Somatic and autonomic function in progressive autonomic failure and multiple system atrophy.

Anhidrosis occurs in the majority of multiple system atrophy (MSA) patients but the underlying site of lesion is not well established. We describe three patients with long-standing MSA and anhidrosis diagnosed on the basis of a thermoregulatory sweating test. In biopsies of anhidrotic skin, immunofluorescence analysis disclosed a well preserved postganglionic sudomotor innervation in all three patients supporting the hypothesis of a preganglionic nerve fiber lesion underlying their anhidrosis. Postganglionic sudomotor fiber integrity was also confirmed by normal electrodermal responses in one patient, whereas such responses and microneurographically detectable skin sympathetic nerve activity were absent in the other two MSA patients, suggesting a functional inactivity of structurally intact postganglionic sympathetic skin fibers.

Phosphorylated α-synuclein and phosphorylated tau-protein in sural nerves may contribute to differentiate Parkinson’s disease from multiple system atrophy and progressive supranuclear paralysis

Disease-modifying therapeutics in the α-synucleinopathies multiple system atrophy (MSA) and Parkinson’s Disease (PD) are in early phases of clinical testing. Involving patients’ preferences including therapy-associated risk willingness in initial stages of therapy development has been increasingly pursued in regulatory approval processes. In our study with 49 MSA and 38 PD patients, therapy-associated risk willingness was quantified using validated standard gamble scenarios for varying severities of potential drug or surgical side effects. Demonstrating a non-gaussian distribution, risk willingness varied markedly within, and between groups. MSA patients accepted a median 1% risk [interquartile range: 0.001–25%] of sudden death for a 99% [interquartile range: 99.999–75%] chance of cure, while PD patients reported a median 0.055% risk [interquartile range: 0.001–5%]. Contrary to our hypothesis, a considerable proportion of MSA patients, despite their substantially impaired quality of life, were not willing to accept increased therapy-associated risks. Satisfaction with life situation, emotional, and nonmotor disease burden were associated with MSA patients’ risk willingness in contrast to PD patients, for whom age, and disease duration were associated factors. An individual approach towards MSA and PD patients is crucial as direct inference from disease (stage) to therapy-associated risk willingness is not feasible. Such studies may be considered by regulatory agencies in their approval processes assisting with the weighting of safety aspects in a patient-centric manner. A systematic quantitative assessment of patients’ risk willingness and associated features may assist physicians in conducting individual consultations with patients who have MSA or PD by facilitating communication of risks and benefits of a treatment option.

Diagnosing dementia in multiple system atrophy by applying Movement Disorder Society diagnostic criteria for Parkinson's disease dementia.

Objective To investigate the differences of candidate cerebrospinal fluid (CSF) biomarkers associated with multiple system atrophy (MSA) and Parkinson's disease (PD). Method Here, a systematic review and meta-analysis were conducted on studies related to CSF biomarkers associated with MSA and PD obtained from PubMed, Web of Science, Embase, and Cochrane databases. Data were pooled where appropriate and used to calculate standardized mean differences (SMDs) with 95% confidence intervals (CI). Heterogeneity was assessed using the I2 statistic while Egger's test was used to test for existing publication bias. Results MSA patients had higher CSF t-tau (SMD = 0.41, 95% CI: 0.10 to 0.72) and YKL-40 (SMD = 0.63, 95% CI 0.12 to1.15) as well as DJ-1 (SMD = 1.05, 95% CI 0.67 to 1.42) levels than PD patients, while CSF p-tau (SMD = −0.17, 95% CI, -0.31 to -0.02) and Aβ-42 (SMD = −0.33, 95% CI, -0.55 to -0.12) levels in MSA patients were lower than those in PD patients. There were no differences in CSF's GFAP and Flt3 ligand levels in both MSA and PD patients. Conclusion The study revealed the differences in CSF biomarker levels between MSA and PD cohorts that can be further explored to clinically distinguish MSA from PD.

BackgroundThe evidence about the language performance profile of multiple system atrophy (MSA) is limited, but its definition may lead to a more comprehensive characterization of the disorder and contribute to clarify the involvement of the basal ganglia in language abilities.ObjectiveThe objectives of the study were: (1) to evaluate the reliability of the Screening for Aphasia in NeuroDegeneration (SAND) in MSA patients; (2) compare the linguistic profiles among MSA and Parkinson’s disease (PD) patients and healthy controls (HC), and (3) assess relationships between language impairment and cognitive status and MSA motor subtypes.Methods and resultsForty patients with a diagnosis of MSA, 22 HC and 17 patients with PD were enrolled in the present study. By excluding the writing task that showed a poor acceptability, we showed that the MSA-tailored SAND Global Score is an acceptable, consistent and reliable tool to screen language disturbances in MSA. MSA patients performed worse than HC, but not than PD, in MSA-tailored SAND Global Score, repetition, reading and semantic association tasks. We did not find significant differences between MSA phenotypes. MSA patients with mild cognitive impairment-multiple domain presented worse language performances as compared to MSA patients with normal cognition and mild cognitive impairment-single domain.ConclusionThe MSA-tailored SAND Global Score is a consistent and reliable tool to screen language disturbances in MSA. Language disturbances characterize MSA patients irrespective of disease phenotype, and parallel the decline of global cognitive functions.

Cardiac sympathetic denervation without Lewy bodies in a case of multiple system atrophy.

Lewy Body Disease (LBD) and Multiple System Atrophy (MSA) are synucleinopathies with distinct prognoses and neuropathologies, however, with overlapping clinical symptoms. Different disease characteristics are proposed to be determined by distinct conformations of alpha-synuclein (α-Syn) aggregates, which can self-propagate and spread between cells via a prion-like mechanism. The goal of this study is to investigate whether α-syn aggregates amplified from brain and CSF samples of LBD and MSA patients using the Seed Amplification Assay (SAA) maintain α-Syn seeding properties similar to those of α-syn aggregates derived from patients' brains. To address this, SAA-amplified and un-amplified α-Syn aggregates from LBD and MSA patients' brains, as well as SAA-amplified α-Syn aggregates from LBD and MSA patients' CSF samples, were used to treat synuclein biosensor cells, and induced intracellular α-Syn inclusions were analyzed by confocal microscopy. Our data indicate that induced α-Syn aggregates from LBD and MSA patients' brains have similar seeding properties and morphological characteristics in the α-Syn biosensor cells as those amplified from LBD and MSA patients' brains, as well as those amplified from LBD and MSA patients' CSF samples. In this study, we demonstrated that, regardless of the source of aggregates, the seeds from LBD and MSA produce cellular accumulation of α-Syn with distinct morphologies, confirming the presence of different conformational strains of α-Syn in LBD and MSA and allowing us to differentiate synucleinopathies based on the morphology of aggregates and seeding properties.

Serum Hcy was higher in MSA patients when compared to healthy subjects, particularly in male patients.Serum UA was lower in MSA patients when compared healthy subjects, particularly in male patients.Serum Hcy levels were significantly positively correlated with the severity of MSA.The ROC curve for the combination of Hcy and UA showed potential diagnostic value in discriminating MSA from healthy subjects. There is evidence suggesting that inflammatory responses play a critical role in the pathogenesis of multiple system atrophy (MSA). Whether inflammatory mediators can be used as reliable biomarkers to detect the severity and progression of MSA remains largely unknown. We performed a cross-sectional study that included 47 patients with MSA and 50 healthy age-matched controls. Serum levels of homocysteine (Hcy), uric acid (UA), and C-reactive protein (CRP) were measured. These levels positively correlated with the severity of MSA, based on both motor and non-motor symptoms. Several scales were used to rate the severity of MSA, including the Unified multiple system atrophy rating scale, Parkinson's disease sleep scale, Non-motor Symptoms Scale, the Schwab & England activities of daily living scale, Webster Scale, modified Hoehn and Yahr staging scale, and the Mini-Mental State Examination. Receiver operating characteristic (ROC) curves was applied to map the diagnostic accuracy of MSA against healthy subjects. Compared with healthy subjects, we found that serum Hcy was higher, UA was lower, and CRP levels were unchanged in MSA patients. These findings were especially prominent in male patients. No significant differences of serum Hcy and UA were observed between patients of MSA and PD. Interestingly, there was a significant correlation between Hcy levels and MSA severity such as movement dysfunction, declined cognition, and cardiovascular symptoms. Additionally, the ROC curve for the combination of Hcy and UA (AUC 0.736) showed potential diagnostic value in discriminating MSA from healthy subjects. Our findings suggest that the inflammatory mediators Hcy and UA may play important roles in the pathogenesis of MSA. The measurement of serum Hcy and UA levels could then be a useful tool to accurately distinguish MSA from healthy subjects.

Hashimoto's encephalopathy with serum anti-NH2-terminal of α-enolase (NAE) antibodies occasionally displays clinical symptoms such as cerebellar ataxia and parkinsonism. We studied the frequency of anti-NAE antibodies in patients with Parkinson-plus syndrome. We examined the positive rates of anti-NAE antibodies in 47 patients with multiple system atrophy (MSA), 29 patients with Parkinson's disease (PD), eight patients with corticobasal syndrome (CBS), and 18 patients with progressive supranuclear palsy (PSP) using conventional immunoblot analysis. Positive anti-NAE antibody rates of 31.9%, 10.3%, 50.0%, and 11.1% were reported in the MSA, PD, CBS, and PSP patients, respectively. The duration from onset to a wheelchair-bound state in seropositive MSA patients tended to be shorter than that in seronegative MSA patients. Anti-NAE antibodies are detected in some patients clinically diagnosed with MSA and CBS. Although its pathophysiological significance remains uncertain, serum anti-NAE antibodies might represent a prognostic marker in the clinical course of MSA.

With video-oculography (VOG), this study aimed to explore and compare visually-guided and self-paced volitional saccades in Parkinson's disease (PD) and multiple system atrophy (MSA).

The objective of this study was to explore the causes of death in Chinese patients with multiple system atrophy (MSA) as well as differences in the cause of death according to sex, subtype, disease onset, and whether the disease was accompanied by nocturnal stridor. A total of 131 MSA patients were enrolled and followed up once every year until their deaths. Clinical information was collected by neurologists, and the cause of death of the MSA patients was obtained from the patients’ relatives or caregivers. The current study included 62 MSA with predominant parkinsonism (MSA-P) and 69 MSA with predominant cerebellar ataxia (MSA-C) patients. Median survival time from disease onset to death of the MSA patients was 5.59 years. The most common cause of death was respiratory infection (65.6%). The second most common cause of death was sudden death (14.5%). Other causes included nutritional disorder due to dysphagia (9.2%), urinary tract infection (3.1%), suicide (2.3%), choking (1.5%), cerebrovascular accident (1.5%), myocardial infarction (1.5%), and lymphoma (0.8%). We found that sudden death was more likely to occur in patients with nocturnal stridor than in those without (P<0.001). There were no significant differences in the cause of death according to subtype, sex, or onset symptoms (autonomic failure or motor symptoms). Sudden death is a relatively common cause of death in MSA patients, second only to respiratory infection, especially in patients with nocturnal stridor. The information provided by our study may help to provide better medical care to MSA patients.

We examined the density of striatal presynaptic monoaminergic terminals, using a ligand for the type 2 vesicular monoamine transporter, (+)-[11C]dihydrotetrabenazine, with positron emission tomography in 7 normal control subjects, 8 multiple system atrophy (MSA) patients with predominantly parkinsonian features (MSA-P), 8 MSA patients with principally cerebellar dysfunction (MSA-C), and 6 sporadic olivopontocerebellar atrophy (sOPCA) patients. The findings were correlated with the results of neurological evaluations and magnetic resonance imaging studies. Specific binding was significantly reduced in the putamen of all patient groups in the order MSA-P < MSA-C < sOPCA, compared with controls. Mean blood-to-brain ligand transport (K1) was significantly decreased in the putamen of all patient groups and in the cerebellar hemispheres of MSA-C and sOPCA but not MSA-P groups, compared with controls. Significant negative correlations were found between striatal binding and the intensity of parkinsonian features and between cerebellar K1 and the intensity of cerebellar dysfunction. The results suggest fundamental differences between MSA-P and MSA-C groups reflecting differential severity of degeneration of nigrostriatal and cerebellar systems in these two forms of MSA. The findings also show that some sOPCA patients have subclinical nigrostriatal dysfunction and are at risk of developing MSA with disease progression.

Chapter 19 - Etiology, Pathology, and Pathogenesis

Introduction: This study aimed to use a novel MRI contrast, the standardized T1-weighted/T2-weighted (sT1w/T2w) ratio, to assess damage of the white matter and gray matter in multiple system atrophy (MSA). Furthermore, this study investigated whether the sT1w/T2w ratio was associated with cognitive impairment in MSA. Methods: The white matter and gray matter sT1w/T2w ratio of 37 MSA patients and 19 healthy controls were measured. Correlation analyses were used to evaluate the relationship between sT1w/T2w ratio values and clinical variables, and a multivariate analysis was used to identify independent factors associated with cognitive impairment in MSA. Results: MSA patients showed a higher white matter sT1w/T2w ratio value than controls (p < 0.001), and the white matter sT1w/T2w ratio value was significantly correlated with the International Cooperative Ataxia Rating Scale score (r = 0.377, p = 0.021) and the Addenbrooke’s cognitive examination III score (r = −0.438, p = 0.007). Cognitively impaired MSA patients had a significantly higher white matter sT1w/T2w ratio value than cognitively preserved MSA patients (p = 0.010), and the multiple logistic regression analysis revealed that the median white matter sT1w/T2w ratio value was independently associated with cognitive impairment in MSA. Conclusion: The sT1w/T2w ratio is sensitive to degenerative changes in the white matter that is associated with cognitive ability in MSA patients.