Untersuchung neuroprotektiver Effekte von Radikalfängern in Tiermodellen des Morbus Parkinson

Im Fluorogold/6-OHDA-Ratten-Modell (FG/6-OHDA) und dem MPTP-Maus-Modell des idiopathischen Parkinsonsyndroms (IPS) sollten in der vorgelegten Studie die Radikalfänger Salicylsäure (SS), alpha-Phenyl-N-Tert-Butyl Nitron (PBN) und Trolox® Methyl Ether (Trolox) auf ihre neuroprotektive Wirkung untersucht werden. Ziel der Arbeit war es die potenziell protektiven Effekte der Substanzen auf den striatalen Dopamingehalt, die Dopaminumsatzrate, die Anzahl nigraler Tyrosinhydroxylase-immunreaktiver (TH-ir) Neurone und im FG/6-OHDA-Modell auf die Anzahl nigraler Fluorogold-positiver (FG-p) Neurone sowie im MPTP-Modell auf die lokomotorische Aktivität der Mäuse zu erfassen. Anhand der genannten Parameter konnte nach unilateral durchgeführter intrastriataler In-jektion von 6-OHDA eine signifikante ipsilaterale Läsion nigraler dopaminerger Neurone mit konsekutiv signifikant veränderten neurochemischen Parametern erhoben werden. SS zeigte bis auf einen tendenziell positiven Effekt auf die Verminderung FG-p Neurone und den striatalen Dopamingehalt keinen schützenden Einfluss auf die durch 6-OHDA hervorgerufenen Veränderungen. Bei mit 10mg/kg KG niedrig dosierter Langzeitbehandlung (2 Wochen pre und 4 Wochen post laesionem; i.p.) im Vergleich zu Studien im MPTP-Modell der Maus mit 5 - 10-facher Dosis der SS, welche einen signifikant protektiven Effekt beschrieben (Aubin et al. 1998), wurde auch für das 6-OHDA-Modell eine neuroprotektive Wirkung in diesem Dosierungsbereich postuliert, zumal die Läsionseffekte so ausgeprägt waren, dass es möglich er-scheint, dass sich die gesehenen tendenziellen Effekte bei unter diesen Voraussetzungen zu geringer Fallzahl nicht signifikant abzeichneten. Dies bleibt durch weitere Studien zu beweisen. Hingewiesen wurde auf die zu erwartenden gastrointestinalen Nebenwirkungen bei chronischer Therapie mit Salicylsäure im Hochdosisbereich. PBN wurde im FG/6-OHDA-Modell niedrig- und hochdosiert 2 Wochen vor und 4 Wochen nach Läsion verabreicht. Auf sämtliche bestimmte Parameter konnte mit beiden Dosierungen kein signifikant neuroprotektiver Effekt erhoben werden. Eine durch 150 mg PBN signifikant verminderte Anzahl nigraler TH-ir Neurone, welche sich tendenziell in der Anzahl FG-p Neurone, allerdings nicht auf neurochemischer Ebene widerspiegelte, ließ sogar einen dosisabhängigen neurotoxischen Effekt in höherer Dosierung vermuten. Entscheidend scheint die lange Behandlungsdauer im Vergleich zu anderen tierexperimentellen Studien im selben Dosierungsbereich, da hier bisher kein toxischer Effekt auf behavioraler Ebene beschrieben wurde. Morphologische Parameter wurden in diesen Arbeiten nicht erhoben. Dies spricht gegen eine neuroprotektive Therapie beim Menschen, da diese am ehesten in Form einer Langzeitbehandlung durchgeführt würde. Eine Stimulation der Dopaminsynthese durch PBN in den residualen nigrostriatalen Neuronen wurde bei fehlender gleichzeitiger Verminderung des striatalen Dopamingehaltes diskutiert. Die einmalige subcutane Applikation von 30 mg/kg KG MPTP führte ebenfalls zu einem signifikanten Rückgang nigraler dopaminerger TH-ir Neurone, welcher sich wiederum signifikant auf die bestimmten neurochemischen und behavioralen Parameter auswirkte. Das fettlösliche Vitamin E Derivat Trolox® wurde in hoher und niedriger Dosierung im MPTP-Maus-Modell mittels einmaliger Gabe s.c. unmittelbar vor Applikation des Toxins getestet. Bis auf eine signifikante Senkung der postläsionell erhöhten Umsatzrate des Dopamins unter Behandlung mit 300 mg/kg KG Trolox® zeigte sich kein signifikant positiver Effekt auf sämtliche Parameter. Bemerkens-werterweise kamen allerdings die Daten für sämtliche Parameter der geschädigten Tiere in der Reihenfolge Trolox 300 > Trolox 100 > NaCl zu liegen, was eine dosisabhängige Wirkung vermuten und die Durchführung weiterer Studien mit höher dosiertem Trolox erfolgversprechend erscheinen lässt, zumal unter den angewandten Dosierungen keine unerwünschten Wirkungen bei den Tieren zu beobachten waren. Darüber hinaus stellten sich auch in diesem Versuch die Läsionseffekte so ausgeprägt dar, dass sich die gesehenen tendenziellen Effekte bei größerer Fallzahl möglicherweise signifikant abzeichnen würden. Zusammenfassend lässt sich sagen, dass ein neuroprotektiver Effekt von Trolox und Salicylsäure in höherer als in der hier verwendeten Dosierung oder bei größerer Fallzahl möglich erscheint. Des weiteren erscheint die Kombination eines wasser-lös-lichen mit einem fettlöslichen Antioxidanz mit differierendem Wirkort und möglicher Addition/Potenzierung der neuroprotektiven Effekte erfolgversprechend. PBN erwies sich im 6-OHDA-Modell der Ratte als nicht neuroprotektiv. Es zeigte in höherer Dosierung sogar neurotoxische Effekte, was insbesondere für Langzeitbehandlungen, wie sie beim Menschen im Falle einer chronisch neurodegenerativen Erkrankung Anwendung finden würde, Relevanz hat und in Folge-Studien näher spezifiziert werden sollte

Circuit imaging biomarkers in preclinical and prodromal Parkinson's disease

Abstract Parkinson’s disease (PD) commences several years before the onset of motor features. Pathophysiological understanding of the pre-clinical or early prodromal stages of PD are essential for the development of new therapeutic strategies. Two categories of patients are ideal to study the early disease stages. Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents a well-known prodromal stage of PD in which pathology is presumed to have reached the lower brainstem. The majority of patients with iRBD will develop manifest PD within years to decades. Another category encompasses non-manifest mutation carriers, i.e. subjects without symptoms, but with a known mutation or genetic variant which gives an increased risk of developing PD. The speed of progression from preclinical or prodromal to full clinical stages varies among patients and cannot be reliably predicted on the individual level. Clinical trials will require inclusion of patients with a predictable conversion within a limited time window. Biomarkers are necessary that can confirm pre-motor PD status and can provide information regarding lead time and speed of progression. Neuroimaging changes occur early in the disease process and may provide such a biomarker. Studies have focused on radiotracer imaging of the dopaminergic nigrostriatal system, which can be assessed with dopamine transporter (DAT) single photon emission computed tomography (SPECT). Loss of DAT binding represents an effect of irreversible structural damage to the nigrostriatal system. This marker can be used to monitor disease progression and identify individuals at specific risk for phenoconversion. However, it is known that changes in neuronal activity precede structural changes. Functional neuro-imaging techniques, such as 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography (18F-FDG PET) and functional magnetic resonance imaging (fMRI), can be used to model the effects of disease on brain networks when combined with advanced analytical methods. Because these changes occur early in the disease process, functional imaging studies are of particular interest in prodromal PD diagnosis. In addition, fMRI and 18F-FDG PET may be able to predict a specific future phenotype in prodromal cohorts, which is not possible with DAT SPECT. The goal of the current review is to discuss the network-level brain changes in pre-motor PD

Validation of mobile eye-tracking as novel and efficient means for differentiating progressive supranuclear palsy from Parkinson's disease

Background: The decreased ability to carry out vertical saccades is a key symptom of Progressive Supranuclear Palsy (PSP). Objective measurement devices can help to reliably detect subtle eye movement disturbances to improve sensitivity and specificity of the clinical diagnosis. The present study aims at transferring findings from restricted stationary video-oculography (VOG) to a wearable head-mounted device, which can be readily applied in clinical practice. Methods: We investigated the eye movements in 10 possible or probable PSP patients, 11 Parkinson's disease (PD) patients, and 10 age-matched healthy controls (HCs) using a mobile, gaze-driven video camera setup (EyeSeeCam). Ocular movements were analyzed during a standardized fixation protocol and in an unrestricted real-life scenario while walking along a corridor. Results: The EyeSeeCam detected prominent impairment of both saccade velocity and amplitude in PSP patients, differentiating them from PD and HCs. Differences were particularly evident for saccades in the vertical plane, and stronger for saccades than for other eye movements. Differences were more pronounced during the standardized protocol than in the real-life scenario. Conclusions: Combined analysis of saccade velocity and saccade amplitude during the fixation protocol with the EyeSeeCam provides a simple, rapid (<20 s), and reliable tool to differentiate clinically established PSP patients from PD and HCs. As such, our findings prepare the ground for using wearable eye-tracking in patients with uncertain diagnoses

Costs of Parkinson's Disease and Antiparkinsonian Pharmacotherapy: An Italian Cohort Study

Objective: Antiparkinsonian pharmacotherapy is costly and the determinants of drug costs in Parkinson's disease (PD) have been poorly investigated. The objective of this study was to investigate the costs of PD and antiparkinsonian drugs in an Italian cohort of patients and identify cost-driving factors of drug therapy. Methods: Seventy outpatients with idiopathic PD were recruited in the Department of Neurology, Napoli University, Italy. Data on resource utilization were collected for 6 months using a bottom-up approach. Clinical status was evaluated using the Unified Parkinson's Disease Rating Scale. Direct and indirect costs were calculated from the societal perspective (figures of year 2009). Independent determinants of total costs and costs of antiparkinsonian drugs were identified using multivariate regression analysis. Results: The total costs of PD were EUR 8,640 (95% CI: EUR 6,700-11,240) per patient over a 6-month period. Direct costs accounted for 70% of the total costs. Antiparkinsonian drugs (EUR 1,450; 95% CI: EUR 1,220-1,760) were the primary component of costs paid by the health insurance (39.6%) and one of the most expensive components of the direct costs (24.0%). The highest copayments made by patients were for antiparkinsonian drugs and medical equipment (58%). Independent determinants of the increased costs of antiparkinsonian pharmacotherapy were younger age and occurrence of motor fluctuations. Conclusions: Antiparkinsonian pharmacotherapy is one of the major cost components of PD-related costs for health insurance. It imposes a considerable economic burden on patients and their families as well. Copyright (C) 2010 S. Karger AG, Base

Occipital hypometabolism is a risk factor for conversion to Parkinson’s disease in isolated REM sleep behaviour disorder

Purpose: Isolated REM sleep behaviour disorder (iRBD) patients are at high risk of developing clinical syndromes of the α-synuclein spectrum. Progression markers are needed to determine the neurodegenerative changes and to predict their conversion. Brain imaging with 18F-FDG PET in iRBD is promising, but longitudinal studies are scarce. We investigated the regional brain changes in iRBD over time, related to phenoconversion.Methods: Twenty iRBD patients underwent two consecutive 18F-FDG PET brain scans and clinical assessments (3.7 ± 0.6 years apart). Seventeen patients also underwent 123I-MIBG and 123I-FP-CIT SPECT scans at baseline. Four subjects phenoconverted to Parkinson’s disease (PD) during follow-up. 18F-FDG PET scans were compared to controls with a voxel-wise single-subject procedure. The relationship between regional brain changes in metabolism and PD-related pattern scores (PDRP) was investigated.Results: Individual hypometabolism t-maps revealed three scenarios: (1) normal 18F-FDG PET scans at baseline and follow-up (N = 10); (2) normal scans at baseline but occipital or occipito-parietal hypometabolism at follow-up (N = 4); (3) occipital hypometabolism at baseline and follow-up (N = 6). All patients in the last group had pathological 123I-MIBG and 123I-FP-CIT SPECT. iRBD converters (N = 4) showed occipital hypometabolism at baseline (third scenario). At the group level, hypometabolism in the frontal and occipito-parietal regions and hypermetabolism in the cerebellum and limbic regions were progressive over time. PDRP z-scores increased over time (0.54 ± 0.36 per year). PDRP expression was driven by occipital hypometabolism and cerebellar hypermetabolism.Conclusions: Our results suggest that occipital hypometabolism at baseline in iRBD implies a short-term conversion to PD. This might help in stratification strategies for disease-modifying trials.</p

Four-YearFollow-upof [F-18]Fluorodeoxyglucose Positron Emission Tomography-Based Parkinson's Disease-Related Pattern Expression in 20 Patients With Isolated Rapid Eye Movement Sleep Behavior Disorder Shows Prodromal Progression

Background: Isolated rapid eye movement sleep behavior disorder is known to be prodromal for alpha-synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies. The [18F]fluorodeoxyglucose-positron emission tomography (PET)–based PD-related brain pattern can be used to monitor disease progression. Objective: We longitudinally investigated PD-related brain pattern expression changes in 20 subjects with isolated rapid eye movement sleep behavior disorder to investigate whether this may be a suitable technique to study prodromal PD progression in these patients and to identify potential phenoconverters. Methods: Subjects underwent two [18F]fluorodeoxyglucose-PET brain scans ~3.7 years apart, along with baseline and repeated motor, cognitive, and olfactory testing within roughly the same time frame. Results: At baseline, 8 of 20 (40%) subjects significantly expressed the PD-related brain pattern (with z scores above the receiver operating characteristic–determined threshold). At follow-up, six additional subjects exhibited significant PD-related brain pattern expression (70% in total). PD-related brain pattern expression increased in all subjects (P = 0.00008). Four subjects (20%), all with significant baseline PD-related brain pattern expression, phenoconverted to clinical PD. Conclusions: Suprathreshold PD-related brain pattern expression and greater score rate of change may signify greater shorter-term risk for phenoconversion. Our results support the use of serial PD-related brain pattern expression measurements as a prodromal PD progression biomarker in patients with isolated rapid eye movement sleep behavior disorder

Плазменное получение тепловой энергии из сульфатного лигнина

This article shows an overview and analysis of the literature on methods of using sludge lignin. This product obtained after treatment of pulp. As a result of calculating the optimum composition of water, organic materials with mechanical impurities from the adiabatic combustion temperature of about 1200 K were determined. Using the obtained results of experimental studies have been carried out in a plasma reactor of the catalytic reactor and has been optimized. The obtained results can be used to create industrial enterprises based on plasma catalytic reactors for waste sludge lignin for the purpose of obtaining heat

Dermal Phospho-Alpha-Synuclein Deposition in Patients With Parkinson's Disease and Mutation of the Glucocerebrosidase Gene

Heterozygous mutations in the glucocerebrosidase gene (GBA1) represent the most common genetic risk factor for Parkinson's disease (PD) and are histopathologically associated with a widespread load of alpha-synuclein in the brain. Therefore, PD patients with GBA1 mutations are a cohort of high interest for clinical trials on disease-modifying therapies targeting alpha-synuclein. There is evidence that detection of phospho-alpha-synuclein (p-syn) in dermal nerve fibers might be a biomarker for the histopathological identification of PD patients even at premotor or very early stages of disease. It is so far unknown whether dermal p-syn deposition can also be found in PD patients with GBA1 mutations and may serve as a biomarker for PD in these patients. Skin biopsies of 10 PD patients with different GBA1 mutations (six N370S, three E326K, one L444P) were analyzed by double-immunofluorescence labeling with anti-p-syn and anti-protein gene product 9.5 (PGP9.5, axonal marker) to detect intraaxonal p-syn deposition. Four biopsy sites (distal, proximal leg, paravertebral Th10, and C7) per patient were studied. P-syn was found in six patients (three N370S, three E326K). P-syn deposition was mainly detected in autonomic nerve fibers, but also in somatosensory fibers and was not restricted to a certain GBA1 mutation. In summary, dermal p-syn in PD patients with GBA1 mutations seems to offer a similar distribution and frequency as observed in patients without a known mutation. Skin biopsy may be suitable to study p-syn deposition in these patients or even to identify premotor patients with GBA1 mutations

The metabolic pattern of idiopathic REM sleep behavior disorder reflects early-stage Parkinson's disease

Rationale: Idiopathic REM sleep behavior disorder (iRBD) is considered a prodromal stage of Parkinson's disease (PD) and other Lewy-body disorders. Spatial covariance analysis of [18F]-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG-PET) data has disclosed a specific brain pattern of altered glucose metabolism in PD. In this study, we identify the metabolic pattern underlying iRBD and compare it to the known PD pattern. To understand the relevance of the iRBD pattern to disease progression, we study the expression of the iRBD pattern in de novo PD patients.Methods:The iRBD-related pattern was identified in18F-FDG-PET scans of 21 patients with polysomnographically-confirmed iRBD and 19 controls using spatial covariance analysis. Expression of the iRBD-related pattern was subsequently computed in18F-FDG-PET scans of 44 controls and 38 de novo, treatment-naïve PD patients. Of these 38 PD patients, 24 had probable RBD according to the Mayo Sleep Questionnaire. Neuropsychological evaluation showed mild cognitive impairment in 20 PD patients (PD-MCI), of whom sixteen also had concomitant RBD and roughly half (11/20) had bilateral motor symptoms.Results:The iRBD-related pattern was characterized by relative hypermetabolism in cerebellum, brainstem, thalamus, sensorimotor cortex, and hippocampus, and by relative hypometabolism in middle cingulate, temporal, occipital and parietal cortices. This topography partially overlapped with the PD-related pattern (PDRP). The iRBD-related pattern was significantly expressed in PD patients compared to controls (P<0.0001). iRBD-related pattern expression was not significantly different between PD patients with and without probable RBD, or between PD patients with unilateral or bilateral parkinsonism. iRBD-related pattern expression was higher in PD-MCI patients, compared to PD patients with preserved cognition (P= 0.001). Subject scores on the iRBD-related pattern were highly correlated to subject scores on the PDRP (r=0.94, P<0.0001).Conclusion:In conclusion, our results show that the iRBDRP is an early manifestation of the PDRP. Expression of both PDRP and iRBDRP was higher in patients with a more severe form of PD (PD-MCI), which indicates that expression of the two patterns increases with disease severity