative correlations were discovered between the expression of miR-214 and the Hamilton Anxiety Scale and Parkinson's Disease Non-Motor Symptom scores (all P < 0.05). Our results demonstrate that the distinctive characteristics of microRNAs differentiate Parkinson's disease and multiple system atrophy patients from healthy controls and may be used for the early diagnosis of Parkinson's disease and multiple system atrophy., Competing Interests: All authors declare no conflicts of interest., (© 2020 Yan et al. Published by IMR press.)

Objective: To develop a diagnostic model based on plasma-derived extracellular vesicle (EV) subpopulations in Parkinson disease (PD) and atypical parkinsonism (AP), we applied an innovative flow cytometric multiplex bead-based platform., Methods: Plasma-derived EVs were isolated from PD, matched healthy controls, multiple system atrophy (MSA), and AP with tauopathies (AP-Tau). The expression levels of 37 EV surface markers were measured by flow cytometry and correlated with clinical scales. A diagnostic model based on EV surface markers expression was built via supervised machine learning algorithms and validated in an external cohort., Results: Distinctive pools of EV surface markers related to inflammatory and immune cells stratified patients according to the clinical diagnosis. PD and MSA displayed a greater pool of overexpressed immune markers, suggesting a different immune dysregulation in PD and MSA vs AP-Tau. The receiver operating characteristic curve analysis of a compound EV marker showed optimal diagnostic performance for PD (area under the curve [AUC] 0.908; sensitivity 96.3%, specificity 78.9%) and MSA (AUC 0.974; sensitivity 100%, specificity 94.7%) and good accuracy for AP-Tau (AUC 0.718; sensitivity 77.8%, specificity 89.5%). A diagnostic model based on EV marker expression correctly classified 88.9% of patients with reliable diagnostic performance after internal and external validations., Conclusions: Immune profiling of plasmatic EVs represents a crucial step toward the identification of biomarkers of disease for PD and AP., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: To determine an exploratory multimodal approach including serum NFL and MR planimetric measures to discriminate Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP)., Methods: MR planimetric measurements and NFL serum levels, with a mean time interval of 60 months relative to symptom onset, were assessed in a retrospective cohort of 11 progressive supranuclear palsy (PSP), 22 Parkinson's disease (PD), 16 multiple system atrophy (MSA) patients and 42 healthy controls (HC). A decision tree model to discriminate PD, PSP, and MSA was constructed using receiver operating characteristic curve analysis and Classification and Regression Trees algorithm., Results: Our multimodal decision tree provided accurate differentiation of PD versus MSA and PSP patients using a serum NFL cut-off of 14.66 ng/L. The pontine-to-midbrain-diameter-ratio (P d /M d ) discriminated MSA from PSP at a cut-off value of 2.06. The combined overall diagnostic yield was an accuracy of 83.7% (95% CI 69.8-90.8%)., Conclusion: We provide a clinically feasible decision algorithm which combines serum NFL levels and a planimetric MRI marker to differentiate PD, MSA and PSP with high diagnostic accuracy., Classification of Evidence: This study provides Class III evidence that the combination of serum NFL levels und MR planimetric measurements discriminates between PD, PSP and MSA., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disease that progresses very rapidly and has a poor prognosis. Some studies indicate that the level of inflammatory cytokines may be related to MSA. However, no consistent conclusion has been drawn yet. The purpose of our research is to perform a meta-analysis to investigate whether the level of inflammatory cytokines is altered in MSA., Methods: Case-control studies on inflammatory cytokine levels in MSA will be searched in the following 3 databases: PubMed, Embase, and Web of Science from the database start time to March 17, 2020. Two independent authors will conduct research selection, data extraction, and quality evaluation. Data synthesis, subgroup analysis, sensitivity analysis, and the meta-analysis will be performed using Stata15.0 software., Results: This study will provide a comprehensive review of all studies on inflammatory cytokine levels in MSA., Conclusion: To the best of our knowledge, this study will be the first meta-analysis that provides the quantitative evidence of inflammatory cytokine levels in MSA., Registration Number: INPLASY202060034.

Objective: Parkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies., Methods: We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins., Results: Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression., Conclusions: Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism., Competing Interests: Competing interests: HW and JR are employees of Eli Lilly and Company., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Multiple system atrophy (MSA) is a rare oligodendroglial synucleinopathy of unknown etiopathogenesis including two major clinical variants with predominant parkinsonism (MSA-P) or cerebellar dysfunction (MSA-C)., Objective: To identify novel disease mechanisms we performed a blood transcriptomic study investigating differential gene expression changes and biological process alterations in MSA and its clinical subtypes., Methods: We compared the transcriptome from rigorously gender and age-balanced groups of 10 probable MSA-P, 10 probable MSA-C cases, 10 controls from the Catalan MSA Registry (CMSAR), and 10 Parkinson Disease (PD) patients., Results: Gene set enrichment analyses showed prominent positive enrichment in processes related to immunity and inflammation in all groups, and a negative enrichment in cell differentiation and development of the nervous system in both MSA-P and PD, in contrast to protein translation and processing in MSA-C. Gene set enrichment analysis using expression patterns in different brain regions as a reference also showed distinct results between the different synucleinopathies., Conclusions: In line with the two major phenotypes described in the clinic, our data suggest that gene expression and biological processes might be differentially affected in MSA-P and MSA-C. Future studies using larger sample sizes are warranted to confirm these results.

Objective: We aimed to investigate the association of the serum urate level with cortical thickness and white matter integrity in multiple system atrophy (MSA)., Methods: We recruited 75 MSA patients and 42 controls who underwent brain MRI and measured serum urate level at baseline. Using cortical thickness and tract-based spatial statistics analyses, we investigated the correlation between serum urate levels and cortical thickness or diffusion tensor imaging (DTI) measures in controls and MSA patients. Interaction effects were analyzed to find different patterns of correlation according to sex and clinical subtype. We evaluated the relationship between serum urate levels, DTI measures, and total UMSARS score, using path analysis., Results: Serum urate levels showed a positive correlation with FA values in the corpus callosum and a negative correlation with MD values in widespread regions including cerebellar, brainstem, and cerebral white matter in patients with MSA. Both sexes showed a negative correlation between serum urate levels and MD values without significant interaction effect. In subgroup analysis according to subtype, patients with cerebellar subtype showed a negative correlation. Serum urate levels did not correlated with cortical thickness. Path analysis showed that MD values in middle and inferior cerebellar peduncle mediated the association between serum urate level and total UMSAR score., Interpretation: The present study demonstrated that serum urate levels played a pivotal role in white matter disintegrity and clinical disability in MSA. It would provide an evidence of the role of urate as a potential neuroprotective factor against white matter neurodegeneration in MSA., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Adiponectin receptors are expressed in the hypothalamus, brainstem, and basal ganglia. Experimentally, adiponectin was immunopositive in the phosphorylated α-synuclein-positive Lewy bodies in the brain of individuals with Parkinson's disease (PD), and treatment with recombinant adiponectin suppressed the aggregation of α-synuclein. The close relationship between adiponectin and PD is suggested., Methods: We assessed whether adiponectin levels may increase in patients with PD and differ in individuals with other neurodegenerative diseases. Blood samples were stored at - 70 °C. Adiponectin levels were measured using a latex turbidimetric immunoassay., Results: Adiponectin levels of patients with PD (p = 0.019) or PD plus multiple systemic atrophy with predominant parkinsonian features (MSA-P) (p = 0.034) increased compared with those of patients with progressive supranuclear palsy (PSP). A multivariate comparison using ANCOVA showed that the adiponectin level was significantly higher in PD plus MSA-P than in patient with PSP, which is independent of age and BMI (adjusted mean difference of 4.388 μg/ml [95% confidence interval 0.602-8.174, p = 0.024]). A significant positive correlation between adiponectin and HDL-C levels was observed in patients with PD on a single linear regression analysis (β, 0.257; p < 0.001; R 2  = 0.271). The results were not significant in patients with MSA-P, PSP, and MSA-P plus PSP., Conclusions: Adiponectin is likely to play roles in the composition of lipid rafts since the adiponectin level of each patient with alpha-synucleinopathy or PSP differed.

Objective: To investigate the oxidized albumin ratio, which is the redox ratio of human nonmercaptalbumin (HNA) to serum albumin (%HNA), as a biomarker in idiopathic Parkinson's disease (iPD) and related neurodegenerative disorders., Methods: This prospective study enrolled 216 iPD patients, 15 patients with autosomal recessive familial PD due to parkin mutations (PARK2), 30 multiple system atrophy (MSA) patients, 32 progressive nuclear palsy (PSP) patients, and 143 healthy controls. HNA was analyzed using modified high-performance liquid chromatography and was evaluated alongside other parameters., Results: iPD and PARK2 patients had a higher %HNA than controls (iPD vs. controls: odds ratio (OR) 1.325, P < 0.001; PARK2 vs. controls: OR 1.712, P < 0.001). Even iPD patients at an early Hoehn & Yahr stage (I and II) showed a higher %HNA than controls. iPD patients had a higher %HNA than MSA and PSP patients (iPD vs. MSA: OR 1.249, P < 0.001, iPD vs. PSP: OR 1.288, P < 0.05). When discriminating iPD patients from controls, %HNA corrected by age achieved an AUC of 0.750; when discriminating iPD patients from MSA and PSP patients, an AUC of 0.747 was achieved. Furthermore, uric acid, an antioxidant compound, was decreased in iPD patients, similar to the change in %HNA., Interpretation: %HNA was significantly increased in iPD and PARK2 patients compared with controls, regardless of disease course and severity. Oxidative stress might be increased from the early stages of iPD and PARK2 and play an important role in their pathomechanisms., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Radiological biomarkers have been reported for multiple system atrophy and progressive supranuclear palsy, but serum/plasma biomarkers for each disorder have not been established. In this context, we performed a pilot study to identify disease-specific plasma biomarkers for multiple system atrophy and progressive supranuclear palsy. Plasma samples collected from 20 progressive supranuclear palsy patients, 16 multiple system atrophy patients and 20 controls were investigated by comprehensive metabolome analysis using capillary electrophoresis mass spectrometry and liquid chromatography mass spectrometry. Medication data were obtained from patients with multiple system atrophy and progressive supranuclear palsy, and correlations with associated metabolites were examined. Receiver operating characteristics curve analyses were used to investigate diagnostic values for each disorder. The levels of 15 and eight metabolites were significantly changed in multiple system atrophy and progressive supranuclear palsy, respectively. Multiple system atrophy was mainly characterized by elevation of long-chain fatty acids and neurosteroids, whereas progressive supranuclear palsy was characterized by changes in the level of oxidative stress-associated metabolites. Receiver operating characteristic curve analyses revealed that patients with multiple system atrophy or progressive supranuclear palsy were effectively differentiated from controls by 15 or 7 metabolites, respectively. Disease-specific metabolic changes of multiple system atrophy and progressive supranuclear palsy were identified. These biomarker sets should be replicated in a larger sample., Competing Interests: The authors have declared that no competing interests exist.

Aggregation of alpha-synuclein (α-syn) is considered to be the major pathological hallmark and driving force of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Immune dysfunctions have been associated with both MSA and PD and recently we reported that the levels of natural occurring autoantibodies (NAbs) with high-affinity/avidity toward α-synuclein are reduced in MSA and PD patients. Here, we aimed to evaluate the plasma immunoglobulin (Ig) composition binding α-syn and other amyloidogenic neuropathological proteins, and to correlate them with disease severity and duration in MSA and PD patients. All participants were recruited from a single neurological unit and the plasma samples were stored for later research at the Bispebjerg Movement Disorder Biobank. All patients were diagnosed according to current consensus criteria. Using multiple variable linear regression analyses, we observed higher levels of anti-α-syn IgG1 and IgG3 NAbs in MSA vs. PD, higher levels of anti-α-syn IgG2 NAbs in PD compared to controls, whereas anti-α-syn IgG4 NAbs were reduced in PD compared to MSA and controls. Anti-α-syn IgM levels were decreased in both MSA and PD. Further our data supported that MSA patients' immune system was affected with reduced IgG1 and IgM global levels compared to PD and controls, with further reduced global IgG2 levels compared to PD. These results suggest distinct autoimmune patterns in MSA and PD. These findings suggest a specific autoimmune physiological mechanism involving responses toward α-syn, differing in neurodegenerative disease with overlapping α-syn pathology., (Copyright © 2019 Folke, Rydbirk, Løkkegaard, Salvesen, Hejl, Starhof, Bech, Winge, Christensen, Pedersen, Aznar, Pakkenberg and Brudek.)

MicroRNAs (miRNAs) are endogenous small (18-25 nt), single-stranded, non-coding RNAs that play key roles in post-transcriptional gene expression regulation. The expression profiles of miRNAs in biofluids and tissues change in various diseases. Multiple system atrophy (MSA) and Parkinson's disease (PD) are both categorized as α-synucleinopathies and often present with similar clinical manifestations. This study aimed to identify miRNAs that are differently expressed in plasma samples of PD patients, MSA patients, and healthy controls. We used microarray analysis to screen for miRNAs that are up- and down-regulated in these patients and analyzed the relative-quantitative expression levels of the identified miRNAs by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Hsa-miR-671-5p, hsa-miR-19b-3p, and hsa-miR-24-3p showed significantly different expression levels among patients with MSA-C, MSA-P, or PD, and healthy controls. Hsa-miR-671-5p levels were lower in the MSA-P and PD than the MSA-C and control groups, hsa-miR-19b-3p levels were higher in the PD than the other groups, and hsa-miR-24-3p levels were higher in the PD than the MSA-C group. Hsa-miR-671-5p was the first miRNA shown to be expressed differently between MSA-C and MSA-P in plasma. Interestingly, the expression levels of hsa-miR-19b-3p and hsa-miR-24-3p were positively correlated, indicating that these miRNAs may be involved in the same processes in PD pathogenesis. Our findings suggest that hsa-miR-671-5p, hsa-miR-19b-3p, and hsa-miR-24-3p may reflect the pathophysiology or symptoms of PD and MSA.

Objective: The objective of this study was to compare iron metabolic variables in the serum and cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis (sALS) with those of patients with multiple system atrophy (MSA) and control subjects. We also assessed the correlations of these variables with sALS progression and severity and estimated their roles in predicting prognosis. Methods: We retrospectively collected iron metabolic parameters, including serum levels of iron, ferritin, transferrin levels and total iron binding capacity and the CSF level of ferritin, from 435 sALS patients, 176 MSA patients and 431 control subjects. Results: Serum ferritin levels were significantly higher in the sALS group compared with the MSA and control groups in both males ( p  = 0.001 and p  < 0.0001, respectively) and females ( p  = 0.034 and p  < 0.0001, respectively). However, serum transferrin levels were significantly lower in females of the sALS group compared with the MSA ( p  = 0.016) and control ( p  = 0.015) groups. The CSF ferritin level and the serum levels of total iron binding capacity and iron were similar among the sALS, MSA and control groups. Survival analysis demonstrated that higher serum ferritin levels were predictors of reduced survival of sALS patients. No correlations between iron metabolic variables and clinical parameters were found. Conclusion: An elevated serum ferritin level is associated with reduced survival of sALS patients. However, the levels of iron metabolic parameters were not associated with clinical deterioration or disease severity at diagnosis.

Multiple system atrophy (MSA) is a neurodegenerative disease that belongs to the α synucleinopathies. Clinically, there is an overlap between MSA and Parkinson's disease (PD), especially at the early disease stage. However, these two pathologies differ in terms of disease progression. Currently, no biomarker exists to differentiate MSA from PD. MicroRNAs are non-coding RNAs implicated in gene expression regulation. MiRNAs modulate cellular activity and they control a range of physiological and pathological functions. miRNAs are found in biofluids, such as blood, serum, plasma, saliva, and cerebrospinal fluid. Many groups, including ours, found that circulating miRNAs are differently expressed in blood, plasma, serum and cerebrospinal fluid of PD and MSA patients. In the present study, our primary aim was to determine if serum mir-30-5p and mir-148b-5p can be used as biomarkers for early diagnosis of PD and/or MSA. Our secondary goal was to determine if serum levels of those miRNAs can be correlated with the patients' clinical profile. Using quantitative PCR (qPCR), we evaluated expression levels of miR-30c-5p and miR148b-5p in serum samples from PD (n = 56), MSA (n = 49), and healthy control (n = 50) subjects. We have found that miR-30c-5p is significantly upregulated in MSA if compared with PD and healthy control subjects. Moreover, serum miR-30c-5p levels correlate with disease duration in both MSA and PD. No significant difference was found in miR-148b-5p among MSA, PD and healthy control subjects. Our results suggest a possible role of serum miR-30-5p as a biomarker for diagnosis and progression of MSA.

Objective: To investigate the diagnostic value of serum neurofilament light chain (NFL) in patients with clear signs of parkinsonism but whose specific diagnosis was yet uncertain., Methods: Serum samples were collected from patients with clear signs of parkinsonism but with uncertain diagnosis at the inclusion. Clinical diagnoses of Parkinson disease (PD) and atypical parkinsonism disorders (APDs) were established after 3 years of follow-up and updated again after a maximum of 12 years in case longer follow-up data were available. Serum NFL was quantified by single molecule array in patients with PD (n = 55) and APD (n = 29, multiple system atrophy = 22, progressive supranuclear palsy = 7) and 53 nonneurologic controls., Results: Serum NFL levels were elevated and differentiated the APD group (mean 23.8 ± 10.3 ng/L) from PD (mean 10.4 ± 4.9 ng/L) and controls (mean 11.5 ± 6.5 ng/L, p < 0.0001) with accuracy levels up to 91% (sensitivity = 86% and specificity = 85%). Serum NFL strongly correlated with CSF NFL levels ( r = 0.72, p < 0.0001) in all groups and with age in PD ( r = 0.78, p < 0.0001) and controls ( r = 0.66, p < 0.0001). In our cohort, the probability of having APD was 76% (positive predictive value) and of having PD 92% (negative predictive value)., Conclusion: Serum NFL levels are markedly elevated in APD compared to PD and discriminate APDs from PD with high accuracy. Serum NFL may be a useful clinical biomarker to identify APD, even at stages when clinical symptoms are not yet conclusive., Classification of Evidence: This study provides Class II evidence that serum NFL levels accurately discriminate APDs from PD., (© 2019 American Academy of Neurology.)

Background: Multiple system atrophy(MSA) is a neurodegenerative disease characterized by intracellular α-synuclein deposits. There is an unmet need for blood-based biomarkers to diagnose MSA. Our previous studies have reported elevated α-synuclein levels in erythrocytes of MSA patients. However, α-synuclein protein in the membrane and cytoplasm of erythrocytes in MSA have not been investigated., Methods: The membrane and cytoplasm were extracted from erythrocytes in 77 patients with MSA and 133 healthy controls. Levels of total and oligomeric α-synuclein were detected using Electrochemiluminescence assays. The correlations between α-synuclein levels and clinical characteristics were explored in MSA group. The diagnostic value of erythrocyte α-synuclein for MSA was determined by Receiver operator characteristic curve., Results: α-synuclein levels in the erythrocyte membrane were significantly elevated in MSA patients compared with the healthy controls (total α-synuclein, p = 0.003; oligomeric α-synuclein/total α-synuclein, p = 0.033; oligomeric α-synuclein/protein, p < 0.001). The combination of total and oligomeric α-synuclein levels in erythrocyte membrane could efficiently distinguish MSA from healthy controls (sensitivity of 79.2%; specificity of 69.2%; area under the curve: 0.771). In contrast, no significant difference was found in erythrocyte cytoplasm α-synuclein levels. In the subgroup of 48 patients with probable MSA, there was a weakly negative correlation between oligomeric α-synuclein/protein in erythrocyte membrane and disease duration (r = -0.336; p = 0.009)., Conclusion: Our pilot study suggests that the membrane fraction of α-synuclein levels in erythrocyte were elevated in patients with MSA, and these levels may be decreased with the development of disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Objective: To explore the alterations of microbial 16s ribosomal (rRNA) gene in the feces and blood of Chinese patients with multiple system atrophy (MSA) and its relationships with clinical features., Methods: 40 MSA patients (MSA-P/MSA-C: 23/17) and their healthy spouses were recruited. Fecal and blood microbiota were investigated by high-throughput IllUmina Miseq sequencing targeted on the V3-V4 functional region of 16s rRNA gene. The relationships between microbiota and clinical characteristics were analyzed., Results: The abundances of Lactobacillus, Gordonibacter, Phascolarctobacterium, and Haemophilus in feces and abundances of Leucobacter, and Bacteroides in blood were different between MSA patients and healthy controls (HC). Combining the taxa from feces and blood, six genera were identified to be predictive of MSA, achieving an area under the curve (AUC) of 0.853. The abundances of Phascolarctobacterium and Ruminococcus in feces were lower in MSA-P than those in MSA-C. The abundances of Blastococcus, Bacillus, and Acinetobacter in blood were different between MSA subtypes. These five genera differentiated MSA subtypes with an AUC of 0.898. Functional predictions indicated that gene functions involving biosynthetic metabolism and bacterial secretion systems were significantly different between the MSA and HC. The differential genera were associated with disease duration, anxiety, and autonomic dysfunctions., Conclusions: We confirmed the alterations of microbial 16s rRNA gene in the feces and blood occurs in Chinese patients with MSA. Microbiota dysbiosis was related to MSA clinical manifestations. Elucidating these differences in microbiomes will be helpful to improve our knowledge of the microbiota in the pathogenesis of MSA.

Introduction: Multiple system atrophy (MSA) is a progressive neurodegenerative disease. Recent studies revealed decreased coenzyme Q10 (COQ10) levels in the cerebellum and blood samples of MSA patients. But few studies focused on the associations of COQ10 with the clinical symptoms of MSA. In this study, we aimed to quantify plasma COQ10 and characterize its association with clinical features., Methods: We recruited 40 patients with MSA, 30 patients with Parkinson's disease (PD), and 30 healthy participants. Plasma COQ10 was quantified by UPLC-MS. The basic demographic data, motor symptoms, and non-motor symptoms were also assessed., Results: Plasma COQ10 levels were significantly different in MSA, PD, and controls (P = 0.001). Post-hoc analysis revealed plasma COQ10 levels in MSA patients were lower than that in controls after adjusting for age, gender, and total cholesterol (P = 0.001). COQ10 levels differentiated MSA patients from controls with modest accuracy (P = 0.001). A sensitivity of 40% and a specificity of 97.5% was calculated with the receiver operating characteristic curve. However, COQ 10 levels did not discriminate between the MSA and PD groups (P = 0.07). Plasma COQ10 levels were correlated with the severity of motor symptoms only in MSA-C patients (b = -0.025, P = 0.009)., Conclusion: The association between decreased COQ10 levels and the severity of motor symptoms in MSA-C patients promotes further research. Plasma COQ10 levels alone may not be a reliable MSA diagnostic biomarker, and cannot be considered a useful biomarker in the differential diagnosis of MSA vs PD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Blood biomarkers in degenerative ataxias are still largely missing. Here, we aimed to provide piloting proof-of-concept that serum Neurofilament light (NfL) could offer a promising peripheral blood biomarker in degenerative ataxias. Specifically, as a marker of neuronal damage, NfL might (1) help to differentiate multiple system atrophy of cerebellar type (MSA-C) from sporadic adult-onset ataxia (SAOA), and (2) show increases in repeat-expansion spinocerebellar ataxias (SCAs) which might be amenable to treatment in the future. To explore these two hypotheses, we measured serum NfL levels by single-molecule array (Simoa) technique in 115 subjects, comprising patients with MSA-C (n = 25), SAOA (n = 25), the most frequent repeat-expansion SCAs (SCA 1, 2, 3 and 6) (n = 20), and age-matched controls (n = 45). Compared to controls, NfL was significantly increased in MSA-C, with levels significantly higher than in SAOA (AUC = 0.74 (0.59-0.89), mean and 95% confidence interval, p = .004). NfL was also significantly increased in SCA patients as compared to controls (AUC = 0.91 (0.81-1.00), p < .001), including NfL increases in SCA1 and SCA3. These findings provide first proof-of-concept that NfL might provide a promising peripheral biomarker in degenerative ataxias, e.g. supporting the differentiation of MSA-C from SAOA, and indicating neuronal damage in repeat-expansion SCAs.

Objectives: Lower serum uric acid (UA) levels are considered to be related to the risk to develop many neurodegenerative disorders. However, the association between serum UA level and multiple system atrophy (MSA) remains controversial. The aim of this meta-analysis was to evaluate the relationship between serum UA level and MSA., Patients and Methods: PubMed, Web of Science, Embase, Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched for eligible studies. Standardized mean difference (SMD) and 95% confidence intervals (95% CI) were calculated in a fixed-effects model or a random-effects model when appropriate. Subgroup analyses were carried out based on gender. A total of 6 eligible studies involving 547 MSA patients and 637 healthy individuals were identified., Results: Meta-analysis results revealed that individuals with MSA had lower sera levels of UA as compared with healthy controls (pooled SMD is -0.51, 95%CI: -0.88 to -0.14; p = 0.006). The subgroup analysis to detect sex differences showed that the pooled SMD was -0.61 (95% CI: -0.82 to -0.40; p < 0.0001) for males and -0.22 (95% CI: -0.55 to 0.10; p = 0.18) for females compared with healthy controls., Conclusion: Our meta-analysis revealed that lower serum level of UA is associated with an increased risk of MSA and the relationship is significant in men but not in women., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Parkinson's disease (PD) is the result of progressive degeneration of the nigrostriatal dopaminergic pathway and depletion of neurotransmitter dopamine in the striatum., Methods: We included 17 patients with PD along with 7 patients of progressive supranuclear palsy (PSP), 6 patients of multiple system atrophy (MSA) and 22 age and sex-matched healthy controls. We analyzed metabolite profiles in the serum of these patients and controls using 1 H NMR spectroscopy., Results: Isoleucine, valine, alanine, glutamine and histidine in PD, PSP and MSA were significantly (P < 0.001) higher than controls, whereas, glutamate and glucose were significantly increased in PD (P < 0.001), PSP and MSA (P < 0.05) vs., Control: Citrate was increased in PD, PSP and MSA (P < 0.05) vs., Control: While, acetone, lactate and formate were higher at P < 0.001, threonine is increased at P < 0.05. The 3D scattered score plot of OPLS-DA model revealed clear differentiation among the groups, R2 = 0.92 and Q2 = 0.78., Conclusion: Significant differences in various metabolite levels were found between control and disease groups. Common amino acids that are significantly higher in all groups include branched chain amino acids, which could increase neuronal excitability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels-suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) ( P <0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) ( P <0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls ( P <0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by α‑synuclein positive glial cytoplasmic inclusions in oligodendrocytes. The clinical diagnosis of MSA is often challenging as there are no established biomarkers and diagnoses are now based on clinical findings alone. At present, the etiology and pathogenesis of MSA are unclear. It has been reported that dysregulation of microRNA (miRNA/miR) serves an important role in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The miRNA profile of patients with MSA remains to be established. The present study investigated the serum miRNA expression level of 10 patients with MSA, using microarray chips including 668 miRNAs. It was identified that 50 miRNAs were significantly upregulated and 17 miRNAs were significantly downregulated in the serum of the patients with MSA. The most upregulated miRNA was miR‑16, which may induce the accumulation of α‑synuclein. The target genes of some miRNAs upregulated in MSA (including miR‑17, 20a, 24, 25, 30d and 451) were associated with autophagy‑associated molecules. The present study concluded that the expression pattern of miRNAs may be a clinical biomarker for MSA and targeting these miRNAs may provide a novel treatment for MSA.

Introduction: Multiple system atrophy (MSA), an adult-onset, fatal disorder of uncertain etiology, characterized by parkinsonism, cerebellar, autonomic and motor dysfunctions, is an α-synucleinopathy with glioneuronal degeneration involving multiple parts of the nervous system. The clinical variants correlate with the morphological phenotypes of striatonigral degeneration (MSA-P), olivoponto-cerebellar atrophy (MSA-C), and mixed type MSA. Neuropathological hallmark is the deposition of aberrant α-synuclein in glia and neurons forming cytoplasmic inclusions that cause cell dysfunction/demise. Areas covered: While our knowledge of the pathogenesis of this proteinopathy is still incomplete, updated consensus criteria and combined biomarkers have increased diagnostic accuracy. Multimodal imaging of structural and functional brain changes gives insight into the pathophysiology and may evaluate disease progression. Currently, the most useful CSF biomarkers are a combination of light chain neurofilament (elevated in MSA), catecholaminergic metabolites, and proteins (α-synuclein, DJ-1, tau). Several blood substances (neurofilament light chain, microRNAs) are non-invasive biomarkers. Expert commentary: Recent studies suggest that the combination of neuroimaging and fluid biomarkers may be more successful than using single markers to increase the accuracy of the clinical (differential) diagnosis of MSA. Multidisciplinary research to develop more reliable markers for a more exact and early diagnosis and targets for effective treatment are urgently needed.

Aims: Neuroinflammation contributed to the pathogenesis of multiple system atrophy (MSA). We aimed to detect the correlation between inflammatory mediators, such as Klotho (Klt), vitamin D (25(OH)D) and homocysteine (Hcy), and disease severity among MSA patients., Methods: A total of 53 MSA patients, 65 PD patients, and 62 normal subjects were recruited in our cross-sectional study. Serum Klotho (Klt), vitamin D (25(OH)D), and homocysteine (Hcy) levels were measured. Several scales were undertaken to assess the motor/nonmotor function and cognitive impairment of MSA., Results: Decreased Serum Klt and 25(OH)D levels and increased Hcy levels were found in patients with MSA, compared with healthy controls. These results were more pronounced in male patients. The three biomarkers also displayed differences between MSA and PD subgroups based on genders. Interestingly, Klt, 25(OH)D and Hcy levels associated with cognition impairment, motor dysfunction, mood/cardiovascular disorder among MSA patients. In addition, the combination of Klt, 25(OH)D and Hcy had a better diagnostic ability for distinguishing MSA patients from healthy subjects, as well as distinguishing male MSA patients from male PD patients., Conclusion: This study suggested that Klt, 25(OH)D and Hcy levels could be a potential predictor for MSA severity evaluation., (© 2017 John Wiley & Sons Ltd.)

Objectives: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder that may be caused in part by oxidative stress. Uric acid (UA) protects neurons in neurodegenerative disorders via antioxidative effects. The aim of this study was to investigate the relationship between the serum UA concentration and disease progression in MSA patients., Patients and Methods: A total of 53 Japanese MSA patients were enrolled in this study. The disease progression rate was estimated by the rate of global disability scale change per year. The relationship between the serum UA concentration and disease progression was assessed by Spearman's correlation analysis. Disease progression depending on the UA concentration was also estimated by multivariate logistic regression analysis., Results: MSA patients with the highest serum UA concentration had lower disease progression rates than those with the lowest concentration. Spearman's correlation analysis showed an inverse correlation between the serum UA concentration and disease progression in male patients. Multivariate logistic regression analysis confirmed that the UA concentration was independently related to disease progression only in male patients., Conclusion: These results suggest that serum UA may be associated with disease progression in male patients with MSA., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of α-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between α-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the glucagon-like peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric α-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the glucagon-like peptide-1 agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Serum uric acid (UA) levels are reported to be decreased in patients with Parkinson's disease (PD) and multiple system atrophy (MSA). However, clinical correlates of serum UA levels are still unclear in PD-related disorders. We conducted a cross-sectional study to evaluate the associations between serum UA levels and disease duration, disease severity, and motor function among PD, MSA, and progressive supranuclear palsy (PSP) patients., Methods: A total of 100 patients with PD, 42 patients with MSA, 30 patients with PSP, and 100 controls were included in this study. Serum UA levels were determined, and associations among serum UA levels and disease duration, disease severity, and motor function in PD, PSP, and MSA patients were evaluated., Results: Serum UA levels were significantly lower in male PD, MSA, and PSP patients compared with the controls, but not in female patients. Serum UA levels were negatively correlated with disease duration and severity in MSA and PSP patients, but no correlations were observed in PD patients. The serum UA levels were significantly decreased in the tauopathy group (PSP patients) compared with the synucleinopathy group (PD and MSA patients) after adjusting for age, gender, and body mass index., Conclusion: We found decreased serum UA levels in male patients with PD-related disorders (PD, MSA, and PSP) compared with male controls, and significant correlations between serum UA levels and disease severity in MSA and PSP patients.

Objective: Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). The aim of this study is to examine oxidant biomarkers including homocysteine (Hcys), bilirubin, uric acid, lipids, and potential environmental risk factors and to ascertain whether these data correlate with MSA in a Chinese population., Methods: In this study, serum levels of Hcys, bilirubin, uric acid, and lipids were studied in 55 MSA patients and 76 healthy controls (HCs). Education, anti-parkinsonian agent usage, smoking, drinking, farming, and living area of the subjects also were analyzed. The Unified MSA Rating Scale (UMSARS), Hoehn & Yahr stage, International Cooperative Ataxia Rating Scale, and Mini-Mental State Examination were used to assess the disease severity, the parkinsonism, ataxia, and the cognitive ability of MSA, respectively., Results: The levels of Hcys were higher (p<0.001) and those of total bilirubin (p=0.007), indirect bilirubin (p=0.011), and total cholesterol (p=0.046) were lower in MSA patients than in healthy controls, whereas uric acid levels did not differ significantly between MSA and healthy controls. Moreover, Hcys levels in MSA patients had positive correlations with illness duration (r s =0.422, p=0.001) and UMSARS-I (r s =0.555, p<0.001), respectively. High-density lipoprotein cholesterol levels were negatively correlated with UMSARS-I (r s =-0.325, p=0.015). Farming was more frequent in MSA patients (1-20 years: odds ratio, 6.36; p20 years: odds ratio, 10.26; p=0.001), whereas current smoking was less frequent (odds ratio, 0.13, p=0.002)., Conclusions: Elevated Hcys and decreased high-density lipoprotein cholesterol may be associated with the disease severity of MSA. Environmental exposures such as farming and smoking may contribute to the occurrence but not the progression of MSA.

Background and Objective: Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by degeneration of both upper and lower motor neurons. In this study, we aimed to measure both plasma and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain (pNF-H) levels in patients with ALS, and determine if there is a correlation. We also evaluated plasma and CSF pNF-H levels to investigate if this biomarker could predict the time to generalization (TTG) in ALS better., Methods: Paired plasma and CSF pNF-H levels of patients with ALS (n=51), multiple system atrophy (n=12) and controls (n=30) were measured by monoclonal sandwich ELISA. TTG, which also indicates the time of symptoms spreading from spinal or bulbar localization to both, was evaluated in all ALS patients., Results: We found a strong correlation between plasma and CSF pNF-H levels within individual patients (r=0.712, p<0.001). The mean TTG in ALS patients was 22.9months (range 1-84months), and there was an inverse correlation between plasma (r=-0.661; p<0.001)/CSF (r=-0.869; p<0.001) pNF-H levels and TTG., Conclusion: The correlation of plasma and CSF pNF-H levels would bring insight into the pathogenesis of ALS. TTG might play an important role in the future study of ALS, as an early indicator of survival., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Importance: Multiple system atrophy (MSA) is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. It has recently been reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10 (CoQ10), are associated with MSA. However, little is known about the role of CoQ10 in the pathogenesis of MSA., Objective: To compare the levels of plasma CoQ10 in patients with MSA with those in age-, sex-, and COQ2 genotype-matched controls., Design, Setting, and Participants: We enrolled 44 Japanese patients with MSA and 39 Japanese controls from September 1, 2012, to December 31, 2015. Patients with MSA were diagnosed on the basis of the second consensus criteria by at least 2 neurologists. Plasma CoQ10 levels were measured by high-performance liquid chromatography with electrochemical detection. Sanger sequencing of COQ2 was performed to determine the COQ2 genotypes. Multiple logistic regression analysis was performed to determine the association between MSA and the plasma CoQ10 level., Main Outcomes and Measures: Plasma CoQ10 levels in patients with MSA were compared with those in controls after adjusting for age, sex, and COQ2 genotype., Results: Among 44 patients with MSA (mean [SD] age, 63.7 [8.3] years) and 39 controls (mean [SD] age, 60.3 [13.0] years), the mean (SD) plasma level of CoQ10 in patients with MSA was lower than that in controls (0.51 [0.22] vs 0.72 [0.42] µg/mL; P = .01) (difference between medians: -0.14; 95% CI, -0.25 to -0.03). The mean (SD) plasma levels of CoQ10 in patients with the cerebellar variant of MSA and those with the parkinsonian variant of MSA were 0.58 (0.19) and 0.49 (0.26) µg/mL, respectively. After adjusting for age, sex, and COQ2 genotype, the levels of plasma CoQ10 were significantly associated with MSA (95% CI, 0.10; range, 0.02 to 0.66) (P = .02)., Conclusions and Relevance: Our data showed decreased levels of plasma CoQ10 in patients with MSA regardless of the COQ2 genotype, supporting a hypothesis that supplementation with CoQ10 is beneficial for patients with MSA.

Introduction: Uric acid is a natural antioxidant, and it has been shown that low levels of uric acid could be a risk factor for the development of PD. Our aim was to investigate whether uric acid plays a role in PSP., Methods: We carried out a cross-sectional study to compare serum uric acid levels between PSP patients, PD patients, and healthy controls. We also analyzed longitudinal uric acid levels in the PSP group., Results: PSP patients showed reduced levels of serum uric acid as compared to healthy controls. This reduction was similar to that found in patients with PD. Uric acid levels of PSP patients did not change with time., Conclusion: Serum uric acid levels are reduced in PSP as well as in PD compared to healthy controls. Our data suggest that high levels of uric acid could be a natural protective factor against PSP., (© 2015 International Parkinson and Movement Disorder Society.)

Objectives: Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Creatine, which is converted to creatinine, has an anti-oxidative effect. Our aim is to clarify the correlations between creatinine and the occurrence as well as the progression of MSA., Methods: A total of 115 patients with probable MSA and 115 age- and gender-matched healthy controls were included in the study. The serum creatinine level of all patients and controls were evaluated and compared., Results: The mean age of MSA patients was 58.18 ± 8.67 years and the mean disease duration was 2.85 ± 1.71 years. The creatinine level of MSA patients was significantly lower than that of healthy controls (P < 0.0001). The occurrence of MSA was decreased in the highest creatinine quartiles compared with the lowest creatinine quartiles. In a gender-specific analysis, patients with the highest quartiles and second quartiles of creatinine level had decreased occurrence than patients with the lowest quartile in females, but not in males. The serum level of creatinine was not found correlated with the mean rate of annualised changes, neither with other independent factors, such as age, body mass index (BMI), sex, Unified MSA Rating Scale (UMSARS) scores and disease duration at the initial visit in patients with MSA., Conclusion: High level of serum creatinine may be associated with a low occurrence of MSA in Chinese population, especially in female. However, serum creatinine does not deteriorate or ameliorate the progression of MSA.

The COQ2 gene encodes an essential enzyme for biogenesis, coenzyme Q10 (CoQ10). Recessive mutations in this gene have recently been identified in families with multiple system atrophy (MSA). Moreover, specific heterozygous variants in the COQ2 gene have also been reported to confer susceptibility to sporadic MSA in Japanese cohorts. These findings have suggested the potential usefulness of CoQ10 as a blood-based biomarker for diagnosing MSA. This study measured serum levels of CoQ10 in 18 patients with MSA, 20 patients with Parkinson's disease and 18 control participants. Although differences in total CoQ10 (i.e., total levels of serum CoQ10 and its reduced form) among the three groups were not significant, total CoQ10 level corrected by serum cholesterol was significantly lower in the MSA group than in the Control group. Our findings suggest that serum CoQ10 can be used as a biomarker in the diagnosis of MSA and to provide supportive evidence for the hypothesis that decreased levels of CoQ10 in brain tissue lead to an increased risk of MSA.

Objective: Chronic inflammatory processes contribute to the eventual death of motor neurons and the development of symptoms in both idiopathic Parkinson disease (PD) and multiple system atrophy (MSA). Given the faster rate of progression and more severe symptoms associated with MSA, we hypothesized that markers of inflammation would be more evident in the peripheral blood of MSA than PD patients, and that evidence of this inflammation might assist early diagnosis of MSA versus PD., Methods: We performed multiplex analysis to determine the concentrations of 37 immune-associated cytokines and chemokines isolated from the plasma of patients with PD (n = 25) and MSA (n = 14) and compared our results to those of age-matched controls (n = 15). We then applied a mixed-effect multiple regression model to determine if the concentration of cytokines in the plasma of patients with PD and MSA changed significantly over time., Results: Patients with MSA had a trend towards overall lower levels of immune-associated cytokines, while serum cytokine levels were increased in patients with PD. Statistically adjusted comparisons of overall changes in cytokine concentrations between the PD and MSA groups revealed higher concentrations of T-cell-associated cytokines TNFβ and IL-7 in PD. Comparison of samples taken over time revealed significantly faster rates of change in 4 different cytokine concentrations (IL-4, IL-15, IL-2, and IL-9) in patients with MSA versus patients with PD., Conclusions: Our results suggest that single measurements of plasma concentrations of inflammation-associated cytokines cannot be used to distinguish disease states. However, measurements made over time may correlate with pathogenesis. The significant changes in T-cell-associated cytokines may shed light on immune mechanisms that contribute to PD and MSA disease progression., (© 2017 S. Karger AG, Basel.)

Background and Objective: Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA) and cognitive impairment. Uric acid has an anti-oxidative effect. Our objective is to clarify the correlations between serum uric acid and cognitive function as well as frontal lobe function in Chinese MSA patients., Methods: All of MSA patients were evaluated using Addenbrooke's Cognitive Examination-Revised (ACE-R), Frontal Assessment Battery (FAB), and Unified MSA Rating Scale (UMSARS). The fasting serum uric acid concentrations of MSA patients were measured., Results: A total of 89 probable MSA patients with a mean age of 58.6 ± 10.0 years old and disease duration of 2.6 ± 1.5 years were included. Thirty-three patients (37.1%) had global cognitive deficits according to ACE-R. Based on FAB, 35 patients (39.3%) had frontal lobe dysfunction. After adjusting for educational years, patients with cognitive deficits had lower uric acid level than patients without cognitive deficits. Patients with frontal lobe dysfunction had lower uric acid level after adjusting for UMSARS scores. In a forward multiple linear regression, uric acid level and educational years were the variables predicting the ACE-R score (F=36.540, R(2)=0.459, p=0.0001), uric acid accounting for 14% of the total variables. Uric acid was the only variable contributing to the FAB score (F=18.551, R(2)=0.176, p=0.0001)., Conclusion: Our study suggested that low level of serum uric acid was associated with cognitive deficits in MSA. Low uric acid level predicting cognitive decline in MSA needs more studies., (Copyright © 2015. Published by Elsevier B.V.)

Purpose: Parkinson disease, an α-synucleinopathy, is associated with reduced insulin sensitivity, impaired glucose tolerance, and diabetes mellitus. Importantly, these metabolic alterations have been shown to contribute to disease progression. The purpose of this study was to determine if reduced insulin sensitivity is also present in other α-synucleinopathies associated with autonomic failure., Methods: We studied 19 patients with multiple system atrophy and 26 patients with pure autonomic failure. For comparison, we studied 8 healthy controls matched for body mass index. Insulin sensitivity and beta cell function were calculated using fasting glucose and insulin levels according to the homeostatic model assessment 2. A multiple linear regression model was performed to determine factors that predict insulin sensitivity in autonomic failure., Results: There was a significant difference in insulin sensitivity among groups (P = 0.048). This difference was due to lower insulin sensitivity in multiple system atrophy patients: 64% [interquartile range (IQR), 43 to 117] compared to healthy controls 139% (IQR, 83 to 212), P = 0.032. The main factor that contributed to the reduced insulin sensitivity was the presence of supine hypertension and residual sympathetic tone., Conclusions: Multiple system atrophy patients have reduced insulin sensitivity that is associated with residual sympathetic activation and supine hypertension. These patients may therefore be at high risk for development of impaired glucose tolerance and diabetes mellitus.

Background: Multiple system atrophy (MSA) is a neurodegenerative disease, and its pathological hallmark is the accumulation of α-synuclein proteins. Homocysteine (Hcy) is an intermediate amino acid generated during the metabolism of methionine. Hcy may contribute to the pathogenesis of neurodegenerative disorders. Vitamin B12 and folate are cofactors necessary for the methylation of homocysteine., Methods: This study compared the levels of serum Hcy, vitamin B12 and folate in patients with MSA with those in healthy people to reveal the possible association between MSA and plasma levels of Hcy, vitamin B12 and folate. We enrolled 161 patients with MSA and 161 healthy people in this study. The association between MSA and the levels of Hcy, vitamin B12 and folate were analyzed using binary logistic regression., Results: The mean level of Hcy in patients with MSA was significantly higher than that in healthy controls (16.23 ± 8.09 umol/l vs 14.04 ± 4.25 umol/l, p < 0.05). After adjusting for age, sex and medical history, the odds ratio for Hcy was 1.07 (95% CI = 1.01-1.13, p < 0.05) for patients with MSA. Vitamin B12 and folate levels were not significantly different between patients with MSA and controls., Conclusion: Our data suggest that higher levels of Hcy may be associated with an increased risk for MSA.