Impacts of Microgravity Analogs to Spaceflight on Cerebral Autoregulation.

It is well known that exposure to microgravity in astronauts leads to a plethora physiological responses such as headward fluid shift, body unloading, and cardiovascular deconditioning. When astronauts return to Earth, some encounter problems related to orthostatic intolerance. An impaired cerebral autoregulation (CA), which could be compromised by the effects of microgravity, has been proposed as one of the mechanisms responsible for orthostatic intolerance. CA is a homeostatic mechanism that maintains cerebral blood flow for any variations in cerebral perfusion pressure by adapting the vascular tone and cerebral vessel diameter. The ground-based models of microgravity are useful tools for determining the gravitational impact of spaceflight on human body. The head-down tilt bed rest (HDTBR), where the subject remains in supine position at -6 degrees for periods ranging from few days to several weeks is the most commonly used ground-based model of microgravity for cardiovascular deconditioning. head-down bed rest (HDBR) is able to replicate cephalic fluid shift, immobilization, confinement, and inactivity. Dry immersion (DI) model is another approach where the subject remains immersed in thermoneutral water covered with an elastic waterproof fabric separating the subject from the water. Regarding DI, this analog imitates absence of any supporting structure for the body, centralization of body fluids, immobilization and hypokinesia observed during spaceflight. However, little is known about the impact of microgravity on CA. Here, we review the fundamental principles and the different mechanisms involved in CA. We also consider the different approaches in order to assess CA. Finally, we focus on the effects of short- and long-term spaceflight on CA and compare these findings with two specific analogs to microgravity: HDBR and DI

Patient-perceived progression in multiple system atrophy: natural history of quality of life

Health-related quality of life (Hr-QoL) scales provide crucial information on neurodegenerative disease progression, help improving patient care, and constitute a meaningful endpoint for therapeutic research. However, Hr-QoL progression is usually poorly documented, as for multiple system atrophy (MSA), a rare and rapidly progressing alpha-synucleinopathy. This work aimed to describe Hr-QoL progression during the natural course of MSA, explore disparities between patients, and identify informative items using a four-step statistical strategy.We leveraged the data of the French MSA cohort comprising annual assessments with the MSA-QoL questionnaire for more than 500 patients over up to 11 years. The four-step strategy (1) determined the subdimensions of Hr-QoL in MSA; (2) modelled the subdimension trajectories over time, accounting for the risk of death; (3) mapped the sequence of item impairments with disease stages; and (4) identified the most informative items specific to each disease stage.Among the 536 patients included, 50% were women and they were aged on average 65.1 years old at entry. Among them, 63.1% died during the follow-up. Four dimensions were identified. In addition to the original motor, nonmotor, and emotional domains, an oropharyngeal component was highlighted. While the motor and oropharyngeal domains deteriorated rapidly, the nonmotor and emotional aspects were already slightly to moderately impaired at cohort entry and deteriorated slowly over the course of the disease. Impairments were associated with sex, diagnosis subtype, and delay since symptom onset. Except for the emotional domain, each dimension was driven by key identified items.Hr-QoL is a multidimensional concept that deteriorates progressively over the course of MSA and brings essential knowledge for improving patient care. As exemplified with MSA, the thorough description of Hr-QoL using the 4-step original analysis can provide new perspectives on neurodegenerative diseases' management to ultimately deliver better support focused on the patient's perspective

Baroreflex Impairment After Subarachnoid Hemorrhage Is Associated With Unfavorable Outcome.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (SAH) is characterized by important changes in the autonomic nervous system with potentially adverse consequences. The baroreflex has a key role in regulating the autonomic nervous system. Its role in SAH outcome is not known. The purpose of this study was to evaluate the association between the baroreflex and the functional 3-month outcome in SAH. METHODS: The study used a prospective database of 101 patients hospitalized for SAH. We excluded patients receiving β-blockers or noradrenaline. Baroreflex sensitivity (BRS) was measured using the cross-correlation method. A good outcome was defined by a Glasgow Outcome Scale score at 4 or 5 at 3 months. RESULTS: Forty-eight patients were included. Median age was 58 years old (36-76 years); women/men: 34/14. The World Federation of Neurosurgery clinical severity score on admission was 1 or 2 for 73% of patients. In the univariate analysis, BRS (P=0.007), sedation (P=0.001), World Federation of Neurosurgery score (P=0.001), Glasgow score (P=0.002), Fisher score (P=0.022), and heart rate (P=0.037) were associated with outcome. The area under the receiver operating characteristic curve for the model with BRS as a single predictor was estimated at 0.835. For each unit increase in BRS, the odds for a good outcome were predicted to increase by 31%. Area under the receiver operating characteristic curve for heart rate alone was 0.670. In the multivariate analysis, BRS (odds ratio, 1.312; 95% confidence interval, 1.048-1.818; P=0.018) and World Federation of Neurosurgery (odds ratio, 0.382; 95% confidence interval, 0.171-0.706; P=0.001) were significantly associated with outcome. Area under the receiver operating characteristic curve was estimated at 0.900. CONCLUSIONS: In SAH, early BRS was associated with 3-month outcome. This conclusion requires confirmation on a larger number of patients in a multicentre study

Alterations in electrochemical skin conductance as a marker of autonomic dysfunction in multiple system atrophy

BACKGROUND: Multiple System Atrophy (MSA) is a rare neurodegenerative disease with pronounced autonomic failure (AF). Severe cardiovascular AF is associated with poor prognosis. Since sweating dysfunction is less well known, we investigated the interest of a quick and non-invasive assessment of sweating using electrochemical skin conductance (ESC) as a marker for AF in MSA. METHODS: 138 MSA patients of the French Reference center for MSA with an annual follow-up including the Unified MSA Rating Scale (UMSARS), COMPASS (autonomic symptoms) and measurements of foot and hand ESC (Sudoscan®) participated to this study (age 65 ± 8 years, 66% probable MSA, 72% AMS-P). Statistical analysis included: (i) correlations between ESC and MSA type, age, disease duration, severity, blood pressure (BP), COMPASS, (ii) comparisons between groups with normal or abnormal ESC, and (iii) multivariate analysis by logistic regression. Relationships between severity progression during follow-up with ESC and other variables were modeled by Generalized Estimating Equation. RESULTS: Hands and feet ESCs were abnormal in 81/138 (59%) and 93/138 (67%) cases, respectively. Abnormal ESCs were significantly correlated to disease severity and several features of AF. ESCs worsening over time was more pronounced than other autonomic features such as orthostatic hypotension. Abnormal ESCs at baseline were significantly associated with a higher progression of UMSARS's score during follow-up. CONCLUSION: Sweating dysfunction assessed by ESC is frequent in MSA and is significantly related to disease severity and AF. The gradual decrease in ESC with disease duration could be useful as a quantitative marker of autonomic dysfunction

A comparative study on vowel articulation in Parkinson's disease and multiple system atrophy

International audienceAcoustic realisation of the working vowel space has been widely studied in Parkinson's disease (PD). However, it has never been studied in atypical parkinsonian disorders (APD). The latter are neurodegenerative diseases which share similar clinical features with PD, rendering the differential diagnosis very challenging in early disease stages. This paper presents the first contribution in vowel space analysis in APD, by comparing corner vowel realisation in PD and the parkinsonian variant of Multiple System Atrophy (MSA-P). Our study has the particularity of focusing exclusively on early stage PD and MSA-P patients, as our main purpose was early differential diagnosis between these two diseases. We analysed the corner vowels, extracted from a spoken sentence, using traditional vowel space metrics. We found no statistical difference between the PD group and healthy controls (HC) while MSA-P exhibited significant differences with the PD and HC groups. We also found that some metrics conveyed complementary discriminative information. Consequently, we argue that restriction in the acoustic realisation of corner vowels cannot be a viable early marker of PD, as hypothesised by some studies, but it might be a candidate as an early hypokinetic marker of MSA-P (when the clinical target is discrimination between PD and MSA-P)

New insights into orthostatic hypotension in multiple system atrophy: a European multicentre cohort study

Objectives: Orthostatic hypotension (OH) is a key feature of multiple system atrophy (MSA), a fatal progressive neurodegenerative disorder associated with autonomic failure, parkinsonism and ataxia. This study aims (1) to determine the clinical spectrum of OH in a large European cohort of patients with MSA and (2) to investigate whether a prolonged postural challenge increases the sensitivity to detect OH in MSA. Methods: Assessment of OH during a 10 min orthostatic test in 349 patients with MSA from seven centres of the European MSA-Study Group (age: 63.6±8.8 years; disease duration: 4.2±2.6 years). Assessment of a possible relationship between OH and MSA subtype (P with predominant parkinsonism or C with predominant cerebellar ataxia), Unified MSA Rating Scale (UMSARS) scores and drug intake. Results: 187 patients (54%) had moderate (>20 mm Hg (systolic blood pressure (SBP)) and/or >10 mm Hg (diastolic blood pressure (DBP)) or severe OH (>30 mm Hg (SBP) and/or >15 mm Hg (DBP)) within 3 min and 250 patients (72%) within 10 min. OH magnitude was significantly associated with disease severity (UMSARS I, II and IV), orthostatic symptoms (UMSARS I) and supine hypertension. OH severity was not associated with MSA subtype. Drug intake did not differ according to OH magnitude except for antihypertensive drugs being less frequently, and antihypotensive drugs more frequently, prescribed in severe OH. Conclusions: This is the largest study of OH in patients with MSA. Our data suggest that the sensitivity to pick up OH increases substantially by a prolonged 10 min orthostatic challenge. These results will help to improve OH management and the design of future clinical trials.Fil: Pavy Le Traon, Anne. University Hospital of Toulouse; Francia. Inserm; FranciaFil: Piedvache, A.. Université Paul Sabatier; FranciaFil: Pérez Lloret, Santiago. University Hospital of Toulouse; Francia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Calandra Buonara, G.. Università di Bologna; Italia. Istituto delle Scienze Neurologiche di Bologna; ItaliaFil: Cochen De Cock, V.. University Hospital of Toulouse; Francia. University of Montpellier; FranciaFil: Colosimo, C.. Sapienza Università di Roma; ItaliaFil: Cortelli, P.. Università di Bologna; Italia. Istituto delle Scienze Neurologiche di Bologna; ItaliaFil: Debs, R.. University Hospital of Toulouse; FranciaFil: Duerr, S.. Universidad de Innsbruck; AustriaFil: Fanciulli, A.. Universidad de Innsbruck; AustriaFil: Foubert Samier, A.. Centre Hospitalier Universitaire de Bordeaux; Francia. Universite de Bordeaux; FranciaFil: Gerdelat, Angela. University Hospital of Toulouse; FranciaFil: Gurevich, T.. Tel-Aviv University; IsraelFil: Krismer, F.. Universidad de Innsbruck; AustriaFil: Poewe, W.. Universidad de Innsbruck; AustriaFil: Tison, Francois. Universite de Bordeaux; Francia. Centre Hospitalier Universitaire de Bordeaux; FranciaFil: Tranchant, C.. University Hospital Hautepierre; FranciaFil: Wenning, G.. Universidad de Innsbruck; AustriaFil: Meissner, Wassilios G.. Universite de Bordeaux; Francia. Centre Hospitalier Universitaire de Bordeaux; FranciaFil: Rascol, Olivier. University Hospital of Toulouse; Franci

Haemodynamic changes during a squat test, pulsatile stress and indices of cardiovascular autonomic neuropathy in patients with long-duration type 1 diabetes.

AIM: Cardiovascular autonomic neuropathy (CAN) and pulsatile stress are considered to be independent cardiovascular risk factors. This study compared haemodynamic changes during an active orthostatic test in adult patients with type 1 diabetes (T1DM), using low versus high RR E/I ratios as a marker of CAN. METHODS: A total of 20 T1DM patients with low RR E/I ratios were compared with 20 T1DM patients with normal RR E/I ratios, matched for gender (1/1 ratio), age (mean: 46years) and diabetes duration (22-26years); 40 matched healthy subjects served as controls. All subjects were evaluated by continuous monitoring of arterial blood pressure (Finapres((R))) and heart rate using a standardized posture test (1-min standing, 1-min squatting, 1-min standing), thus allowing calculation of baroreflex gain. RESULTS: Compared with controls, T1DM patients showed lower RR E/I ratios, reduced baroreflex gains, higher pulsatile stress (pulse pressurexheart rate), greater squatting-induced pulse pressure rises, orthostatic hypotension and reduced reflex tachycardia. Compared with T1DM patients with preserved RR E/I ratios, T1DM patients with low RR E/I ratios showed reduced post-standing reflex tachycardia and baroreflex gain, and delayed blood pressure recovery, but no markers of increased pulsatile stress. Interestingly, decreased baroreflex gain was significantly associated with both pulsatile stress and microalbuminuria. CONCLUSION: The use of RR E/I ratios to separate T1DM patients allows the detection of other CAN markers during an orthostatic posture test, but with no significant differences in pulsatile stress or microalbuminuria. In this context, squatting-derived baroreflex gain appears to be more informative.Peer reviewe

Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies

Several studies have confirmed α-synuclein real-time quaking-induced conversion (αSyn-RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF aSyn-RT-QuIC quantitative parameters in regard to disease progression, stratification, and conversion in synucleinopathies. We performed αSyn-RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. αSyn-RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. UPDRS motor) but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in UMSARS). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that αSyn-RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. The quantitative parameters however did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for αSyn-RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between αSyn-RT-QuIC signature and the progression from prodromal to different synucleinopathies

Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies

Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies. We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. Unified Parkinson's Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies