Recent Advances in Clinical Trials in Multiple System Atrophy.

PURPOSE OF REVIEW: This review summarizes previous and ongoing neuroprotection trials in multiple system atrophy (MSA), a rare and fatal neurodegenerative disease characterized by parkinsonism, cerebellar, and autonomic dysfunction. It also describes the preclinical therapeutic pipeline and provides some considerations relevant to successfully conducting clinical trials in MSA, i.e., diagnosis, endpoints, and trial design. RECENT FINDINGS: Over 30 compounds have been tested in clinical trials in MSA. While this illustrates a strong treatment pipeline, only two have reached their primary endpoint. Ongoing clinical trials primarily focus on targeting α-synuclein, the neuropathological hallmark of MSA being α-synuclein-bearing glial cytoplasmic inclusions. The mostly negative trial outcomes highlight the importance of better understanding underlying disease mechanisms and improving preclinical models. Together with efforts to refine clinical measurement tools, innovative statistical methods, and developments in biomarker research, this will enhance the design of future neuroprotection trials in MSA and the likelihood of positive outcomes.

EFAS/EAN survey on the influence of the COVID-19 pandemic on European clinical autonomic education and research.

PURPOSE: To understand the influence of the coronavirus disease 2019 (COVID-19) pandemic on clinical autonomic education and research in Europe. METHODS: We invited 84 European autonomic centers to complete an online survey, recorded the pre-pandemic-to-pandemic percentage of junior participants in the annual congresses of the European Federation of Autonomic Societies (EFAS) and European Academy of Neurology (EAN) and the pre-pandemic-to-pandemic number of PubMed publications on neurological disorders. RESULTS: Forty-six centers answered the survey (55%). Twenty-nine centers were involved in clinical autonomic education and experienced pandemic-related didactic interruptions for 9 (5; 9) months. Ninety percent (n = 26/29) of autonomic educational centers reported a negative impact of the COVID-19 pandemic on education quality, and 93% (n = 27/29) established e-learning models. Both the 2020 joint EAN-EFAS virtual congress and the 2021 (virtual) and 2022 (hybrid) EFAS and EAN congresses marked higher percentages of junior participants than in 2019. Forty-one respondents (89%) were autonomic researchers, and 29 of them reported pandemic-related trial interruptions for 5 (2; 9) months. Since the pandemic begin, almost half of the respondents had less time for scientific writing. Likewise, the number of PubMed publications on autonomic topics showed the smallest increase compared with other neurological fields in 2020-2021 and the highest drop in 2022. Autonomic research centers that amended their trial protocols for telemedicine (38%, n = 16/41) maintained higher clinical caseloads during the first pandemic year. CONCLUSIONS: The COVID-19 pandemic had a substantial negative impact on European clinical autonomic education and research. At the same time, it promoted digitalization, favoring more equitable access to autonomic education and improved trial design.

Sedentary behavior and the biological hallmarks of aging.

While the benefits of physical exercise for a healthy aging are well-recognized, a growing body of evidence shows that sedentary behavior has deleterious health effects independently, to some extent, of physical activity levels. Yet, the increasing prevalence of sedentariness constitutes a major public health issue that contributes to premature aging but the potential cellular mechanisms through which prolonged immobilization may accelerate biological aging remain unestablished. This narrative review summarizes the impact of sedentary behavior using different models of extreme sedentary behaviors including bedrest, unilateral limb suspension and space travel studies, on the hallmarks of aging such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. We further highlight the remaining knowledge gaps that need more research in order to promote healthspan extension and to provide future contributions to the field of geroscience.

Neurofilament light levels predict clinical progression and death in multiple system atrophy.

Disease-modifying treatments are currently being trialled in multiple system atrophy. Approaches based solely on clinical measures are challenged by heterogeneity of phenotype and pathogenic complexity. Neurofilament light chain protein has been explored as a reliable biomarker in several neurodegenerative disorders but data on multiple system atrophy have been limited. Therefore, neurofilament light chain is not yet routinely used as an outcome measure in multiple system atrophy. We aimed to comprehensively investigate the role and dynamics of neurofilament light chain in multiple system atrophy combined with cross-sectional and longitudinal clinical and imaging scales and for subject trial selection. In this cohort study, we recruited cross-sectional and longitudinal cases in a multicentre European set-up. Plasma and CSF neurofilament light chain concentrations were measured at baseline from 212 multiple system atrophy cases, annually for a mean period of 2 years in 44 multiple system atrophy patients in conjunction with clinical, neuropsychological and MRI brain assessments. Baseline neurofilament light chain characteristics were compared between groups. Cox regression was used to assess survival; receiver operating characteristic analysis to assess the ability of neurofilament light chain to distinguish between multiple system atrophy patients and healthy controls. Multivariate linear mixed-effects models were used to analyse longitudinal neurofilament light chain changes and correlated with clinical and imaging parameters. Polynomial models were used to determine the differential trajectories of neurofilament light chain in multiple system atrophy. We estimated sample sizes for trials aiming to decrease neurofilament light chain levels. We show that in multiple system atrophy, baseline plasma neurofilament light chain levels were better predictors of clinical progression, survival and degree of brain atrophy than the neurofilament light chain rate of change. Comparative analysis of multiple system atrophy progression over the course of disease, using plasma neurofilament light chain and clinical rating scales, indicated that neurofilament light chain levels rise as the motor symptoms progress, followed by deceleration in advanced stages. Sample size prediction suggested that significantly lower trial participant numbers would be needed to demonstrate treatment effects when incorporating plasma neurofilament light chain values into multiple system atrophy clinical trials in comparison to clinical measures alone. In conclusion, neurofilament light chain correlates with clinical disease severity, progression and prognosis in multiple system atrophy. Combined with clinical and imaging analysis, neurofilament light chain can inform patient stratification and serve as a reliable biomarker of treatment response in future multiple system atrophy trials of putative disease-modifying agents.

WISE-2005: effect of aerobic and resistive exercises on orthostatic tolerance during 60 days bed rest in women.

Cardiovascular deconditioning after long duration spaceflight is especially challenging in women who have a lower orthostatic tolerance (OT) compared with men. We hypothesized that an exercise prescription, combining supine aerobic treadmill exercise in a lower body negative pressure (LBNP) chamber followed by 10 min of resting LBNP, three to four times a week, and flywheel resistive training every third day would maintain orthostatic tolerance (OT) in women during a 60-day head-down-tilt bed rest (HDBR). Sixteen women were assigned to two groups (exercise, control). Pre and post HDBR OT was assessed with a tilt/LBNP test until presyncope. OT time (mean +/- SE) decreased from 17.5 +/- 1.0 min to 9.1 +/- 1.5 min (-50 +/- 6%) in control group (P < 0.001) and from 19.3 +/- 1.3 min to 13.0 +/- 1.9 min (-35 +/- 7%) in exercise group (P < 0.001), with no significant difference in OT time between the two groups after HDBR (P = 0.13). Nevertheless, compared with controls post HDBR, exercisers had a lower heart rate during supine rest (mean +/- SE, 71 +/- 3 vs. 85 +/- 4, P < 0.01), a slower increase in heart rate and a slower decrease in stroke volume over the course of tilt/LBNP test (P < 0.05). Blood volume (mean +/- SE) decreased in controls (-9 +/- 2%, P < 0.01) but was maintained in exercisers (-4 +/- 3%, P = 0.17).Our results suggest that the combined exercise countermeasure did not significantly improve OT but protected blood volume and cardiovascular response to sub tolerance levels of orthostatic stress.

Influence of simulated weightlessness on the intramuscular and oral pharmacokinetics of promethazine in 12 human volunteers.

The National Aeronautics and Space Administration (NASA) recommends using promethazine to prevent and treat space motion sickness, but pharmacologic responses in space and on Earth are different. Twelve volunteers were given 50 mg promethazine orally or intramuscularly before and after 48 hours of bed rest to simulate weightlessness. The maximum measured plasma concentration (C(max)), time to C(max) (t(max)), and area under plasma concentration versus time curve from 0 to infinity (AUC(inf)) were determined, and the bioequivalence was tested between bed-rest and ambulatory status for the intramuscular and oral routes as well as between both routes for bed-rest and ambulatory position. Simulated weightlessness did not influence the ratio AUC(bed rest)/AUC(ambulatory) after intramuscular injection, whereas a significant increase (26%) in the ratio was seen after oral administration, probably because of a prolonged contact time between promethazine and the intestinal wall associated with an increase in the intestinal transit time. The AUC was 3-fold higher when the drug was administered by the intramuscular route during both positions. Thus, intramuscular administration could be a good alternative to the oral route.

Influence of simulated weightlessness on the oral pharmacokinetics of acetaminophen as a gastric emptying probe in man: a plasma and a saliva study.

This study evaluated the effect of simulated weightlessness on gastric emptying, using acetaminophen as a probe and -6 degrees head-down bed rest to simulate zero gravity. Eighteen volunteers were given 1 g of acetaminophen orally before the bed rest and at days 1, 18, and 80. Cmax, tmax, AUC0- infinity, AUC0-t, and t1/2 were calculated for plasma and saliva. The plasma Cmax showed a significant increase (10.43 microg/mL [day 1] to 14.74 microg/mL [day 80]), while tmax significantly decreased (1.41 h [day 1] to 0.91 h [day 80]). Similar results were obtained with saliva, and there were significant increases in the AUCs. The good correlation between the plasma and saliva data suggests that saliva sampling can be valid for acetaminophen pharmacokinetics. The changes in Cmax and tmax indicated more rapid drug absorption, which could have been as a result of faster gastric emptying or an increased blood flow to the intestine.

Changes in intraocular pressure during prolonged (7-day) head-down tilt bedrest.

PURPOSE: To determine the change in intraocular pressure (IOP) due to postural changes in young healthy volunteers. MATERIALS AND METHODS: Intraocular pressure was measured using a calibrated Pulsair noncontact tonometer in both eyes of 25 female volunteers in a sitting position and after 1, 3, and 10 minutes in a supine position. In the second part of the experiment (a 7-day -6 degrees head-down tilt [HDT]), IOP (at 8 am, 12 am and 6 pm) and corneal thickness (12 am) were monitored in 8 female volunteers before, during, and after the HDT period. Blood pressure, hematocrit, plasma volume and osmolality, and plasma catecholamines concentrations were also measured. RESULTS: Intraocular pressure was significantly higher in the supine position (16.1 +/- 3.6 mm Hg) than in the sitting position, with a mean pressure difference of 2.23 +/- 2.9 mm Hg after 1 minute, 0.9 +/- 3 mm Hg after 3 minutes, and 1.9 +/- 3.8 mm Hg after 10 minutes in a supine position (P < 0.001). During the period of HDT, IOP values decreased significantly on the fifth day (13.3 +/- 1.6 mm Hg, P = 0.03) and the seventh day (12.7 +/- 1.7 mm Hg, P = 0.02) when compared with IOP in the supine position (14.26 +/- 2 mm Hg). The corneal thickness increased significantly (P < 0.0001) at day 5 (549.25 +/- 48.7 microm) and day 7 (540.31 +/- 46.9 microm) compared with baseline (532.45 +/- 38.6 microm). Two days after the end of the HDT bedrest, the mean supine IOP significantly increased (14.1 +/- 1.8 mm Hg, P = 0.003) and corneal thickness was similar to that found at baseline. The mean decrease of IOP was positively correlated with that of the plasma volume (-10%, r = 0.61, P = 0.02) and negatively correlated with the mean rise of hematocrit (r = -0.5, P = 0.07), variables that are considered to be indirect measures of plasma dehydration. CONCLUSIONS: During a 7-day HDT bedrest experiment in healthy women, eyes seemed to compensate the moderate rise of IOP described between a sitting and a supine position, and exhibited a slight and progressive average decrease of 1.3 mm Hg. These physiological modifications could be related to an ocular dehydration or to systemic cardiovascular and hormonal variations during bedrest.

High rate of recanalization of middle cerebral artery occlusion during 2-MHz transcranial color-coded Doppler continuous monitoring without thrombolytic drug.

BACKGROUND AND PURPOSE: Experimental evidence indicates that ultrasound can accelerate thrombolysis. We report our findings on early recanalization during transcranial color-coded Doppler (TCCD) continuous monitoring in acute stroke patients with middle cerebral artery (MCA) main stem occlusion. METHODS: We performed continuous TCCD monitorings in 6 consecutive patients with acute MCA main stem occlusion using a 2-MHz transducer. Patients were not treated with recombinant tissue plasminogen activator. RESULTS: Partial recanalization, defined as blunted waveforms, occurred during monitoring in 5 patients (83%). The mean time to beginning of recanalization was 17.2+/-9.6 minutes. Complete recanalization at 24 hours occurred in only 1 patient. The mean National Institutes of Health Stroke Scale score in the patients who recanalized during monitoring was 21.2+/-4.1 at baseline, 19.2+/-5 at 2 hours, and 15.6+/-3.4 at 24 hours (P=0.1). CONCLUSIONS: In this short series of patients with acute MCA main stem occlusion, not treated with recombinant tissue plasminogen activator, we found a high rate of early partial recanalization during continuous exposure to 2-MHz ultrasound.