Neuroprotection after cardiac arrest with 2-iminobiotin: a single center phase IIa study on safety, tolerability, and pharmacokinetics

BackgroundBrain injury is a serious problem in patients who survive out-of-hospital cardiac arrest (OHCA). Neuroprotective drugs could reduce hypoxic–ischemic reperfusion injury. The aim of this study was to investigate the safety, tolerability, and pharmacokinetics (PK) of 2-iminobiotin (2-IB), a selective inhibitor of neuronal nitric oxide synthase.MethodsSingle-center, open-label dose-escalation study in adult OHCA patients, investigating three 2-IB dosing schedules (targeting an AUC0-24h of 600–1,200 ng*h/m in cohort A, of 2,100–3,300 ng*h/mL in cohort B, and 7,200–8,400 of ng*h/mL in cohort C). Safety was investigated by monitoring vital signs until 15 min after study drug administration and adverse events up to 30 days after admission. Blood sampling for PK analysis was performed. Brain biomarkers and patient outcomes were collected 30 days after OHCA.ResultsA total of 21 patients was included, eight in cohort A and B and five in cohort C. No changes in vital signs were observed, and no adverse events related to 2-IB were reported. A two-compartment PK model described data the best. Exposure in group A (dosed on bodyweight) was three times higher than targeted (median AUC0-24h 2,398 ng*h/mL). Renal function was an important covariate; therefore, in cohort B, dosing was performed on eGFR on admission. In cohort B and C, the targeted exposure was met (median AUC0-24h 2,917 and 7,323 ng*h/mL, respectively).ConclusionThe administration of 2-IB to adults after OHCA is feasible and safe. PK can be well predicted with correction for renal function on admission. Efficacy studies with 2-IB after OHCA are needed

COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015), a global--clinical evaluations, serum biomarkers, genetic studies and neuroimaging--prospective, multicenter, non-interventional, long-term study on Parkinson's disease progressio

Background: Parkinson?s disease (PD) is a progressive neurodegenerative disorder causing motor and non-motor symptoms that can affect independence, social adjustment and the quality of life (QoL) of both patients and caregivers. Studies designed to find diagnostic and/or progression biomarkers of PD are needed. We describe here the study protocol of COPPADIS-2015 (COhort of Patients with PArkinson?s DIsease in Spain, 2015), an integral PD project based on four aspects/concepts: 1) PD as a global disease (motor and non-motor symptoms); 2) QoL and caregiver issues; 3) Biomarkers; 4) Disease progression.Methods/design: Observational, descriptive, non-interventional, 5-year follow-up, national (Spain), multicenter (45 centers from 15 autonomous communities), evaluation study. Specific goals: (1) detailed study (clinical evaluations, serum biomarkers, genetic studies and neuroimaging) of a population of PD patients from different areas of Spain, (2) comparison with a control group and (3) follow-up for 5 years. COPPADIS-2015 has been specifically designed to assess 17 proposed objectives. Study population: approximately 800 non-dementia PD patients, 600 principal caregivers and 400 control subjects. Study evaluations: (1) baseline includes motor assessment (e.g., Unified Parkinson?s Disease Rating Scale part III), non-motor symptoms (e.g., Non-Motor Symptoms Scale), cognition (e.g., Parkinson?s Disease Cognitive Rating Scale), mood and neuropsychiatric symptoms (e.g., Neuropsychiatric Inventory), disability, QoL (e.g., 39-item Parkinson?s disease Quality of Life Questionnaire Summary-Index) and caregiver status (e.g., Zarit Caregiver Burden Inventory); (2) follow-up includes annual (patients) or biannual (caregivers and controls) evaluations. Serum biomarkers (S-100b protein, TNF-?, IL-1, IL-2, IL-6, vitamin B12, methylmalonic acid, homocysteine, uric acid, C-reactive protein, ferritin, iron) and brain MRI (volumetry, tractography and MTAi [Medial Temporal Atrophy Index]), at baseline and at the end of follow-up, and genetic studies (DNA and RNA) at baseline will be performed in a subgroup of subjects (300 PD patients and 100 control subjects). Study periods: (1) recruitment period, from November, 2015 to February, 2017 (basal assessment); (2) follow-up period, 5 years; (3) closing date of clinical follow-up, May, 2022. Funding: Public/Private. Discussion: COPPADIS-2015 is a challenging initiative. This project will provide important information on the natural history of PD and the value of various biomarkers

A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5x10(-10), PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci

The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Evolution of mild cognitive impairment in Parkinson disease

Objective: We examined the development of Parkinson disease (PD)-mild cognitive impairment (MCI) in patients with newly diagnosed PD over 5 years using recently proposed consensus criteria, and we assessed the reliability of the criteria. Methods: Patients with PD (n = 123) underwent extensive neuropsychological testing at baseline and after 3 (n = 93) and 5 years (n = 59). Two neuropsychologists independently applied the PD-MCI criteria to examine the interrater and intrarater reliability. Results: At baseline, 35% of patients had PD-MCI. Three years later, 53% of the patients had PD-MCI. At 5-year follow-up, 20 patients who had PD-MCI at an earlier assessment had converted to PD dementia and 50% of the remaining patients without dementia had MCI. The interrater reliability (kappa) was 0.91. The intrarater reliabilities were 0.85 and 0.96. Conclusion: Approximately one-third of patients with newly diagnosed PD fulfill the consensus criteria for PD-MCI; after 5 years, this proportion is approximately 50% of patients without dementia. The criteria have good interrater and intrarater reliabilit

Outdoor education - a complement to mathematics teaching

Syftet med studien är att få en djupare förståelse för begreppet utomhuspedagogik och ta reda på om utomhuspedagogik, som ett komplement till den traditionella undervisningen, är en undervisningsform som kan bidra till ökad förståelse inom ämnet matematik. Studien är en litteraturstudie där tidigare forskning har granskats och analyserats. Resultatet visar att utomhuspedagogik inom matematik inte bara ger direkt betydelsefull kunskap vid koppling av skola och samhället utan förbättrar även elevers hälsa, ökar elevers motivation till matematikämnet, elevers sociala förmågor utvecklas samt ger fler sinnen stimulans vilket gör elever mer alerta och mottagliga för inlärning. Mer tid till ämnet matematik och mer utbildning inom utomhuspedagogik är två avgörande faktorer för att lyckas integrera utomhuspedagogik i undervisningen