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      Classification of advanced stages of Parkinson’s disease: translation into stratified treatments

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          Abstract

          Advanced stages of Parkinson’s disease (advPD) still impose a challenge in terms of classification and related stage-adapted treatment recommendations. Previous concepts that define advPD by certain milestones of motor disability apparently fall short in addressing the increasingly recognized complexity of motor and non-motor symptoms and do not allow to account for the clinical heterogeneity that require more personalized approaches. Therefore, deep phenotyping approaches are required to characterize the broad-scaled, continuous and multidimensional spectrum of disease-related motor and non-motor symptoms and their progression under real-life conditions. This will also facilitate the reasoning for clinical care and therapeutic decisions, as neurologists currently have to refer to clinical trials that provide guidance on a group level; however, this does not always account for the individual needs of patients. Here, we provide an overview on different classifications for advPD that translate into critical phenotypic patterns requiring the differential therapeutic adjustments. New concepts refer to precision medicine approaches also in PD and first studies on genetic stratification for therapeutic outcomes provide a potential for more objective treatment recommendations. We define novel treatment targets that align with this concept and make use of emerging device-based assessments of real-life information on PD symptoms. As these approaches require empowerment of patients and integration into treatment decisions, we present communication strategies and decision support based on new technologies to adjust treatment of advPD according to patient demands and safety.

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          Pharmacogenomics in the clinic.

          After decades of discovery, inherited variations have been identified in approximately 20 genes that affect about 80 medications and are actionable in the clinic. And some somatically acquired genetic variants direct the choice of 'targeted' anticancer drugs for individual patients. Current efforts that focus on the processes required to appropriately act on pharmacogenomic variability in the clinic are moving away from discovery and towards implementation of an evidenced-based strategy for improving the use of medications, thereby providing a cornerstone for precision medicine.
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            Technology in Parkinson's disease: Challenges and opportunities.

            The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. © 2016 International Parkinson and Movement Disorder Society.
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              Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study.

              Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥ 30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994. From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4.04 h (SE 0.65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2.14 h (0.66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference -1.91 h [95% CI -3.05 to -0.76]; p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 h (SE 0.75) in the intestinal gel group and 2.24 h (0.76) in the immediate-release oral group (difference 1.86 [95% CI 0.56 to 3.17]; p=0.0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study. AbbVie. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                rejko.krueger@uni.lu
                Journal
                J Neural Transm (Vienna)
                J Neural Transm (Vienna)
                Journal of Neural Transmission
                Springer Vienna (Vienna )
                0300-9564
                1435-1463
                24 March 2017
                24 March 2017
                2017
                : 124
                : 8
                : 1015-1027
                Affiliations
                [1 ]ISNI 0000 0001 2295 9843, GRID grid.16008.3f, Luxembourg Centre for Systems Biomedicine (LCSB), , University of Luxembourg, ; Esch-Sur-Alzette, Luxembourg
                [2 ]ISNI 0000 0004 0578 0421, GRID grid.418041.8, , Centre Hospitalier de Luxembourg (CHL), ; Luxembourg, Luxembourg
                [3 ]ISNI 0000 0001 2107 3311, GRID grid.5330.5, Molecular Neurology, , University of Erlangen, ; Erlangen, Germany
                [4 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Department for Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, Center for Neurology, , University of Tübingen, ; Tübingen, Germany
                [5 ]GRID grid.416438.c, , Department of Neurology of the Ruhr-University Bochum at St Josef-Hospital, ; Gudrunstrasse 56, 44791 Bochum, Germany
                [6 ]Center of Mental Health, Clinic and Policlinic of Psychiatry, Psychosomatics and Psychotherapy, University Hospital, Würzburg, Germany
                [7 ]Nervenarztpraxis Gerresheim, Düsseldorf, Germany
                [8 ]ISNI 0000 0004 0558 9854, GRID grid.470005.6, Department of Neurology, , Klinikum Hanau GmbH, ; Hanau, Germany
                [9 ]GRID grid.460029.9, Department of Neurology, , St. Joseph Hospital Berlin-Weissensee, ; Berlin, Germany
                Article
                1707
                10.1007/s00702-017-1707-x
                5514193
                28342083
                82ac1cf2-cb27-4e0e-b889-a98674171112
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 23 January 2017
                : 11 March 2017
                Funding
                Funded by: Luxembourg National Research Fund FNR
                Award ID: P13/6682797
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007601, Horizon 2020;
                Award ID: 692320
                Award Recipient :
                Categories
                Neurology and Preclinical Neurological Studies - Review Article
                Custom metadata
                © Springer-Verlag GmbH Austria 2017

                advanced parkinson's disease,stratification,personalized medicine,invasive therapies

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