Systems pharmacology and blood-brain barrier functionality in Parkinson's disease

Parkinson__s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain barrier (BBB) is a key player in the relationship between plasma and brain pharmacokinetics, the influences of disease states on BBB functionality in the various stages of the disease is important in order to judge on drug effects. This warrants a systems pharmacology approach to the development of novel drug treatments of Parkinson__s disease. Animal models of disease are an essential asset in this research. The research described in this thesis shows that the intracerebral rotenone rat model is a chronic and progressive animal model for Parkinson__s disease, displaying alpha-synuclein immunoreactivity and aggregation in several cases. The model has also shown that no changes were found in passive BBB permeability, nor in BBB transport modes of L-DOPA. However, a diseased condition was present as indicated by the clear effect of rotenone on the levels and elimination rates of DOPAC and HVA in brain that provided information on decreased dopamine concentrations at the diseased brain side. Altogether, it can be concluded that the intracerebral rotenone rat model is an animal model which is suitable as a tool in systems pharmacology research on Parkinson__s disease.UBL - phd migration 201

Incidence and Risk Factors of Second Eye Involvement in Myopic Macular Neovascularization

Purpose: To report the cumulative incidence and risk factors of second eye involvement after diagnosis of myopic macular neovascularization (MNV) in the first eye. Design: Retrospective analysis of longitudinal data from a tertiary hospital in the Netherlands. Participants:Patients with high myopia (spherical equivalent [SE] ≤ − 6 diopters [D]), of European ethnicity, who were diagnosed with active MNV lesion in 1 eye between 2005 and 2018. Fellow eyes were free of MNV or macular atrophy at baseline, and data were collected on the SE, axial length, and presence of diffuse or patchy chorioretinal atrophy and lacquer cracks.Methods:Incidence rate and 2-, 5-, and 10-year cumulative incidences were calculated; hazard ratios (HRs) of second eye involvement were analyzed for potential risk factors using Cox proportional hazard models. Main outcomes measures: Incidence of second eye involvement after onset of myopic MNV in the first eye. Results: We included 88 patients over a period of 13 years with a mean age of 58 ± 15 years, mean axial length of 30 ± 1.7 mm and SE −14 ± 4 D at baseline. Twenty-four fellow eyes (27%) developed a myopic MNV during follow-up. This resulted in an incidence rate of 4.6 (95% confidence interval [CI], 2.9–6.7) per 100 person-years and a cumulative incidence of 8%, 21%, and 38% at 2, 5, and 10 years, respectively. Mean time until MNV development in the fellow eye was 48 ± 37 months. Patients aged &lt; 40 years at the initial presentation had a 3.8 times higher risk of bilateral myopic MNV (HR, 3.8; 95% CI, 1.65–8.69; P = 0.002). The presence of lacquer cracks in the second eye seemed to increase risk, but this did not reach statistical significance (HR, 2.25; 95% CI, 0.94–5.39; P = 0.07). Conclusions: Our study of high myopes of European descent shows very similar incidence rates for second eye myopic MNV compared with Asian studies. Our findings substantiate the importance for clinicians to monitor closely and create awareness, especially in younger patients. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.</p

Empowering patients with high myopia:The significance of education

Purpose: To investigate the status of patient education among highly myopic individuals focusing on the presence, sources, content, timing of the education and impact on patients. Methods: Self-reported data were collected through an online 13-item questionnaire consisting of open and multiple-choice questions. The questionnaire was sent to 250 highly myopic members of a patient organization in the Netherlands, of whom 128 (51%) responded. Results: At least one acute event had occurred in 66% (84/128) of participants at the time of the questionnaire. Among all participants, 25% (32/128) had not received patient education regarding alarm symptoms for any of these events. Among those who had been informed, the ophthalmologist was the most frequent (57%, 73/128) source of information. Participants who visited the ophthalmologist annually were more frequently informed than participants without annual visits (53%, 26/49 versus 26%, 9/35, p = 0.002). Those not informed were more likely to have a more than 3 days patient delay (92%, 12/13). Doctors delay was also present; 26% (22/84) of the participants with alarm symptoms had to wait 2 or more days before the first appointment. Long-term consequences of myopia had been discussed with 102 participants (80%, 102/128), again with the ophthalmologist as the most frequent source (59%, 76/128). Perspectives: Many myopic individuals have not been educated about their increased risk of acute events, which can result in patient delay and serious consequences with respect to visual prognosis. These findings underscore the critical importance of integrating patient education across the entire ophthalmic care chain for myopia.</p

Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease

Abstract Background Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease. Methods In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere. Results Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher. Conclusions Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.</p

Biobased Plastics 2012

Dit boek geeft inzicht in de huidige op de markt verkrijgbare biobased plastics en de te verwachten ontwikkelingen. Er wordt gekeken naar zowel thermoplastische als thermohardende materialen. Het boek biedt inzicht in de productie, verwerking en eigenschappen van de verschillende types. Daarnaast worden mogelijke toepassingen, afvalbeheer en technische-, economische- en milieu-uitdagingen verder toegelicht

A view from the clinic – Perspectives from Dutch patients and professionals on high myopia care

Purpose: To understand and compare perspectives of patients and professionals on current ophthalmologic care for high myopia, and to identify challenges and future opportunities. Methods: Self-reported data were collected through two online questionnaires. Patient perspective was obtained from highly myopic members of a patient organisation based in the Netherlands using a 17-item questionnaire consisting of open and multiple-choice questions regarding personal experience with myopia care. The ophthalmologist perspective was obtained from practising Dutch ophthalmologists with a 12-item questionnaire of multiple-choice questions on work-related demographics, myopia care in daily practice and need for improvement. The response rate for patients was 27% (n = 136/500) and for ophthalmologists, 24% (n = 169/716). Results: Patients were highly concerned about personal progressive loss of vision (69%) and feared their psychological well-being (82%) in case this would happen. The quality of performance of care provided by ophthalmologists was rated as excellent or satisfactory by 64% of the patients. These ratings for multidisciplinary care and insurance reimbursement were as low as 28% and 18% respectively. The mean concern among ophthalmologists about the rise in high myopia was 6.9 (SEM 0.1) on a 10-point scale. Sixty-nine per cent of the ophthalmologists reported that asymptomatic myopic patients should not be examined regularly at outpatient clinics. Ophthalmologists urged the development of clinical guidelines (74%), but did report (95%) that they informed patients about risk factors and complications. This contrasted with the view of patients, of whom 42% were discontent with information provided by ophthalmologists. Conclusions: These questionnaires demonstrated that the current clinical care delivered to highly myopic patients is in need of improvement. The expected higher demand for myopia care in the near future requires preferred practice patterns, professionals specifically trained to manage myopic pathology, accurate and comprehensive information exchange and collaboration of in- and out-of-hospital professionals across the full eye care chain.</p

Stereotaxical Infusion of Rotenone: A Reliable Rodent Model for Parkinson's Disease

A clinically-related animal model of Parkinson's disease (PD) may enable the elucidation of the etiology of the disease and assist the development of medications. However, none of the current neurotoxin-based models recapitulates the main clinical features of the disease or the pathological hallmarks, such as dopamine (DA) neuron specificity of degeneration and Lewy body formation, which limits the use of these models in PD research. To overcome these limitations, we developed a rat model by stereotaxically (ST) infusing small doses of the mitochondrial complex-I inhibitor, rotenone, into two brain sites: the right ventral tegmental area and the substantia nigra. Four weeks after ST rotenone administration, tyrosine hydroxylase (TH) immunoreactivity in the infusion side decreased by 43.7%, in contrast to a 75.8% decrease observed in rats treated systemically with rotenone (SYS). The rotenone infusion also reduced the DA content, the glutathione and superoxide dismutase activities, and induced alpha-synuclein expression, when compared to the contralateral side. This ST model displays neither peripheral toxicity or mortality and has a high success rate. This rotenone-based ST model thus recapitulates the slow and specific loss of DA neurons and better mimics the clinical features of idiopathic PD, representing a reliable and more clinically-related model for PD research

Parkinson’s disease mouse models in translational research

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research