BACKGROUND: Multiple system atrophy (MSA), an atypical parkinsonian syndrome, is a rapidly progressive neurodegenerative disease with currently no established fluid biomarkers available. MSA is characterized by an oligodendroglial α-synucleinopathy, progressive neuronal cell loss and concomitant astrocytosis. Here, we investigate glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as fluid biomarkers for differential diagnosis, assessment of clinical disease severity and prediction of disease progression in MSA.
METHODS: GFAP and NfL levels were analyzed in plasma and CSF samples of 47 MSA patients as well as 24 Parkinson\'s disease (PD) and 25 healthy controls (HC) as reference cohorts. In MSA, biomarker levels were correlated to baseline and longitudinal clinical disease severity (UMSARS scores).
RESULTS: In MSA, GFAP levels in CSF and plasma predicted baseline clinical disease severity as indicated by UMSARS scores, while NfL levels predicted clinical disease progression as indicated by longitudinal changes in UMSARS scores. Cross-sectionally, NfL levels in CSF and plasma were significantly elevated in MSA compared to both PD and HC. Receiver operating curves (ROC) indicated high diagnostic accuracy of NfL for distinguishing MSA from PD (CSF: AUC = 0.97, 95% CI 0.90-1.00; plasma: AUC = 0.90, 95% CI 0.81-1.00).
CONCLUSIONS: In MSA, GFAP shows promise as novel biomarker for assessing current clinical disease severity, while NfL might serve as biomarker for prediction of disease progression and differential diagnosis of MSA against PD.

UNASSIGNED: Alpha-synuclein oligomers (o-α-syn) are pivotal in the pathogenesis of α-synucleinopathy. Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) serves as an early indicator of the disease, offering insights into disease mechanisms and early intervention. Nevertheless, the diagnostic and predictive potential of o-α-syn in iRBD remains largely unexplored. This study aimed to evaluate the plasma levels of o-α-syn in patients and investigate their utility as biomarkers for diagnosis of and predicting phenoconversion in iRBD.
UNASSIGNED: A total of 143 participants, including 77 polysomnography-confirmed iRBD patients and 66 normal controls (NC), were recruited for this longitudinal observational study. Baseline clinical assessments and plasma collection were conducted for all iRBD patients, with 72 of them undergoing regularly prospective follow-up assessments for parkinsonism or dementia. Plasma levels of o-α-syn were quantified using enzyme-linked immunosorbent assay, and were compared between groups using a general linear model adjusted for age and sex. The diagnostic performance of plasma o-α-syn in iRBD was evaluated by area under the receiver operating characteristic curve (AUC) with 95% CI. Cox regression analysis and Kaplan-Meier survival curves were employed to assess the predictive value of plasma o-α-syn for phenoconversion in iRBD.
UNASSIGNED: Plasma o-α-syn levels did not exhibit statistically significant differences among iRBD converter patients, iRBD nonconverter patients, and NC. The AUC for distinguishing NC from iRBD was 0.52 (95% CI: 0.42-0.62, p = 0.682). Spearman correlation analysis revealed a significant positive correlation between plasma o-α-syn levels and MOCA scores in the iRBD group (p < 0.001). Subgroup analyses indicated that iRBD patients with cognitive decline (p = 0.058) and depressive symptoms (p = 0.017) had notably lower o-α-syn levels compared to those without such symptoms. Over a median follow-up period of 5.83 years, 26 iRBD patients developed neurodegenerative synucleinopathies. Cox regression and Kaplan-Meier survival curve analyses indicated that plasma level of o-α-syn lacked a predictive value for disease conversion in iRBD patients.
UNASSIGNED: Despite a potential role in the pathophysiology of iRBD, o-α-syn are not appropriate biomarkers for diagnosing or predicting disease progression. While this study offers insights into the pathogenesis of iRBD and neurodegenerative synucleinopathies, further large-scale longitudinal studies are warranted to validate these findings.

The \"hot cross bun\" sign is a rare radiologic sign seen on magnetic resonance imaging that can help direct the diagnosis of the cerebellar subtype of multiple system atrophy. It indicates damage to the transverse pontocerebellar fibers and can be seen in other pathologies including spinocerebellar ataxia. The name for this radiologic sign was coined in 1998, likening the cruciform hyperintensity on imaging to the English spiced bun marked with a cross and historically eaten on the Christian religious holiday Good Friday.

UNASSIGNED: Sleep-related breathing disorder (SRBD) is a prevalent non-motor symptom in multiple system atrophy (MSA). However, the reported prevalence of SRBD in MSA from different studies has shown inconsistency. Additionally, only one study has examined the impact of SRBD on both motor and non-motor symptoms in MSA.
UNASSIGNED: Cross-sectional study of 66 patients with probable MSA from China. SRBD was ascertained with polysomnography (PSG). All the MSA individuals were assessed using the Epworth Sleepiness Scale (ESS), Unified Multiple-System Atrophy Rating Scale (UMSARS), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), the Mini-mental State Examination (MMSE), Non-Motor Symptoms Scale (NMSS), and Pittsburgh Sleep Quality Index (PSQI). Moreover, a meta-analysis was conducted by searching studies related to MSA and SRBD in PubMed, Web of Science, Embase, and Cochrane databases. Data were pooled as necessary to calculate prevalence of SBRD with 95% confidence intervals (CI).
UNASSIGNED: Our study included 66 patients with MSA, 52 of whom had a diagnosis of SRBD (78.8%). There were no significant differences between the MSA with SRBD and without SRBD groups on the age, sex, disease onset, disease duration, UMSARS I, II, and IV, the NMSS, the HAMA, HAMD, the ESS the FSS, the MMSE, and the PSQI scales. However, MSA patients with SRBD having a significant higher obstructive apnea index and percentage of snoring during sleep than MSA patients without SRBD [10.0 (4.1-10.6) vs. 0.1 (0-0.3), and 8.3 (5.1-12.2) vs. 4.2 (0-7.5)]. Also, between the two groups, the mean and minimum oxygen concentrations during sleep were lower in MSA patients with SRBD than in those without SRBD [93.7 (93-95) vs. 95.5 (95.8-97), p = 0.001] and [83.9 (81.2-89.0) vs. 90.3 (89.8-93.3), p = 0.000]. The primary search strategy identified 701 articles, with 10 meeting the inclusion criteria. The overall prevalence of SRBD in a combined sample of 295 MSA patients was found to be 60.5% (95% CI, 43.2-76.5%). Further analysis revealed that the prevalence of SRBD in MSA patients in Asia was 79.2% (95% CI, 54.7-96.3%), which was higher than that in Europe (41.6, 95% CI, 32-51.5%).
UNASSIGNED: The study found a prevalence of 78.8% of SRBD in MSA patients, with a notably higher prevalence in Asia compared to Europe. The majority of SRBD cases in MSA were attributed to obstructive apnea. Furthermore, the presence of SRBD did not show a significant impact on the motor and non-motor symptoms of MSA patients.

BACKGROUND: Multiple system atrophy (MSA), a rare neurodegenerative disease, is usually accompanied by brain morphological alterations. However, the causal relationships between progressive gray matter atrophy in MSA parkinsonian (MSA-P) subtype remain unknown.
METHODS: In total, thirty-five MSA-P patients and thirty-five healthy controls (HC) underwent three-dimensional high-resolution T1-weighted structural imaging and voxel-based morphometry analysis. The causal structural covariance network (CaSCN) of gray matter was assessed to explore the causal relationships in MSA-P.
RESULTS: With greater illness duration, the reduction of gray matter was originated from right cerebellum and progressed to bilateral cerebellum, fusiform gyrus, insula, putamen, caudate nucleus, frontal lobe, right angular gyrus, right precuneus, left middle occipital lobe and left inferior temporal lobe, then expanded to midbrain, bilateral para-hippocampus, thalamus, temporal lobe, inferior parietal lobule (IPL), precentral gyrus, postcentral gyrus and middle cingulate cortex. The right cerebellum was revealed to be the core node of the directional network and projected positive causal effects to bilateral cerebellum, caudate nucleus and left IPL.
CONCLUSIONS: MSA-P patients showed progression of gray matter atrophy over time, with the right cerebellum probably as a primary hub. Furthermore, the early structural vulnerability of cerebellum in MSA-P may play a pivotal role in the modulation of motor and non-motor circuits at the structural level.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease that often causes vocal cord paralysis (VCP), Parkinsonism, cerebellar ataxia, and autonomic dysfunction. VCP is the most fatal symptom that affects the prognosis of patients with MSA. Coronavirus disease 2019 (COVID-19) is often associated with neurological complications and it has recently been reported to induce VCP in patients without neurodegenerative diseases. We herein present two cases of patients with MSA in whom VCP worsened after COVID-19 and this led to the need to perform emergency tracheostomies. As VCP may deteriorate after COVID-19 in patients with MSA, it is important to prevent COVID-19 in these patients and closely monitor such patients for any signs of VCP deterioration post-infection to improve their prognosis.

BACKGROUND: Severe dysphagia poses a significant challenge for clinicians regarding feeding tube choices, practices, and timing due to a lack of evidence-based guidance.
OBJECTIVE: To assess national clinical practices and opinions on gastrostomy use in patients with atypical parkinsonian syndromes (APS) across the UK.
METHODS: Online survey was administered to clinicians and allied health professionals regarding availability of services, current use, perceived advantages, and problems associated with gastrostomy insertion.
RESULTS: We received responses from 47 respondents across 12 UK centers, including 44 clinicians specialized in APS. Consensus was observed regarding primary indications for gastrostomy insertion and circumstances justifying avoidance of the procedure. Limitations in recommending gastrostomy due to insufficient evidence on safety and outcomes, survival and quality of life were identified. Widespread agreement on delays in gastrostomy discussions was highlighted as a challenge in optimizing patient care, together with variability in current practices and concerns over the lack of a standardized gastrostomy pathway, emphasizing the need for further research to address existing evidence gaps.
CONCLUSIONS: This multi-center survey highlights agreement among clinicians on key aspects of indication, challenges, and limitations such as delayed decision-making and the absence of standardized pathways regarding the timing, method, and overall approach to gastrostomy insertion in APS. This study identified next steps to facilitate a more structured approach to future research toward a consensus on best practices for gastrostomy in APS. Addressing these challenges is crucial for enhancing patient outcomes and overall care quality in APS.

UNASSIGNED: Vagal atrophy is a hallmark of Parkinson\'s disease (PD) and has been found to be associated with autonomic dysfunction, while analyses of the vagus nerve (VN) in atypical Parkinsonian syndromes (APS) have not yet been performed. We here investigate the characteristics of the VN in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and, in a second step, its potential as a possible biomarker for orthostatic dysregulation.
UNASSIGNED: The aim was to compare the VN pathology in MSA and PSP with healthy individuals and patients with PD as a differentiating factor and to further analyse the correlation of the VN with clinical parameters and cardiovascular response.
UNASSIGNED: We conducted a monocentric, cross-sectional cohort study in 41 APS patients and compared nerve ultrasound (NUS) parameters with 90 PD patients and 39 healthy controls.
UNASSIGNED: In addition to a detailed neurological history and examination, several clinical severity and motor scores were obtained. Autonomic symptoms were reported in the Scales for Outcomes in Parkinson\'s Disease - Autonomic questionnaire. Further scores were used to detect other non-motor symptoms, quality of life and cognition. Additionally, we performed a head up tilt test (HUTT) and NUS of the VN. We conducted correlation analyses of the VN cross-sectional area (CSA) with clinical scores and the heart rate and blood pressure variability parameters of the HUTT.
UNASSIGNED: The examination demonstrated a high prevalence of abnormal autonomic response in both MSA (90%) and PSP (80%). The VN CSA correlated with spectral parameters of the HUTT, which are associated with sympatho-vagal imbalance. In addition, the CSA of the VN in patients with PD and PSP were significantly smaller than in healthy controls. In MSA, however, there was no marked vagal atrophy in comparison.
UNASSIGNED: The occurrence of autonomic dysfunction was high in MSA and PSP, which underlines its impact on these syndromes. Our findings indicate a connection between vagal pathology and autonomic dysfunction and might contribute to a better comprehension of APS. To further evaluate the clinical relevance and the VN as a possible marker of autonomic dysfunction in APS, prospective longitudinal observations are necessary.

Abnormal α-synuclein (αSyn), including an oligomeric form of αSyn, accumulates and causes neuronal dysfunction in the brains of patients with multiple system atrophy. Neuroprotective drugs that target abnormal αSyn aggregation have not been developed for the treatment of multiple system atrophy. In addition, treating diseases at an early stage is crucial to halting the progress of neuronal damage in neurodegeneration. In this study, using early-stage multiple system atrophy mouse model and in vitro kinetic analysis, we investigated how intranasal and oral administration of trehalose can improve multiple system atrophy pathology and clinical symptoms. The multiple system atrophy model showed memory impairment at least four weeks after αSyn induction. Behavioural and physiological analyses showed that intranasal and oral administration of trehalose reversed memory impairments to near-normal levels. Notably, trehalose treatment reduced the amount of toxic αSyn and increased the aggregated form of αSyn in the multiple system atrophy model brain. In vitro kinetic analysis confirmed that trehalose accelerated the aggregate formation of αSyn. Based on our findings, we propose a novel strategy whereby accelerated αSyn aggregate formation leads to reduced exposure to toxic αSyn oligomers, particularly during the early phase of disease progression.

The molecular pathogenesis of degenerative parkinsonisms, including Parkinson\'s disease (PD), progressive supranuclear palsy (PSP), and Multiple system atrophy (MSA), remains largely unknown. To gain novel insight into molecular processes associated with these diseases, we conducted a proteome-wide expression study in prefrontal cortex tissue from a cohort of 181 individuals, comprising PD (N = 73), PSP (N = 18), MSA (N = 17) and healthy control (N = 73). Using marker gene profiles, we first assess the cellular composition of the samples and, subsequently, identify distinct protein signatures for each disease, while correcting for cell composition. Our findings indicate that all three diseases are characterized by a structural and/or functional loss of deep cortical neurons, while PD exhibits an additional decrease in somatostatin-expressing interneurons, as well as in endothelial cells. Differential protein expression analysis identified multiple proteins and pathways with disease-specific expression, some of which have previously been associated with parkinsonism or neurodegeneration in general. Notably, we observed a strong mitochondrial signature which was present in both PD and PSP, albeit of a different composition and most pronounced in PSP, but not in MSA where immunological/inflammation-related pathways dominated. Additionally, we identified protein signatures associated with the severity of α-synuclein pathology in PD and showed that these are highly enriched in an upregulation of mitochondrial processes, specifically related to oxidative phosphorylation and in particular respiratory complexes I and IV. We identify multiple novel signatures of protein expression, associated with PD, PSP, and MSA, as well as with the severity of α-synuclein pathology in the PD brain.