Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis.

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum

Instrumental Assessment of Stepping in Place Captures Clinically Relevant Motor Symptoms of Parkinson’s Disease

Fluctuations of motor symptoms make clinical assessment in Parkinson's disease a complex task. New technologies aim to quantify motor symptoms, and their remote application holds potential for a closer monitoring of treatment effects. The focus of this study was to explore the potential of a stepping in place task using RGB-Depth (RGBD) camera technology to assess motor symptoms of people with Parkinson's disease. In total, 25 persons performed a 40 s stepping in place task in front of a single RGBD camera (Kinect for Xbox One) in up to two different therapeutic states. Eight kinematic parameters were derived from knee movements to describe features of hypokinesia, asymmetry, and arrhythmicity of stepping. To explore their potential clinical utility, these parameters were analyzed for their Spearman's Rho rank correlation to clinical ratings, and for intraindividual changes between treatment conditions using standard response mean and paired t-test. Test performance not only differed between ON and OFF treatment conditions, but showed moderate correlations to clinical ratings, specifically ratings of postural instability (pull test). Furthermore, the test elicited freezing in some subjects. Results suggest that this single standardized motor task is a promising candidate to assess an array of relevant motor symptoms of Parkinson's disease. The simple technical test setup would allow future use by patients themselves

Five years of ocrelizumab in relapsing multiple sclerosis : OPERA studies open-label extension

Objective: To assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA: I/II studies in relapsing multiple sclerosis. Methods:After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-β-1a (44 g 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed. Results:Of patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-β-1a (16.1% vs 21.3% at year 5; p = 0.014). Patients continuing OCR maintained and those switching from IFN-β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3-5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-β-1a (-1.87% vs-2.15% at year 5; p < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.ConclusionCompared with patients switching from IFN-β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.Classification of evidenceThis study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.Clinical trial identifiersNCT01247324/NCT01412333

Statistische Analyse microarraybasierter DNA-Methylierungsdaten

Innerhalb der letzten Jahre hat das Interesse an epigenetischen Mechanismen, insbesondere der DNA-Methylierung, dramatisch zugenommen. Die fundamentale Bedeutung epigenetischer Veränderungen wurde insbesondere in der Onkologie etabliert. Aberrierende DNA-Methylierung entsteht in einem frühen Stadium der Onkogenese, ist stabil und kann in Geweben und Körperflüssigkeiten nachgewiesen werden. Daher können Gene mit aberrierender DNA-Methylierung Hinweise zum Verständnis von Signaltransduktionswegen in Tumoren liefern und sind attraktive Kandidaten für die Detektion früher neoplastischer Veränderungen. Allerdings wurde eine groß angelegte Analyse von Kandidatengenen durch einen Mangel an Hochdurchsatzmethoden zur Methylierungsmessung gehemmt. Die Einführung des ersten Microarrays zur Messung von DNA-Methylierung hat dieses Problem gelöst indem es die gleichzeitige Messung mehrerer hundert ausgewählter CpG-Dinukleotide erlaubt. DNA-Microarray-Technologie hat bereits die Analyse von mRNA Expression revolutioniert. Sie hat allerdings auch eine Unmenge statistischer Probleme wie die der Qualitätskontrolle, der Markerselektion und der Klassifikation in hochdimensionalen Datenräumen aufgeworfen. In dieser Arbeit werden neuartige statistische Methoden zur Datenanalyse von DNA-Methylierungs-Microarrays entwickelt. Ausgehend von einem einfachen generativen Modell des Microarray-Messprozesses werden Algorithmen zur Normalisierung, Varianzstabilisierung und Bestimmung der DNA-Methylierungsrate hergeleitet. Diese Vorverarbeitungsmethoden erlauben eine optimale Schätzung der DNA-Methylierungsmuster einer gegebenen Probe aus den Microarray-Hybridisierungsintensitäten. Es wird eine Methodik zur Qualitäts- und Prozesskontrolle eingeführt, die es erlaubt die Qualität individueller Microarrays nur auf der Basis der eigentlichen Messwerte und ohne zusätzliche replizierte Experimente zu bestimmen. Dies erlaubt systematische experimentelle Fehler zuverlässig zu detektieren und damit die Datenqualität zu erhöhen. Weiterhin wird gezeigt wie phenotypische Klassen auf der Basis von Microarraymesswerten vorhergesagt werden können indem Verfahren der Merkmalsselektion und Diskriminanzanalyse verbunden werden. Durch den Vergleich verschiedener Merkmalsselektionsverfahren wird gezeigt, dass die richtige Strategie zur Dimensionsreduktion von entscheidender Bedeutung für eine gute Klassifikationsleistung ist. Die vorgestellten Methoden zur Qualitätskontrolle, Merkmalsselektion und Klassifikation sind so generisch, dass sie sowohl auf DNA-Methylierungs- als auch mRNA-Microarrays anwendbar sind. Die entwickelten Methoden werden auf eine große Microarraystudie zur Identifizierung von DNA-Methylierungsmarkern für Kolorektalkarzinome angewandt. In dieser Studie wurden 43 Kandidatengene auf DNA von 89 kolorektalen Adenokarzinomen, 55 kolorektalen Polypen, 31 chronisch entzündlichen Darmerkrankungen, 115 nicht kolorektalen Karzinomen und 67 gesunden Gewebeproben gemessen. Die 20 meistdiskriminierenden Marker sind hochgradig methyliert in kolorektalen Neoplasien (AUC>0.8; P0.8; P<0.0001). Normal epithelium and extracolonic cancers reveal significantly lower methylation. Results are validated on an independent sample set by real-time PCR. The discovered markers with high specificity for colorectal cancer have potential as blood-based screening markers whereas markers that are specific for multiple cancers could potentially be used as prognostic indicators or biomarkers for therapeutic response monitoring. The results clearly demonstrate that DNA methylation microarrays in combination with the developed analysis methods constitute a valuable tool for the discovery of novel epigenetic tumor markers and DNA methylation research in general

Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO

AimsOcrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS were assessed.MethodsA population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation.ResultsThe ocrelizumab serum concentration vs time course was accurately described by a 2-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing &lt;60&nbsp;kg and 21% lower for patients weighing &gt;90&nbsp;kg when compared with the 60-90&nbsp;kg group. The terminal half-life of ocrelizumab was estimated as 26&nbsp;days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure.ConclusionThe pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure

Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO.

AimsOcrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS were assessed.MethodsA population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation.ResultsThe ocrelizumab serum concentration vs time course was accurately described by a 2-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing &lt;60&nbsp;kg and 21% lower for patients weighing &gt;90&nbsp;kg when compared with the 60-90&nbsp;kg group. The terminal half-life of ocrelizumab was estimated as 26&nbsp;days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure.ConclusionThe pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure

Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis.

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum

MEASUREMENT OF THE FREE-SURFACE ELEVATION FOR FLOWS IN COMPLEX TOPOGRAPHY USING PHOTOGRAMMETRY

Predicting the flow in rivers is an important concern regarding potential damages induced by floods. Numerical models, if they can be used as predicting tool, need to be tested to assess their reliability. This can be done by comparing their results to field measurements or experimental data. However, such comparisons are often not easy to interpret since the differences can come from a multitude of causes. Therefore, it is preferred to use well-documented experimental data obtained in a well-controlled environment. As regards water level measurements, several methods exist. Gauges provide information on a small area (point measurement method). Other techniques (imagery based analysis) such as filming through a side panel provide the water level along the considered axis but require an optical access to the area which is not always possible. This paper investigates the use of photogrammetry to measure the water level. Photogrammetry is a non-intrusive method allowing for the capture of the water level over a large area in one run of the experiment. However, its application still presents numerous challenges. The work presented here compares the results obtained using photogrammetry to other more classical measurement methods on the case of a steady flow in an arbitrary topography built in concrete. The results show good agreement between both measurement techniques and highlight the capabilities of using photogrammetry in the laboratory