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Parkinson Disease: HELP
Articles by Claudia Trenkwalder
Based on 91 articles published since 2010
(Why 91 articles?)
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Between 2010 and 2020, C. Trenkwalder wrote the following 91 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial What would Dr. James Parkinson think today? The 21st Annual Congress of the International Parkinson's disease and movement disorders society. 2017

Obeso, Jose A / Trenkwalder, Claudia. ·HM CINAC, HM Puerta del Sur, and CEU-San Pablo University, Madrid. CIBERNED, Institute Carlos III, Spain. · Department of Neurosurgery, University Medical Center, Goettingen, and Paracelsus-Elena Hospital, Kassel, Germany. ·Mov Disord · Pubmed #28712120.

ABSTRACT: -- No abstract --

2 Review Clinical trials in REM sleep behavioural disorder: challenges and opportunities. 2020

Videnovic, Aleksandar / Ju, Yo-El S / Arnulf, Isabelle / Cochen-De Cock, Valérie / Högl, Birgit / Kunz, Dieter / Provini, Federica / Ratti, Pietro-Luca / Schiess, Mya C / Schenck, Carlos H / Trenkwalder, Claudia / Anonymous7441199. ·Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA AVIDENOVIC@mgh.harvard.edu. · Department of Neurology, Washington University in Saint Louis, Saint Louis, Missouri, USA. · Assistance Publique Hôpitaux de Paris, Service des pathologies du Sommeil, Hôpital Pitié-Salpêtrière, Paris, France. · UMR S 1127, CNRS UMR 7225, ICM, Sorbonne Universités, UPMC University Paris, Paris, France. · Neurologie et sommeil, Clinique Beau Soleil, Montpellier, France. · Laboratoire Movement to Health (M2H), EuroMov, Université Montpellier, Montpellier, France. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Clinic for Sleep and Chronomedicine, Berlin, Germany. · IRCCS Institute of Neurological Sciences of Bologna, University of Bologna, Bologna, Italy. · Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. · Neurocenter of Southern Switzerland, Lugano, Switzerland. · Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, USA. · Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota, USA. · Minnesota Regional Sleep Disorders Center, Minneapolis, Minnesota, USA. · Paracelsus Elena Klinik, Kassel, Germany. · Department of Neurosurgery, University Medical Center, Göttingen, Germany. ·J Neurol Neurosurg Psychiatry · Pubmed #32404379.

ABSTRACT: The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.

3 Review Mastering nocturnal jigsaws in Parkinson's disease: a dusk-to-dawn review of night-time symptoms. 2020

Bhidayasiri, Roongroj / Sringean, Jirada / Trenkwalder, Claudia. ·Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, 1873 Rama 4 Road, Bangkok, 10330, Thailand. rbh@chulapd.org. · Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, 1873 Rama 4 Road, Bangkok, 10330, Thailand. · Department of Neurosurgery, University Medical Centre Goettingen, Paracelsus-Elena Hospital, Kassel, Germany. ·J Neural Transm (Vienna) · Pubmed #32172472.

ABSTRACT: Finding out about night-time symptoms from Parkinson's disease (PD) patients can be a challenge as many patients and their carers cannot recall many symptoms that occur during the night, resulting in an under-recognition or a large variability of responses from clinical interviews and scales. Moreover, technology-based assessments for most night-time symptoms are still not universally available for use in a patient's home environment. Therefore, most physicians rely on their clinical acumen to capture these night-time symptoms based on pieces of patients' history, bedpartner's reports, clinical features, associated symptoms or conditions. To capture more night-time symptoms, the authors identified common nocturnal symptoms based on how they manifest from dusk to dawn with selected features relevant to PD. While some symptoms occur in healthy individuals, in PD patients, they may impact differently. The authors intend this narrative review to provide a practical guide on how these common night-time symptoms manifest and highlight pertinent issues by focusing on prevalence, clinical symptomatology, and specific relationships to PD. It is also important to recognise that PD-specific sleep disturbances increase with advancing disease with additional contributions from ageing, comorbidities, and medication side effects. However, the relative contribution of each factor to individual symptom may be different in individual patient, necessitating clinical expertise for individual interpretation. While there are debatable issues in certain areas, they underlie the complexity of night-time symptoms. Understanding night-time symptoms in PD is like re-arranging jigsaw pieces of clinical information to create, but never complete, a picture for physicians to instigate appropriate management.

4 Review Pain in Parkinson's disease: facts and uncertainties. 2018

Antonini, A / Tinazzi, M / Abbruzzese, G / Berardelli, A / Chaudhuri, K R / Defazio, G / Ferreira, J / Martinez-Martin, P / Trenkwalder, C / Rascol, O. ·University of Padua, Padua. · University of Verona, Verona. · University of Genoa, Genoa. · University of Rome, Rome. · IRCCS NEUROMED, Isernia, Italy. · Kings College London, London, UK. · University of Cagliari, Cagliari, Italy. · Hospital de Santa Maria, Lisbon, Portugal. · National Center of Epidemiology and CIBERNED, Madrid, Spain. · University Medical Center Goettingen, Goettingen, Germany. · Université de Toulouse, Toulouse, France. ·Eur J Neurol · Pubmed #29520899.

ABSTRACT: Pain is one of the most common and troublesome non-motor symptoms of Parkinson's disease (PD). It can appear at any time during the disease and is often present before diagnosis. However, there is little or no consensus on its definition. An expert group of clinicians with relevant research experience met to review the existing evidence and to identify gaps in our understanding leading towards AUTHOR: 'understanding towards' has been changed to 'understanding leading towards'. Please check and confirm that this is appropriate an optimized therapy of pain in PD. Key findings from epidemiologic, neurophysiologic, neuroimaging and clinical studies are reviewed. In each case, the evidence base is limited by wide variations in the definitions of pain applied, study methodologies and populations evaluated. Disease-related and medical conditions trigger spontaneous pain in patients with PD, which is then abnormally processed and results in painful manifestations in specific body parts. Dopaminergic medications, such as rotigotine, as well as opiate analgesics, such as oxycodone, have shown positive results but future studies with more detailed pain characterization at inclusion are warranted.

5 Review Getting a good night sleep? The importance of recognizing and treating nocturnal hypokinesia in Parkinson's disease. 2018

Bhidayasiri, Roongroj / Trenkwalder, Claudia. ·Chulalongkorn Center of Excellence on Parkinson Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand; Department of Rehabilitation Medicine, Juntendo University, Tokyo, Japan. Electronic address: rbh@chulapd.org. · Department of Neurosurgery, University Medical Center Gottingen, Paracelsus Elena Hospital, Kassel, Germany. ·Parkinsonism Relat Disord · Pubmed #29336905.

ABSTRACT: When Parkinson's disease (PD) patients are asked about the quality of their sleep, their answers are dominated by difficulties associated with impaired mobility in bed, medically referred to as nocturnal hypokinesia. Nocturnal hypokinesia is symptomatic from the mid-stage of the disease, affecting up to 70% of PD patients, and contributes to poor sleep quality, and increased carer burden. Here we explore four areas of nocturnal hypokinesia that are relevant to clinical practice, namely: manifestations and definition; clinical assessment and objective monitoring; etiologies and contributing factors; and evidence-based therapeutic approaches. In addition, we provide an operational definition of what constitutes nocturnal hypokinesia and outline different methods of assessment, ranging from clinical interviews and rating scales to objective night-time monitoring with inertial sensors. Optimal management of nocturnal hypokinesia in PD begins with recognizing its manifestation by inquiring about cardinal symptoms and contributing factors from, not only patients, but also carers, followed by formal assessment, and the application of individualized evidence-based treatment. Night-time dopaminergic treatment is the primary therapy; however, careful clinical judgment is required to balance the benefits with the potential adverse events related to nocturnal dopaminergic stimulation. Future studies are needed to explore the practicality of home-based objective assessment of nocturnal hypokinesia, new therapeutic options not limited to dopaminergic medications, and non-pharmacologic approaches, including training on compensatory strategies and bedroom adaptations.

6 Review [Pharmacotherapy of Parkinson's disease : Aspects of drug safety]. 2017

Müller-Rebstein, S / Trenkwalder, C / Oertel, W H / Culmsee, C / Eckermann, G / Höglinger, G U. ·Klinik für Neurologie, Klinikum rechts der Isar, Technische Universität München und Lehrstuhl für Translationale Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE) München, Feodor-Lynen Str. 17, 81377, München, Deutschland. · Institut für Pharmakologie und Klinische Pharmazie, Philipps-Universität Marburg, Marburg, Deutschland. · Paracelsus Elena-Klinik Kassel, Klinik für Neurochirurgie, Universitätsmedizin Göttingen, Göttingen, Deutschland. · Klinik für Neurologie, Philipps-Universität Marburg, Marburg, Deutschland. · Institut für Neurogenomik, Helmholtz Zentrum für Gesundheit und Umwelt München, München, Deutschland. · Fachkrankenhaus für Psychiatrie, Psychotherapie, Psychosomatik und Neurologie, Bezirkskrankenhaus Kaufbeuren, Kaufbeuren, Deutschland. · Klinik für Neurologie, Klinikum rechts der Isar, Technische Universität München und Lehrstuhl für Translationale Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE) München, Feodor-Lynen Str. 17, 81377, München, Deutschland. Guenter.Hoeglinger@tum.de. ·Nervenarzt · Pubmed #28497256.

ABSTRACT: BACKGROUND: This overview focuses on the aspects of the pharmacotherapy of Parkinson's disease, which is one of the most common disorders of the nervous system. This article presents the complexity of the pharmacotherapy of geriatric patients with neurological diseases. OBJECTIVES: Information about the potential risk factors and aspects of drug safety in the pharmacotherapy of Parkinson's disease. MATERIALS AND METHODS: Selective literature search using PubMed and the scientific-clinical experience of the authors. RESULTS: Patients with Parkinson's disease are usually geriatric patients with concomitant diseases. As a result they are often treated with comedication which leads to a complex medication regime with more than five drugs. Such polypharmacy increases the risk of adverse drug events due to the rising number of possible interactions and contraindications. To control this risk and maintain a safe therapy, certain measures should be considered. This implies additional need for educational work in order to create awareness regarding potential adverse drug events. In certain cases of diagnosed comorbidities or relevant drug prescriptions in the medication regime, follow-up examinations should be conducted. CONCLUSION: Specific parameters of Parkinson's disease, the health-related quality of life of affected patients and the quality of pharmacotherapeutic drug safety can be improved by targeted monitoring of the medication regime. As a result, the overall drug safety can be increased.

7 Review Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease--Clinical practice recommendations. 2015

Trenkwalder, Claudia / Chaudhuri, K Ray / García Ruiz, Pedro J / LeWitt, Peter / Katzenschlager, Regina / Sixel-Döring, Friederike / Henriksen, Tove / Sesar, Ángel / Poewe, Werner / Anonymous6190836 / Baker, Mary / Ceballos-Baumann, Andres / Deuschl, Günther / Drapier, Sophie / Ebersbach, Georg / Evans, Andrew / Fernandez, Hubert / Isaacson, Stuart / van Laar, Teus / Lees, Andrew / Lewis, Simon / Martínez Castrillo, Juan Carlos / Martinez-Martin, Pablo / Odin, Per / O'Sullivan, John / Tagaris, Georgios / Wenzel, Karoline. ·Centre of Parkinsonism and Movement Disorders, Paracelsus-Elena Hospital, Kassel, Germany; Department of Neurosurgery, University Medical Centre, Goettingen, Germany. Electronic address: trenkwalder@pk-mx.de. · National Parkinson Foundation Centre of Excellence, Kings College Hospital, Denmark Hill Campus, London, UK. · Movement Disorders Unit, Department of Neurology, Fundacion Jimenez Diaz, Madrid, Spain. · Wayne State University School of Medicine, Parkinson's Disease and Movement Disorders Program, Henry Ford West Bloomfield Hospital, West Bloomfield, MI, USA. · Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Danube Hospital, Vienna, Austria. · Centre of Parkinsonism and Movement Disorders, Paracelsus-Elena Hospital, Kassel, Germany; Department of Neurology, Philipps-University, Marburg, Germany. · Movement Disorder Clinic, Bispebjerg Hospital, Copenhagen, Denmark. · Department of Neurology, Hospital Clínico Universitario, Santiago de Compostela, Spain. · Department of Neurology, Medical University of Innsbruck, Austria. ·Parkinsonism Relat Disord · Pubmed #26189414.

ABSTRACT: Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical practice. This document outlines best-practice recommendations for selecting appropriate candidates for apomorphine intermittent injection (the pen-injection formulation) or apomorphine continuous infusion (the pump formulation), for initiating patients onto therapy and for managing their ongoing treatment. Apomorphine is a suitable therapeutic option for PD patients who experience troublesome 'off' periods despite optimized treatment with oral PD medications. Due to its speed of onset, apomorphine injection is particularly suited to those patients requiring rapid, reliable relief of both unpredictable and predictable 'off' periods, those who require reliable and fast relief when anticipating an 'off', those with levodopa absorption or gastric emptying problems resulting in delayed or failed 'on', or for rapid relief of early morning dystonia or akinesia. Apomorphine infusion(1) is suited for patients whose 'off' periods can no longer be adequately controlled by standard oral PD treatment or for those in whom rescue doses of apomorphine injection are effective but either needed too frequently (more than 4-6 times per day), or are associated with increasing dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine infusion may be effective for the management of specific non-motor symptoms of PD associated with 'off' periods. Apomorphine infusion is less invasive than other non-oral treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain stimulation.

8 Review Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease. 2013

Ferreira, J J / Katzenschlager, R / Bloem, B R / Bonuccelli, U / Burn, D / Deuschl, G / Dietrichs, E / Fabbrini, G / Friedman, A / Kanovsky, P / Kostic, V / Nieuwboer, A / Odin, P / Poewe, W / Rascol, O / Sampaio, C / Schüpbach, M / Tolosa, E / Trenkwalder, C / Schapira, A / Berardelli, A / Oertel, W H. ·Laboratory of Clinical Pharmacology and Therapeutics and Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal. ·Eur J Neurol · Pubmed #23279439.

ABSTRACT: OBJECTIVE: To summarize the 2010 EFNS/MDS-ES evidence-based treatment recommendations for the management of Parkinson's disease (PD). This summary includes the treatment recommendations for early and late PD. METHODS: For the 2010 publication, a literature search was undertaken for articles published up to September 2009. For this summary, an additional literature search was undertaken up to December 2010. Classification of scientific evidence and the rating of recommendations were made according to the EFNS guidance. In cases where there was insufficient scientific evidence, a consensus statement ('good practice point') is made. RESULTS AND CONCLUSIONS: For each clinical indication, a list of therapeutic interventions is provided, including classification of evidence.

9 Review Lewy body and parkinsonian dementia: common, but often misdiagnosed conditions. 2010

Mollenhauer, Brit / Förstl, Hans / Deuschl, Günther / Storch, Alexander / Oertel, Wolfgang / Trenkwalder, Claudia. ·Paracelsus-Elena-Klinik, Kassel, Germany. brit.mollenhauer@pk-mx.de ·Dtsch Arztebl Int · Pubmed #20963199.

ABSTRACT: BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are the two most common types of dementing neurodegenerative disease after Alzheimer's disease (AD). Both of these conditions are often diagnosed late or not at all. METHODS: Selective literature review. RESULTS: The severe cholinergic and dopaminergic deficits that are present in both DLB and PDD produce not only motor manifestations, but also cognitive deficits, mainly in the executive and visual-constructive areas, as well as psychotic manifestations such as visual hallucinations, delusions, and agitation. The intensity of these manifestations can fluctuate markedly over the course of the day, particularly in DLB. Useful tests for differential diagnosis include magnetic resonance imaging and electroencephalography; in case of clinical uncertainty, nuclear medical procedures and cerebrospinal fluid analysis can be helpful as well. Neuropathological studies have revealed progressive alpha-synuclein aggregation in affected areas of the brain. In DLB, beta-amyloid abnormalities are often seen as well. CONCLUSION: DLB should be included in the differential diagnosis of early dementia. If motor manifestations arise within one year (DLB), dopaminergic treatment should be initiated. On the other hand, patients with Parkinson's disease should undergo early screening for signs of dementia so that further diagnostic and therapeutic steps can be taken in timely fashion, as indicated. Cholinesterase inhibitors are useful for the treatment of cognitive deficits and experiential/behavioral disturbances in both DLB (off-label indication) and PDD (approved indication).

10 Review Quantification of α-synuclein in cerebrospinal fluid as a biomarker candidate: review of the literature and considerations for future studies. 2010

Mollenhauer, Brit / El-Agnaf, Omar M A / Marcus, Katrin / Trenkwalder, Claudia / Schlossmacher, Michael G. ·Paracelsus-Elena-Klinik, Kassel, Klinikstrasse 16, 34128 Kassel, Germany. brit.mollenhauer@pk-mx.de ·Biomark Med · Pubmed #20945981.

ABSTRACT: The pursuit of laboratory tests that allow for the reliable and inexpensive identification of subjects with parkinsonism represents a hot topic in translational neuroscience. This unmet need affects the counseling of presymptomatic, at-risk subjects and delays the accurate diagnosis of already symptomatic individuals. The absence of validated markers that are closely linked to the pathological disease process also compromises the objective monitoring of therapeutic interventions in clinical trials. Typical Parkinson's disease represents a heterogenous syndrome (but the majority of patients suffer from neurodegeneration) that is linked to the misprocessing of α-synuclein (α-Syn). The identification of α-Syn as a bona fide constituent of human cerebrospinal fluid and its quantification in early cross-sectional studies represent the beginning of a new chapter in Parkinson's disease research. It will determine what role, if any, cerebrospinal fluid α-Syn plays as a biomarker candidate in Lewy inclusion-positive forms of parkinsonism. This article focuses on the progress that has been made in seven recently published papers and highlights the challenges that lie ahead. We also provide specific information regarding standardized operating procedures for cerebrospinal fluid collection in PD biomarker research efforts.

11 Review Scales to assess sleep impairment in Parkinson's disease: critique and recommendations. 2010

Högl, Birgit / Arnulf, Isabelle / Comella, Cynthia / Ferreira, Joaquim / Iranzo, Alex / Tilley, Barbara / Trenkwalder, Claudia / Poewe, Werner / Rascol, Olivier / Sampaio, Cristina / Stebbins, Glenn T / Schrag, Anette / Goetz, Christopher G. ·Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. birgit.ho@i-med.ac.at ·Mov Disord · Pubmed #20931631.

ABSTRACT: There is a broad spectrum of sleep disturbances observed in Parkinson's disease (PD). A variety of scales have been applied to the evaluation of PD sleep and wakefulness, but only a small number have been assessed specifically for clinimetric properties in the PD population. The movement disorder society has commissioned this task force to examine these scales and to assess their use in PD. A systematic literature review was conducted to explore the use of sleep scales in PD and to determine which scales qualified for a detailed critique. The task force members, all of whom have extensive experience in assessing sleep in PD reviewed each of the scales using a structured proforma. Scales were categorized into recommended, suggested and listed according to predefined criteria. A total of 48 potential scales were identified from the search and reviewed. Twenty-nine were excluded because they did not meet review criteria or were variations of scales already included, leaving 19 scales that were critiqued and rated by the task force based on the rating criteria. Only six were found to meet criteria for recommendation or suggestion by the task force: the PD sleep scale (PDSS) and the Pittsburgh sleep quality index (PSQI) are recommended for rating overall sleep problems to screen and to measure severity, the SCOPA-sleep (SCOPA) is recommended for rating overall sleep problems both to screen and to measure severity, and for rating daytime sleepiness; the Epworth sleepiness scale (ESS) is recommended for rating daytime sleepiness to screen and to measure severity; the inappropriate sleep composite score (ISCS) is suggested for rating severe daytime sleepiness or sleep attacks to screen and to measure severity; and the Stanford sleepiness scale (SSS) is suggested for rating sleepiness and to measure severity at a specific moment. The task force does not recommend the development of new scales, but emphasizes the need for educational efforts to train physicians in sleep interview techniques and polysomnography.

12 Clinical Trial Increased dose of carbidopa with levodopa and entacapone improves "off" time in a randomized trial. 2019

Trenkwalder, Claudia / Kuoppamäki, Mikko / Vahteristo, Mikko / Müller, Thomas / Ellmén, Juha. ·From the Clinic of Neurosurgery (C.T.), University Medical Center of Goettingen, Germany · Orion Pharma (M.K., M.V., J.E.), Espoo, Finland · and Klink für Neurologie (T.M.), Alexianer St. Joseph Berlin-Weissensee GmbH, Germany. ·Neurology · Pubmed #30824559.

ABSTRACT: OBJECTIVE: To investigate whether increased fixed carbidopa doses of 65 or 105 mg (ODM-101/65 and ODM-101/105) in combination with 75, 100, 125, or 150 mg of levodopa and 200 mg of entacapone might improve "off" time in fluctuating Parkinson disease (PD) compared to the standard combination of 4:1 levodopa/carbidopa with the usual 200 mg of entacapone (LCE) during a 4-week treatment period. METHODS: This was a randomized, double-blind, double-dummy, active-controlled, crossover, multicenter, phase II, proof-of-concept study in patients with fluctuating PD. RESULTS: One hundred seventeen patients were randomized into the study (mean age 67.0 years; daily "off" time 5.3 hours; mean daily levodopa dose 610 mg). Carryover-adjusted mean changes from baseline "off" times were during ODM-101/65, -1.53 hours ( CONCLUSION: Increasing the dose of carbidopa in combination with levodopa and entacapone should be considered in the treatment of fluctuating PD to improve daily "off" times. Genotyping patients with PD according to COMT activity may improve individual treatment strategies. CLINICALTRIALSGOV IDENTIFIER: NCT01766258. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that an increased dose of carbidopa improves motor fluctuations when administered with levodopa and entacapone.

13 Clinical Trial Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. 2019

Postuma, Ronald B / Iranzo, Alex / Hu, Michele / Högl, Birgit / Boeve, Bradley F / Manni, Raffaele / Oertel, Wolfgang H / Arnulf, Isabelle / Ferini-Strambi, Luigi / Puligheddu, Monica / Antelmi, Elena / Cochen De Cock, Valerie / Arnaldi, Dario / Mollenhauer, Brit / Videnovic, Aleksandar / Sonka, Karel / Jung, Ki-Young / Kunz, Dieter / Dauvilliers, Yves / Provini, Federica / Lewis, Simon J / Buskova, Jitka / Pavlova, Milena / Heidbreder, Anna / Montplaisir, Jacques Y / Santamaria, Joan / Barber, Thomas R / Stefani, Ambra / St Louis, Erik K / Terzaghi, Michele / Janzen, Annette / Leu-Semenescu, Smandra / Plazzi, Guiseppe / Nobili, Flavio / Sixel-Doering, Friederike / Dusek, Petr / Bes, Frederik / Cortelli, Pietro / Ehgoetz Martens, Kaylena / Gagnon, Jean-Francois / Gaig, Carles / Zucconi, Marco / Trenkwalder, Claudia / Gan-Or, Ziv / Lo, Christine / Rolinski, Michal / Mahlknecht, Philip / Holzknecht, Evi / Boeve, Angel R / Teigen, Luke N / Toscano, Gianpaolo / Mayer, Geert / Morbelli, Silvia / Dawson, Benjamin / Pelletier, Amelie. ·Department of Neurology, McGill University, Montreal General Hospital, Montreal, Canada. · Centre d'Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, Canada. · Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Oxford Parkinson's Disease Centre (OPDC) and Oxford University, Oxford, UK. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Mayo Clinic, Rochester, MN, USA. · Unit of Sleep Medicine and Epilepsy, IRCCS, C.Mondino Foundation, Pavia, Italy. · Department of Neurology, Philipps-Universität, Marburg, Germany. · Sleep disorders unit, Pitie-Salpetriere Hospital, IHU@ICM and Sorbonne University, Paris, France. · Sleep Disorders Center, Department of Neurology, Scientific Institute Ospedale San Raffaele, Vita-Salute University, Milan, Italy. · Sleep Center, Department of Cardiovascular and Neurological Sciences, University of Cagliari, Italy. · Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. · IRCCS Institute of the Neurological Sciences, Ospedale Bellaria, ASL di Bologna, Bologna, Italy. · Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France; EuroMov, University of Montpellier, Montpellier, France. · Clinical Neurology, Dept. of Neuroscience (DINOGMI), University of Genoa, and Polyclinic San Martino Hospital, Genoa, Italy. · Department of Neurosurgery (C.T.) University Medical Center, Göttingen; Paracelsus-Elena-Klinik (B.M., C.T. F. S-D.), Kassel, Germany. · Movement Disorders Unit and Division of Sleep Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Neurology and Centre of Clinical Neurosciences of the First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. · Neuroscience Research Institute, Seoul National University College of Medicine, Department of Neurology, Seoul National University Hospital, Seoul, Korea. · Institute of Physiology Charité-Universitätsmedizin Berlin. Germany. · Sleep Unit, Department of Neurology, Hôpital Gui de Chauliac, Montpellier, INSERM U1061, Montpellier, F-34093 Cedex 5 France. · Department of Biomedical and Neuromotor Sciences, Bellaria Hospital, University of Bologna, Bologna, Italy. · IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy. · Brain and Mind Centre University of Sydney, Camperdown, Australia. · National Institute of Mental Health, Klecany, Third Faculty of Medicine, Charles Unviersity, Prague, Czech Republic. · Department of Neurology, Brigham and Women's Hospital, Boston; Harvard Medical School, Boston, USA. · Institute for Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Muenster, Germany. · Department of Psychology, Université du Québec à Montréal, Montreal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Canada. · Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada. · Department of Neurology, Hephata Klinik, Schwalmstadt-Treysa, Germany. · Nuclear Medicine, Department of Health Sciences (DISSAL), University of Genoa and Polyclinic San Martino Hospital, Genoa, Italy. ·Brain · Pubmed #30789229.

ABSTRACT: Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

14 Clinical Trial Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. 2018

Katzenschlager, Regina / Poewe, Werner / Rascol, Olivier / Trenkwalder, Claudia / Deuschl, Günther / Chaudhuri, K Ray / Henriksen, Tove / van Laar, Teus / Spivey, Kevin / Vel, Senthil / Staines, Harry / Lees, Andrew. ·Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Danube Hospital, Vienna, Austria. Electronic address: regina.katzenschlager@wienkav.at. · Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. · Université de Toulouse 3, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; Centre d'Investigation Clinique CIC1436, Réseau Ns-Park, French Clinical Research Infrastructure Network, Centre Expert Parkinson de Toulouse, Centre d'Excellence en Maladies Neuro-dégénératives NeuroToul, Department of Clinical Pharmacology and Neurosciences, Toulouse University Hospital, Toulouse, France. · Department of Neurosurgery, University Medical Center Goettingen, and Centre of Parkinsonism and Movement Disorders, Elena Hospital, Kassel, Germany. · Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany; Christian-Albrechts University, Kiel, Germany. · National Parkinson Foundation Centre of Excellence, Kings College Hospital, London, UK. · Movement Disorder Clinic, Bispebjerg Hospital, Copenhagen, Denmark. · Department of Neurology, University Medical Centre, Groningen, Netherlands. · Britannia Pharmaceuticals, Reading, UK. · Sigma Statistical Services, Balmullo, UK. · University College London Institute of Neurology, London, UK. ·Lancet Neurol · Pubmed #30055903.

ABSTRACT: BACKGROUND: Subcutaneous apomorphine infusion is a clinically established therapy for patients with Parkinson's disease with motor fluctuations not optimally controlled by oral medication. Open-label studies have shown that apomorphine infusion is effective in reducing off time (periods when antiparkinsonian drugs have no effect), dyskinesias, and levodopa dose, but confirmatory evidence from double-blind, controlled studies is lacking. We aimed to investigate the efficacy and safety of apomorphine infusion compared with placebo in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal treatment. METHODS: In this randomised, placebo-controlled, double-blind, multicentre trial, we enrolled patients at 23 European hospitals who had been diagnosed with Parkinson's disease more than 3 years previously and had motor fluctuations not adequately controlled by medical treatment. Patients were randomly assigned (1:1) with a computer-generated randomisation code, stratified by site, to receive 3-8 mg/h apomorphine or placebo saline infusion during waking hours (16 h a day [range 14-18 was acceptable]) for 12 weeks. The flow rate of the study drug and other oral medications could be adjusted during the first 4 weeks on the basis of individual efficacy and tolerability, after which patients entered an 8-week maintenance period. The primary endpoint was the absolute change in daily off time based on patient's diaries, and was assessed in the full analysis set, which was defined as all patients who received at least one dose of allocated study drug and had efficacy data available at any timepoint post-baseline. Safety was assessed in all patients who received at least one dose of apomorphine or placebo. All study participants and investigators were masked to treatment assignment. Both the 12-week double-blind phase and the 52-week open-label phase of this study are now complete; this paper reports results for the double-blind phase only. This study is registered with ClinicalTrials.gov (NCT02006121). FINDINGS: Between March 3, 2014, and March 1, 2016, 128 patients were screened for eligibility and 107 were randomly assigned, of whom 106 were included in the full analysis set (n=53 in both groups). Apomorphine infusion (mean final dose 4·68 mg/h [SD 1·50]) significantly reduced off time compared with placebo (-2·47 h per day [SD 3·70] in the apomorphine group vs -0·58 h per day [2·80] in the placebo group; difference -1·89 h per day, 95% CI -3·16 to -0·62; p=0·0025). Apomorphine was well tolerated without any unexpected safety signals. Six patients in the apomorphine group withdrew from the study because of treatment-related adverse events. INTERPRETATION: Apomorphine infusion results in a clinically meaningful reduction in off time in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal therapy. FUNDING: Britannia Pharmaceuticals.

15 Clinical Trial Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's disease (EASE LID 3). 2017

Oertel, Wolfgang / Eggert, Karla / Pahwa, Rajesh / Tanner, Caroline M / Hauser, Robert A / Trenkwalder, Claudia / Ehret, Reinhard / Azulay, Jean Philippe / Isaacson, Stuart / Felt, Larissa / Stempien, Mary Jean. ·Philipps University, Marburg, Germany. · University of Kansas Medical Center, Kansas City, Kansas, USA. · University of California San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, California, USA. · University of South Florida, Tampa, Florida, USA. · Paracelsus-Elena-Klinik, Kassel and Clinic Neurosurgery, University Medical Center, Goettingen, Germany. · Praxis Neurologie, Berlin, Germany. · Hôpital de la Timone, Marseille, France. · Parkinson's Disease and Movement Disorders Center, Boca Raton, Florida, USA. · Adamas Pharmaceuticals, Inc., Emeryville, California, USA. ·Mov Disord · Pubmed #28833562.

ABSTRACT: BACKGROUND: The treatment of levodopa-induced dyskinesia in Parkinson's disease (PD) is an unmet need with no approved drug therapy. OBJECTIVE: The purpose of this study was to investigate the efficacy and safety of 274 mg ADS-5102 (amantadine) extended-release capsules (equivalent to 340-mg amantadine HCl) for levodopa-induced dyskinesia in a randomized controlled trial. METHODS: PD patients with ≥1 hour of troublesome dyskinesia and at least mild functional impact were randomized to placebo or ADS-5102 once daily at bedtime for 13 weeks. The primary efficacy analysis was based on change from baseline to week 12 on the Unified Dyskinesia Rating Scale total score in the modified intent-to-treat population. OFF time was a key secondary measure. RESULTS: At week 12, least-squares mean change in the Unified Dyskinesia Rating Scale was -20.7 (standard error 2.2) for ADS-5102 (n = 37) and -6.3 (standard error 2.1) for placebo (n = 38; treatment difference -14.4, 95% confidence interval -20.4 to -8.3, P < .0001), indicating improvement in levodopa-induced dyskinesia. OFF time decreased 0.5 hours (standard error 0.3) for ADS-5102 from a baseline mean of 2.6 hours and increased 0.6 hours (standard error 0.3) for placebo from a baseline mean of 2.0 hours (treatment difference -1.1 hours, 95% confidence interval -2.0 to -0.2, P = .0199). The most common adverse events (ADS-5102 versus placebo) included dry mouth (13.5% versus 2.6%), nausea (13.5% versus 2.6%), decreased appetite (10.8% versus 0%), insomnia (10.8% versus 0%), orthostatic hypotension (10.8% versus 0%), constipation (8.1% versus 0%), falls (8.1% versus 5.3%), and visual hallucinations (8.1% versus 5.3%). Adverse events led to treatment discontinuation in 19% versus 8%, respectively. CONCLUSION: ADS-5102 274 mg is an oral pharmacotherapy demonstrating a significant decrease in levodopa-induced dyskinesia and improving OFF time. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

16 Clinical Trial A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease. 2016

Tison, François / Keywood, Charlotte / Wakefield, Mark / Durif, Franck / Corvol, Jean-Christophe / Eggert, Karla / Lew, Mark / Isaacson, Stuart / Bezard, Erwan / Poli, Sonia-Maria / Goetz, Christopher G / Trenkwalder, Claudia / Rascol, Olivier. ·Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France. francois.tison@chu-bordeaux.fr. · CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. francois.tison@chu-bordeaux.fr. · Service de Neurologie, CHU de Bordeaux, Bordeaux, France. francois.tison@chu-bordeaux.fr. · NS-Park/FCRIN Network, UMS 015, Toulouse, France. francois.tison@chu-bordeaux.fr. · Addex Pharma SA, Plan Les Ouates, Switzerland. · NS-Park/FCRIN Network, UMS 015, Toulouse, France. · Neurology Service, A, Hôpital Gabriel Montpied, Clermont Ferrand, France. · Sorbonne Universités and UPMC Univ Paris 06, INSERM UMRS-1127 and CIC-1422; CNRS UMR-7225; AP-HP; and ICM, Hôpital Pitié-Salpêtrière, Paris, France. · Universitätsklinikum Giessen und Marburg, Klinik für Neurologie, Marburg, Germany. · Department of Neurology USC/Keck School of Medicine, Los Angeles, California, USA. · Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, Florida, USA. · Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France. · CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France. · Rush University Medical Center, Dept. of Neurological Sciences, Movement Disorder Section, Chicago, Illinois, USA. · Paracelsus Elena Klinik, centre for Parkinson's Disease & Movement Disorders, Kassel, Germany. · CIC9302, Departments of Clinical Pharmacology and Neurosciences and NeuroToul COEN Center; INSERM, University Hospital of Toulouse and University of Toulouse 3, Toulouse, France. ·Mov Disord · Pubmed #27214664.

ABSTRACT: BACKGROUND: The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa-induced dyskinesia in Parkinson's disease (PD). METHODS: The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. RESULTS: Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. CONCLUSIONS: Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society.

17 Clinical Trial Mavoglurant in Parkinson's patients with l-Dopa-induced dyskinesias: Two randomized phase 2 studies. 2016

Trenkwalder, Claudia / Stocchi, Fabrizio / Poewe, Werner / Dronamraju, Nalina / Kenney, Chris / Shah, Amy / von Raison, Florian / Graf, Ana. ·Paracelsus-Elena Klinik, Kassel 34128, Germany; Department of Neurosurgery, University Medical Center, Goettingen, Germany. · IRCCS San Raffaele Pisana, Rome, Italy. · Department of Neurology, Medical University, Innsbruck, Austria. · Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. · Novartis Pharma AG, Basel, Switzerland. ·Mov Disord · Pubmed #27214258.

ABSTRACT: BACKGROUND: Two phase 2 randomized, double-blind studies were designed to evaluate efficacy and safety of immediate-release (study 1) and modified-release (study 2) mavoglurant formulations in PD l-dopa-induced dyskinesia. METHODS: Patients were randomized to mavoglurant 100-mg or placebo (4:3) groups (study 1) and mavoglurant 200-mg, mavoglurant 150-mg, or placebo (2:1:1) groups (study 2). Primary outcome was antidyskinetic efficacy, as measured by change from baseline to week 12 in modified Abnormal Involuntary Movement Scale total score. RESULTS: Differences in least-squares mean (standard error) change in modified Abnormal Involuntary Movement Scale total score in week 12 did not reach statistical significance in either study (study 1: mavoglurant 100 mg twice a day versus placebo, 1.7 [1.31]; study 2: mavoglurant 150 mg twice a day (-1.3 [1.16]) and 200 mg twice a day (-0.2 [1.03]) versus placebo). Adverse events incidence was higher with mavoglurant than with placebo. CONCLUSIONS: Both studies failed to meet the primary objective of demonstrating improvement of dyskinesia with mavoglurant treatment. © 2016 International Parkinson and Movement Disorder Society.

18 Clinical Trial A Placebo-Controlled Trial of AQW051 in Patients With Moderate to Severe Levodopa-Induced Dyskinesia. 2016

Trenkwalder, Claudia / Berg, Daniela / Rascol, Olivier / Eggert, Karla / Ceballos-Baumann, Andres / Corvol, Jean-Christophe / Storch, Alexander / Zhang, Lin / Azulay, Jean-Philippe / Broussolle, Emmanuel / Defebvre, Luc / Geny, Christian / Gostkowski, Michal / Stocchi, Fabrizio / Tranchant, Christine / Derkinderen, Pascal / Durif, Franck / Espay, Alberto J / Feigin, Andrew / Houeto, Jean-Luc / Schwarz, Johannes / Di Paolo, Thérèse / Feuerbach, Dominik / Hockey, Hans-Ulrich / Jaeger, Judith / Jakab, Annamaria / Johns, Donald / Linazasoro, Gurutz / Maruff, Paul / Rozenberg, Izabela / Sovago, Judit / Weiss, Markus / Gomez-Mancilla, Baltazar. ·Paracelsus-Elena Hospital, Kassel, Germany. · Department of Neurosurgery, University Medical Center, Goettingen, Germany. · German Parkinson Study Group, Marburg, Germany. · Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, Tübingen, Germany. · Department of Clinical Pharmacology and Neurosciences, NeuroToul Excellence Center for Neurodegenerative Disorders, University UPS of Toulouse III, CIC-9302/INSERM UMR825, Hôpital Purpan - Pavillon Riser, Toulouse, France. · NS PARK/FCRIN Network, France. · Department of Neurology, Philipps-University of Marburg, Marburg, Germany. · Schön Klinik München-Schwabing, München, Germany. · Sorbonne Universités, UPMC Univ Paris 06, and INSERM UMRS 1127 /CIC-1422, and CNRS UMR 7225, and AP-HP, and ICM, Hôpital Pitié-Salpêtrière, Département des maladies du système nerveux, Paris, France. · Division of Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany. · Department of Neurology, UC Davis MIND Institute, Sacramento, California, USA. · Service de Neurologie et pathologie du Mouvement, Hôpital de la Timone, Marseille Cedex, France. · Univisité Lyon 1, Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, Lyon, France. · CNRS UMR 5229, Centre de Neurosciences Cognitives, Team Basal Ganglia, Bron, France. · Service de Neurologie et Pathologie du movement, EA 1046, CHU de Lille, Hôpital Roger Salengro, Lille, France. · Movement to Health (M2H) laboratory, Euromov, University Montpellier 1, Hôpital gui de Chauliac, Montpellier, France. · Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio, USA. · Department of Neurology, Institute for Research and Medical Care, IROCS, Rome, Italy. · Service de Neurologie, Hôpital de Hautepierre, Strasbourg, France. · Centre Investigation Clinique Neurologie, CHU Nantes, Hôpital G&R Laennec, Nantes, France. · Service de Neurologie, Hôpital Gabriel Montpied, Clermont-Ferrand, France. · Department of Neurology, James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati Academic Health Center, Cincinnati, Ohio, USA. · Feinstein Institute for Medical Research, North Shore - LIJ Health System, Manhasset, New York, USA. · Service de Neurologie, CIC-INSERM 1402, CHU de Poitiers, Université de Poitiers, Poitiers, France. · Klinik Haag, Haag, Germany. · Neuroscience Research Unit, Centre de recherche du CHU de Québec, Québec, Canada. · Faculty of Pharmacy, Laval University, Québec, Canada. · Novartis Institutes for BioMedical Research, Basel, Switzerland. · Biometrics Matters Ltd, Hamilton, New Zealand. · Albert Einstein College of Medicine, New York, NY, USA, and CognitionMetrics, LLC, Wilmington, Delaware, USA. · Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. · Inbiomed, San Sebastian, Spain. · CogState, Inc, New Haven, Connecticut, USA. · Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada. ·Mov Disord · Pubmed #26990766.

ABSTRACT: BACKGROUND: This phase 2 randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the nicotinic acetylcholine receptor α7 agonist AQW051 in patients with Parkinson's disease and levodopa-induced dyskinesia. METHODS: Patients with idiopathic Parkinson's disease and moderate to severe levodopa-induced dyskinesia were randomized to AQW051 10 mg (n = 24), AQW051 50 mg (n = 24), or placebo (n = 23) once daily for 28 days. Coprimary end points were change in Modified Abnormal Involuntary Movement Scale and Unified Parkinson's Disease Rating Scale part III scores. Secondary outcomes included pharmacokinetics. RESULTS: In total, 67 patients completed the study. AQW051-treated patients experienced no significant improvements in Modified Abnormal Involuntary Movement Scale or Unified Parkinson's Disease Rating Scale part III scores by day 28. AQW051 was well tolerated; the most common adverse events were dyskinesia, fatigue, nausea, and falls. CONCLUSIONS: AQW051 did not significantly reduce dyskinesia or parkinsonian severity. © 2016 International Parkinson and Movement Disorder Society.

19 Clinical Trial Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson's disease (PANDA): a double-blind, randomised, placebo-controlled trial. 2015

Trenkwalder, Claudia / Chaudhuri, K Ray / Martinez-Martin, Pablo / Rascol, Olivier / Ehret, Reinhard / Vališ, Martin / Sátori, Maria / Krygowska-Wajs, Anna / Marti, Maria J / Reimer, Karen / Oksche, Alexander / Lomax, Mark / DeCesare, Julia / Hopp, Michael / Anonymous5340846. ·Paracelsus-Elena Hospital, Kassel, Germany; Department of Neurosurgery, University Medical Centre, Goettingen, Germany. Electronic address: ctrenkwalder@gmx.de. · National Parkinson's Foundation, Parkinson's Centre of Excellence, King's College Hospital, London, UK; Biomedical Research Unit for Dementia, King's College, London, UK. · National Centre of Epidemiology, Carlos III Institute of Health, Madrid, Spain. · Clinical Investigation Centre 1436, INSERM, Toulouse, France; University Hospital, Toulouse, France. · Neurologie Berlin, Gemeinschaftspraxis, Berlin, Germany. · Poliklinika Chocen Neuro, Chocen, Czech Republic; Department of Neurology, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Hradec Králové, Czech Republic. · Department of Neurology, Vaszary Kolos Hospital, Esztergom, Hungary. · Department of Neurology, Jagiellonian University, Krakow, Poland. · Parkinson's Disease and Movement Disorders Unit, Department of Neurology, Hospital Clinic, CIBERNED, Barcelona, Spain. · Mundipharma Research, Limburg an der Lahn, Germany; Private University Witten/Herdecke, Faculty of Health, Witten, Germany. · Mundipharma Research, Limburg an der Lahn, Germany; Rudolf-Buchheim Institute of Pharmacology, Justus-Liebig-Universität Giessen, Germany. · Mundipharma Research, Cambridge, UK. · Mundipharma Research, Limburg an der Lahn, Germany. ·Lancet Neurol · Pubmed #26494524.

ABSTRACT: BACKGROUND: Pain is a common non-motor symptom of Parkinson's disease. We investigated the analgesic efficacy of prolonged-release oxycodone-naloxone (OXN PR) in patients with Parkinson's disease and chronic, severe pain. METHODS: We did this phase 2 study in 47 secondary care centres in the Czech Republic, Germany, Hungary, Poland, Romania, Spain, and the UK. We enrolled patients with Hoehn and Yahr Stage II-IV Parkinson's disease, at least one type of severe pain, and an average 24-h pain score of at least 6 (assessed on an 11-point rating scale from 0=no pain to 10=pain as bad as you can imagine). Participants were randomly assigned (1:1) with a validated automated system (block size four) to either oral OXN PR or placebo for 16 weeks (starting dose oxycodone 5 mg, naloxone 2·5 mg, twice daily). Patients and investigators were masked to treatment assignment. The primary endpoint was average 24-h pain score at 16 weeks in the full analysis population. This study is registered with EudraCT (2011-002901-31) and ClinicalTrials.gov (NCT01439100). FINDINGS: We enrolled 202 patients; 93 were assigned to OXN PR and 109 to placebo; the full analysis population consisted of 88 patients versus 106 patients. Least squares mean average 24-h pain score at 16 weeks in the full analysis population was 5·0 (95% CI 4·5 to 5·5) in the OXN PR group versus 5·6 (5·1 to 6·0) in the placebo group (difference -0·6, 95% CI -1·3 to 0·0; p=0·058). Similar proportions of patients in each group had adverse events (60/92 [65%] vs 76/109 [70%]), treatment-related adverse events (52/92 [57%] vs 62/109 [57%]), and serious adverse events (5/92 [5%] vs 7/109 [6%]). Treatment-related nausea was more common in the OXN PR group than in the placebo group (16/92 [17%] vs 10/109 [9%]), as was treatment-related constipation (16/92 [17%] vs 6/109 [6%]). INTERPRETATION: The primary endpoint, based on the full analysis population at week 16, was not significant. Nonetheless, the results of this study highlight the potential efficacy of OXN PR for patients with Parkinson's disease-related pain and might warrant further research on OXN PR in this setting. FUNDING: Mundipharma Research.

20 Clinical Trial Rare variants in PLXNA4 and Parkinson's disease. 2013

Schulte, Eva C / Stahl, Immanuel / Czamara, Darina / Ellwanger, Daniel C / Eck, Sebastian / Graf, Elisabeth / Mollenhauer, Brit / Zimprich, Alexander / Lichtner, Peter / Haubenberger, Dietrich / Pirker, Walter / Brücke, Thomas / Bereznai, Benjamin / Molnar, Maria J / Peters, Annette / Gieger, Christian / Müller-Myhsok, Bertram / Trenkwalder, Claudia / Winkelmann, Juliane. ·Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität, München, Munich, Germany ; Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany. ·PLoS One · Pubmed #24244438.

ABSTRACT: Approximately 20% of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.

21 Article Impact of the COVID-19 Pandemic on Parkinson's Disease and Movement Disorders. 2020

Papa, Stella M / Brundin, Patrik / Fung, Victor S C / Kang, Un Jung / Burn, David J / Colosimo, Carlo / Chiang, Han-Lin / Alcalay, Roy N / Trenkwalder, Claudia / Anonymous3591192. ·Yerkes National Primate Research Center, Department of Neurology Emory University School of Medicine Atlanta Georgia USA. · Van Andel Institute, Center for Neurodegenerative Science Grand Rapids Michigan USA. · Movement Disorders Unit, Department of Neurology Westmead Hospital and Sydney Medical School, University of Sydney Sydney NSW Australia. · Department of Neurology New York University Grossman School of Medicine New York New York USA. · Department of Medical Sciences Newcastle University Medical School Newcastle United Kingdom. · Department of Neurology Santa Maria University Hospital Terni Italy. · Department of Neurology Neurological Institute, Taipei Veterans General Hospital Taipei Taiwan. · Department of Neurology Columbia University Irving Medical Center New York New York USA. · Paracelsus-Elena Klinik, Kassel, Department of Neurosurgery University Medical Center Goettingen Goettingen Germany. ·Mov Disord Clin Pract · Pubmed #32373651.

ABSTRACT: -- No abstract --

22 Article Rare Variants in Specific Lysosomal Genes Are Associated with Parkinson's Disease. 2020

Hopfner, Franziska / Mueller, Stefanie H / Szymczak, Silke / Junge, Olaf / Tittmann, Lukas / May, Sandra / Lohmann, Katja / Grallert, Harald / Lieb, Wolfgang / Strauch, Konstantin / Müller-Nurasyid, Martina / Berger, Klaus / Schormair, Barbara / Winkelmann, Juliane / Mollenhauer, Brit / Trenkwalder, Claudia / Maetzler, Walter / Berg, Daniela / Kasten, Meike / Klein, Christine / Höglinger, Günter U / Gasser, Thomas / Deuschl, Günther / Franke, André / Krawczak, Michael / Dempfle, Astrid / Kuhlenbäumer, Gregor. ·Department of Neurology, Universitätsklinikum Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany. · Department of Neurology, Hannover Medical School, Hannover, Germany. · Institute of Health Informatics, University College London, London, United Kingdom. · Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Epidemiology, University of Kiel, Kiel, Germany. · Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. · Institute of Epidemiology II, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany. · Research Unit of Molecular Epidemiology, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany. · German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany. · Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany. · Department of Medicine I, Ludwig-Maximilians-Universität, Munich, Germany. · DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. · Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany. · Institute of Neurogenomics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Human Genetics, Faculty of Medicine, Technical University Munich, Munich, Germany. · Munich Cluster for Systems Neurology (SyNergy), München, Deutschland. · Paracelsus-Elena-Klinik Kassel, Kassel, Germany. · Department of Neurology, University Medical Center Göttingen, Göttingen, Germany. · Clinic for Neurosurgery, University Medical Centre, Georg August University Göttingen, Göttingen, Germany. · Paracelsus-Elena Hospital, Kassel, Germany. · Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany. · Technical University of Munich, School of Medicine, Department of Neurology, Munich, Germany. · German Center for Neurodegenerative Diseases, Munich, Germany. · Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University Clinic Tuebingen, Tuebingen, Germany. ·Mov Disord · Pubmed #32267580.

ABSTRACT: OBJECTIVE: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. METHODS: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. RESULTS: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. CONCLUSION: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society.

23 Article Delivering patient-centered care in Parkinson's disease: Challenges and consensus from an international panel. 2020

Bhidayasiri, Roongroj / Panyakaew, Pattamon / Trenkwalder, Claudia / Jeon, Beomseok / Hattori, Nobutaka / Jagota, Priya / Wu, Yih-Ru / Moro, Elena / Lim, Shen-Yang / Shang, Huifang / Rosales, Raymond / Lee, Jee-Young / Thit, Win Min / Tan, Eng-King / Lim, Thien Thien / Tran, Ngoc Tai / Binh, Nguyen Thanh / Phoumindr, Appasone / Boonmongkol, Thanatat / Phokaewvarangkul, Onanong / Thongchuam, Yuwadee / Vorachit, Somchit / Plengsri, Rachaneewan / Chokpatcharavate, Marisa / Fernandez, Hubert H. ·Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, 10330, Thailand. Electronic address: rbh@chulapd.org. · Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, 10330, Thailand. · Department of Neurosurgery, University Medical Centre Goettingen, Paracelsus-Elena Hospital, Kassel, Germany. · Movement Disorder Centre at Seoul National University Hospital, Seoul, South Korea. · Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. · Department of Neurology, Chang-Gung Memorial Hospital, Linkou Medical Centre and Chang-Gung University College of Medicine, Taipei, Taiwan. · Movement Disorder Centre, Centre Hospitalier Universitaire (CHU) of Grenoble, Grenoble Alpes University, INSERM U1216, France. · Division of Neurology, Department of Medicine and the Mah Pooi Soo and Tan Chin Nam Centre for Parkinson's and Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Department of Neurology, West China Hospital, Sichuan University, China. · Neuroscience Institute, Department of Neurology and Psychiatry, University of Santo Tomas Hospital, Manila, Philippines. · Department of Neurology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center & Seoul National University College of Medicine, Seoul, South Korea. · Department of Neurology, University of Medicine, Yangon General Hospital, Yangon, Myanmar. · National Neuroscience Institute, DUKE NUS Medical School, Singapore. · Department of Neurology, Island Hospital, Penang, Malaysia. · Movement Disorder Unit, Neurology Department, University Medical Centre, Ho Chi Minh City University of Medicine and Pharmacy, Ho Chi Minh, Viet Nam. · Department of Neurology, Hanoi Medical University and National Geriatric Hospital, Hanoi, Viet Nam. · University of Health Science, Vientiane, Laos. · Chulalongkorn Parkinson Patients' Support Group, Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Bangkok, Thailand. · Center for Neurorestoration, Cleveland Clinic, Cleveland, OH, USA. ·Parkinsonism Relat Disord · Pubmed #32146380.

ABSTRACT: An international panel of movement disorders specialists explored the views and perceptions of people with Parkinson's disease (PD) about their condition and its treatment, including the potential mismatch between the clinician's view of the patient's condition and their own view of what aspects of the disease most affect their daily lives. The initiative was focused on Asian countries, so participants comprised experts in the management of PD from key centers in Asia, with additional insight provided by European and the North American movement disorders experts. Analysis of peer-reviewed publications on patient perceptions of PD and the factors that they consider important to their wellbeing identified several contributing factors to the mismatch of views, including gaps in knowledge of PD and its treatment, an understanding of the clinical heterogeneity of PD, and the importance of a multidisciplinary approach to patient care. The faculty proposed options to bridge these gaps to ensure that PD patients receive the personalized treatment they need to achieve the best possible outcomes. It was considered essential to improve patient knowledge about PD and its treatment, as well as increasing the awareness of clinicians of PD heterogeneity in presentation and treatment response. A multidisciplinary and shared-care approach to PD was needed alongside the use of patient-centered outcome measures in clinical trials and clinical practice to better capture the patient experience and improve the delivery of individualized therapy.

24 Article Aberrant functional connectivity of resting state networks related to misperceptions and intra-individual variability in Parkinson's disease. 2020

Miloserdov, Kristina / Schmidt-Samoa, Carsten / Williams, Kathleen / Weinrich, Christiane Anne / Kagan, Igor / Bürk, Katrin / Trenkwalder, Claudia / Bähr, Mathias / Wilke, Melanie. ·Department of Cognitive Neurology, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany; German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, Goettingen 37077, Germany; Leibniz Science Campus Primate Cognition, German Primate Center, Kellnerweg 4, Goettingen 37077, Germany. · Department of Cognitive Neurology, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany. · Department of Cognitive Neurology, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany; Department of Neurology, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany. · Kliniken Schmieder Stuttgart-Gerlingen, Solitudestraße 20, Gerlingen 70839, Germany. · Paracelsus-Elena Klinik, Klinikstraße 16, Kassel 34128, Germany; Department of Neurosurgery, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany. · Department of Neurology, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany. · Department of Cognitive Neurology, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany; German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, Goettingen 37077, Germany; Leibniz Science Campus Primate Cognition, German Primate Center, Kellnerweg 4, Goettingen 37077, Germany. Electronic address: melanie.wilke@med.uni-goettingen.de. ·Neuroimage Clin · Pubmed #31794926.

ABSTRACT: Patients with Parkinson's disease (PD) frequently suffer from visual misperceptions and hallucinations, which are difficult to objectify and quantify. We aimed to develop an image recognition task to objectify misperceptions and to assess performance fluctuations in PD patients with and without self-reported hallucinations. Thirty-two non-demented patients with Parkinson's disease (16 with and 16 without self-reported visual hallucinations) and 25 age-matched healthy controls (HC) were tested. Participants performed a dynamic image recognition task with real and scrambled images. We assessed misperception scores and intra-individual variability in recognition times. To gain insight into possible neural mechanisms related to misperceptions and performance fluctuations we correlated resting state network connectivity to the behavioral outcomes in a subsample of Parkinson's disease patients (N = 16). We found that PD patients with self-reported hallucinations (PD-VH) exhibited higher perceptual error rates, due to decreased perceptual sensitivity and not due to changed decision criteria. In addition, PD-VH patients exhibited higher intra-individual variability in recognition times than HC or PD-nonVH patients. Both, misperceptions and intra-individual variability were negatively correlated with resting state functional connectivity involving frontal and parietal brain regions, albeit in partly different subregions. Consistent with previous research suggesting that hallucinations arise from dysfunction in attentional networks, misperception scores correlated with reduced functional connectivity between the dorsal attention and salience network. Intra-individual variability correlated with decreased connectivity between somatomotor and right fronto-parietal networks. We conclude that our task can detect visual misperceptions that are more prevalent in PD-VH patients. In addition, fluctuating visual performance appear to be a signature of PD-VH patients, which might assist further studies of the underlying pathophysiological mechanisms and cognitive processes.

25 Article Elemental fingerprint: Reassessment of a cerebrospinal fluid biomarker for Parkinson's disease. 2020

Maass, Fabian / Michalke, Bernhard / Willkommen, Desiree / Leha, Andreas / Schulte, Claudia / Tönges, Lars / Mollenhauer, Brit / Trenkwalder, Claudia / Rückamp, Daniel / Börger, Matthias / Zerr, Inga / Bähr, Mathias / Lingor, Paul. ·Department of Neurology, University Medical Center Goettingen, Germany. Electronic address: fabian.maass@med.uni-goettingen.de. · Research Unit Analytical BioGeoChemistry, German Research Center for Environmental Health, Helmholtz Zentrum Munich, Neuherberg, Germany. Electronic address: bernhard.michalke@helmholtz-muenchen.de. · Research Unit Analytical BioGeoChemistry, German Research Center for Environmental Health, Helmholtz Zentrum Munich, Neuherberg, Germany. Electronic address: desi.willkommen@gmx.de. · Department of Medical Statistics, University Medical Center, Goettingen, Germany. Electronic address: andreas.leha@med.uni-goettingen.de. · DZNE, German Center for Neurodegenerative Diseases, University of Tuebingen, Germany; Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Germany. Electronic address: claudia.schulte@uni-tuebingen.de. · Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Bochum, Germany. Electronic address: lars.toenges@rub.de. · Department of Neurology, University Medical Center Goettingen, Germany; Paracelsus-Elena-Klinik, Kassel, Germany. Electronic address: brit.mollenhauer@med.uni-goettingen.de. · Paracelsus-Elena-Klinik, Kassel, Germany; Dept. Neurosurgery, University Medical Center, Goettingen, Germany. · Federal Institute for Geosciences and Natural Resources, Hannover, Germany. Electronic address: daniel.rueckamp@bgr.de. · Department of Neurology, University Medical Center Goettingen, Germany. Electronic address: matthias.boerger@med.uni-goettingen.de. · Department of Neurology, University Medical Center Goettingen, Germany; DZNE, German Center for Neurodegenerative Diseases Goettingen, Germany. Electronic address: ingazerr@med.uni-goettingen.de. · Department of Neurology, University Medical Center Goettingen, Germany; Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Goettingen, Germany. Electronic address: mbaehr@gwdg.de. · Department of Neurology, University Medical Center Goettingen, Germany; DZNE, German Center for Neurodegenerative Diseases Goettingen, Germany; Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Goettingen, Germany; Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center Goettingen, Germany; Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University Munich, 81675 Munich, Germany. Electronic address: paul.lingor@tum.de. ·Neurobiol Dis · Pubmed #31733347.

ABSTRACT: The aim of the study was to validate a predictive biomarker machine learning model for the classification of Parkinson's disease (PD) and age-matched controls (AMC), based on bioelement abundance in the cerebrospinal fluid (CSF). For this multicentric trial, participants were enrolled from four different centers. CSF was collected according to standardized protocols. For bioelement determination, CSF samples were subjected to inductively coupled plasma mass spectrometry. A predefined Support Vector Machine (SVM) model, trained on a previous discovery cohort was applied for differentiation, based on the levels of six different bioelements. 82 PD patients, 68 age-matched controls and 7 additional Normal Pressure Hydrocephalus (NPH) patients were included to validate a predefined SVM model. Six differentiating elements (As, Fe, Mg, Ni, Se, Sr) were quantified. Based on their levels, SVM was successfully applied to a new local cohort (AUROC 0.76, Sensitivity 0.80, Specificity 0.83), without taking any additional features into account. The same model did not discriminate PD and AMCs / NPH from three external cohorts, likely due to center effects. However, discrimination was possible in cohorts with a full elemental data set, now using center-specific discovery cohorts and a cross validated approach (AUROC 0.78 and 0.88, respectively). Pooled PD CSF iron levels showed a clear correlation with disease duration (p = .0001). In summary, bioelemental CSF patterns, obtained by mass spectrometry and integrated into a predictive model yield the potential to facilitate the differentiation of PD and AMC. Center-specific biases interfere with application in external cohorts. This must be carefully addressed using center-defined, local reference values and models.

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