AimsDysfunction of nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate signalling is implicated in the pathophysiology of cognitive impairment. Zagociguat is a central... Show moreAimsDysfunction of nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate signalling is implicated in the pathophysiology of cognitive impairment. Zagociguat is a central nervous system (CNS) penetrant sGC stimulator designed to amplify nitric oxide-cyclic guanosine monophosphate signalling in the CNS. This article describes a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. MethodsIn this randomized crossover study, 24 healthy participants aged & GE;65 years were planned to receive 15 mg zagociguat or placebo once daily for 2 15-day periods separated by a 27-day washout. Adverse events, vital signs, electrocardiograms and laboratory tests were conducted to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and cerebrospinal fluid (CSF). Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco-electroencephalography, passive leg movement and biomarkers in blood, CSF and brain. ResultsTwenty-four participants were enrolled; 12 participants completed both treatment periods, while the other 12 participants completed only 1 treatment period. Zagociguat was well-tolerated and penetrated the blood-brain barrier, with a CSF/free plasma concentration ratio of 0.45 (standard deviation 0.092) measured 5 h after the last dose of zagociguat on Day 15. Zagociguat induced modest decreases in blood pressure. No consistent effects of zagociguat on other pharmacodynamic parameters were detected. ConclusionZagociguat was well-tolerated and induced modest blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound. Show less
Blaauw, J.; Boxum, A.G.; Jacobs, B.; Groen, R.J.M.; Peul, W.C.; Jellema, K.; ... ; Naalt, J. van der 2020
Chronic subdural hematoma (CSDH) is a frequently occurring neurological disease associated with older age and use of anticoagulants. Symptoms vary from headaches to coma, but cognitive deficits can... Show moreChronic subdural hematoma (CSDH) is a frequently occurring neurological disease associated with older age and use of anticoagulants. Symptoms vary from headaches to coma, but cognitive deficits can also be present. However, exact prevalence and severity of cognitive deficits in CSDH are still unknown. In this systematic review, we aim to assess cognitive status of patients with CSDH, at presentation and after treatment. PubMed, Embase and PsycInfo were searched for articles concerning cognition in CSDH. We divided cognitive changes into subjective cognitive deficit (cognitive complaints [CC]) and objective cognitive deficit (cognitive impairment [CI]). Two reviewers independently selected studies for inclusion and subsequently extracted data. Quality assessment was done by means of the Newcastle-Ottawa Scale. Reported prevalence of CC and CI was pooled with random effects meta-analysis. Out of 799 identified references, 22 met inclusion criteria. Twenty-one articles reported on prevalence of CC/CI and one study reported solely on CSDH patients with cognitive deficit. Estimated pooled prevalence of both CC and CI in CSDH at presentation was 45% (95% confidence interval [CI]: 36-54%). Four studies concerned a prospective evaluation of the effect of surgical treatment on cognition. These proved to be of fair to good quality after quality assessment. The estimated pre-treatment prevalence of objectified cognitive impairment was 61% (95% CI: 51-70%) decreasing to 18% (95% CI: 8-32%) post-surgery. From this review it can be concluded that CC and CI are very common in CSDH, with a tendency to improve after treatment. Therefore, we underline the importance of increased attention to cognitive status of these patients, with proper testing methods and treatment-testing intervals. Show less
Iwaki, H.; Blauwendraat, C.; Leonard, H.L.; Makarious, M.B.; Kim, J.J.; Liu, G.Q.; ... ; Nalls, M.A. 2020
Background Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. Objectives We examined sex associations... Show moreBackground Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. Objectives We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. Methods We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. Results Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. Conclusions We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. (c) 2020 International Parkinson and Movement Disorder Society Show less
Objectives Delirium is a frequent problem among older patients in the emergency department (ED) and early detection is important to prevent its associated adverse outcomes. Several screening tools... Show moreObjectives Delirium is a frequent problem among older patients in the emergency department (ED) and early detection is important to prevent its associated adverse outcomes. Several screening tools for delirium have been proposed for the ED, such as the 6-Item Cognitive Impairment Test (6-CIT) and the Confusion Assessment Method-ICU (CAM-ICU). Previous validation of the CAM-ICU for use in the ED showed varying results, possibly because it was administered at different or unknown time points. The aim was to study the prevalence of delirium in older (>= 70 years) ED patients using the CAM-ICU and 6-CIT.Participants and methods A prospective cohort study was carried out in one tertiary care and one secondary care hospital in the Netherlands. Patients aged 70 years and older attending the ED were included. Delirium screening was performed within 1 h after ED registration using the CAM-ICU. The 6-CIT was determined for comparison using a cut-off point of at least 14 points indicating possible delirium.Results A total of 997 patients were included in the study, with a median age of 78 years (interquartile range 74-84). Delirium as assessed with CAM-ICU was positive in only 13 (1.3%, 95% confidence interval: 0.8-2.2) patients. Ninety-five (9.5% 95% confidence interval: 7.9-11.5) patients had 6-CIT more than or equal to 14.Conclusion We found a delirium prevalence of 1.3% using the CAM-ICU, which was much lower than the expected prevalence of around 10% as being frequently reported in the literature and what we found when using the 6-CIT. On the basis of these results, caution is warranted to use the CAM-ICU for early screening in the ED. (C) 2018 Wolters Kluwer Health, Inc. All rights reserved. Show less
