Trial of Prasinezumab in Early-Stage Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease. METHODS: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS: A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS: Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).

Effects of Dehydration on Brain Functioning: A Life-Span Perspective.

BACKGROUND: In the last 10 years, there has been an increase in the publication of literature dealing with the effects of mild dehydration on cognition in healthy adults. Fewer studies, leading to less consistent data, involved other age groups. SUMMARY: In healthy young adults refraining from drinking or participating in dehydration protocols, it was found that mild dehydration had no impact on performance, whereas the mood was widely impaired. Several studies have also been conducted in young children either as observational studies or as interventional studies. Nevertheless, methodological differences in (de)hydration monitoring, in cognitive assessments, and in the age/brain maturation of study participants, often resulted in contradictory findings regarding the cognitive functions impacted by (de)hydration. Although not consistent, these data showed that not only mood but also performance tend to be impaired by dehydration in children. Even if older adults are likely to be more vulnerable to dehydration than younger adults, very few studies have been conducted in this regard in this population. The results show that, like it is in children, cognition tends to be impaired when the elderly are dehydrated. Taken together, these studies suggest that dehydration has greater detrimental effects in vulnerable populations. Recent imaging data suggest that the brain of children and elderly adults may have fewer resources to manage the effects of dehydration. Consequently, cognitive tasks may be more demanding for younger and older brains and performance more likely to be impaired in these populations, in comparison to young healthy subjects who have greater and more efficient resources.

Pharmacodynamic interactions of a solid formulation of sodium oxybate and ethanol in healthy volunteers.

AIM: The pharmacologic effects of sodium oxybate (SO) have a number of similarities with those of alcohol. This study evaluated the pharmacodynamic interaction of SMO.IR (a solid immediate release formulation of SO) and alcohol (0.7 (males) or 0.57 (females) g kg(-1) alcohol using 40% vodka). METHODS: In a randomized, double-blind, double-dummy, crossover trial, 24 healthy volunteers received randomly a) 2.25 g SMO.IR and placebo alcohol preparation, b) 2.25 g f SMO.IR and alcohol, c) 2.25 g SMO.IR matching placebo and alcohol and d) 2.25 g of SMO.IR matching placebo and placebo alcohol preparation. Objective and subjective cognitive parameters, adverse events and vital signs were assessed before, 15 and 165 min after treatment administration. RESULTS: Alcohol produced the expected cognitive impairment and the expected subjective sedation rapidly after intake (from 15 min). The objective effects of SMO.IR were much less pronounced than those of alcohol. The reverse was observed for subjective complaints, which were related to lesser stimulation and greater sedation. Nevertheless, 165 min after administration this sedation feeling was less with SMO.IR than with alcohol. There was a significant interaction between SMO.IR and alcohol at 15 min (i.e. increase in alertness and stimulation and decrease in sedation). In addition, an isolated mild decrease in digit vigilance accuracy occurred at 165 min post-dose after the combination. The co-administration of SMO.IR and alcohol was safe and well-tolerated. CONCLUSION: SMO.IR and alcohol have distinct adverse effect profiles. The objective effects of SMO.IR are much less marked than those of alcohol. No deleterious interaction was observed.

Influence of progressive fluid restriction on mood and physiological markers of dehydration in women.

The present study evaluated, using a well-controlled dehydration protocol, the effects of 24 h fluid deprivation (FD) on selected mood and physiological parameters. In the present cross-over study, twenty healthy women (age 25 (SE 0.78) years) participated in two randomised sessions: FD-induced dehydration v. a fully hydrated control condition. In the FD period, the last water intake was between 18.00 and 19.00 hours and no beverages were allowed until 18.00 hours on the next day (23-24 h). Water intake was only permitted at fixed periods during the control condition. Physiological parameters in the urine, blood and saliva (osmolality) as well as mood and sensations (headache and thirst) were compared across the experimental conditions. Safety was monitored throughout the study. The FD protocol was effective as indicated by a significant reduction in urine output. No clinical abnormalities of biological parameters or vital signs were observed, although heart rate was increased by FD. Increased urine specific gravity, darker urine colour and increased thirst were early markers of dehydration. Interestingly, dehydration also induced a significant increase in saliva osmolality at the end of the 24 h FD period but plasma osmolality remained unchanged. The significant effects of FD on mood included decreased alertness and increased sleepiness, fatigue and confusion. The most consistent effects of mild dehydration on mood are on sleep/wake parameters. Urine specific gravity appears to be the best physiological measure of hydration status in subjects with a normal level of activity; saliva osmolality is another reliable and non-invasive method for assessing hydration status.

Circadian variation and responsiveness of hydration biomarkers to changes in daily water intake.

Biomarkers of hydration change in response to acute dehydration; however, their responsiveness to changes in fluid intake volume, without exercise or heat exposure, has not been adequately described. Moreover, patterns of circadian variation in hydration biomarkers have not been established. The study aims were to (1) assess the response of hydration biomarkers to changes in daily water intake; and (2) evaluate circadian variation in urinary and salivary biomarkers. Fifty-two adults (24.8 ± 3.1 years; 22.3 ± 1.6 kg/m(2); 79 % female), grouped based on habitual fluid intake (low drinkers, n = 30, <1.2 L/day; high drinkers, n = 22, >2.0 L/day), completed a 5-day inpatient crossover trial. On days 1 and 2, low drinkers received 1.0 L/day of water while high drinkers received 2.5 L/day. On days 3 through 5, intake was reversed between groups. Plasma and saliva osmolality were assessed daily at predetermined times, and all urine produced over 24 h was collected in timed intervals. ANOVA with intake (1.0 vs. 2.5 L/day), day, and time revealed that (1) urine concentration (osmolality, specific gravity, color) and volume, but not plasma nor saliva osmolality, responded to changes in water intake; (2) urinary hydration biomarkers and saliva osmolality vary as a function of the time of day; and (3) urine osmolality measured in samples collected during the afternoon most closely reflects the corresponding 24 h value. Overall, urinary hydration biomarkers are responsive to changes in water intake, and stabilize within 24 h of modifying intake volume. Moreover, short afternoon urine collections may be able to replace 24 h collections for more convenience in hydration assessment.

Effects of changes in water intake on mood of high and low drinkers.

OBJECTIVE: To evaluate the effects of a change in water intake on mood and sensation in 22 habitual high-volume (HIGH; 2-4 L/d) and 30 low-volume (LOW; <1.2 L/d) drinkers who were asked to respectively decrease and increase their daily water intake. METHOD: During baseline HIGH consumed 2.5 L and LOW 1 L of water/day. During 3 controlled intervention days HIGH's water intake was restricted to 1 L/day whereas LOW's was increased to 2.5 L water/day. Several mood scales (Bond & Lader Visual Analog Scale (VAS), Profile of Mood States, Karolinska Sleepiness Scale, Thirst & Emotional VAS) were administered at different time points during the study. ANOVA including intervention, time point and intervention by time point as fixed effects on mean values (i.e.; baseline data vs. mean of 3 intervention days) for each mood scale was performed. RESULTS: At baseline HIGH and LOW were comparable in mood state, except for thirst scores (estimate = 17.16, p<0.001) and POMS depression-dejection scores (estimate = 0.55, p<0.05) which were both higher in the HIGH vs. LOW. In HIGH the restricted water intake resulted in a significant increase in thirst (p<0.001) and a decrease in contentedness (p<0.05), calmness (p<0.01), positive emotions (p<0.05) and vigor/activity (p<0.001). In LOW, increased water consumption resulted in a significant decrease in fatigue/inertia (p<0.001), confusion/bewilderment (p = 0.05) and thirst (p<0.001) and a trend to lower sleepiness (p = 0.07) compared to baseline. CONCLUSION: Increasing water intake has beneficial effects in LOW, especially sleep/wake feelings, whereas decreasing water intake has detrimental effects on HIGH's mood. These deleterious effects in HIGH were observed in some sleep/wake moods as well as calmness, satisfaction and positive emotions.