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Parkinson Disease: HELP
Articles by Eduardo S. Tolosa
Based on 138 articles published since 2010
(Why 138 articles?)
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Between 2010 and 2020, E. Tolosa wrote the following 138 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Editorial Idiopathic Parkinson's syndrome. Preface. 2011

Korczyn, Amos D / Reichmann, Heinz / Tolosa, Eduardo. · ·J Neurol Sci · Pubmed #21893323.

ABSTRACT: -- No abstract --

2 Review LRRK2 in Parkinson disease: challenges of clinical trials. 2020

Tolosa, Eduardo / Vila, Miquel / Klein, Christine / Rascol, Olivier. ·Parkinson and Movement Disorders Unit, Neurology Service, Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain. etolosa@clinic.cat. · Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain. etolosa@clinic.cat. · Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain. · Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR), Autonomous University of Barcelona, Barcelona, Spain. · Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. · Institute of Neurogenetics, University of Lübeck, Lübeck, Germany. · Clinical Investigation Center CIC1436, Departments of Clinical Pharmacology and Neurosciences, NS-Park/FCRIN network and NeuroToul Center of Excellence for Neurodegeneration, INSERM, University Hospital of Toulouse and University of Toulouse, Toulouse, France. ·Nat Rev Neurol · Pubmed #31980808.

ABSTRACT: One of the most common monogenic forms of Parkinson disease (PD) is caused by mutations in the LRRK2 gene that encodes leucine-rich repeat kinase 2 (LRRK2). LRRK2 mutations, and particularly the most common mutation Gly2019Ser, are observed in patients with autosomal dominant PD and in those with apparent sporadic PD, who are clinically indistinguishable from those with idiopathic PD. The discoveries that pathogenic mutations in the LRRK2 gene increase LRRK2 kinase activity and that small-molecule LRRK2 kinase inhibitors can be neuroprotective in preclinical models of PD have placed LRRK2 at the centre of disease modification efforts in PD. Recent investigations also suggest that LRRK2 has a role in the pathogenesis of idiopathic PD and that LRRK2 therapies might, therefore, be beneficial in this common subtype of PD. In this Review, we describe the characteristics of LRRK2-associated PD that are most relevant to the development of LRRK2-targeted therapies and the design and implementation of clinical trials. We highlight strategies for correcting the effects of mutations in the LRRK2 gene, focusing on how to identify which patients are the optimal candidates and how to decide on the timing of such trials. In addition, we discuss challenges in implementing trials of disease-modifying treatment in people who carry LRRK2 mutations.

3 Review Emergencies and critical issues in Parkinson's disease. 2020

Simonet, Cristina / Tolosa, Eduardo / Camara, Ana / Valldeoriola, Francesc. ·Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, London, UK. · Neurology Department, Hospital Clinic de Barcelona, Barcelona, Spain. · Neurology Department, Hospital Clinic de Barcelona, Barcelona, Spain etolosa@clinic.ub.es. · Neuroscience Department, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain. ·Pract Neurol · Pubmed #31427383.

ABSTRACT: Complications from Parkinson's disease may develop over the disease course, sometimes unexpectedly, and require prompt or even urgent medical intervention. The most common are associated with aggravation of motor symptoms; serious non-motor complications, such as psychosis, orthostatic hypotension or sleep attacks, also occur. Here we review such complications, their clinical presentation, precipitating factors and management, including those related to using device-aided therapies. Early recognition and prompt attention to these critical situations is challenging, even for the Parkinson's disease specialist, but is essential to prevent serious problems.

4 Review Opicapone for the treatment of Parkinson's disease: A review of a new licensed medicine. 2018

Fabbri, Margherita / Ferreira, Joaquim J / Lees, Andrew / Stocchi, Fabrizio / Poewe, Werner / Tolosa, Eduardo / Rascol, Olivier. ·Instituto de Medicina Molecular, Lisbon, Portugal. · Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal. · CNS - Campus Neurológico Sénior, Torres Vedras, Portugal. · The National Hospital, Queen Square, London, UK. · University and Institute for Research and Medical Care, IRCCS San Raffaele, Rome, Italy. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Movement Disorder Unit, Neurology Service, Hospital Clínic of Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Departments of Clinical Pharmacology and Neurosciences, Clinical Investigation Center CIC 1436, NS-Park/FCRIN network and NeuroToul COEN Center, INSERM, CHU de Toulouse, Université de Toulouse 3, Toulouse, France. ·Mov Disord · Pubmed #30264443.

ABSTRACT: Catechol-O-methyl transferase inhibitors are currently used as first-line add-on therapy to levodopa for the treatment of end-of-dose motor fluctuations in Parkinson's disease patients, as they increase levodopa bioavailability. Several factors hamper the use of current available catechol-O-methyl transferase inhibitors, that is, the moderate efficacy and multiple dosing for entacapone and the risk of liver toxicity with tolcapone. Opicapone, a new long-acting, peripherally selective, once-daily catechol-O-methyl transferase inhibitor, was recently licensed in Europe. Two phase 3 double-blind clinical trials demonstrated opicapone efficacy in reducing OFF time by an average of about 60 minutes daily compared with placebo, without increasing ON time with troublesome dyskinesias. These effects were also maintained during a subsequent open-label extension consisting of 1-year follow-up. Opicapone showed a good safety profile. From June 2016, Opicapone received the approval for marketing authorization from the European Commission as adjunctive therapy to levodopa/DOPA decarboxylase inhibitors in patients with PD and end-of-dose motor fluctuations. We aimed to review the clinical pharmacological data of opicapone, summarize its clinical efficacy and safety issues, and discuss its potential role in the management of Parkinson's disease. © 2018 International Parkinson and Movement Disorder Society.

5 Review Two-hundred Years Later: Is Parkinson's Disease a Single Defined Entity? 2017

Rodríguez-Violante, Mayela / Cervantes-Arriaga, Amin / Fahn, Stanley / Tolosa, Eduardo. ·Movement Disorders Clinic, National Institute of Neurology and Neurosurgery, Mexico City, Mexico, USA. · Department of Neurology, Columbia University Medical Center, New York, USA. · Neurological Tissue Bank, Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid and Universidad de Barcelona, Barcelona, Spain. ·Rev Invest Clin · Pubmed #29265118.

ABSTRACT: An Essay on the Shaking Palsy, by James Parkinson, was published in 1817. Later, Jean-Martin Charcot better described some of the motor features of the disease and named the condition as "La Maladie de Parkinson." As understanding about the disease progressed, aided by both clinical expertise and technological developments, the definition of what is Parkinson's disease has evolved. Motor phenotype, non-motor symptoms, monogenic mutations, genetic risk factors, disease subtyping, and data-driven clusters, among other concepts, have given rise to the hypothesis that Parkinson's disease may be not one well-defined entity but several different diseases encompassed as a levodopa-responsive Parkinsonism. This review present and discusses several of these factors and how they may support or not the notion of Parkinson's being one or more diseases. In summary, current evidence appears to be insufficient at this moment to clarify this issue. Parkinson's disease will continue to be an evolving concept over the years to come.

6 Review Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. 2017

Obeso, J A / Stamelou, M / Goetz, C G / Poewe, W / Lang, A E / Weintraub, D / Burn, D / Halliday, G M / Bezard, E / Przedborski, S / Lehericy, S / Brooks, D J / Rothwell, J C / Hallett, M / DeLong, M R / Marras, C / Tanner, C M / Ross, G W / Langston, J W / Klein, C / Bonifati, V / Jankovic, J / Lozano, A M / Deuschl, G / Bergman, H / Tolosa, E / Rodriguez-Violante, M / Fahn, S / Postuma, R B / Berg, D / Marek, K / Standaert, D G / Surmeier, D J / Olanow, C W / Kordower, J H / Calabresi, P / Schapira, A H V / Stoessl, A J. ·HM CINAC, Hospital Universitario HM Puerta del Sur, Mostoles, Madrid, Spain. · Universidad CEU San Pablo, Madrid, Spain. · CIBERNED, Madrid, Spain. · Department of Neurology, Philipps University, Marburg, Germany. · Parkinson's Disease and Movement Disorders Department, HYGEIA Hospital and Attikon Hospital, University of Athens, Athens, Greece. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. · Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Canada. · Department of Medicine, University of Toronto, Toronto, Canada. · Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC), Corporal Michael J. Crescenz Veteran's Affairs Medical Center, Philadelphia, Pennsylvania, USA. · Medical Sciences, Newcastle University, Newcastle, UK. · Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia. · School of Medical Sciences, University of New South Wales and Neuroscience Research Australia, Sydney, Australia. · Université de Bordeaux, Institut des Maladies Neurodégénératives, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, Institut des Maladies Neurodégénératives, Bordeaux, France. · China Academy of Medical Sciences, Institute of Lab Animal Sciences, Beijing, China. · Departments of Neurology, Pathology, and Cell Biology, the Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA. · Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA. · Institut du Cerveau et de la Moelle épinière - ICM, Centre de NeuroImagerie de Recherche - CENIR, Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Paris, France. · Groupe Hospitalier Pitié-Salpêtrière, Paris, France. · Clinical Sciences Department, Newcastle University, Newcastle, UK. · Department of Nuclear Medicine, Aarhus University, Aarhus, Denmark. · Human Neurophysiology, Sobell Department, UCL Institute of Neurology, London, UK. · Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. · Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson's disease, Toronto Western Hospital, University of Toronto, Toronto, Canada. · Movement Disorders and Neuromodulation Center, Department of Neurology, University of California-San Francisco, San Francisco, California, USA. · Parkinson's Disease Research, Education and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA. · Veterans Affairs Pacific Islands Health Care System, Honolulu, Hawaii, USA. · Parkinson's Institute, Sunnyvale, California, USA. · Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. · Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Department of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada. · Department of Neurology, Universitätsklinikum Schleswig-Holstein, Christian Albrechts University Kiel, Kiel, Germany. · Department of Medical Neurobiology, Institute of Medical Research Israel-Canada, Jerusalem, Israel. · Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel. · Department of Neurosurgery, Hadassah University Hospital, Jerusalem, Israel. · Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Barcelona, Spain. · Department of Medicine, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona, Spain. · Movement Disorders Clinic, Clinical Neurodegenerative Research Unit, Mexico City, Mexico. · Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico. · Department of Neurology, Columbia University Medical Center, New York, New York, USA. · Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada. · Klinik für Neurologie, UKSH, Campus Kiel, Christian-Albrechts-Universität, Kiel, Germany. · Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA. · Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. · Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, New York, USA. · Research Center for Brain Repair, Rush University Medical Center, Chicago, Illinois, USA. · Neuroscience Graduate Program, Rush University Medical Center, Chicago, Illinois, USA. · Neurological Clinic, Department of Medicine, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy. · Laboratory of Neurophysiology, Santa Lucia Foundation, IRCCS, Rome, Italy. · University Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, London, UK. · Pacific Parkinson's Research Centre, Division of Neurology & Djavadf Mowafaghian Centre for Brain Health, University of British Columbia, British Columbia, Canada. · Vancouver Coastal Health, Vancouver, British Columbia, Canada. ·Mov Disord · Pubmed #28887905.

ABSTRACT: This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

7 Review Opicapone for the management of end-of-dose motor fluctuations in patients with Parkinson's disease treated with L-DOPA. 2017

Lees, Andrew J / Ferreira, Joaquim / Rascol, Olivier / Reichmann, Heinz / Stocchi, Fabrizio / Tolosa, Eduardo / Poewe, Werner. ·a Reta Lila Weston Institute for Neurological Studies, UCL , London , UK. · b Centro de Estudos Egas Moniz , Hospital de Santa Maria , Lisbon , Portugal. · c Departments of Clinical Pharmacology and Neurosciences, Clinical Investigation Center CIC 1436, NS-Park/FCRIN network and NeuroToul COEN Center , INSERM, Toulouse University Hospital and Toulouse3 University , Toulouse , France. · d Department of Neurology , Technische Universitaet Dresden , Dresden , Germany. · e Institute of Neurology , IRCCS San Raffaele Pisana , Rome , Italy. · f Neurology Service, Centro de Investigación Biomódica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic, IDIBAPS , Universitat de Barcelona , Barcelona , Spain ​​​​. · g Department of Neurology , Innsbruck Medical University , Innsbruck , Austria. ·Expert Rev Neurother · Pubmed #28580819.

ABSTRACT: INTRODUCTION: Opicapone is a third generation, highly potent and effective catechol O‑methyltransferase (COMT) inhibitor that optimizes the pharmacokinetics and bioavailability of L-DOPA therapy. Areas covered: In this review, the authors describe the preclinical and clinical development of opicapone. In PD patients with motor fluctuations, once daily opicapone administration was well-tolerated and consistently reduced OFF-time and increased ON-time without increasing the frequency of troublesome dyskinesia, and these benefits were maintained over at least a year of continued open-label therapy. Expert commentary: With its convenient once-daily regimen, adjunct opicapone should be considered as an effective option for use in L-DOPA treated PD patients experiencing motor fluctuations.

8 Review Challenges of modifying disease progression in prediagnostic Parkinson's disease. 2016

Salat, David / Noyce, Alastair J / Schrag, Anette / Tolosa, Eduardo. ·Neurology Service, Hospital Vall d'Hebron, Barcelona, Spain. · Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK. · Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. · Parkinson's Disease Research, August Pi i Sunyer Biomedical Research Institute, University of Barcelona, Barcelona, Spain; Parkinson Disease and Movement Disorder Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universidad de Barcelona, Barcelona, Spain. Electronic address: etolosa@clinic.ub.es. ·Lancet Neurol · Pubmed #26993435.

ABSTRACT: Neurodegeneration in Parkinson's disease starts years before a clinical diagnosis can be reliably made. The prediagnostic phase of the disease offers a window of opportunity in which disease-modifying therapies-ie, those aimed at delaying or preventing the progression to overt disease and its many complications-could be most beneficial, but no such therapies are available at present. The unravelling of the mechanisms of neurodegeneration from the earliest stages, however, could lead to the development of new interventions whose therapeutic potential will need to be assessed in adequately designed clinical trials. Advances in the understanding of this prediagnostic phase of Parkinson's disease (for which the clinical diagnostic and prognostic markers used in more advanced disease stages are not applicable) will lead to the identification of biomarkers of neurodegeneration and its progression. These biomarkers will, in turn, help to identify the optimum population to be included and the most appropriate outcomes to be assessed in trials of disease-modifying drugs. Potential risks to minimally symptomatic participants, some of whom might not progress to manifest Parkinson's disease, and individuals who do not wish to know their mutation carrier status, could pose specific ethical dilemmas in the design of these trials.

9 Review Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr. 2015

Lees, Andrew J / Tolosa, Eduardo / Olanow, C Warren. ·The National Hospital, Queen Square and University College London, London, UK. ·Mov Disord · Pubmed #25488030.

ABSTRACT: Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that levodopa (l-dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the l-dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,l-dopa. As reported in his 1967 article, d,l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of l-dopa, and almost 50 years later l-dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success.

10 Review Levodopa in the treatment of Parkinson's disease: current status and new developments. 2013

Salat, David / Tolosa, Eduardo. ·Universitat Autònoma de Barcelona, Barcelona, Spain. ·J Parkinsons Dis · Pubmed #23948989.

ABSTRACT: Levodopa, a dopamine precursor, is an effective and well-tolerated dopamine replacement agent used to treat Parkinson's disease (PD). Oral levodopa has been widely used for over 40 years, often in combination with a dopa-decarboxylase inhibitor (DDCI), which reduces many treatment complications, extending its half-life and increasing levodopa availability to the brain. Entacapone, a catechol-O-methyltransferase inhibitor, can also be used to improve the bioavailability of levodopa, especially when used in conjunction with a DDCI. During early-stage PD, treatment will depend on the severity of symptoms; if greater symptomatic effect is required then levodopa or dopamine agonists are usually the drugs of choice. The ability to remain employable or physically active is an important goal in younger patients, therefore, in some instances levodopa initiation should be considered early on, either as a monotherapy or in combination with other drugs. The clinical use of levodopa may eventually be limited by the development of various treatment-related complications, including response fluctuations, dyskinesia and psychiatric problems. Motor complications are related to the intermittent delivery of dopamine-replacing drugs to the brain. Triple combination of levodopa/carbidopa/entacapone available in a single tablet in multiple levodopa dose strengths offers flexibility and helps control response fluctuations. Recent developments in treatment with levodopa try to obtain continuous delivery with levodopa and include duodenal infusion of a levodopa/carbidopa, transdermal levodopa patch, and oral pro-levodopa. Levodopa remains the most potent dopaminergic therapy for PD.

11 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.

12 Review Impulse control disorders in Parkinson's disease. 2012

Vilas, Dolores / Pont-Sunyer, Claustre / Tolosa, Eduardo. ·Institut Clínic de Neurodències, Hospital Clínic de Barcelona, Department of Medicine, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain. ·Parkinsonism Relat Disord · Pubmed #22166463.

ABSTRACT: Impulse control disorders (ICDs), a group of complex behavioral disorders, occur more commonly in Parkinson's disease (PD) patients than in the general population, with a reported prevalence up to 13.6% in some studies. The most common ICDs reported are pathological gambling (PG), hypersexuality (HS), compulsive shopping and compulsive eating. More than a quarter of the patients with ICDs have 2 or more behavioral addictions. These abnormal behaviors impair activities of daily living and have a negative impact on quality of life of patients and their families. As with many other non motor symptoms in PD, ICDs are frequently under-reported by patients and caregivers and may be under-recognized by the treating physicians. Treatment with dopamine agonists (DA) is the main risk factor for developing ICDs, and stimulation of mesolimbic D3 receptors by DA is thought to underlie their development. The DA effect seems to be a class effect and not specific for any DA. Levodopa can also induce ICDs but much less so than the DAs. The management of ICDs in PD is complex. Modifications in dopaminergic drug treatment are frequently necessary. In some cases alternative therapies such as atypical antipsychotics, antidepressants or deep brain stimulation if motor symptoms become incapacitating after adjustment of dopamine replacement therapy should be considered.

13 Review Brain structural MRI correlates of cognitive dysfunctions in Parkinson's disease. 2011

Ibarretxe-Bilbao, Naroa / Junque, Carme / Marti, Maria J / Tolosa, Eduardo. ·Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic de Barcelona, Spain. naroa.ibarretxe@deusto.es ·J Neurol Sci · Pubmed #21864849.

ABSTRACT: Cognitive dysfunction occurs at early stages of Parkinson's disease (PD). Initial studies reported that cognitive dysfunction in early PD only affected fronto-striatal circuits, provoking a marked executive dysfunction. Memory impairment in PD was thought to depend on a problem in retrieving stored information, therefore also reflecting a fronto-striatal dysfunction. However, there is increasing structural MRI evidence of medial temporal lobe atrophy in PD, which may be responsible for memory dysfunction. Other neuropsychological functions usually impaired in PD are semantic fluency, visuoperceptual and visuospatial functions, decision-making and recognition of facial emotions; and impairments in these functions are associated with cortical structural changes assessed by MRI. Overall, although the literature on the topic is scarce, there is increasing evidence of brain structural changes, detectable by MRI, which can explain the neuropsychological deficits early in the clinical disease course before dementia develops. In this review, we summarize the papers that have used structural MRI to study the neuroanatomical correlates of cognitive dysfunctions in PD.

14 Review Cerebral basis of visual hallucinations in Parkinson's disease: structural and functional MRI studies. 2011

Ibarretxe-Bilbao, Naroa / Junque, Carme / Marti, Maria J / Tolosa, Eduardo. ·Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic de Barcelona, Spain. naroa.ibarretxe@deusto.es ·J Neurol Sci · Pubmed #21705027.

ABSTRACT: The presence of visual hallucinations (VH) is a significant predictor of dementia in Parkinson's disease (PD) and it is associated with a more rapid cognitive decline. Non-demented PD patients with VH present greater neuropsychological impairment than those without VH in domains such as verbal and visual memory, language comprehension, and visuospatial and visuoperceptive functions. Frontal dysfunction has also been described in PD with VH, including deficits in verbal fluency, sustained attention, and inhibition. In PD with VH, structural and functional abnormalities within the primary visual system and visual association areas, including ventral and dorsal pathways, have been reported. Structural MRI studies have shown that non-demented PD patients with VH present grey matter reduction in parieto-occipital areas and the hippocampal head. A follow-up study performed at a mean of 30 months revealed that unlike PD patients without VH, PD patients with VH frequently develop dementia associated with progressive atrophy in limbic, paralimbic and neocortical areas. Functional MRI (fMRI) studies have revealed altered activation in occipito-temporal and frontal areas in response to simple and complex visual stimuli in PD patients with VH, suggesting a marked impairment in bottom-up visual processing, as well as an attentional deficit in the pathophysiology of VH in PD.

15 Review Progress in defining the premotor phase of Parkinson's disease. 2011

Tolosa, Eduardo / Pont-Sunyer, Claustre. ·Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Universitat de Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. etolosa@clinic.ub.es ·J Neurol Sci · Pubmed #21679972.

ABSTRACT: Several studies have suggested that a variety of non-motor symptoms (NMS) frequently antedate the development of the classical motor symptoms in Parkinson's disease (PD). Some of these premotor symptoms are well known, like REM sleep behaviour disorder, smell loss and constipation and can precede the motor symptoms by years or even decades. The appearance of these symptoms seems to correlate with the neuropathological changes occurring during Braaks stages I to III. Also studies of the nigrostriatal dopaminergic pathways with neuroimaging show that substantia nigra degeneration occurs before motor symptoms onset. Studies on the premotor phase of PD are important for our understanding of when and where does PD start and how it evolves in these initial stages. Several ongoing studies combine clinical, genetic and neuroimaging investigations to study the premotor phase in subjects at high risk for developing such as hyposmic individuals (PARS study) or nonmanifesting carriers of LRRK2 mutations (ASAP Study). The diagnosis of premotor PD remains still elusive but the information becoming available on premotor PD should guide the search for predictive biomarkers and the identification of risk or protective factors for PD.

16 Review Molecular and clinical prodrome of Parkinson disease: implications for treatment. 2010

Schapira, Anthony H V / Tolosa, Eduardo. ·Department of Clinical Neurosciences, Institute of Neurology, University College Medical School, Rowland Hill Street, London NW3 2PF, UK. a.schapira@medsch.ucl.ac.uk ·Nat Rev Neurol · Pubmed #20479780.

ABSTRACT: The development of interventions to slow or prevent progression represents an important aim for current research into Parkinson disease (PD). General agreement prevails that success in this endeavor will depend on a clearer understanding of etiology and pathogenesis, and several important advances have recently been made, particularly in defining the genetic causes of PD. Studies of the biochemical consequences of the mutations that cause familial PD, and postmortem brain studies of idiopathic, sporadic PD, have highlighted mitochondrial dysfunction, oxidative stress, and protein metabolism by the ubiquitin-proteasomal and autophagy systems as being central to pathogenesis. In parallel with advances in etiopathogenesis, a clearer perception has developed of the clinical prodrome of PD, offering an opportunity to identify individuals who are at risk of PD, as well as those in the earliest clinical phase of the disease that might even precede the onset of motor symptoms. These populations are potentially the most suitable in which to test new protective therapies, and to study potential peripheral markers of disease progression. The awareness of the early symptomatic period of PD also raises the possibility of providing treatments that not only improve motor function but might also favorably modify outcome.

17 Clinical Trial Perampanel, an AMPA antagonist, found to have no benefit in reducing "off" time in Parkinson's disease. 2012

Lees, Andrew / Fahn, Stanley / Eggert, Karla M / Jankovic, Joseph / Lang, Anthony / Micheli, Federico / Mouradian, M Maral / Oertel, Wolfgang H / Olanow, C Warren / Poewe, Werner / Rascol, Olivier / Tolosa, Eduardo / Squillacote, David / Kumar, Dinesh. ·Reta Lila Weston Institute for Neurological Studies, University College London, London, UK. alees@ion.ucl.ac.uk ·Mov Disord · Pubmed #22161845.

ABSTRACT: BACKGROUND: Perampanel is a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist. Two multicenter randomized, double-blind, placebo-controlled, parallel-group phase III studies assessed the efficacy and safety of adjunctive perampanel in patients with Parkinson's disease and motor fluctuations. METHODS: In both phase III studies (301 and 302), levodopa-treated patients were randomized and treated with once-daily oral placebo (n = 504), perampanel 2 mg (n = 509), or perampanel 4 mg (n = 501). The primary end point was change in daily "off" time from baseline. The treatment period was 30 weeks in study 301 and 20 weeks in study 302. RESULTS: For any efficacy end point, perampanel 2 or 4 mg was not superior to placebo. Perampanel was well tolerated up to 4 mg/day. CONCLUSIONS: Perampanel failed to significantly improve motor symptoms versus placebo. There was also no effect on the duration or disability of levodopa-induced dyskinesia.

18 Article Lack of Asymmetry of Nigrostriatal Dopaminergic Function in Healthy Subjects. 2020

Garrido, Alicia / Iranzo, Alex / Stefani, Ambra / Serradell, Mònica / Muñoz-Lopetegi, Amaia / Marrero, Paula / Högl, Birgit / Gaig, Carles / Santamaria, Joan / Tolosa, Eduard / Poewe, Werner / Anonymous5011110. ·Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Center for Sleep Disorders, Neurology Service, Hospital Clinic de Barcelona, IDIBAPS, CIBERNED, Barcelona, Spain. · Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. ·Mov Disord · Pubmed #32141653.

ABSTRACT: OBJECTIVE: In right-handed patients with Parkinson's disease (PD) or isolated rapid eye movement sleep behavior disorder, dopamine transporter (DAT) [(123)I]β-carboxymethyoxy-3-β-(4-iodophenyl) tropane single photon emission computed tomography (SPECT) shows predominant nigrostriatal deficit in the left striatum. This suggests that in PD patients, the nigrostriatal system of the dominant hemisphere is more susceptible to disease-related dysfunction. To confirm this hypothesis, we investigated whether the nigrostriatal function is symmetric in healthy controls and in patients with PD. METHODS: In 113 right-handed healthy controls and 279 right-handed early-PD patients, we examined the striatal dopaminergic terminals function in each hemisphere using DAT-SPECT. RESULTS: In the controls, DAT-SPECT showed symmetric specific binding ratios in the putamen and caudate nucleus of each hemisphere. In patients with PD, the specific binding ratio was lower in the left than in the right putamen. CONCLUSIONS: Right-handed healthy controls have symmetric nigrostriatal dopaminergic function. The left hemispheric predominance of nigrostriatal deficit seen in right-handed premotor and manifest PD represents an early pathological feature of the disease. © 2020 International Parkinson and Movement Disorder Society.

19 Article None 2019

Morén, Constanza / Juárez-Flores, Diana Luz / Chau, Kai-Yin / Gegg, Matthew / Garrabou, Glòria / González-Casacuberta, Ingrid / Guitart-Mampel, Mariona / Tolosa, Eduardo / Martí, María José / Cardellach, Francesc / Schapira, Anthony Henry Vernon. ·Cellex, IDIBAPS, University of Barcelona-Hospital Clínic of Barcelona, Barcelona 08036, Spain. · Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), Madrid 28029, Spain. · Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London NW3 2PF, UK. · Neurology Department, Hospital Clínic of Barcelona, Barcelona 08036, Spain. ·Aging (Albany NY) · Pubmed #31751314.

ABSTRACT: Glucocerebrosidase (

20 Article Cholinergic denervation in patients with idiopathic rapid eye movement sleep behaviour disorder. 2019

Gersel Stokholm, M / Iranzo, A / Østergaard, K / Serradell, M / Otto, M / Bacher Svendsen, K / Garrido, A / Vilas, D / Fedorova, T D / Santamaria, J / Møller, A / Gaig, C / Hiraoka, K / Brooks, D J / Okamura, N / Borghammer, P / Tolosa, E / Pavese, N. ·Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Aarhus, Denmark. · Department of Neurology, Hospital Clínic de Barcelona, Barcelona. · Centro de Investigación Biomédica en Red sobre Enfermedades eurodegenerativas (CIBERNED) Hospital Clínic, IDIBAPS, Universitat de Barcelona, Catalonia. · Multidisciplinary Sleep Unit, Hospital Clinic, Barcelona, Spain. · Department of Neurology, Aarhus University Hospital, Aarhus. · Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark. · Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Catalonia, Spain. · Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan. · Division of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. · Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan. ·Eur J Neurol · Pubmed #31725927.

ABSTRACT: BACKGROUND AND PURPOSE: Cholinergic dysfunction appears to play a role in the cognitive impairment observed in Parkinson's disease and dementia with Lewy bodies. The occurrence of cholinergic dysfunction in the early stages of these conditions, however, has not been investigated. The objective of this study was to investigate cholinergic function in patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD), a disorder recognized to be an early stage of both Parkinson's disease and dementia with Lewy bodies. METHODS: A total of 21 patients with polysomnography-confirmed iRBD with no evidence of parkinsonism and cognitive impairment and 10 controls underwent positron emission tomography (PET) to assess brain acetylcholinesterase levels ( RESULTS: The CONCLUSION: Reduced neocortical

21 Article The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight. 2019

Bandres-Ciga, Sara / Ahmed, Sarah / Sabir, Marya S / Blauwendraat, Cornelis / Adarmes-Gómez, Astrid D / Bernal-Bernal, Inmaculada / Bonilla-Toribio, Marta / Buiza-Rueda, Dolores / Carrillo, Fátima / Carrión-Claro, Mario / Gómez-Garre, Pilar / Jesús, Silvia / Labrador-Espinosa, Miguel A / Macias, Daniel / Méndez-Del-Barrio, Carlota / Periñán-Tocino, Teresa / Tejera-Parrado, Cristina / Vargas-González, Laura / Diez-Fairen, Monica / Alvarez, Ignacio / Tartari, Juan Pablo / Buongiorno, Mariateresa / Aguilar, Miquel / Gorostidi, Ana / Bergareche, Jesús Alberto / Mondragon, Elisabet / Vinagre-Aragon, Ana / Croitoru, Ioana / Ruiz-Martínez, Javier / Dols-Icardo, Oriol / Kulisevsky, Jaime / Marín-Lahoz, Juan / Pagonabarraga, Javier / Pascual-Sedano, Berta / Ezquerra, Mario / Cámara, Ana / Compta, Yaroslau / Fernández, Manel / Fernández-Santiago, Rubén / Muñoz, Esteban / Tolosa, Eduard / Valldeoriola, Francesc / Gonzalez-Aramburu, Isabel / Sanchez Rodriguez, Antonio / Sierra, María / Menéndez-González, Manuel / Blazquez, Marta / Garcia, Ciara / Suarez-San Martin, Esther / García-Ruiz, Pedro / Martínez-Castrillo, Juan Carlos / Vela-Desojo, Lydia / Ruz, Clara / Barrero, Francisco Javier / Escamilla-Sevilla, Francisco / Mínguez-Castellanos, Adolfo / Cerdan, Debora / Tabernero, Cesar / Gomez Heredia, Maria Jose / Perez Errazquin, Francisco / Romero-Acebal, Manolo / Feliz, Cici / Lopez-Sendon, Jose Luis / Mata, Marina / Martínez Torres, Irene / Kim, Jonggeol Jeffrey / Dalgard, Clifton L / Anonymous1451065 / Brooks, Janet / Saez-Atienzar, Sara / Gibbs, J Raphael / Jorda, Rafael / Botia, Juan A / Bonet-Ponce, Luis / Morrison, Karen E / Clarke, Carl / Tan, Manuela / Morris, Huw / Edsall, Connor / Hernandez, Dena / Simon-Sanchez, Javier / Nalls, Mike A / Scholz, Sonja W / Jimenez-Escrig, Adriano / Duarte, Jacinto / Vives, Francisco / Duran, Raquel / Hoenicka, Janet / Alvarez, Victoria / Infante, Jon / Marti, Maria José / Clarimón, Jordi / López de Munain, Adolfo / Pastor, Pau / Mir, Pablo / Singleton, Andrew / Anonymous1461065. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Seville, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. · Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mútua de Terrassa, Terrassa, Barcelona, Spain. · Neurodegenerative Disorders Area, Biodonostia Health Research Institute, San Sebastián, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Plataforma de Genomica, Instituto de Investigacion Biodonostia, San Sebastián, Spain. · Unidad de Trastornos de Movimiento, Departamento de Neurologia, Hospital Universitario de Donostia, San Sebastián, Spain. · Genetics of Neurodegenerative Disorders Unit, IIB Sant Pau, and Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. · Movement Disorders Unit, Neurology Department, Sant Pau Hospital, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. · Lab. of Parkinson disease and Other Neurodegenerative Movement Disorders, IDIBAPS-Institut d'Investigacions Biomèdiques, Barcelona, Catalonia, Spain. · Unitat de Parkinson i Trastorns del Moviment. Servicio de Neurologia, Hospital Clínic de Barcelona and Institut de Neurociencies de la Universitat de Barcelona (Maria de Maetzu Center), Catalonia, Spain. · Servicio de Neurología, Hospital Universitario Marqués de Valdecilla (IDIVAL) and Universidad de Cantabria, Santander, Spain. · Servicio de Neurología, Hospital Universitario Central de Asturias, Asturias, Spain. · Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain. · Departamento de Neurologia, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain. · Departamento de Neurologia, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain. · Servicio de Neurologia, Hospital Universitario Fundación Alcorcón, Madrid, Spain. · Centro de Investigacion Biomedica and Departamento de Fisiologia, Facultad de Medicina, Universidad de Granada, Granada, Spain. · Servicio de Neurología, Hospital Universitario San Cecilio, Granada, Universidad de Granada, Spain. · Servicio de Neurología, Hospital Universitario Virgen de las Nieves, Granada, Spain. · Servicio de Neurología, Hospital General de Segovia, Segovia, Spain. · Servicio de Neurología, Hospital Universitario Virgen de la Victoria, Malaga, Spain. · Departamento de Neurologia, Hospital Universitario Infanta Sofía, Madrid, Spain. · Departamento de Neurologia, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain. · Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. · The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. · Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain. · Department of Molecular Neuroscience, UCL, Institute of Neurology, London, United Kingdom. · Department of Neurology, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. · University of Birmingham, Birmingham, United Kingdom. · Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom. · Department of Clinical Neuroscience, University College London, London, United Kingdom. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. · Data Tecnica International, Glen Echo, Maryland, USA. · Department of Neurology, Johns Hopkins Medical Center, Baltimore, Maryland, USA. · Laboratorio de Neurogenética y Medicina Molecular, Institut de Recerca Sant Joan de Déu, Barcelona, Spain. · Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain. · Laboratorio de Genética, Hospital Universitario Central de Asturias, Asturias, Spain. · Departamento de Neurociencias. UPV-EHU, Servicio de Neurología, Hospital Universitario Donostia, San Sebastián, Spain. ·Mov Disord · Pubmed #31660654.

ABSTRACT: BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country. METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.

22 Article Accumulation of mitochondrial 7S DNA in idiopathic and LRRK2 associated Parkinson's disease. 2019

Podlesniy, Petar / Puigròs, Margalida / Serra, Núria / Fernández-Santiago, Rubén / Ezquerra, Mario / Tolosa, Eduardo / Trullas, Ramon. ·Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. Electronic address: petar.podlesniy@iibb.csic.es. · Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Neurology Service, Parkinson's Disease and Movement Disorders Unit, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. Electronic address: ramon.trullas@iibb.csic.es. ·EBioMedicine · Pubmed #31631040.

ABSTRACT: BACKGROUND: Both idiopathic and familial Parkinson's disease are associated with mitochondrial dysfunction. Mitochondria have their own mitochondrial DNA (mtDNA) and previous studies have reported that the release of mtDNA is a biomarker of Parkinson's disease. METHODS: We have now investigated the relationship between mtDNA replication, transcription and release in fibroblasts from patients with idiopathic (iPD) and Leucine-rich repeat kinase 2 FINDINGS: In comparison with healthy controls, we found that fibroblasts from patients with iPD or LRRK2-PD had a high amount of mitochondrial 7S DNA along with a low mtDNA replication rate that was associated with a reduction of cf-mtDNA release. Accumulation of 7S DNA in iPD and LRRK2-PD fibroblasts was related with an increase in H-strand mtDNA transcription. INTERPRETATION: These results show that 7S DNA accumulation, low mtDNA replication, high H-strand transcription, and low mtDNA release compose a pattern of mtDNA dysfunction shared by both iPD and LRRK2-PD fibroblasts. Moreover, these results suggest that the deregulation of the genetic switch formed by 7SDNA that alternates between mtDNA replication and transcription is a fundamental pathophysiological mechanism in both idiopathic and monogenic Parkinson's disease.

23 Article Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls. 2019

Agalliu, Ilir / Ortega, Roberto A / Luciano, Marta San / Mirelman, Anat / Pont-Sunyer, Claustre / Brockmann, Kathrin / Vilas, Dolores / Tolosa, Eduardo / Berg, Daniela / Warø, Bjørg / Glickman, Amanda / Raymond, Deborah / Inzelberg, Rivka / Ruiz-Martinez, Javier / Mondragon, Elisabet / Friedman, Eitan / Hassin-Baer, Sharon / Alcalay, Roy N / Mejia-Santana, Helen / Aasly, Jan / Foroud, Tatiana / Marder, Karen / Giladi, Nir / Bressman, Susan / Saunders-Pullman, Rachel. ·Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA. · Department of Neurology, Mount Sinai Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Neurology, University of California San Francisco, San Francisco, California, USA. · Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel. · Neurology Service, Hospital Clínic, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Universitat de Barcelona, Catalonia, Spain. · Neurology Unit, Hospital General de Granollers, Universitat Internacional de Catalunya, Granollers, Barcelona, Spain. · Hertie-Institut für klinische Hirnforschung, Tubingen, Germany. · Movement Disorders Unit, Neurology Service, Hospital Universitari Germans Trias I Pujol, Badalona, Barcelona, Spain. · Department of Neurology, Christian-Albrechts-University, Kiel, Germany. · Department of Neurology, St. Olavs Hospital, and Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. · Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Neurology Department, Donostia University Hospital, Biodonostia Institut Research, Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas, San Sebastian, Gipuzkoa, Spain. · The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer and the Departments of Internal Medicine and Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel. · Parkinson's Disease and Movement Disorders Clinic and Department of Neurology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel. · Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA. ·Mov Disord · Pubmed #31348549.

ABSTRACT: BACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.

24 Article Whole-genome DNA hyper-methylation in iPSC-derived dopaminergic neurons from Parkinson's disease patients. 2019

Fernández-Santiago, Rubén / Merkel, Angelika / Castellano, Giancarlo / Heath, Simon / Raya, Ángel / Tolosa, Eduard / Martí, María-José / Consiglio, Antonella / Ezquerra, Mario. ·Department of Neurology, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Faculty of Medicine (UB), University of Barcelona, Casanova 143, Floor 3B, 08036, Barcelona, Spain. ruben.fernandez.santiago@gmail.com. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain. ruben.fernandez.santiago@gmail.com. · Statistical Genomics Team at the Centro Nacional de Análisis Genómico (CNAG-CRG), Centre de Regulacio Genómico (CRG), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain. · Dept. of Anatomic Pathology, Pharmacology and Microbiology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036, Barcelona, Spain. · Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, 08908, Barcelona, Spain. · Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain. · Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain. · Department of Neurology, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Faculty of Medicine (UB), University of Barcelona, Casanova 143, Floor 3B, 08036, Barcelona, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain. · Movement Disorders Unit, Dept. of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036, Barcelona, Spain. · Department of Pathology and Experimental Therapeutics, Faculty of Medicine, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), University of Barcelona, 08907, Barcelona, Spain. · Institute of Biomedicine of the University of Barcelona (IBUB), 08028, Barcelona, Spain. · Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy. · Department of Neurology, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Faculty of Medicine (UB), University of Barcelona, Casanova 143, Floor 3B, 08036, Barcelona, Spain. ezquerra@clinic.ub.es. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain. ezquerra@clinic.ub.es. ·Clin Epigenetics · Pubmed #31337434.

ABSTRACT: BACKGROUND: Parkinson's disease (PD) is characterized by the loss of midbrain dopaminergic neurons (DAn). Previously, we described the presence of DNA hyper- and hypo-methylation alterations in induced pluripotent stem cells (iPSC)-derived DAn from PD patients using the Illumina 450K array which prominently covers gene regulatory regions. METHODS: To expand and contextualize previous findings, we performed the first whole-genome DNA bisulfite sequencing (WGBS) using iPSC-derived DAn from representative PD subjects: one sporadic PD (sPD) patient, one monogenic LRRK2-associated PD patient (L2PD), and one control. RESULTS: At the whole-genome level, we detected global DNA hyper-methylation in the PD which was similarly spread across the genome in both sPD and L2PD and mostly affected intergenic regions. CONCLUSION: This study implements previous epigenetic knowledge in PD at a whole genome level providing the first comprehensive and unbiased CpG DNA methylation data using iPSC-derived DAn from PD patients. Our results indicate that DAn from monogenic or sporadic PD exhibit global DNA hyper-methylation changes. Findings from this exploratory study are to be validated in further studies analyzing other PD cell models and patient tissues.

25 Article SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease. 2019

Fernández-Santiago, Rubén / Martín-Flores, Núria / Antonelli, Francesca / Cerquera, Catalina / Moreno, Verónica / Bandres-Ciga, Sara / Manduchi, Elisabetta / Tolosa, Eduard / Singleton, Andrew B / Moore, Jason H / Anonymous3481045 / Martí, María-Josep / Ezquerra, Mario / Malagelada, Cristina. ·Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain. · Neurology Service, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain. · Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain. · Department of Biomedicine, Unit of Biochemistry, Universitat de Barcelona, Barcelona, Catalonia, Spain. · Institute of Neurosciences, University of Barcelona, Barcelona, Catalonia, Spain. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain. · The Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA. ·Mov Disord · Pubmed #31234232.

ABSTRACT: BACKGROUND: Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. OBJECTIVES: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. METHODS: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. RESULTS: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. CONCLUSIONS: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society.

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