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1. Economic Burden of Parkinson’s Disease: A Multinational, Real-World, Cost-of-Illness Study

Author

K. Ray Chaudhuri, Jean-Philippe Azulay, Per Odin, Susanna Lindvall, Josefa Domingos, Ali Alobaidi, Prasanna L. Kandukuri, Vivek S. Chaudhari, Juan Carlos Parra, Toru Yamazaki, Julia Oddsdottir, Jack Wright, and Pablo Martinez-Martin

Subjects
Therapeutics. Pharmacology, RM1-950, Pharmacy and materia medica, RS1-441
Abstract

Abstract Background Parkinson’s disease is now one of the fastest-growing neurodegenerative disorders in the developed world, with an increasing prevalence and associated socioeconomic costs. Progression of the disease leads to a gradual deterioration in patients’ quality of life, despite optimal treatment, and both medical and societal needs increase, often with the assistance of paid and/or unpaid caregivers. Objective We aimed to quantify the incremental economic burden of Parkinson’s disease by disease severity in a real-world setting across differing geographic regions. Methods Demographics, clinical characteristics, health status, patient quality of life, caregiver burden, and healthcare resource utilization data were drawn from the Adelphi Parkinson’s Disease Specific Program™, conducted in the USA, five European countries, and Japan. Results A total of 563 neurologists provided data for 5299 individuals with Parkinson’s disease; 61% were male, with a mean age of 64 years. Approximately 15% of individuals were deemed to have advanced disease, with significantly more comorbidities, and a poorer quality of life, than those with non-advanced disease. Overall, the mean annual healthcare resource utilization increased significantly with advancing disease, and resulted in a three-fold difference in the USA and Europe. The main drivers behind the high economic burden included hospitalizations, prescription medications, and indirect costs. Conclusions People with Parkinson’s disease, and their caregivers, incur a higher economic burden as their disease progresses. Future interventions that can control symptoms or slow disease progression could reduce the burden on people with Parkinson’s disease and their caregivers, whilst also substantially impacting societal costs.

Published
2024
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2. Imbalanced motivated behaviors according to motor sign asymmetry in drug-naïve Parkinson’s disease

Author

Matthieu Béreau, Anna Castrioto, Mathieu Servant, Eugénie Lhommée, Maxime Desmarets, Amélie Bichon, Pierre Pélissier, Emmanuelle Schmitt, Hélène Klinger, Nadine Longato, Clélie Phillipps, Thomas Wirth, Valérie Fraix, Isabelle Benatru, Franck Durif, Jean-Philippe Azulay, Elena Moro, Emmanuel Broussolle, Stéphane Thobois, Christine Tranchant, Paul Krack, and Mathieu Anheim

Subjects
Medicine, Science
Abstract

Abstract Few studies have considered the influence of motor sign asymmetry on motivated behaviors in de novo drug-naïve Parkinson’s disease (PD). We tested whether motor sign asymmetry could be associated with different motivated behavior patterns in de novo drug-naïve PD. We performed a cross-sectional study in 128 de novo drug-naïve PD patients and used the Ardouin Scale of Behavior in Parkinson’s disease (ASBPD) to assess a set of motivated behaviors. We assessed motor asymmetry based on (i) side of motor onset and (ii) MDS-UPDRS motor score, then we compared right hemibody Parkinson’s disease to left hemibody Parkinson’s disease. According to the MDS-UPDRS motor score, patients with de novo right hemibody PD had significantly lower frequency of approach behaviors (p = 0.031), including nocturnal hyperactivity (p = 0.040), eating behavior (p = 0.040), creativity (p = 0.040), and excess of motivation (p = 0.017) than patients with de novo left hemibody PD. Patients with de novo left hemibody PD did not significantly differ from those with de novo right hemibody PD regarding avoidance behaviors including apathy, anxiety and depression. Our findings suggest that motor sign asymmetry may be associated with an imbalance between motivated behaviors in de novo drug-naïve Parkinson’s disease.

Published
2023
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3. Subthalamic stimulation breaks the balance between distal and axial signs in Parkinson’s disease

Author

Cyril Atkinson-Clement, Émilie Cavazzini, Alexandre Zénon, Thierry Legou, Tatiana Witjas, Frédérique Fluchère, Jean-Philippe Azulay, Christelle Baunez, Serge Pinto, and Alexandre Eusebio

Subjects
Medicine, Science
Abstract

Abstract In Parkinson’s disease (PD), the effects of both Ldopa and subthalamic deep brain stimulation (STN-DBS) are known to change cost-valuation. However, this was mostly studied through reward-effort task involving distal movements, while axial effort, less responsive to treatments, have been barely studied. Thus, our objective was to compare the influence of both Ldopa and STN-DBS on cost-valuation between two efforts modalities: vowel production (as an example of axial movement) and hand squeezing (as an example of distal movement). Twelve PD patients were recruited to participate in this study. The task consisted in deciding whether to accept or reject trials based on a reward-effort trade-off. Participants performed two blocks with hand squeezing, and two with vowel production, in the four treatment conditions (Ldopa On/Off; STN-DBS On/Off). We found that STN-DBS changed the ratio difference between hand and phonation efforts. Vowel production effort was estimated easier to perform with STN-DBS alone, and harder when associated with Ldopa. The difference between hand and phonation efforts was correlated with quality of life in Off/Off and On Ldopa alone conditions, and with impulsive assessment On STN-DBS alone. We highlighted that STN-DBS could introduce an imbalance between the actual motor impairments and their subjective costs. With this finding, we also suggest paying particular attention to the different treatment effects that should be expected for axial and distal movement dysfunctions.

Published
2021
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4. Hoehn and Yahr Stage and Striatal Dat-SPECT Uptake Are Predictors of Parkinson’s Disease Motor Progression

Author

Holly Jackson, Judith Anzures-Cabrera, Kirsten I. Taylor, Gennaro Pagano, PASADENA Investigators, Prasinezumab Study Group, Claudia Altendorf, Chareyna Anandan, Giulia Andrews, Solène Ansquer, Raphaele Arrouasse, Sana Aslam, Jean-Philippe Azulay, Jeanette Baker, Ernest Balaguer Martinez, Shadi Barbu, Kara Bardram, Danny Bega, Helena Bejr-Kasem Marco, Isabelle Benatru, Eve Benchetrit, Felix Bernhard, Amir Besharat, Sagari Bette, Amelie Bichon, Andrew Billnitzer, Sophie Blondeau, Thomas Boraud, Freiderike Borngräber, James Boyd, Kathrin Brockmann, Matthew Brodsky, Ethan Brown, Christof Bruecke, Fabienne Calvas, Monica Canelo, Federico Carbone, Claire Carroll, Laura Casado Fernandez, Catherine Cassé-Perrot, Anna Castrioto, Helene Catala, Justine Chan, Samia Cheriet, Anthony Ciabarra, Joseph Classen, Juliana Coleman, Robert Coleman, Yaroslau Compta, Anne-Gaëlle Corbillé, Jean-Christophe Corvol, Mariana Cosgaya, Nabila Dahodwala, Philippe Damier, Elodie David, Thomas Davis, Marissa Dean, Berengere Debilly, Janell DeGiorgio, Andres Deik, Laure Delaby, Marie-Helene Delfini, Pascal Derkinderen, Philipp Derost, Maria de Toledo, Lisa Deuel, Ann Marie Diaz-Hernandez, Cameron Dietiker, Karina Dimenshteyn, Julio Dotor, Franck Durif, Jens Ebentheuer, Karla Maria Eggert, Sara Eichau Madueño, Claudia Eickhoff, Aaron Ellenbogen, Philipp Ellmerer, Ines Esparragosa Vazquez, Alexandre Eusebio, Siobhan Ewert, John Fang, Danielle Feigenbaum, Frederique Fluchere, Alexandra Foubert-Samier, Marie Fournier, Anne Fradet, Valerie Fraix, Samuel Frank, Franca Fries, Monique Galitzky, Marisol Gallardó Pérez, Jose Manuel García Moreno, Carmen Gasca, Thomas Gasser, Joyce Gibbons, Caroline Giordana, Alicia Gonzalez Martinez, Ira Goodman, Arantza Gorospe, Marie Goubeaud, David Grabli, Mangone Graziella, Stephan Grimaldi, Jeffrey Gross, Raquel Guimaraes-Costa, Andreas Hartmann, Christian Hartmann, Travis Hassell, Robert Hauser, Antonio Hernandez, Jorge Hernandez-Vara, Guenter Hoeglinger, Christian Homedes, Andrea Horta-Barba, Jean-Luc Houeto, Julius Huebl, Jennifer Hui, Stuart Isaacson, Joseph Jankovic, Annette Janzen, Junior Jauregui, Jocelyne Jiao, Maria Jose Marti Domenech, Xavier Joseph, Srinath Kadimi, Pat Kaminski, Silja Kannenberg, Jan Kassubek, Maya Katz, Kevin Klos, Shannon Klos, Christopher Kobet, Jennifer Koebert, Patricia Krause, Andrea Kuehn, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Martin Kunz, Lille Kurvits, Kimberly Kwei, Simon Laganiere, Brice Laurens, Johannes Levin, Oren Levy, Peter LeWitt, Gurutz Linazasoro Cristóbal, Irene Litvan, Karlo Lizarraga, Katherine Longardner, Rocio Lopez, Lydia Lopez Manzanares, Sara Lucas del Pozo, Maria Rosario Luquin Puido, Nijee Luthra, Kelly Lyons, Sylvia Maass, Gerrit Machetanz, Yolanda Macias, David Maltete, Jorge Uriel Manez Miro, Louise-Laure Mariani, Juan Marin, Kathrin Marini, Ana Marques, Gloria Marti, Saul Martinez, Wassilios Meissner, Sara Meoni, Brit Mollenhauer, Dunia Mon Martinez, Johnson Moon, Elena Moro, Peter Morrison, Christoph Muehlberg, Manpreet Multani, Christine Murphy, Anthony Nicholas, Rajesh Pahwa, Antonio Palasi, Heidi Pape, Neepa Patel, Prity Patel, Marina Peball, Elizabeth Peckham, Terry Peery, Rafael Perez, Jesus Perez, Alisa Petit, Elmar Pinkhardt, Werner Poewe, Elsa Pomies, Cecile Preterre, Joseph Quinn, Olivier Rascol, Philippe Remy, Irene Richard, Benjamin Roeben, Emily Ruether, Jost-Julian Rumpf, David Russell, Hayet Salhi, Daniela Samaniego-Toro, Alexandra Samier-Foubert, Antonio Sanchez, Emmanuelle Schmitt, Alfons Schnitzler, Oliver Schorr, Julie Schwartzbard, Kerstin Schweyer, Klaus Seppi, Victoria Sergo, Holly Shill, Andrew Siderowf, Tanya Simuni, Umberto Spampinato, Ashok Sriram, Natividad Stover, Caroline Tanner, Arjun Tarakad, Carolyn Taylor, Claire Thalamus, Thomas Toothaker, Nadege Van Blercom, Nora Vanegas-Arrogave, Lydia Vela, Sylvian Vergnet, Tiphaine Vidal, Jonathan Vöglein, Ryan Walsh, Cheryl Waters, Mirko Wegscheider, Endy Weidinger, Caroline Weill, Gregor Wenzel, Tatiana Witjas, Isabel Wurster, Brenton Wright, Milan Zimmermann, Rafael Zuzuarregui, Markus Abt, Atieh Bamdadian, Teresa Barata, Nicholas Barbet, Sara Belli, Frank Boess, Azad Bonni, Edilio Borroni, Anne Boulay, Markus Britschgi, Jerome Chague, Valerie Cosson, Christian Czech, Dennis Deptula, Cheikh Diack, Rachelle Doody, Juergen Dukart, Giulia D’Urso, Sebastian Dziadek, Hannah Eddleston, Chris Edgar, Laurent Essioux, Morgan Farell, Rebecca Finch, Paulo Fontoura, Waltraud Gruenbauer, Andrea Hahn, Stefan Holiga, Michael Honer, Shirin Jadidi, Kelly Johnson-Wood, Markus Keller, Timothy Kilchenmann, Martin Koller, Thomas Kremer, Thomas Kustermann, Claire Landsdall, Michael Lindemann, Florian Lipsmeier, Cecile Luzy, Marianne Manchester, Maddalena Marchesi, Ferenc Martenyi, Meret Martin-Facklam, Katerina Mironova, Annabelle Monnet, Emma Moore, Daniel K Ness, Markus Niggli, Tania Nikolcheva, Susanne Ostrowitzki GP, Benedicte Passmard, Agnes Poirier, Anke Post, Megana Prasad, Nathalie Pross, Tiffany Quock, Benedicte Ricci, Ellen Rose, Christoph Sarry, Christine Schubert, Dennis Selkoe, Jeff Sevigny, Kaycee Sink, Hannah Staunton, Tim Steven, Alexander Strasak, Hanno Svoboda KT, Radhika Tripuraneni, Dylan Trundell, Daniel Umbricht, Lynne Verselis, Annamarie Vogt, Ekaterina Volkova-Volkmar, Cornelia Weber, Silke Weber, and Wagner Zago

Subjects
PASADENA, PPMI (Parkinson’s Progression Markers Initiative), Parkinson’s disease, progression predictors, ridge regression, disease stage, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Currently, no treatments available for Parkinson’s disease (PD) can slow PD progression. At the early stage of the disease, only a subset of individuals with PD progress quickly, while the majority have a slowly progressive form of the disease. In developing treatments that aim to slow PD progression, clinical trials aim to include individuals who are likely to progress faster, such that a treatment effect, if one exists, can be identified easier and earlier. The aim of the present study was to identify baseline predictors of clinical progression in early PD. We analyzed 12-month data acquired from the PASADENA trial Part 1 (NCT03100149, n = 76 participants who were allocated to the placebo arm and did not start symptomatic therapy) and the Parkinson’s Progression Markers Initiative (PPMI) study (n = 139 demographically and clinically matched participants). By using ridge regression models including clinical characteristics, imaging, and non-imaging biomarkers, we found that Hoehn and Yahr stage and dopamine transporter single-photon emission computed tomography specific binding ratios (Dat-SPECT SBR) in putamen ipsilateral to the side of motor symptom onset predicted PD progression at the early stage of the disease. Further studies are needed to confirm the validity of these predictors to identify with high accuracy individuals with early PD with a faster progression phenotype.

Published
2021
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5. A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data

Author

Gennaro Pagano, Frank G. Boess, Kirsten I. Taylor, Benedicte Ricci, Brit Mollenhauer, Werner Poewe, Anne Boulay, Judith Anzures-Cabrera, Annamarie Vogt, Maddalena Marchesi, Anke Post, Tania Nikolcheva, Gene G. Kinney, Wagner M. Zago, Daniel K. Ness, Hanno Svoboda, Markus Britschgi, Susanne Ostrowitzki, Tanya Simuni, Kenneth Marek, Martin Koller, Jeff Sevigny, Rachelle Doody, Paulo Fontoura, Daniel Umbricht, Azad Bonni, PASADENA Investigators, Prasinezumab Study Group, Claudia Altendorf, Chareyna Anandan, Giulia Andrews, Solène Ansquer, Raphaele Arrouasse, Sana Aslam, Jean-Philippe Azulay, Jeanette Baker, Ernest Balaguer Martinez, Shadi Barbu, Kara Bardram, Danny Bega, Helena Bejr-Kasem Marco, Isabelle Benatru, Eve Benchetrit, Felix Bernhard, Amir Besharat, Sagari Bette, Amelie Bichon, Andrew Billnitzer, Sophie Blondeau, Thomas Boraud, Freiderike Borngräber, James Boyd, Kathrin Brockmann, Matthew Brodsky, Ethan Brown, Christof Bruecke, Fabienne Calvas, Monica Canelo, Federico Carbone, Claire Carroll, Laura Casado Fernandez, Catherine Cassé-Perrot, Anna Castrioto, Helene Catala, Justine Chan, Samia Cheriet, Anthony Ciabarra, Joseph Classen, Juliana Coleman, Robert Coleman, Yaroslau Compta, Anne-Gaëlle Corbillé, Jean-Christophe Corvol, Mariana Cosgaya, Nabila Dahodwala, Philippe Damier, Elodie David, Thomas Davis, Marissa Dean, Berengere Debilly, Janell DeGiorgio, Andres Deik, Laure Delaby, Marie-Helene Delfini, Pascal Derkinderen, Philipp Derost, Maria de Toledo, Lisa Deuel, Ann Marie Diaz-Hernandez, Cameron Dietiker, Karina Dimenshteyn, Julio Dotor, Franck Durif, Jens Ebentheuer, Karla Maria Eggert, Sara Eichau Madueño, Claudia Eickhoff, Aaron Ellenbogen, Philipp Ellmerer, Ines Esparragosa Vazquez, Alexandre Eusebio, Siobhan Ewert, John Fang, Danielle Feigenbaum, Frederique Fluchere, Alexandra Foubert-Samier, Marie Fournier, Anne Fradet, Valerie Fraix, Samuel Frank, Franca Fries, Monique Galitzky, Marisol Gallardó Pérez, Jose Manuel García Moreno, Carmen Gasca, Thomas Gasser, Joyce Gibbons, Caroline Giordana, Alicia Gonzalez Martinez, Ira Goodman, Arantza Gorospe, Marie Goubeaud, David Grabli, Mangone Graziella, Stephan Grimaldi, Jeffrey Gross, Raquel Guimaraes-Costa, Andreas Hartmann, Christian Hartmann, Travis Hassell, Robert Hauser, Antonio Hernandez, Jorge Hernandez-Vara, Günter Höglinger, Christian Homedes, Andrea Horta-Barba, Jean-Luc Houeto, Julius Huebl, Jennifer Hui, Stuart Isaacson, Joseph Jankovic, Annette Janzen, Junior Jauregui, Jocelyne Jiao, Maria Jose Marti Domenech, Xavier Joseph, Srinath Kadimi, Pat Kaminski, Silja Kannenberg, Jan Kassubek, Maya Katz, Kevin Klos, Shannon Klos, Christopher Kobet, Jennifer Koebert, Patricia Krause, Andrea Kuehn, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Martin Kunz, Lille Kurvits, Kimberly Kwei, Simon Laganiere, Brice Laurens, Johannes Levin, Oren Levy, Peter LeWitt, Gurutz Linazasoro Cristóbal, Irene Litvan, Karlo Lizarraga, Katherine Longardner, Rocio Lopez, Lydia Lopez Manzanares, Sara Lucas del Pozo, Maria Rosario Luquin Puido, Nijee Luthra, Kelly Lyons, Sylvia Maass, Gerrit Machetanz, Yolanda Macias, David Maltete, Jorge Uriel Manez Miro, Louise-Laure Mariani, Juan Marin, Kathrin Marini, Ana Marques, Gloria Marti, Saul Martinez, Wassilios Meissner, Sara Meoni, Dunia Mon Martinez, Johnson Moon, Elena Moro, Peter Morrison, Christoph Muehlberg, Manpreet Multani, Christine Murphy, Anthony Nicholas, Rajesh Pahwa, Antonio Palasi, Heidi Pape, Neepa Patel, Prity Patel, Marina Peball, Elizabeth Peckham, Terry Peery, Rafael Perez, Jesus Perez, Alisa Petit, Elmar Pinkhardt, Elsa Pomies, Cecile Preterre, Joseph Quinn, Olivier Rascol, Philippe Remy, Irene Richard, Benjamin Roeben, Emily Ruether, Jost-Julian Rumpf, David Russell, Hayet Salhi, Daniela Samaniego-Toro, Alexandra Samier-Foubert, Antonio Sanchez, Emmanuelle Schmitt, Alfons Schnitzler, Oliver Schorr, Julie Schwartzbard, Kerstin Schweyer, Klaus Seppi, Victoria Sergo, Holly Shill, Andrew Siderowf, Umberto Spampinato, Ashok Sriram, Natividad Stover, Caroline Tanner, Arjun Tarakad, Carolyn Taylor, Claire Thalamus, Thomas Toothaker, Nadege Van Blercom, Nora Vanegas-Arrogave, Lydia Vela, Sylvian Vergnet, Tiphaine Vidal, Jonathan Vöglein, Ryan Walsh, Cheryl Waters, Mirko Wegscheider, Endy Weidinger, Caroline Weill, Gregor Wenzel, Tatiana Witjas, Isabel Wurster, Brenton Wright, Milan Zimmermann, Rafael Zuzuarregui, Markus Abt, Atieh Bamdadian, Teresa Barata, Nicholas Barbet, Sara Belli, Frank Boess, Edilio Borroni, Jerome Chague, Valerie Cosson, Christian Czech, Dennis Deptula, Cheikh Diack, Juergen Dukart, Giulia D'Urso, Sebastian Dziadek, Hannah Eddleston, Chris Edgar, Laurent Essioux, Morgan Farell, Rebecca Finch, Waltraud Gruenbauer, Andrea Hahn, Stefan Holiga, Michael Honer, Shirin Jadidi, Kelly Johnson-Wood, Markus Keller, Timothy Kilchenmann, Thomas Kremer, Thomas Kustermann, Claire Landsdall, Michael Lindemann, Florian Lipsmeier, Cecile Luzy, Marianne Manchester, Ferenc Martenyi, Meret Martin-Facklam, Katerina Mironova, Annabelle Monnet, Emma Moore, Daniel K Ness, Markus Niggli, Benedicte Passmard, Agnes Poirier, Megana Prasad, Nathalie Pross, Tiffany Quock, Ellen Rose, Christoph Sarry, Christine Schubert, Dennis Selkoe, Kaycee Sink, Hannah Staunton, Tim Steven, Alexander Strasak, Kirsten Taylor, Radhika Tripuraneni, Dylan Trundell, Lynne Verselis, Ekaterina Volkova-Volkmar, Cornelia Weber, Silke Weber, and Wagner Zago

Subjects
Parkinson's disease, alpha-synuclein (α-syn), prasinezumab, monoclonal antibodies, disease progression, MDS-UPDRS = Movement Disorder Society—Unified Parkinson's Disease Rating Scale, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease.Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD.Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society—Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.Trial Registration: NCT03100149.

Published
2021
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6. Increased Sodium Concentration in Substantia Nigra in Early Parkinson's Disease: A Preliminary Study With Ultra-High Field (7T) MRI

Author

Stephan Grimaldi, Mohamed Mounir El Mendili, Wafaa Zaaraoui, Jean-Philippe Ranjeva, Jean-Philippe Azulay, Alexandre Eusebio, and Maxime Guye

Subjects
Parkinson's disease, neurodegeneration, sodium, biomarker, ultra high field magnetic resonance imaging, Neurology. Diseases of the nervous system, RC346-429
Abstract

Pathophysiology of idiopathic Parkinson's disease (iPD) is complex and still misunderstood. At a time when treatments with disease-modifying potential are being developed, identification of early markers of neurodegeneration is essential. Intracerebral sodium accumulation could be one of them. Indeed, it may be in relation to the mitochondrial dysfunction that early exists in iPD. For the first time, we used brain sodium (23Na) MRI to explore sodium concentration changes that have already been reported to be related to neurodegeneration in other diseases. We prospectively included 10 iPD patients (mean age 52.2 ± 5.9 years-old) with motor symptoms that started

Published
2021
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7. Beta burst coupling across the motor circuit in Parkinson's disease

Author

Gerd Tinkhauser, Flavie Torrecillos, Yann Duclos, Huiling Tan, Alek Pogosyan, Petra Fischer, Romain Carron, Marie-Laure Welter, Carine Karachi, Wim Vandenberghe, Bart Nuttin, Tatiana Witjas, Jean Régis, Jean-Philippe Azulay, Alexandre Eusebio, and Peter Brown

Subjects
Parkinson's disease, Beta oscillations, Basal ganglia-cortical network, Beta bursts, Local field potentials, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Exaggerated activity in the beta band (13–35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment.

Published
2018
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8. Movement Speed-Accuracy Trade-Off in Parkinson's Disease

Author

Laure Fernandez, Raoul Huys, Johann Issartel, Jean-Philippe Azulay, and Alexandre Eusebio

Subjects
parkinson's disease, dopamine, speed-accuracy trade-off, rhythmicity, goal-directed movement, Neurology. Diseases of the nervous system, RC346-429
Abstract

Patients with Parkinson's disease (PD) often have difficulties generating rhythmic movements, and also difficulties on movement adjustments to accuracy constraints. In the reciprocal aiming task, maintaining a high accuracy comes with the cost of diminished movement speed, whereas increasing movement speed disrupts end-point accuracy, a phenomenon well known as the speed-accuracy trade-off. The aim of this study was to examine how PD impacts speed-accuracy trade-off during rhythmic aiming movements by studying the structural kinematic movement organization and to determine the influence of dopamine replacement therapy on continuous movement speed and accuracy. Eighteen patients with advanced idiopathic Parkinson's disease performed a reciprocal aiming task, where the difficulty of the task was manipulated through target width. All patients were tested in two different sessions: ON-medication and OFF-medication state. A control group composed of healthy age-matched participants was also included in the study. The following variables were used for the analyses: Movement time, Error rate, effective target width, and Performance Index. Percentage of acceleration time and percentage of non-linearity were completed with kinematics patterns description using Rayleigh-Duffing model. Both groups traded off speed against accuracy as the constraints pertaining to the latter increased. The trade-off was more pronounced with the PD patients. Dopamine therapy allowed the PD patients to move faster, but at the cost of movement accuracy. Surprisingly, the structural kinematic organization did not differ across group nor across medication condition. These results suggest that PD patients, when involved in a reciprocal aiming task, are able to produce rhythmic movements. PD patients' overall slowing down seems to reflect a global adaptation to the disease in the absence of a structurally altered kinematic organization.

Published
2018
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9. Association between caffeine intake and age at onset in Huntington's disease

Author

Clémence Simonin, Cécile Duru, Julia Salleron, Pascale Hincker, Perrine Charles, Arnaud Delval, Katia Youssov, Sylvie Burnouf, Jean-Philippe Azulay, Christophe Verny, Clarisse Scherer, Christine Tranchant, Cyril Goizet, Sabrina Debruxelles, Luc Defebvre, Bernard Sablonnière, Monique Romon-Rousseaux, Luc Buée, Alain Destée, Olivier Godefroy, Alexandra Dürr, Bernhard Landwehrmeyer, Anne-Catherine Bachoud-Levi, Florence Richard, David Blum, and Pierre Krystkowiak

Subjects
Huntington's disease, Caffeine, Adenosine receptors, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Habitual consumption of caffeine, a non-selective adenosine receptor (AR) antagonist, has been suggested to be beneficial in Parkinson's and Alzheimer's diseases. Experimental evidence support that ARs play a role in Huntington's disease (HD) raising the hypothesis that caffeine may be a life-style modifier in HD. To determine a possible relationship between caffeine consumption and age at onset (AAO) in HD, we retrospectively assessed caffeine consumption in 80 HD patients using a dietary survey and determined relationship with AAO. Following adjustment for gender, smoking status and CAG repeat length, caffeine consumption greater than 190 mg/day was significantly associated with an earlier AAO. These data support an association between habitual caffeine intake and AAO in HD patients, but further studies are warranted to understand the link between these variables.

Published
2013
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10. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.

Author

Ruth de Diego-Balaguer, Catherine Schramm, Isabelle Rebeix, Emmanuel Dupoux, Alexandra Durr, Alexis Brice, Perrine Charles, Laurent Cleret de Langavant, Katia Youssov, Christophe Verny, Vincent Damotte, Jean-Philippe Azulay, Cyril Goizet, Clémence Simonin, Christine Tranchant, Patrick Maison, Amandine Rialland, David Schmitz, Charlotte Jacquemot, Bertrand Fontaine, Anne-Catherine Bachoud-Lévi, and French Speaking Huntington Group

Subjects
Medicine, Science
Abstract

Little is known about the genetic factors modulating the progression of Huntington's disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington's Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression.

Published
2016
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11. Insulin-Like Growth Factor-1 but Not Insulin Predicts Cognitive Decline in Huntington's Disease.

Author

Linda Salem, Nadine Saleh, Gaelle Désaméricq, Katia Youssov, Guillaume Dolbeau, Laurent Cleret, Marie-Laure Bourhis, Jean-Philippe Azulay, Pierre Krystkowiak, Christophe Verny, Françoise Morin, Stéphane Moutereau, French Huntington Study Group, Anne-Catherine Bachoud-Lévi, and Patrick Maison

Subjects
Medicine, Science
Abstract

BACKGROUND:Huntington's disease (HD) is one of several neurodegenerative disorders that have been associated with metabolic alterations. Changes in Insulin Growth Factor 1 (IGF-1) and/or insulin input to the brain may underlie or contribute to the progress of neurodegenerative processes. Here, we investigated the association over time between changes in plasma levels of IGF-1 and insulin and the cognitive decline in HD patients. METHODS:We conducted a multicentric cohort study in 156 patients with genetically documented HD aged from 22 to 80 years. Among them, 146 patients were assessed at least twice with a follow-up of 3.5 ± 1.8 years. We assessed their cognitive decline using the Unified Huntington's Disease Rating Scale, and their IGF-1 and insulin plasmatic levels, at baseline and once a year during the follow-up. Associations were evaluated using a mixed-effect linear model. RESULTS:In the cross-sectional analysis at baseline, higher levels of IGF-1 and insulin were associated with lower cognitive scores and thus with a higher degree of cognitive impairment. In the longitudinal analysis, the decrease of all cognitive scores, except the Stroop interference, was associated with the IGF-1 level over time but not of insulin. CONCLUSIONS:IGF-1 levels, unlike insulin, predict the decline of cognitive function in HD.

Published
2016
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12. Effectiveness of anti-psychotics and related drugs in the Huntington French-speaking group cohort.

Author

Gaëlle Désaméricq, Guillaume Dolbeau, Christophe Verny, Perrine Charles, Alexandra Durr, Katia Youssov, Clémence Simonin, Jean-Philippe Azulay, Christine Tranchant, Cyril Goizet, Philippe Damier, Emmanuel Broussolle, Jean-François Demonet, Graca Morgado, Laurent Cleret de Langavant, Isabelle Macquin-Mavier, Anne-Catherine Bachoud-Lévi, and Patrick Maison

Subjects
Medicine, Science
Abstract

PURPOSE: Huntington's disease is a rare condition. Patients are commonly treated with antipsychotics and tetrabenazine. The evidence of their effect on disease progression is limited and no comparative study between these drugs has been conducted. We therefore compared the effectiveness of antipsychotics on disease progression. METHODS: 956 patients from the Huntington French Speaking Group were followed for up to 8 years between 2002 and 2010. The effectiveness of treatments was assessed using Unified Huntington's Disease Rating Scale (UHDRS) scores and then compared using a mixed model adjusted on a multiple propensity score. RESULTS: 63% of patients were treated with antipsychotics during the survey period. The most commonly prescribed medications were dibenzodiazepines (38%), risperidone (13%), tetrabenazine (12%) and benzamides (12%). There was no difference between treatments on the motor and behavioural declines observed, after taking the patient profiles at the start of the drug prescription into account. In contrast, the functional decline was lower in the dibenzodiazepine group than the other antipsychotic groups (Total Functional Capacity: 0.41 ± 0.17 units per year vs. risperidone and 0.54 ± 0.19 vs. tetrabenazine, both p

Published
2014
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13. A genetic variation in the ADORA2A gene modifies age at onset in Huntington's disease

Author

Claire-Marie Dhaenens, Sylvie Burnouf, Clémence Simonin, Edwige Van Brussel, Alain Duhamel, Luc Defebvre, Cécile Duru, Isabelle Vuillaume, Cécile Cazeneuve, Perrine Charles, Patrick Maison, Sabrina Debruxelles, Christophe Verny, Hélène Gervais, Jean-Philippe Azulay, Christine Tranchant, Anne-Catherine Bachoud-Levi, Alexandra Dürr, Luc Buée, Pierre Krystkowiak, Bernard Sablonnière, and David Blum

Subjects
Huntington's disease, A2A receptors, Polymorphism, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Based on the pathophysiological role of adenosine A2A receptors in HD, we have evaluated the association of the 1976C/T single-nucleotide polymorphism in the ADORA2A gene (rs5751876) with residual age at onset (AAO) in HD. The study population consisted of 791 unrelated patients belonging to the Huntington French Speaking Network. The variability in AAO attributable to the CAG repeats number was calculated by linear regression using the log (AAO) as the dependent variable, and the respective rs5751876 genotypes as independent variables. We show that the rs5751876 variant significantly influences the variability in AAO. The R2 statistic rose slightly but significantly (p=0.019) when rs5751876 T/T genotype was added to the regression model. Patients harbouring T/T genotype have an earlier AAO of 3.8 years as compared to C/C genotype (p=0.02). Our data thus strengthens the pathophysiological role of A2A receptors in Huntington's disease.

Published
2009
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14. Neuroendocrine disturbances in Huntington's disease.

Author

Nadine Saleh, Stéphane Moutereau, Alexandra Durr, Pierre Krystkowiak, Jean-Philippe Azulay, Christine Tranchant, Emmanuel Broussolle, Françoise Morin, Anne-Catherine Bachoud-Lévi, and Patrick Maison

Subjects
Medicine, Science
Abstract

BACKGROUND: Huntington's disease (HD) is a severe inherited neurodegenerative disorder characterized, in addition to neurological impairment, by weight loss suggesting endocrine disturbances. The aims of this study were to look for neuroendocrine disturbances in patients with Huntington's disease (HD) and to determine the relationship with weight loss seen in HD METHODS AND FINDING: We compared plasma levels of hormones from the five pituitary axes in 219 patients with genetically documented HD and in 71 sex- and age-matched controls. Relationships between hormone levels and disease severity, including weight-loss severity, were evaluated. Growth hormone (GH) and standard deviation score of insulin-like growth factor 1 (SDS IGF-1) were significantly higher in patients than in controls (0.25 (0.01-5.89) vs. 0.15 (0.005-4.89) ng/ml, p = 0.013 and 0.16+/-1.02 vs. 0.06+/-0.91, p = 0.039; respectively). Cortisol was higher (p = 0.002) in patients (399.14+/-160.5 nmol/L vs. 279.8+/-130.1 nmol/L), whereas no differences were found for other hormone axes. In patients, elevations in GH and IGF-1 and decreases in thyroid-stimulating hormone, free triiodothyronine and testosterone (in men) were associated with severity of impairments (Independence scale, Functional score, Total Functional Capacity, Total Motor score, Behavioral score). Only GH was independently associated with body mass index (beta = -0.26, p = 0.001). CONCLUSION: Our data suggest that the thyrotropic and in men gonadotropic axes are altered in HD according to the severity of the disease. The somatotropic axis is overactive even in patients with early disease, and could be related to the weight loss seen in HD patients.

Published
2009
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15. Personality assessment with Temperament and Character Inventory in Parkinson's disease

Author

Moreau, Caroline, Defebvre, Pr Luc, Carriere, Dr Nicolas, Grolez, Dr Guillaume, Baille, Dr Guillaume, Kreisler, Dr, Jean-Pierre Pruvo, Pr, Leclerc, Pr, Lopes, Dr Renaud, Viard, Dr Romain, Kuchcinski, Dr Gregory, Dumont, Mr Julien, Dujardin, Pr Kathy, Delliaux, Mme M., Brion, Mrs M., Touzet, Dr Gustavo, Reyns, Pr Nicolas, Delval, Pr Arnaud, Santraine, Mrs Valerie, Pleuvret, Mrs Marie, Dautrevaux, Mrs Nolwen, Laugeais, Mr Victor, Ouk, Thavarak, Potey, Camille, Leclercq, Celine, Gers, Elise, Corvol, Jean-Christophe, Marie-Vidailhet, Hainque, Elodie, Welter, Marie-Laure, Lacomblez, Lucette, Grabli, David, Roze, Emmanuel, Worbe, Yulia, Delorme, Cécile, You, Hana, Ihle, Jonas, Guimeraes-Costa, Raquel, Cormier-Dequaire, Florence, Méneret, Aurélie, Hartmann, Andréas, Mariani, Louise-Laure, Lehericy, Stéphane, Czernecki, Virginie, Pineau, Fanny, Bozon, Frédérique, Huiban, Camille, Benchetrit, Eve, Karachi, Carine, Navarro, Soledad, Cornu, Philippe, Welaratne, Arlette, Dongmo-Kenfack, Carole, Mantisi, Lise, Jarry, Nathalie, Aix, Sophie, Lefort, Carine, Rouaud, Dr Tiphaine, Damier, Pr Philippe, Derkinderen, Pr Pascal, Anne-Gaelle Corbille, Dr, Calvier-Auffray, Dr Elisabeth, Rocher, Mrs Laetitia, Anne-Laure Deruet, Mrs, Sylvie, Dr Raoul, Vincent, Dr Roualdes, Le Dily Séverine, Mrs, Marques, Dr Ana, Debilly, Dr Berangere, Durif, Pr Franck, Derost, Dr Philippe, Beal, Dr Charlotte, Chassain, Carine, Delaby, Laure, Vidal, Tiphaine, Jacques Lemaire, Pr Jean, Rieu, Isabelle, Durand, Elodie, Eusebio, Pr Alexandre, Jean-Philippe Azulay, Pr, Witjas, Dr Tatiana, Fluchère, Dr Frédérique, Grimaldi, Dr Stephan, Girard, Pr Nadine, Delfini, Marie, Carron, Dr Romain, Regis, Pr Jean, Spatola, Dr Giorgio, Magnaudet, Camille, Solène, Dr Ansquer, Isabelle, Dr Benatru, Olivier, Dr Colin, Houeto Jl, Pr, Remy, Pr Guillevin, Anne, Mrs Fradet, Manssouri, Mrs Anziza, Sophie, Mrs Blondeau, Philippe, Dr Richard, Philippe, Dr Cam, Philippe, Dr Page, Benoit, Pr Bataille, Emilie, Mrs Rabois, Annie, Mrs Guillemain, Sophie, Dr Drapier, Leh, Dr Frédérique, Bonnet, Dr Alexandre, Vérin, Pr Marc, Jean-Christophe Ferré, Dr, François Houvenaghel, Mr Jean, Haegelen, Pr Claire, Kestens, Mrs Francoise, Ory, Mrs Solenn, Burbaud, Pr Pierre, Damon-Perriere, Dr Nathalie, Meissner, Pr Wassilios, Tison, Pr Francois, Bannier, Dr Stéphanie, Krim, Dr Elsa, Guehl, Pr Dominique, Molinier-Blossier, Sandrine, Ollivier, Morgan, Lacoste, Marion, Auzou, Nicolas, Bonnet, Marie, Cuny, Pr Emmanuel, Engelhardt, Dr Julien, Branchard, Olivier, Huet, Clotilde, Blanchard, Julie, Olivier, Pr Rascol, Brefel Courbon, Dr Christine, Ory Magne, Dr Fabienne, Simonetta Moreau, Dr Marion, Arbus, Pr Christophe, Bonneville, Pr Fabrice, Albert Lotterie, Dr Jean, Sarrail, Marion, Scotto d’Apollonia, Charlotte, Chaynes, Pr Patrick, Caire, Pr François, Harroch, Estelle, Maltete, Pr David, Lefaucheur, Dr Romain, Fetter, Dr Damien, Magne, Dr Nicolas, Bioux, Mrs Sandrine, Loubeyre, Mrs Maud, Bliaux, Mrs Evangéline, Pouliquen, Mrs Dorothée, Derrey, Pr Stéphane, Vernon, Mrs Linda, Ziegler, Dr Frédéric, Anheim, Mathieu, Lagha-Boukbiza, Ouhaid, Tranchant, Christine, Gebus, Odile, Montaut, Solveig, Kremer, S., Longato, Nadine, Phillips, Clélie, Voirin, Jimmy, Santin, Marie des Neiges, Chaussemy, Dominique, Mengin, Dr Amaury, Giordana, Dr Caroline, Marsé, Dr Claire, Mondot, Lydiane, Giordana, Bruno, Kardous, Robin, Bailet, Bernadette, Joly, Héloise, Fontaine, Denys, Leplus, Dr Aurélie, Faustini, Amélie, Ferrier, Vanessa, Krystkowiak, Pr Pierre, Tir, Dr Mélissa, Jean-Marc Constans, Pr, Wannepain, Sandrine, Seling, Audrey, Lefranc, Dr Michel, Blin, Stéphanie, Schuler, Béatrice, Thobois, Pr Stephane, Danaila, Dr Teodor, Laurencin, Dr Chloe, Berthezene, Pr Yves, Ameli, Dr Roxana, Klinger, Helene, Polo, Dr Gustavo, Mertens, Patrick, Nunes, A., Metereau, Elise, Hopes, Dr Lucie, Frismand, Dr Solène, Schmitt, Dr Emmanuelle, Meyer, Mrs Mylène, Dillier, Mrs Céline, Colnat, Pr Sophie, Chatelain, Mrs Anne, Philippe Brandel, Dr Jean, Hubsch, Dr Cécile, Karsenti, Dr Patte, Lebouteux, Dr Marie, Ziegler, Dr Marc, Delmaire, Dr Christine, Savatowky, Dr Julien, Vrillac, Mrs Juliette, Nakache, Mrs Claire, D'Hardemare, Dr Vincent, Belamri, Mr Lhaouas, Mesnage, Dr Valérie, Bonnet, Dr Cécilia, Correa Lino, Dr Jarbas, Jr., Decrocq, Dr Camille, Boulin, Dr Anne, Barre, Mrs Inès, Manouvrier, Mrs Jordane, Gardel, Dr Bérénice, Jarraya, Pr Béchir, Ziz, Mrs Catherine, Prette, Mrs Lydie, Douzane, Mr Hassen, Gay, David, Bonicel, Robin, El Mountassir, Fouzia, Fischer, Clara, Mangin, Jean-François, Chupin, Marie, Cointepas, Yann, Accart, Bertrand, Gelé, Patrick, Fievet, Florine, Chabel, Matthieu, Derenaucourt, Virginie, Facon, Loïc, Njosse, Yanick Tchantchou, Deplanque, Dominique, Duhamel, Alain, Djemmane, Lynda, Duflot, Florence, Boussac, Mathilde, Arbus, Christophe, Colin, Olivier, Laurencin, Chloé, Eusebio, Alexandre, Corvol, Jean Christophe, Versace, Nathalie, Rascol, Olivier, Rousseau, Vanessa, Ory-Magne, Fabienne, Fabbri, Margherita, Rolland, Anne-Sophie, Jarraya, Béchir, Maltête, David, Drapier, Sophie, Marques, Ana-Raquel, Wirth, Thomas, Meyer, Mylène, Tir, Mélissa, Rouaud, Tiphaine, Devos, David, and Brefel-Courbon, Christine

Published
2022
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16. Deep Brain Stimulation–Withdrawal Syndrome in Parkinson’s Disease: Risk Factors and Pathophysiological Hypotheses of a Life-Threatening Emergency

Author

Stephan Grimaldi, Alexandre Eusebio, Romain Carron, Jean-Marie Regis, Lionel Velly, Jean-Philippe Azulay, Tatiana Witjas, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), and Department of Neurology and Movement Disorders, Timone University Hospital, Aix-Marseille University, Marseille

Subjects
Anesthesiology and Pain Medicine, Neurology, Neurology (clinical), General Medicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Subthalamic nucleus deep brain stimulation (DBS) is the most common therapeutic surgical procedure for patients with Parkinson's disease with motor fluctuations, dyskinesia, or tremor. Routine follow-up of patients allows clinicians to anticipate replacement of the DBS battery reaching the end of its life. Patients who experience a sudden stop of the DBS battery experience a rapid worsening of symptoms unresponsive to high dose of levodopa, in a life-threatening phenomenon called "DBS-withdrawal syndrome." In the current context of the COVID-19 pandemic, in which many surgeries are being deprogrammed, it is of utmost importance to determine to what extent DBS battery replacement surgeries should be considered an emergency. In this study, we attempt to identify risk factors of DBS-withdrawal syndrome and provide new insights about pathophysiological hypotheses. We then elaborate on the optimal approach to avoid and manage such a situation.We conducted a systematic review of the literature on the subject and reported the cases of 20 patients (including five from our experience) with DBS-withdrawal syndrome, comparing them with 15 undisturbed patients (including three from our experience), all having undergone neurostimulation discontinuation.A long disease duration at battery removal and many years of DBS therapy are the main potential identified risk factors (p 0.005). In addition, a trend for older age at the event and higher Unified Parkinson's Disease Rating Scale motor score before initial DBS implantation (evaluated in OFF-drug condition) was found (p 0.05). We discuss several hypotheses that might explain this phenomenon, including discontinued functioning of the thalamic-basal ganglia loop due to DBS-stimulation cessation in a context in which cortical-basal ganglia loop had lost its cortical input, and possible onset of a severe bradykinesia through the simultaneous occurrence of an alpha and high-beta synchronized state.The patients' clinical condition may deteriorate rapidly, be unresponsive to high dose of levodopa, and become life-threatening. Hospitalization is suggested for clinical monitoring. In the context of the current COVID-19 pandemic, it is important to widely communicate the replacement of DBS batteries reaching the end of their life. More importantly, in cases in which the battery has stopped, there should be no delay in performing replacement as an emergent surgery.

Published
2023

17. Personality Assessment with Temperament and Character Inventory in Parkinson's Disease

Author

Mathilde Boussac, Christophe Arbus, Olivier Colin, Chloé Laurencin, Alexandre Eusebio, Elodie Hainque, Jean Christophe Corvol, Nathalie Versace, Olivier Rascol, Vanessa Rousseau, Estelle Harroch, Fabienne Ory-Magne, Margherita Fabbri, Caroline Moreau, Anne-Sophie Rolland, Béchir Jarraya, David Maltête, Sophie Drapier, Ana-Raquel Marques, Nicolas Auzou, Thomas Wirth, Mylène Meyer, Bruno Giordana, Mélissa Tir, Tiphaine Rouaud, David Devos, Christine Brefel-Courbon, Pr Luc Defebvre, Dr Nicolas Carriere, Dr Guillaume Grolez, Dr Guillaume Baille, Dr Kreisler, Pr Jean-Pierre Pruvo, Pr Leclerc, Dr Renaud Lopes, Dr Romain Viard, Dr Gregory Kuchcinski, Mr Julien Dumont, Pr Kathy Dujardin, Mme M. Delliaux, Mrs M. Brion, Dr Gustavo Touzet, Pr Nicolas Reyns, Pr Arnaud Delval, Mrs Valerie Santraine, Mrs Marie Pleuvret, Mrs Nolwen Dautrevaux, Mr Victor Laugeais, Thavarak Ouk, Camille Potey, Celine Leclercq, Elise Gers, Jean-Christophe Corvol, null Marie-Vidailhet, Marie-Laure Welter, Lucette Lacomblez, David Grabli, Emmanuel Roze, Yulia Worbe, Cécile Delorme, Hana You, Jonas Ihle, Raquel Guimeraes-Costa, Florence Cormier-Dequaire, Aurélie Méneret, Andréas Hartmann, Louise-Laure Mariani, Stéphane Lehericy, Virginie Czernecki, Fanny Pineau, Frédérique Bozon, Camille Huiban, Eve Benchetrit, Carine Karachi, Soledad Navarro, Philippe Cornu, Arlette Welaratne, Carole Dongmo-Kenfack, Lise Mantisi, Nathalie Jarry, Sophie Aix, Carine Lefort, Dr Tiphaine Rouaud, Pr Philippe Damier, Pr Pascal Derkinderen, Dr Anne-Gaelle Corbille, Dr Elisabeth Calvier-Auffray, Mrs Laetitia Rocher, Mrs Anne-Laure Deruet, Dr Raoul Sylvie, Dr Roualdes Vincent, Mrs Le Dily Séverine, Dr Ana Marques, Dr Berangere Debilly, Pr Franck Durif, Dr Philippe Derost, Dr Charlotte Beal, Carine Chassain, Laure Delaby, Tiphaine Vidal, Pr Jean Jacques Lemaire, Isabelle Rieu, Elodie Durand, Pr Alexandre Eusebio, Pr Jean-Philippe Azulay, Dr Tatiana Witjas, Dr Frédérique Fluchère, Dr Stephan Grimaldi, Pr Nadine Girard, Marie Delfini, Dr Romain Carron, Pr Jean Regis, Dr Giorgio Spatola, Camille Magnaudet, Dr Ansquer Solène, Dr Benatru Isabelle, Dr Colin Olivier, Pr Houeto Jl, Pr Guillevin Remy, Mrs Fradet Anne, Mrs Anziza Manssouri, Mrs Blondeau Sophie, Dr Richard Philippe, Dr Cam Philippe, Dr Page Philippe, Pr Bataille Benoit, Mrs Rabois Emilie, Mrs Guillemain Annie, Dr Drapier Sophie, Dr Frédérique Leh, Dr Alexandre Bonnet, Pr Marc Vérin, Dr Jean-Christophe Ferré, Mr Jean François Houvenaghel, Pr Claire Haegelen, Mrs Francoise Kestens, Mrs Solenn Ory, Pr Pierre Burbaud, Dr Nathalie Damon-Perriere, Pr Wassilios Meissner, Pr Francois Tison, Dr Stéphanie Bannier, Dr Elsa Krim, Pr Dominique Guehl, Sandrine Molinier-Blossier, Morgan Ollivier, Marion Lacoste, Marie Bonnet, Pr Emmanuel Cuny, Dr Julien Engelhardt, Olivier Branchard, Clotilde Huet, Julie Blanchard, Pr Rascol Olivier, Dr Christine Brefel Courbon, Dr Fabienne Ory Magne, Dr Marion Simonetta Moreau, Pr Christophe Arbus, Pr Fabrice Bonneville, Dr Jean Albert Lotterie, Marion Sarrail, Charlotte Scotto d’Apollonia, Pr Patrick Chaynes, Pr François Caire, Pr David Maltete, Dr Romain Lefaucheur, Dr Damien Fetter, Dr Nicolas Magne, Mrs Sandrine Bioux, Mrs Maud Loubeyre, Mrs Evangéline Bliaux, Mrs Dorothée Pouliquen, Pr Stéphane Derrey, Mrs Linda Vernon, Dr Frédéric Ziegler, Mathieu Anheim, Ouhaid Lagha-Boukbiza, Christine Tranchant, Odile Gebus, Solveig Montaut, S. Kremer, Nadine Longato, Clélie Phillips, Jimmy Voirin, Marie des Neiges Santin, Dominique Chaussemy, Dr Amaury Mengin, Dr Caroline Giordana, Dr Claire Marsé, Lydiane Mondot, Robin Kardous, Bernadette Bailet, Héloise Joly, Denys Fontaine, Dr Aurélie Leplus, Amélie Faustini, Vanessa Ferrier, Pr Pierre Krystkowiak, Dr Mélissa Tir, Pr Jean-Marc Constans, Sandrine Wannepain, Audrey Seling, Dr Michel Lefranc, Stéphanie Blin, Béatrice Schuler, Pr Stephane Thobois, Dr Teodor Danaila, Dr Chloe Laurencin, Pr Yves Berthezene, Dr Roxana Ameli, Helene Klinger, Dr Gustavo Polo, Patrick Mertens, A. Nunes, Elise Metereau, Dr Lucie Hopes, Dr Solène Frismand, Dr Emmanuelle Schmitt, Mrs Mylène Meyer, Mrs Céline Dillier, Pr Sophie Colnat, Mrs Anne Chatelain, Dr Jean- Philippe Brandel, Dr Cécile Hubsch, Dr Patte Karsenti, Dr Marie Lebouteux, Dr Marc Ziegler, Dr Christine Delmaire, Dr Julien Savatowky, Mrs Juliette Vrillac, Mrs Claire Nakache, Dr Vincent D'Hardemare, Mr Lhaouas Belamri, Dr Valérie Mesnage, Dr Cécilia Bonnet, Dr Jarbas Correa Lino, Dr Camille Decrocq, Dr Anne Boulin, Mrs Inès Barre, Mrs Jordane Manouvrier, Dr Bérénice Gardel, Pr Béchir Jarraya, Mrs Catherine Ziz, Mrs Lydie Prette, Mr Hassen Douzane, David Gay, Robin Bonicel, Fouzia El Mountassir, Clara Fischer, Jean-François Mangin, Marie Chupin, Yann Cointepas, Bertrand Accart, Patrick Gelé, Florine Fievet, Matthieu Chabel, Virginie Derenaucourt, Loïc Facon, Yanick Tchantchou Njosse, Dominique Deplanque, Alain Duhamel, Lynda Djemmane, Florence Duflot, Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier de Brive-la-Gaillarde (CH Brive), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), CHU Marseille, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Excellence en Maladies Neurodégénératives (NeuroToul), CIC - Biotherapie - Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Foch [Suresnes], Neuroimagerie cognitive - Psychologie cognitive expérimentale (UNICOG-U992), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA), Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), CHU Bordeaux [Bordeaux], Les Hôpitaux Universitaires de Strasbourg (HUS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by the France Parkinson charity and French Ministry of Health (PHRC national 2012). This is an ancillary study to Protocol ID: 2013-A00193-42, ClinicalTrials.gov: NCT02360683., Centre Hospitalier Brive-la-Gaillarde, and Hôpital P.P.-Riquet

Subjects
Personality Inventory, Temperament and character inventory, Parkinson's disease, Parkinson Disease, Personality Assessment, Antidepressive Agents, Neurology, Anti-Anxiety Agents, Fluctuating PD patients, Quality of Life, Humans, Neurology (clinical), Geriatrics and Gerontology, Temperament, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Personality
Abstract

International audience; INTRODUCTION: There is a growing interest in personality evaluation in Parkinson's disease (PD), following observations of specific temperaments in PD patients. Therefore, our objective was to evaluate personality dimensions from the Temperament and Character Inventory (TCI) in a cohort of fluctuating PD patients considered for deep brain stimulation. METHODS: Fluctuating PD patients from the PREDISTIM cohort were included. Description of TCI dimensions and comparison with a French normative cohort were performed. Pearson correlations between TCI dimensions and motor, behavioral and cognitive variables were investigated. Structural and internal consistency analysis of the TCI were further assessed. RESULTS: The 570 PD patients presented significant higher scores in Harm Avoidance, Reward Dependence, Persistence, Self-Directedness and Cooperativeness and significant lower scores in Self-Transcendence compared to the French normative cohort; only Novelty Seeking scores were not different. Harm Avoidance and Self-directedness scores were correlated with PDQ-39 total, HAMD, HAMA scores, and anxiolytic/antidepressant treatment. Novelty Seeking scores were correlated with impulsivity. Pearson correlations between TCI dimensions, principal component analysis of TCI sub-dimensions and Cronbach's alpha coefficients showed adequate psychometric proprieties. CONCLUSION: The TCI seems to be an adequate tool to evaluate personality dimensions in PD with good structural and internal consistencies. These fluctuating PD patients also have specific personality dimensions compared to normative French population. Moreover, Harm Avoidance and Self-Directedness scores are associated with anxio-depressive state or quality of life and, and Novelty Seeking scores with impulsivity.

Published
2022

18. Early Parkinson's Disease Phenotypes Tailored by Personality, Behavior, and Motor Symptoms

Author

Bruna, Meira, Eugénie, Lhommée, Emmanuelle, Schmitt, Hélène, Klinger, Amélie, Bichon, Pierre, Pélissier, Mathieu, Anheim, Christine, Tranchant, Valérie, Fraix, Sara, Meoni, Franck, Durif, Jean-Luc, Houeto, Jean Philippe, Azulay, Elena, Moro, Stéphane, Thobois, Paul, Krack, and Anna, Castrioto

Subjects
Cellular and Molecular Neuroscience, Phenotype, Quality of Life, Humans, Parkinson Disease, Neurology (clinical), Personality Disorders, Personality
Abstract

Background: Previous studies described a parkinsonian personality characterized as rigid, introverted, and cautious; however, little is known about personality traits in de novo Parkinson’s disease (PD) patients and their relationships with motor and neuropsychiatric symptoms. Objective: To investigate personality in de novo PD and explore its relationship with PD symptoms. Methods: Using Cloninger’s biosocial model, we assessed personality in 193 de novo PD patients. Motor and non-motor symptoms were measured using several validated scales. Cluster analysis was conducted to investigate the interrelationship of personality traits, motor, and non-motor symptoms. Results: PD patients showed low novelty seeking, high harm avoidance, and normal reward dependence and persistence scores. Harm avoidance was positively correlated with the severity of depression, anxiety, and apathy (rs = [0.435, 0.676], p

Published
2022

19. SARS-CoV-2 and neurological disorders: the revelance of biomarkers?

Author

Katell Peoc'h, Vincent Sapin, Marie Christine Beauvieux, Sylvain Lehmann, Jean Philippe Azulay, Benoit Rucheton, Beaudeux Jl, Edith Bigot-Corbel, Cécile Delorme, Celia Raulet, and Aymeric Lanore

Subjects
medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, Context (language use), General Medicine, Prognosis, medicine.disease, Predictive Value of Tests, Acute disseminated encephalomyelitis, Pandemic, Disease Progression, medicine, Humans, Nervous System Diseases, Intensive care medicine, business, Pandemics, Neurological impairment, Biomarkers, Biochemical markers
Abstract

Soon after the pandemic, numerous publications described cases of neurological disorders associated with the SARS-CoV-2 infection. The range of neurological symptoms is becoming increasingly more extensive as the pandemic progresses. However, it is not yet well established whether the manifestations are due to direct viral damage to the nervous system or indirect consequences of the infection. This review presents an inventory of the biochemical markers studied in the context of neurological disorders related to SARS-CoV-2. By reflecting various physiopathological mechanisms, these biomarkers allow both a better understanding of the pathophysiology of Covid-19 and a contribution to the diagnosis of neurologic troubles; they could participate in the prognostic evaluation of patients.

Published
2021

20. THN 102 for excessive daytime sleepiness associated with Parkinson's disease: a phase 2a trial

Author

Jean-Christophe, Corvol, Jean-Philippe, Azulay, Björn, Bosse, Yves, Dauvilliers, Luc, Defebvre, Fabian, Klostermann, Norbert, Kovacs, David, Maltête, William G, Ondo, Rajesh, Pahwa, Werner, Rein, Stéphane, Thobois, Martin, Valis, Aleksandar, Videnovic, Olivier, Rascol, Katarina, Zárubová, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), NS-Park/FCRIN Network, UMS 015, Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Montpellier, Université de Montpellier (UM), Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Pécs Medical School (UP MS), University of Pecs, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Center for neurogenetics [Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York], Weill Medical College of Cornell University [New York], University of Kansas Medical Center [Kansas City, KS, USA], Theranexus [Lyon], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Charles University [Prague] (CU), Massachusetts General Hospital [Boston], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), THN102-202 Study Investigators: Jean-Christophe Corvol, Jean-Philippe Azulay, Marek Baláž, Ralf Bodenschatz, Magdolna Bokor, Hana Brožová, Yves Dauvilliers, Luc Defebvre, Ondraj Fiala, Andràs Folyovich, Heinz Peter Herbst, Fabian Klostermann, Norbert Kovacs, Julianna Lajtos, Paul Lingor, David Maltête, Christian Oehlwein, Rajesh Pahwa, Jan Peregrin, Olivier Rascol, Daniela Rau, Ali Safavi, Joachim Springub, Jindra Svátová, Stéphane Thobois, Univ Lyon, Martin Valis, Làszlo Vécsei, Aleksandar Videnovic, Olga Waln, Katarina Zárubová, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Kansas Medical Center [Lawrence], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, CHU Toulouse [Toulouse], and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Parkinson's disease, Excessive daytime sleepiness, Disorders of Excessive Somnolence, Placebo, sleepiness, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, medicine, Clinical endpoint, Humans, 030304 developmental biology, 0303 health sciences, business.industry, Epworth Sleepiness Scale, Modafinil, Parkinson Disease, clinical trial, medicine.disease, Crossover study, 3. Good health, flecainide, Clinical trial, Drug Combinations, Neurology, Anesthesia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, modafinil, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; BackgroundExcessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide.ObjectiveThe aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS.MethodsThe method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score.ResultsBoth doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: −1.4 [−2.49; −0.31], P = 0.012) but did not change significantly with the 200/18 dosage.ConclusionsTHN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society

Published
2021

23. Fatigue in de novo Parkinson's Disease: Expanding the Neuropsychiatric Triad?

Author

Matthieu Béreau, Anna Castrioto, Eugénie Lhommée, Audrey Maillet, Aurélie Gérazime, Amélie Bichon, Pierre Pélissier, Emmanuelle Schmitt, Hélène Klinger, Nadine Longato, Valérie Fraix, Isabelle Benatru, Franck Durif, Jean-Philippe Azulay, Elena Moro, Emmanuel Broussolle, Christine Tranchant, Mathieu Anheim, Stéphane Thobois, and Paul Krack

Subjects
Cellular and Molecular Neuroscience, Cross-Sectional Studies, Apathy, Quality of Life, Humans, Female, Parkinson Disease, Neurology (clinical), Fatigue
Abstract

Background: Fatigue is a frequent and troublesome symptom present from the early stages of Parkinson’s disease (PD). Objective: To examine the relationship between fatigue and the neuropsychiatric triad, which includes apathy, depression, and anxiety, in de novo PD. Methods: We performed a cross-sectional study including 197 patients with de novo PD and assessed fatigue using the Parkinson’s Disease Fatigue Scale (PDFS-16). We evaluated motor status using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III score and evaluated neuropsychiatric status using the Ardouin Scale of Behavior in Parkinson’s Disease (ASBPD). We carried out univariate and multivariate analyses to model association between motor signs, non-motor signs, and fatigue risk. Results: Frequency of fatigue (28.9%) was of the same order of magnitude as that of apathy. PD patients with fatigue reported a lower quality of life than patients without fatigue (p

Published
2022

24. Musical sonification improves motor control in Parkinson's disease: a proof of concept with handwriting

Author

Jérémy Danna, Serge Pinto, Tatiana Witjas, Lauriane Véron-Delor, Jean-Philippe Azulay, Alexandre Eusebio, Jean-Luc Velay, Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Parole et Langage (LPL), Institut de Neurosciences de la Timone (INT), Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance Publique - Hôpitaux de Marseille (APHM), ANR-16-CONV-0002,ILCB,ILCB: Institute of Language Communication and the Brain(2016), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Véron-Delor, Lauriane

Subjects
Male, medicine.medical_specialty, Movement disorders, Movement, Parkinson's disease, medicine.medical_treatment, behavioral disciplines and activities, 050105 experimental psychology, General Biochemistry, Genetics and Molecular Biology, Session (web analytics), rehabilitation, Task (project management), 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, History and Philosophy of Science, Handwriting, medicine, Humans, 0501 psychology and cognitive sciences, Music Therapy, Rehabilitation, Movement (music), [SCCO.NEUR]Cognitive science/Neuroscience, General Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, 05 social sciences, Motor control, Parkinson Disease, musical sonification, Middle Aged, humanities, Motor Skills, Sonification, Female, medicine.symptom, Psychology, human activities, Music, 030217 neurology & neurosurgery, handwriting
Abstract

International audience; A growing number of studies postulate the use of music to improve motor control in patients with Parkinson's disease (PD). The effects of music are greatly variable from one individual to the other and do not always reach the expected benefits. This study aimed to optimize the use of music in the management of movement disorders inherent to PD in a handwriting task. We developed and tested musical sonification (MS), a method that transforms in real-time kinematic variables into music. Twelve patients with PD, on medication, and 12 healthy controls were recruited in a pretest/training/posttest design experiment. Three training sessions were compared, for which participants were asked to produce graphomotor exercises: one session with music (unrelated to handwriting), one with MS (controlled by handwriting), and one in silence. Results showed that the performance in training was better under MS than under silence or background music, for both groups. After training, the benefits of MS were still present for both groups, with a higher effect for PD patients than for control group. Our results provide a proof of concept to consider MS as a relevant auditory guidance strategy for movement rehabilitation in patients with PD.

Published
2020

25. Subthalamic stimulation breaks the balance between distal and axial signs in Parkinson’s disease

Author

Serge Pinto, Christelle Baunez, Cyril Atkinson-Clement, Thierry Legou, Tatiana Witjas, Jean-Philippe Azulay, Alexandre Zénon, Frédérique Fluchère, Émilie Cavazzini, Alexandre Eusebio, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences de la Timone (INT), CHU Marseille, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, medicine.medical_specialty, Parkinson's disease, Deep brain stimulation, Deep Brain Stimulation, Science, medicine.medical_treatment, behavioral disciplines and activities, Article, Antiparkinson Agents, Levodopa, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Reward, Quality of life, Vowel, Humans, Medicine, Phonation, Aged, 030304 developmental biology, Balance (ability), Motivation, 0303 health sciences, Multidisciplinary, business.industry, Parkinson Disease, Middle Aged, medicine.disease, nervous system diseases, Treatment Outcome, surgical procedures, operative, nervous system, Subthalamus, Subthalamic stimulation, Basal ganglia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, therapeutics, 030217 neurology & neurosurgery
Abstract

In Parkinson’s disease (PD), the effects of both Ldopa and subthalamic deep brain stimulation (STN-DBS) are known to change cost-valuation. However, this was mostly studied through reward-effort task involving distal movements, while axial effort, less responsive to treatments, have been barely studied. Thus, our objective was to compare the influence of both Ldopa and STN-DBS on cost-valuation between two efforts modalities: vowel production (as an example of axial movement) and hand squeezing (as an example of distal movement). Twelve PD patients were recruited to participate in this study. The task consisted in deciding whether to accept or reject trials based on a reward-effort trade-off. Participants performed two blocks with hand squeezing, and two with vowel production, in the four treatment conditions (LdopaOn/Off; STN-DBS On/Off). We found that STN-DBS changed the ratio difference between hand and phonation efforts. Vowel production effort was estimated easier to perform with STN-DBS alone, and harder when associated with Ldopa. The difference between hand and phonation efforts was correlated with quality of life in Off/Off and On Ldopa alone conditions, and with impulsive assessment On STN-DBS alone. We highlighted that STN-DBS could introduce an imbalance between the actual motor impairments and their subjective costs. With this finding, we also suggest paying particular attention to the different treatment effects that should be expected for axial and distal movement dysfunctions.

Published
2021

26. Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies

Author

Olivier Rascol, Lars Tönges, Tina deVries, Mark Jaros, Adrian Quartel, David Jacobs, Jean-Philippe Azulay, Ernest Balaguer, Perminder Bhatia, Ivan Bodis-Wollner, Paul Brownstone, Nicolas Boulloche, Gerald J. Calegan, Giovanni Castelnovo, Kelvin L. Chou, Jean-Christophe Corvol, Fabio Danisi, Luc Defebvre, Lydia Vela Desojo, Franck Durif, Reinhard Ehret, Bradley K. Evans, Concetta Forchetti, Joseph H. Friedman, Wolfgang Fogel, Matilde Calopa Garniga, Ramon A. Gil, Paul L. Ginsberg, Mark R. Glasberg, Alida Griffith, Jeffrey W. Groves, Mark Gudesblatt, Neal Hermanowicz, Maria A. Herrera, Jean-Luc Houeto, Robert M. Hutchman, Stuart H. Isaacson, Singar Jagadeesan, Mandar Jog, Andrew Keegan, Fabian Klostermann, Pierre Krystkowiak, Jaime Kulisevsky Bojarsky, Rajeev Kumar, Dennis Lacey, Bruce Lasker, John LaVaccare, Michelle M. Lavallee, Maria Rosario Luquin Piudo, Andreas Mahler, Maria José Martí Domenech, Juan Carlos Martinez Castrillo, Laszlo J. Mate, Tilak Mendis, Leonard Verhagen Metman, Siegfried Martin Muhlack, Thomas Müller, Ariane Park, James Patton, Elizabeth Peckham, Francisco Grandas Pérez, Marcie Rabin, Gerd Reifschneider, Philippe Remy, Pablo Mir Rivera, Johannes Schwarz, Isabelle Roullet-Solignac, Gabriel Salazar, Stephen M. Sergay, Scott Sherman, Richard Shubin, Lorraine Spikol, Frank Steigerwald, Daniel D. Truong, Antonio Ugarte, Francisco Vivancos Matellano, Arnold Witte, Theresa Zesiewicz, and Sarah Elizabeth Zauber

Subjects
Antiparkinson Agents, Levodopa, Dyskinesia, Drug-Induced, Treatment Outcome, Neurology, Double-Blind Method, Amantadine, Humans, Parkinson Disease, Neurology (clinical), Geriatrics and Gerontology
Abstract

Immediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER®) contains an IR outer layer and ER core for once-daily dosing.Report individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID.PD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale.Overall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were -5.5 [-9.8, -1.2], p = 0.012 and -5.2 [-9.5, -0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively).IR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

Published
2021

27. Early atypical signs and insula hypometabolism predict survival in multiple system atrophy

Author

Tatiana Witjas, Eric Guedj, Stephan Grimaldi, Frédérique Fluchère, Mohamed Boucekine, Alexandre Eusebio, Jean-Philippe Azulay, Service de médecine nucléaire [Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Imagerie MOléculaire pour applications THéranostiques personnalisées (IMOTHEP), Institut FRESNEL (FRESNEL), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), and Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Oncology, 0303 health sciences, medicine.medical_specialty, Framingham Risk Score, Proportional hazards model, business.industry, Serotonin reuptake inhibitor, medicine.disease, 3. Good health, 03 medical and health sciences, Psychiatry and Mental health, Orthostatic vital signs, 0302 clinical medicine, Atrophy, Internal medicine, Cohort, medicine, Surgery, Neurology (clinical), business, Insula, Survival rate, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology
Abstract

ObjectiveWe aim to search for predictors of survival among clinical and brain 18F-FDG positron emission tomography (PET) metabolic features in our cohort of patients with multiple system atrophy (MSA).MethodsWe included patients with a ‘probable’ MSA diagnosis for whom a clinical evaluation and a brain PET were performed early in the course of the disease (median 3 years, IQR 2–5). A retrospective analysis was conducted using standardised data collection. Brain PET metabolism was characterised using the Automated Anatomical Labelling Atlas. A Cox model was applied to look for factors influencing survival. Kaplan-Meier method estimated the survival rate. We proposed to develop a predictive ‘risk score’, categorised into low-risk and high-risk groups, using significant variables entered in multivariate Cox regression analysis.ResultsEighty-five patients were included. The overall median survival was 8 years (CI 6.64 to 9.36). Poor prognostic factors were orthostatic hypotension (HR=6.04 (CI 1.58 to 23.12), p=0.009), stridor (HR=3.41 (CI 1.31 to 8.87), p=0.012) and glucose PET hypometabolism in the left insula (HR=0.78 (CI 0.66 to 0.92), p=0.004). Good prognostic factors were time to diagnosis (HR=0.68 (CI 0.54 to 0.86), p=0.001) and use of selective serotonin reuptake inhibitor (SSRI) (HR=0.17 (CI 0.06 to 0.46), pConclusionThe clinical prognosis factors we have described support published studies. Here, we also suggest that brain PET is of interest for prognosis assessment and in particular in the search for left insula hypometabolism. Moreover, SSRIs are a potential drug candidate to slow the progression of the disease.

Published
2021

28. Digitalized spiral drawing in Parkinson’s disease: A tool for evaluating beyond the written trace

Author

Alexandre Eusebio, Lauriane Véron-Delor, Jérémy Danna, Serge Pinto, Jean-Luc Velay, Jean-Philippe Azulay, Tatiana Witjas, Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire Parole et Langage (LPL), ANR-16-CONV-0002,ILCB,ILCB: Institute of Language Communication and the Brain(2016), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Adult, Male, Parkinson's disease, Movement, Writing, Biophysics, Experimental and Cognitive Psychology, Functional Laterality, Task (project management), 03 medical and health sciences, Fluency, Graphonomics, 0302 clinical medicine, Drawing Tasks, medicine, Humans, Orthopedics and Sports Medicine, Motor assessment, Digitizer, Spiral, Aged, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Medical treatment, [SCCO.NEUR]Cognitive science/Neuroscience, Parkinson Disease, 030229 sport sciences, General Medicine, Middle Aged, Hand, medicine.disease, Biomechanical Phenomena, Trace (semiology), Motor Skills, Case-Control Studies, Female, Psychology, Psychomotor Performance, 030217 neurology & neurosurgery, Cognitive psychology
Abstract

International audience; One of the current scientific challenges is to propose novel tools and tasks designed to identify new motor biomarkers in Parkinson’s disease (PD). Among these, a focus has placed on drawing tasks. Independently from clinical ratings, this study aimed to evaluate the pen movement and holding in digitalized spiral drawing in individuals with PD without and with medical treatment and in healthy controls. A three-step data-driven analysis was conducted. First, the effects of spatial and temporal constraints on several variables were determined. Second, the relationship between handedness and dominance of PD symptoms was investigated for the most relevant variables. Finally, a third analysis was conducted to assess the occurrence of changes associated with PD. The first analysis revealed that the number of velocity peaks and pen altitude variations were the most relevant variables in spiral drawing for evaluating the effect of the disease and medication. The second analysis revealed that the effect of medication was present for the movement fluency only, when spirals with spatial constraints were produced at a spontaneous speed by the hand on the side of dominant PD signs. Finally, the third analysis showed that the effect of medication was greater at the beginning of drawing than at the end. Digitalized spiral drawing makes it possible to observe precisely when the kinematic changes related to the disease occur during the task. Such a simple and quick task might be of great relevance to contribute to the diagnosis and follow-up of PD.

Published
2019

29. Effects of subthalamic nucleus stimulation and levodopa on decision‐making in Parkinson's disease

Author

Christelle Baunez, Jean-Philippe Azulay, Alexandre Zénon, Cyril Atkinson-Clement, Frédérique Fluchère, Émilie Cavazzini, Tatiana Witjas, Alexandre Eusebio, Université Catholique de Louvain = Catholic University of Louvain (UCL), Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut de Neurosciences de la Timone (INT), Université Catholique de Louvain (UCL), Hôpital de la Timone [CHU - APHM] (TIMONE), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Levodopa, medicine.medical_specialty, Parkinson's disease, Deep brain stimulation, Deep Brain Stimulation, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.medical_treatment, Decision Making, Disease, Neuropsychological Tests, Impulsivity, Antiparkinson Agents, 03 medical and health sciences, Cognition, 0302 clinical medicine, Physical medicine and rehabilitation, Reward, Subthalamic Nucleus, Dopamine, Basal ganglia, medicine, Humans, Apathy, ComputingMilieux_MISCELLANEOUS, Aged, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Parkinson Disease, Middle Aged, medicine.disease, nervous system diseases, 3. Good health, 030104 developmental biology, Neurology, Quality of Life, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Background Parkinson's disease (PD) is frequently associated with behavioral disorders, particularly within the spectrum of motivated behaviors such as apathy or impulsivity. Both pharmacological and neurosurgical treatments have an impact on these impairments. However, there still is controversy as to whether subthalamic nucleus deep brain stimulation (STN-DBS) can cause or reduce impulsive behaviors. Objectives We aimed to identify the influence of functional surgery on decision-making processes in PD. Methods We studied 13 PD patients and 13 healthy controls. The experimental task involved squeezing a dynamometer with variable force to obtain rewards of various values under four conditions: without treatment, with l-dopa or subthalamic stimulation alone, and with both l-dopa and subthalamic stimulation. Statistical analyses consisted of generalized linear mixed models including treatment condition, reward value, level of effort, and their interactions. We analyzed acceptance rate (the percentage of accepted trials), decision time, and force applied. Results Comparatively to controls, patients without treatment exhibited lower acceptance rate and force applied. Patients under l-dopa alone did not exhibit increased acceptance rate. With subthalamic stimulation, either with or without added l-dopa, all measures were improved so that patients' behaviors were undistinguishable from healthy controls'. Conclusions Our study shows that l-dopa administration does not fully restore cost-benefit decision-making processes, whereas STN-DBS fully normalizes patients' behaviors. These findings suggest that dopamine is partly involved in cost-benefit valuation, and that STN-DBS can have a beneficial effect on motivated behaviors in PD and may improve certain forms of impulsive behaviors. © 2019 International Parkinson and Movement Disorder Society.

Published
2019

30. Anterior Thalamic Stimulation Induced Relapsing Encephalitis

Author

Fabrice Bartolomei, Emilie Doche, Jean-Paul Stahl, Jean Régis, Jean-Philippe Azulay, Stephan Chabardes, Elsa E. Robin, and Hussein Hamdi

Subjects
medicine.medical_specialty, Deep brain stimulation, business.industry, medicine.medical_treatment, Meningoencephalitis, Stimulation, medicine.disease, Gastroenterology, 030218 nuclear medicine & medical imaging, Temporal lobe, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Internal medicine, medicine, Surgery, Neurology (clinical), business, Contraindication, Thalamic stimulator, 030217 neurology & neurosurgery, Encephalitis
Abstract

Deep brain stimulation of the anterior thalamic nucleus is one of the promising therapeutic options for epilepsy. Several studies are still under way to further strengthen and clarify the mechanism, efficacy, and complications. Contrary to hardware-related and operation-related events, the stimulation-related adverse effect is mild, target-dependent, and adjustable. We present a case of relapsing herpes simplex encephalitis (HSE) as a newly reported and potentially fatal stimulation-related adverse effect following stimulation of the anterior thalamic nucleus (ANT-DBS) accompanied by fever, confusion, and cognitive impairment in a 32-year-old epileptic patient with a history of herpes meningoencephalitis 31 years earlier. The T2-weighted/FLAIR high-signal intensity in the temporal lobe developed at a “distance” from the stimulation target. The positive polymerase chain reaction of herpes virus deoxyribonucleic acid in the cerebrospinal fluid confirmed the diagnosis. The condition improved partially on acyclovir and stimulation stopped. Seizures disappeared and then returned after few months. The unique case report presents a rationale for considering history of herpes encephalitis as a relative contraindication for ANT-DBS, and HSE relapse should be suspected in patients with post-stimulation fever and/or altered consciousness.

Published
2019

31. Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease

Author

Mathieu Anheim, Ouhaid Lagha-Boukbiza, Emmanuel Roze, Florence Cormier-Dequaire, Paul Krack, Alexis Brice, Lucette Lacomblez, Jean-Christophe Corvol, Solène Ansquer, Samir Bekadar, Sophie Tezenas du Montcel, Isabelle Benatru, Bénédicte Lebrun-Vignes, Pierre-Michel Llorca, Olivier Rascol, Graziella Mangone, Luc Defebvre, David Maltête, Ana Marques‐Raquel, Fabienne Ory-Magne, Anna Castrioto, Marie Vidailhet, Franck Durif, Said Lebbah, Eugénie Lhommée, Jean-Philippe Azulay, Fanny Charbonnier-Beaupel, Alexandre Kreisler, Suzanne Lesage, Antoine Pelissolo, Christine Tranchant, David Grabli, Christine Brefel-Courbon, Mélissa Tir, and Pierre Krystkowiak

Subjects
0301 basic medicine, Oncology, Candidate gene, medicine.medical_specialty, Parkinson's disease, Population, Disease, Logistic regression, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Internal medicine, Medicine, Family history, education, education.field_of_study, business.industry, medicine.disease, 3. Good health, Impulse control, 030104 developmental biology, Bonferroni correction, Neurology, symbols, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

BACKGROUND Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. METHODS We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. RESULTS The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P

Published
2018

32. Fluoxetine for the Symptomatic Treatment of Multiple System Atrophy: The MSA-FLUO Trial

Author

Marc Vérin, Anne Pavy-Le Traon, Vanessa Rousseau, Margherita Fabbri, Alexandra Foubert-Samier, Wassilios G. Meissner, François Tison, Philippe Couratier, Agnès Sommet, Luc Defebvre, Valérie Cochen De Cock, Santiago Perez-Lloret, Franck Durif, Christine Tranchant, Claire Thalamas, Jean-Philippe Azulay, Philippe Remy, Jean-Christophe Corvol, Philippe Damier, Olivier Rascol, Jean-Luc Houeto, Christian Geny, Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), CHU Bordeaux [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Limoges, Centre hospitalier universitaire de Nantes (CHU Nantes), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Clermont-Ferrand, Neuro-Psycho Pharmacologie des Systèmes Dopimanégiques sous-corticaux (NPsy-Sydo), CHU Clermont-Ferrand-Université Clermont Auvergne (UCA), Euromov (EuroMov), Université de Montpellier (UM), CHI Créteil, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Comportement et noyaux gris centraux = Behavior and Basal Ganglia [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR), CHU Pontchaillou [Rennes], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), NS-Park/FCRIN Network, UMS 015, Centre d’Excellence en Maladies Neurodégénératives (NeuroToul), CHU Toulouse [Toulouse], Clinique Beau Soleil [Montpellier], Pontifical Catholic University of Argentina (UCA), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Nord Laennec [CHU Nantes], Lille Neurosciences & Cognition - U 1172 (LilNCog), CHU Lille, CHU Clermont-Ferrand-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Les Hôpitaux Universitaires de Strasbourg (HUS), University of Otago [Dunedin, Nouvelle-Zélande], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor [Créteil], and Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes = Institute of Clinical Neurosciences of Rennes (INCR)

Subjects
0301 basic medicine, medicine.medical_specialty, Serotonin reuptake inhibitor, [SDV]Life Sciences [q-bio], multiple system atrophy, ENSAYO CLINICO, Placebo, law.invention, 03 medical and health sciences, NEUROBIOLOGIA, 0302 clinical medicine, Atrophy, Randomized controlled trial, Double-Blind Method, Rating scale, law, Internal medicine, Surveys and Questionnaires, medicine, ATROFIA MULTISISTÉMICA, Humans, symptomatic treatment, Fluoxetine, business.industry, Beck Depression Inventory, fluoxetine, ENFERMEDADES NEURODEGENERATIVAS, Parkinson Disease, clinical trial, medicine.disease, Confidence interval, 3. Good health, ENFERMEDAD DE PARKINSON, 030104 developmental biology, Treatment Outcome, Neurology, Quality of Life, placebo, TRATAMIENTO MEDICO, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Fil: Rascol, Olivier. Universidad de Toulouse. Hospital Universitario de Toulouse; Francia Fil: Rascol, Olivier. Centro NeuroToul COEN; Francia Fil: Rascol, Olivier. Clínica de Toulouse. Centro de Investigación. Departamentos de Neurociencias y Farmacología Clínica; Francia Fil: Cochen De Cock, Valérie. Clínica Beau Soleil. Departamento de Neurología; Francia Fil: Cochen De Cock, Valérie. Universidad de Montpellier. EuroMov Digital Health in Motion; Francia Fil: Pavy-Le Traon, Anne. Centro de referencia de atrofia multisistémica; Francia Fil: Pavy-Le Traon, Anne. Universidad de Toulouse. Hospital Universitario de Toulouse. Instituto de Enfermedades Cardiovasculares y Metabólicas. Centro de Investigación Clínica de Toulouse. Departamento de Neurociencias; Francia Fil: Foubert-Samier, Alexandra. Universidad de Toulouse. Hospital Universitario de Toulouse. Instituto de Enfermedades Cardiovasculares y Metabólicas. Departamento de Neurociencias, Centro de investigación Clínica de Toulouse; Francia Fil: Thalamas, Claire. Universidad de Toulouse. Hospital Universitario de Toulouse. Centro de Investigación Clínica de Toulouse; Francia Fil: Thalamas, Claire. Hospital Universitario de Burdeos; Francia Fil: Sommet, Agnès. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Pérez Lloret, Santiago. Universidad Abierta Interamericana. Centro de Investigaciones Biomédicas; Argentina Fil: Pérez Lloret, Santiago. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas; Argentina Fil: Fabbri, Margherita. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Azulay, Jean Philippe. Universidad de Aix-Marsella. Sistema de Hospitales Universitarios Públicos de Marsella; Francia Fil: Corvol, Jean-Christophe. Universidad de la Sorbona; Francia Fil: Corvol, Jean-Christophe. Hospital de la Pitié-Salpêtrière; Francia Fil: Corvol, Jean-Christophe. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Couratier, Philippe. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Damier, Philippe. Hospital Nord Laennec. Centro de Investigación Clínica; Francia Fil: Defebvre, Luc. Universidad en Lille; Francia Fil: Defebvre, Luc. Hospital Universitario de Marsella. Departamento de Neurología y Patología del Movimiento; Francia Fil: Durif, Franck. Centro Hospitalario Universitario, Clermont-Ferrand. Departamento de Neurología; Francia Fil: Durif, Franck. Red Francesa de Infraestructura de Investigación Clínica; Francia Fil: Geny, Christian. Universidad de Montpellier. Departamento de Neurología; Francia Fil: Houeto, Jean-Luc. Centro Hospitalario Universitario de Limoges; Francia Fil: Houeto, Jean-Luc. Centro de referencia de atrofia multisistémica. Departamento de Neurología. Centro de Expertos en Parkinson; Francia Fil: Rascol, Olivier. Centro de referencia de atrofia multisistémica; Francia Fil: Remy, Philippe. Red Francesa de Infraestructura de Investigación Clínica. Centros Expertos en Parkinson; Francia Fil: Remy, Philippe. Instituto de Investigaciones Biomédicas Mondor; Francia Fil: Tranchant, Christine. Hospital Universitario de Estrasburgo. Red Francesa de Infraestructura de Investigación Clínica. Departamento de Neurología; Francia Fil: Verin, Marc. Universidad de Rennes. Hospital Universitario de Rennes. Red Francesa de Infraestructura de Investigación Clínica. Centro de expertos en Parkinson; Francia Fil: Tison, François. Centro de referencia de atrofia multisistémica. Departamento de Neurología de Enfermedades Neurodegenerativas; Francia Fil: Meissner, Wassilios G. Instituto de Investigación del Cerebro; Nueva Zelanda Fil: Meissner, Wassilios G. Universidad de Otago. Departamento de Medicina; Nueva Zelanda Abstract: Background: There are no effective treatments for multiple system atrophy (MSA). Objective: The objective of this study was to assess the efficacy and safety of the serotonin reuptake inhibitor fluoxetine (40 mg/d) for the symptomatic treatment of MSA. Methods: This was a double-blind, parallel-group, placebo-controlled, randomized trial in patients with "probable" MSA. The primary outcome was the change from baseline to week 12 in the mean total score of the Unified MSA Rating Scale (UMSARS Parts I + II). Secondary outcomes included change from baseline to week 6 in total UMSARS, and change from baseline to week 12 in the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction, Beck Depression Inventory, and different domains of the MSA-Quality of Life Questionnaire. Exploratory outcomes included change from baseline to week 12 in the UMSARS Parts I and II separately and change from baseline to week 24 in the total UMSARS score. Results: A total of 81 patients were randomly assigned, with no significant difference in the primary outcome (-2.13 units [95% confidence interval, CI, -4.55 to 0.29]; P = 0.08). There was a greater reduction on fluoxetine in the change from baseline to 12-week in UMSARS Part II (exploratory outcome: -1.41 units [95% CI, -2.84; 0.03]; p = 0.05) and in MSA-QoL emotional/social dimension (secondary outcome: -6.99 units [95% CI, -13.40; -0.56]; p < 0.03). A total of 5 deaths occurred (3 on fluoxetine and 2 on placebo). Conclusion: The MSA-FLUO failed to demonstrate fluoxetine superiority over placebo on the total UMSARS score, whereas trends in motor and emotional secondary/exploratory outcomes deserve further investigation.

Published
2021

33. Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations

Author

Marie Coutelier, Kristina Lidström, Malin Kvarnung, Rayomand Press, Rita Rodrigues, Jean-Philippe Azulay, Meriem Tazir, Giovanni Vazza, Sara Morais, Guillaume Banneau, Elena Pegoraro, Mélanie Papin, Giovanni Stevanin, José Leal Loureiro, Giulia Coarelli, Eric Le Guern, Alexandra Durr, Isabel Alonso, Alexis Brice, Jean-Loup Méreaux, Per Svenningsson, Daniel Nilsson, Frederic Taithe, Vincent Huin, Cyril Goizet, Rémi Valter, Cristina Firanescu, Martin Paucar, Livia Parodi, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Karolinska University Hospital [Stockholm]

Subjects
Male, Neurology, Dysarthria, CAPN1, 0302 clinical medicine, Spastic, Missense mutation, Age of Onset, Child, Genetics (clinical), Genetics, Sanger sequencing, 0303 health sciences, Calpain, 3. Good health, Pedigree, Phenotype, Muscle Spasticity, symbols, Cerebellar atrophy, Female, Original Article, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Cerebellar ataxia, Neurodegeneration, Spastic ataxia, Spastic paraplegia, Adult, medicine.medical_specialty, Cerebellar Ataxia, 03 medical and health sciences, Cellular and Molecular Neuroscience, symbols.namesake, Young Adult, Intellectual Disability, medicine, Humans, Spinocerebellar Ataxias, Spasticity, Genetic Association Studies, 030304 developmental biology, business.industry, Spastic Paraplegia, Hereditary, nervous system diseases, Optic Atrophy, Mutation, business, 030217 neurology & neurosurgery
Abstract

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.

Published
2021

34. Correction: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Thomas Roux, Mathieu Barbier, Mélanie Papin, Claire-Sophie Davoine, Sabrina Sayah, Giulia Coarelli, Perrine Charles, Cecilia Marelli, Livia Parodi, Christine Tranchant, Cyril Goizet, Stephan Klebe, Ebba Lohmann, Lionel Van Maldergem, Christine van Broeckhoven, Marie Coutelier, Christelle Tesson, Giovanni Stevanin, Charles Duyckaerts, Alexis Brice, Alexandra Durr, Frédéric Darios, Sylvie Forlani, Pitié-Salpêtrière Site, Guillaume Banneau, Cécile Cazeneuve, Bertrand Fontaine, Jean-Philippe Azulay, Odile Boesfplug-Tanguy, Didier Hannequin, Jamilé Hazan, Andrea Burgo, Christophe Verny, Michel Koenig, Pierre Labauge, Karine N’guyen, Diana Rodriguez, Soraya Belarbi, Abdelmadjid Hamri, Meriem Tazir, Sylvia Boesch, Massimo Pandolfo, Jardim Laura, Velina Guergueltcheva, Ivalo Tournev, Olga Lucia Pedraza Linarès, Jørgen E. Nielsen, Kirsten Svenstrup, Maha Zaki, Peter Bauer, Lüdger Schöls, Rebecca Schüle, Alexander Lossos, Maria-Teresa Bassi, Manuela Basso, Enrico Bertini, Alfredo Brusco, Carlo Casali, Giorgio Casari, Chiara Criscuolo, Alessandro Filla, Laura Orsi, Filippo M. Santorelli, Enza Maria Valente, Marinela Vavla, Giovanni Vazza, André Megarbane, Ali Benomar, Berry Kremer, Willeke Van Roon-Mom, Richard Roxburgh, Anne Kjersti Erichsen, Chantal Tallaksen, Isabel Alonso, Paula Coutinho, José Léal Loureiro, Jorge Sequeiros, Mustapha Salih, Vladimir S Kostic, Idoia Rouco Axpe, Liena Elsayed, Martin Arce Paucar, Samir Roumani, Soong Bing-Wen, Evan Reid, Nethisinghe Suran, Thomas Warner, and Nicholas Wood

Subjects
Medizin, Genetics (clinical)
Abstract

Korrektur zu 10.1038/s41436-020-0899-x

Published
2021

35. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Thomas Roux, Mathieu Barbier, Mélanie Papin, Claire-Sophie Davoine, Sabrina Sayah, Giulia Coarelli, Perrine Charles, Cecilia Marelli, Livia Parodi, Christine Tranchant, Cyril Goizet, Stephan Klebe, Ebba Lohmann, Lionel Van Maldergem, Christine van Broeckhoven, Marie Coutelier, Christelle Tesson, Giovanni Stevanin, Charles Duyckaerts, Alexis Brice, Alexandra Durr, Frédéric Darios, Sylvie Forlani, Pitié-Salpêtrière Site, Guillaume Banneau, Cécile Cazeneuve, Bertrand Fontaine, Jean-Philippe Azulay, Odile Boesfplug-Tanguy, Didier Hannequin, Jamilé Hazan, Andrea Burgo, Christophe Verny, Michel Koenig, Pierre Labauge, Karine N’guyen, Diana Rodriguez, Soraya Belarbi, Abdelmadjid Hamri, Meriem Tazir, Sylvia Boesch, Massimo Pandolfo, Jardim Laura, Velina Guergueltcheva, Ivalo Tournev, Olga Lucia Pedraza Linarès, Jørgen E. Nielsen, Kirsten Svenstrup, Maha Zaki, Peter Bauer, Lüdger Schöls, Rebecca Schüle, Alexander Lossos, Maria-Teresa Bassi, Manuela Basso, Enrico Bertini, Alfredo Brusco, Carlo Casali, Giorgio Casari, Chiara Criscuolo, Alessandro Filla, Laura Orsi, Filippo M. Santorelli, Enza Maria Valente, Marinela Vavla, Giovanni Vazza, André Megarbane, Ali Benomar, Berry Kremer, Willeke Van Roon-Mom, Richard Roxburgh, Anne Kjersti Erichsen, Chantal Tallaksen, Isabel Alonso, Paula Coutinho, José Léal Loureiro, Jorge Sequeiros, Mustapha Salih, Vladimir S. Kostic, Idoia Rouco Axpe, Liena Elsayed, Martin Arce Paucar, Samir Roumani, Soong Bing-Wen, Evan Reid, Nethisinghe Suran, Thomas Warner, Nicholas Wood, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), CHU Strasbourg, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), University of Tübingen, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), University of Antwerp (UA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), SPATAX Network, Roux, T., Barbier, M., Papin, M., Davoine, C. -S., Sayah, S., Coarelli, G., Charles, P., Marelli, C., Parodi, L., Tranchant, C., Goizet, C., Klebe, S., Lohmann, E., Van Maldergen, L., van Broeckhoven, C., Coutelier, M., Tesson, C., Stevanin, G., Duyckaerts, C., Brice, A., Durr, A., Darios, F., Forlani, S., Site, P. -S., Banneau, G., Cazeneuve, C., Fontaine, B., Azulay, J. -P., Boesfplug-Tanguy, O., Hannequin, D., Hazan, J., Burgo, A., Verny, C., Koenig, M., Labauge, P., N'Guyen, K., Rodriguez, D., Belarbi, S., Hamri, A., Tazir, M., Boesch, S., Pandolfo, M., Laura, J., Guergueltcheva, V., Tournev, I., Pedraza Linares, O. L., Nielsen, J. E., Svenstrup, K., Zaki, M., Bauer, P., Schols, L., Schule, R., Lossos, A., Bassi, M. -T., Basso, M., Bertini, E., Brusco, A., Casali, C., Casari, G., Criscuolo, C., Filla, A., Orsi, L., Santorelli, F. M., Valente, E. M., Vavla, M., Vazza, G., Megarbane, A., Benomar, A., Kremer, B., Van Roon-Mom, W., Roxburgh, R., Erichsen, A. K., Tallaksen, C., Alonso, I., Coutinho, P., Loureiro, J. L., Sequeiros, J., Salih, M., Kostic, V. S., Rouco Axpe, I., Elsayed, L., Paucar, M. A., Roumani, S., Bing-Wen, S., Reid, E., Suran, N., Warner, T., and Wood, N.

Subjects
Male, Pathology, MESH: Ataxia, Purkinje cell, Medizin, MESH: Cognitive Dysfunction, 0302 clinical medicine, spinocerebellar ataxia, ATP-Dependent Proteases, SCA48, Medicine, Genetics (clinical), 0303 health sciences, Penetrance, 3. Good health, MESH: Cerebellar Ataxia, MESH: ATPases Associated with Diverse Cellular Activities, medicine.anatomical_structure, Spinocerebellar ataxia, Female, medicine.symptom, Frontotemporal dementia, medicine.medical_specialty, Ataxia, Cerebellar Ataxia, MESH: Spinocerebellar Ataxias, Ubiquitin-Protein Ligases, Neuropathology, 03 medical and health sciences, MESH: ATP-Dependent Proteases, Atrophy, Humans, Spinocerebellar Ataxias, Cognitive Dysfunction, 030304 developmental biology, cognitive impairment, SCAR16, STUB1, MESH: Humans, Cerebellar ataxia, business.industry, medicine.disease, MESH: Ubiquitin-Protein Ligases, MESH: Male, ATPases Associated with Diverse Cellular Activities, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Human medicine, business, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48).Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance.Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects.Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

Published
2020

36. Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients

Author

Hubert H. Fernandez, Tihomir V. Ilić, James C. Norton, David L Kreitzman, Srdjan Stankovic, Jean-Philippe Azulay, Stuart Isaacson, Clive Ballard, Bruce Coate, Victor Abler, Joaquim J. Ferreira, and Repositório da Universidade de Lisboa

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Psychosis, Parkinson's disease, Peripheral edema, Pimavanserin, Placebo, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, Piperidines, Internal medicine, Outcome Assessment, Health Care, medicine, Humans, Urea, Adverse effect, Aged, Response rate (survey), Aged, 80 and over, business.industry, Parkinson Disease, Middle Aged, medicine.disease, 030104 developmental biology, Neurology, chemistry, Psychotic Disorders, Clinical Global Impression, Female, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery, Antipsychotic Agents
Abstract

© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license., Introduction: Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment. Methods: This was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit. Results: Of 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was -1.8 (5.5) and for SAPS-H + D was -2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D -3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) CONCLUSIONS: Patients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.

Published
2020

37. Clinical Phenotypes in Corticobasal Syndrome with or without Amyloidosis Biomarkers

Author

Alexandre Eusebio, Olivier Felician, Agnès Benvenutto, Eric Guedj, Lejla Koric, Jean-Philippe Azulay, Mathieu Ceccaldi, Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Service Central de Biophysique et de Médecine Nucléaire, Hôpital de la Timone [CHU - APHM] (TIMONE), Imagerie MOléculaire pour applications THéranostiques personnalisées (IMOTHEP), Institut FRESNEL (FRESNEL), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Centre Mémoire de Ressources et de Recherche, CHU Marseille, Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), and Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
0301 basic medicine, Male, Pathology, Eye Movements, 0302 clinical medicine, Cerebrospinal fluid, Cognition, ComputingMilieux_MISCELLANEOUS, Dystonia, Cerebral Cortex, Movement Disorders, biology, General Neuroscience, Parkinsonism, Amyloidosis, Dopaminergic, General Medicine, Syndrome, Middle Aged, Mental Status and Dementia Tests, 3. Good health, Psychiatry and Mental health, Clinical Psychology, Female, inorganic chemicals, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Amyloid, 03 medical and health sciences, Alzheimer Disease, Spect imaging, medicine, Saccades, Humans, Dopamine transporter, Aged, Tomography, Emission-Computed, Single-Photon, Dopamine Plasma Membrane Transport Proteins, business.industry, organic chemicals, nutritional and metabolic diseases, medicine.disease, 030104 developmental biology, Positron-Emission Tomography, biology.protein, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers, Psychomotor Performance, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Brain Stem
Abstract

Corticobasal syndrome (CBS) is a neuropathologically heterogeneous entity. The use of cerebrospinal fluid and amyloid biomarkers enables detection of underlying Alzheimer's disease (AD) pathology. We thus compared clinical, eye movement, and 18FDG-PET imaging characteristics in CBS in two groups of patients divided according to their amyloid biomarkers profile. Fourteen patients presenting with CBS and amyloidosis (CBS-A+) were compared with 16 CBS patients without amyloidosis (CBS-A-). The two groups showed similar motor abnormalities (parkinsonism, dystonia) and global cognitive functions. Unlike CBS-A+ patients who displayed more posterior cortical abnormalities, CBS-A- patients demonstrated more anterior cortical and brain stem dysfunctions on the basis of neuropsychological testing, study of saccade velocities and brain hypometabolism areas on 18FDG-PET. Interestingly, Dopamine Transporter SPECT imaging showed similar levels of dopaminergic degeneration in both groups. These findings confirm common and distinct brain abnormalities between the different neurodegenerative diseases that result in CBS. We demonstrate the importance of a multidisciplinary approach to improve diagnosis in vivo in particular on oculomotor examination.

Published
2020

38. From metabolic connectivity to molecular connectivity: application to dopaminergic pathways

Author

Manon Bordonne, Antoine Verger, Nadine Girard, Jean-Philippe Azulay, Alexandre Eusebio, Mohammad B. Chawki, Tatiana Horowitz, Eric Guedj, Service de Médecine Nucléaire [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut FRESNEL (FRESNEL), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Service de médecine nucléaire [Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service Central de Biophysique et de Médecine Nucléaire, Service de Médecine Nucléaire [Nancy], Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Dopamine, Single-photon emission computed tomography, Biology, computer.software_genre, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Voxel, Iodine-123, medicine, Humans, Radiology, Nuclear Medicine and imaging, neurotransmission, Tomography, Emission-Computed, Single-Photon, Dopamine Plasma Membrane Transport Proteins, Connectivity, medicine.diagnostic_test, Dopaminergic, Binding potential, dopaminergic pathways, Parkinson Disease, General Medicine, molecular imaging, medicine.anatomical_structure, PET, Dopaminergic pathways, Positron-Emission Tomography, 030220 oncology & carcinogenesis, SPECT, Radiopharmaceuticals, Molecular imaging, Neuroscience, computer, metabolism, Emission computed tomography, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Introduction: This study aims to reveal the feasibility and potential of molecular connectivity based on neurotransmission in comparison with the metabolic connectivity with an application to dopaminergic pathways. For this purpose, we propose to compare the neurotransmission connectivity findings using 123I-FP-CIT SPECT and 18F-FDOPA PET with the metabolic connectivity findings using 18F-FDG PET.Methods: 18F-FDG PET and 123I-FP-CIT SPECT images from 47 subjects and 18F-FDOPA PET images from 177 subjects, who had no neurological or psychiatric disorders, were studied. Interregional correlation analyses were performed at the group level to determine the midbrain's connectivity via glucose metabolic rate using 18F-FDG PET and via dopaminergic binding potential using 123I-FP-CIT SPECT and 18F-FDOPA PET. SPM-T maps of each radiotracer were generated, and masks used to highlight the significant differences obtained among the imaging modalities and targets.Results: The three dopaminergic pathways (i.e., nigrostriatal, mesolimbic, and mesocortical) were identified by 18F-FDG PET (1599 voxels, with a Tmax value of 12.6), 123I-FP-CIT SPECT (1120 voxels, with Tmax value of 5.1), and 18F-FDOPA PET (6054 voxels, with Tmax value of 11.7) for a T voxel threshold of 5.10, 2.80, and 5.10, respectively. Using the same T voxel threshold of 5.10, 18F-FDOPA PET showed more specific findings than 18F-FDG PET with less voxels identified outside these pathways (- 9323 voxels), whereas no significant voxels were obtained with 123I-FP-CIT SPECT at this threshold.Conclusion: The present study illustrates the feasibility and interest in using molecular connectivity with 18F-FDOPA PET for dopaminergic pathways. Such analyses could be applied to specific diseases involving the dopaminergic system.

Published
2020

39. Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson's disease psychosis

Author

Stuart Isaacson, Srdjan Stankovic, Tihomir V. Ilić, George Demos, David L Kreitzman, Jean-Philippe Azulay, Hubert H. Fernandez, I-Yuan Liu, James C. Norton, Clive Ballard, Joaquim J. Ferreira, and Victor Abler

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Psychosis, Parkinson's disease, Hallucinations, Urinary system, Pimavanserin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, Internal medicine, medicine, Humans, Urea, Adverse effect, Aged, Aged, 80 and over, business.industry, Mortality rate, Parkinson Disease, Middle Aged, medicine.disease, Discontinuation, 030104 developmental biology, Neurology, chemistry, Tolerability, Psychotic Disorders, Female, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Antipsychotic Agents
Abstract

Introduction Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Results from short-term, placebo-controlled studies demonstrated a positive benefit/risk profile. This multi-year, open-label study assessed long-term safety and tolerability of pimavanserin. Methods This was an open-label extension (OLE) study in patients previously completing a double-blind, placebo-controlled study or a previous OLE study. Safety was evaluated from adverse events (AEs), clinical laboratory results, motor symptoms, electrocardiograms (ECG), and mortality. Durability of response was assessed from the Clinical Global Impression-Severity (CGI-S) scale and Caregiver Burden Scale (CBS). Results Of 459 participants treated in this OLE study (average age 71.2 years), the median duration of treatment was 454 days. Over the entire study period (approximately 11 years), ≥1 AE occurred in 392 (85.4%) patients; the majority were of mild to moderate intensity, with fall (32.0%), urinary tract infection (19.0%), and hallucination (13.7%) most common. Serious AEs occurred in 188 (41.0%) patients, and an AE leading to study termination or dose discontinuation occurred in 133 (29.0%) patients. Sixty-one patients died, 59 (12.9%) during treatment or within 30 days after the last dose of study drug; the observed mortality rate was 6.45 per 100 patient-years of exposure. Mean scores for the CGI-S scale and CBS generally remained stable for up to 192 weeks (>3.5 years). Conclusions Long-term treatment with pimavanserin 34 mg once daily demonstrated a favorable benefit/risk profile with no unexpected safety concerns. Mortality rates suggested no increased risk following long-term treatment.

Published
2020

40. Subthalamic nucleus stimulation, dopaminergic treatment and impulsivity in Parkinson's disease

Author

Jean-Philippe Azulay, Wery P. M. van den Wildenberg, Frédérique Fluchère, Thierry Hasbroucq, Tatiana Witjas, Franck Vidal, Alexandre Eusebio, Boris Burle, Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), University of Amsterdam [Amsterdam] (UvA), Hôpital de la Timone [CHU - APHM] (TIMONE), European Project: 241077,EC:FP7:ERC,ERC-2009-StG,PRORECONT(2010), Laboratoire de Neurosciences Cognitives [Marseille] ( LNC ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), University of Amsterdam [Amsterdam] ( UvA ), Hôpital de la Timone [CHU - APHM] ( TIMONE ), Ontwikkelingspsychologie (Psychologie, FMG), Brain and Cognition, FMG, and Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Male, Parkinson's disease, Deep Brain Stimulation, medicine.medical_treatment, Dopamine Agents, [ SCCO.PSYC ] Cognitive science/Psychology, Neuropsychological Tests, Severity of Illness Index, Behavioral Neuroscience, 0302 clinical medicine, motor control, Parkinson, 05 social sciences, Dopaminergic, Parkinson Disease, Middle Aged, Subthalamic nucleus, surgical procedures, operative, [ SCCO.NEUR ] Cognitive science/Neuroscience, [SCCO.PSYC]Cognitive science/Psychology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], dopamine, Psychology, therapeutics, Deep brain stimulation, Cognitive Neuroscience, impulsivity, Experimental and Cognitive Psychology, Sensory system, 050105 experimental psychology, 03 medical and health sciences, Subthalamic Nucleus, Motor system, Reaction Time, medicine, Humans, 0501 psychology and cognitive sciences, STN stimulation, Aged, Psychiatric Status Rating Scales, Electromyography, [SCCO.NEUR]Cognitive science/Neuroscience, Subliminal stimuli, decision's threshold, Motor control, Evoked Potentials, Motor, medicine.disease, nervous system diseases, nervous system, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Impulsive Behavior, Neuroscience, 030217 neurology & neurosurgery
Abstract

BackgroundDeep brain stimulation of the subthalamic nucleus (STN DBS) is known to increase response speed and lower response accuracy in Parkinson's disease (PD) patients. It has been proposed that this speed-accuracy tradeoff is due to enhanced sensitivity of the motor system to sensory information. An alternative possibility is that this effect is due to weakened suppressive processes. The two alternative interpretations can be tested by analyzing the electromyographic activity (EMG) of the response agonists when the patients perform conflict reaction time tasks. In those tasks, fast subthreshold muscle impulses often occur in the agonist of the incorrect response. These impulses are partial errors that are suppressed before being behaviourally committed.Material and methodsHere we analyzed the EMG of the response agonists recorded while sixteen PD patients performed a Simon task that elicits prepotent response tendencies so as to decipher (i) whether STN DBS affects the expression and/or suppression of subthreshold muscle impulses that are critical for action control and (ii) the interaction between dopaminergic treatment and STN DBS. The patients were tested On and Off STN DBS and On and Off dopaminergic medication in a full factorial design.ResultsSTN DBS not only impaired the proficiency to suppress subliminal action impulses (p = 0.01) but also favoured the muscular expression of fast incorrect impulses (p ConclusionContrary to a recent proposal, STN DBS impaired rather than improved action control by weakening erroneous impulse suppression, whether the patients were On or Off their usual medication. These findings are discussed in light of a recent proposal (Servant M, White C, Montagnini A, Burle B, 2015) that reconciles partial errors with accumulation-to-bound models of decision making. Our results suggest that medication specifically lowers the mechanical threshold while STN DBS lowers the mechanical threshold and to a lesser extent the EMG-threshold.

Published
2018

41. Brain PET substrate of impulse control disorders in Parkinson's disease: A metabolic connectivity study

Author

Antoine Verger, Elsa Klesse, Jean-Philippe Azulay, Tatiana Witjas, Eric Guedj, Alexandre Eusebio, Mohammad B. Chawki, Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut FRESNEL (FRESNEL), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)

Subjects
Male, 0301 basic medicine, Pet substrate, Parkinson's disease, impulse control disorders, 03 medical and health sciences, 0302 clinical medicine, Betweenness centrality, Fluorodeoxyglucose F18, Neural Pathways, medicine, Humans, Radiology, Nuclear Medicine and imaging, In patient, FDG-PET, Research Articles, Brain Mapping, Radiological and Ultrasound Technology, medicine.diagnostic_test, business.industry, Brain, Parkinson Disease, Middle Aged, medicine.disease, Disruptive, Impulse Control, and Conduct Disorders, 030104 developmental biology, Neurology, Positron emission tomography, Positron-Emission Tomography, Correlation analysis, metabolic connectivity, Female, Orbitofrontal cortex, Neurology (clinical), Radiopharmaceuticals, Anatomy, business, Neuroscience, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

International audience; Impulse control disorders (ICDs) have received increased attention in Parkinson's disease (PD) because of potentially dramatic consequences. Their physiopathology, however, remains incompletely understood. An overstimulation of the mesocorticolimbic system has been reported, while a larger network has recently been suggested. The aim of this study is to specifically describe the metabolic PET substrate and related connectivity changes in PD patients with ICDs. Eighteen PD patients with ICDs and 18 PD patients without ICDs were evaluated using cerebral 18F-fluorodeoxyglucose positron emission tomography. SPM-T maps comparisons were performed between groups and metabolic connectivity was evaluated by interregional correlation analysis (IRCA; p < .005, uncorrected; k > 130) and by graph theory (p < .05). PD patients with ICDs had relative increased metabolism in the right middle and inferior temporal gyri compared to those without ICDs. The connectivity of this area was increased mostly with the mesocorticolimbic system, positively with the orbitofrontal region, and negatively with both the right parahippocampus and the left caudate (IRCA). Moreover, the betweenness centrality of this area with the mesocorticolimbic system was lost in patients with ICDs (graph analysis). ICDs are associated in PD with the dysfunction of a network exceeding the mesocorticolimbic system, and especially the caudate, the parahippocampus, and the orbitofrontal cortex, remotely including the right middle and inferior temporal gyri. This latest area loses its central place with the mesocorticolimbic system through a connectivity dysregulation.

Published
2018

42. Identification of genetic variants associated with Huntington's disease progression

Author

Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, Peter Holmans, Lesley Jones, Sarah J Tabrizi, A Coleman, R Dar Santos, J Decolongon, A Sturrock, E Bardinet, C Jauff Ret, D Justo, S Lehericy, C Marelli, K Nigaud, R Valabrègue, SJA van den Bogaard, E M Dumas, J van der Grond, EP t'Hart, C Jurgens, M-N Witjes-Ane, N Arran, J Callaghan, C Stopford, C Frost, R Jones, N Hobbs, N Lahiri, R Ordidge, G Owen, T Pepple, J Read, M Say, E Wild, A Patel, N C Fox, C Gibbard, I Malone, H Crawford, D Whitehead, S Keenan, D M Cash, C Berna, N Bechtel, S Bohlen, A Hoff Man, P Kraus, E Axelson, C Wang, T Acharya, S Lee, W Monaco, C Campbell, S Queller, K Whitlock, M Campbell, E Frajman, C Milchman, A O'Regan, I Labuschagne, J Stout, B Landwehrmeyer, D Craufurd, R Scahill, S Hicks, C Kennard, H Johnson, A Tobin, HD Rosas, R Reilmann, B Borowsky, C Pourchot, S C Andrews, Anne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael Bonelli, Jean-Marc Burgunder, Stephen Dunnett, Joaquim Ferreira, Olivia Handley, Arvid Heiberg, Torsten Illmann, G. Bernhard Landwehrmeyer, Jamie Levey, Maria A. Ramos-Arroyo, Jørgen Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A.C. Roos, A Rojo Sebastián, Sarah Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Monica Bascuñana Garde, Sabrina Betz, Reineke Bos, Jenny Callaghan, Adrien Come, Leonor Correia Guedes, Daniel Ecker, Ana Maria Finisterra, Ruth Fullam, Mette Gilling, Lena Gustafsson, Olivia J Handley, Carina Hvalstedt, Christine Held, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saül Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Michael Orth, Hélène Padieu, Laurent Paterski, Nadia Peppa, Martina Di Renzo, Amandine Rialland, Niini Røren, Pavla Šašinková, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Wildson Vieira da Silva, Marleen R van Walsem, Carina Whalstedt, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Raphael M. Bonelli, Sabine Lilek, Karen Hecht, Brigitte Herranhof, Anna Holl, Hans-Peter Kapfhammer, Michael Koppitz, Markus Magnet, Nicole Müller, Daniela Otti, Annamaria Painold, Karin Reisinger, Monika Scheibl, Helmut Schöggl, Jasmin Ullah, Eva-Maria Braunwarth, Florian Brugger, Lisa Buratti, Eva-Maria Hametner, Caroline Hepperger, Christiane Holas, Anna Hotter, Anna Hussl, Christoph Müller, Werner Poewe, Klaus Seppi, Fabienne Sprenger, Gregor Wenning, Andrea Boogaerts, Godelinde Calmeyn, Isabelle Delvaux, Dirk Liessens, Nele Somers, Michel Dupuit, Cécile Minet, Dominique van Paemel, Pascale Ribaï, Dimphna van Reijen, Jirí Klempír, Veronika Majerová, Jan Roth, Irena Stárková, Lena E. Hjermind, Oda Jacobsen, Jørgen E. Nielsen, Ida Unmack Larsen, Tua Vinther-Jensen, Heli Hiivola, Hannele Hyppönen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau, Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Rekha Barthélémy, Christelle De Bruycker, Maryline Cabaret Anne-Sophie Carette, Eric Decorte Luc Defebvre, Marie Delliaux, Arnaud Delval, Alain Destee, Kathy Dujardin, Marie-Hélène Lemaire, Sylvie Manouvrier, Mireille Peter, Lucie Plomhouse, Bernard Sablonnière, Clémence Simonin, Stéphanie Thibault-Tanchou, Isabelle Vuillaume, Marcellin Bellonet, Hassan Berrissoul, Stéphanie Blin, Françoise Courtin, Cécile Duru, Véronique Fasquel, Olivier Godefroy, Pierre Krystkowiak, Béatrice Mantaux, Martine Roussel, Sandrine Wannepain, Jean-Philippe Azulay, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Laura Mundler, Mathieu Anheim, Celine Julié, Ouhaid Lagha Boukbiza, Nadine Longato, Gabrielle Rudolf, Christine Tranchant, Marie-Agathe Zimmermann, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J. Werner, Harald Gelderblom, Josef Priller, Harald Prüß, Eike Jakob Spruth, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Peter Kotz, Christian Prehn, Carsten Saft, Herwig Lange, Robert Maiwald, Matthias Löhle, Antonia Maass, Simone Schmidt, Cecile Bosredon, Alexander Storch, Annett Wolz, Martin Wolz, Philipp Capetian, Johann Lambeck, Birgit Zucker, Kai Boelmans, Christos Ganos, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Heike Gorzolla, Christoph Schrader, Pawel Tacik, Michael Ribbat, Bernhard Longinus, Katrin Bürk, Jens Carsten Möller, Ida Rissling, Mark Mühlau, Alexander Peinemann, Michael Städtler, Adolf Weindl, Juliane Winkelmann, Cornelia Ziegler, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Eva Hölzner, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Natalia Weber, Matthias Dose, Gabriele Leythäuser, Ralf Marquard, Tina Raab, Alexandra Wiedemann, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Christina Lang, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süßmuth, Sonja Trautmann, Patrick Weydt, Claudia Cormio, Vittorio Sciruicchio, Claudia Serpino, Marina de Tommaso, Sabina Capellari, Pietro Cortelli, Roberto Galassi, Giovanni Rizzo, Roberto Poda, Cesa Scaglione, Elisabetta Bertini, Elena Ghelli, Andrea Ginestroni, Francesca Massaro, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giovanni Abbruzzese, Monica Bandettini di Poggio, Giovanna Ferrandes, Paola Mandich, Roberta Marchese, Alberto Albanese, Daniela Di Bella, Anna Castaldo, Stefano Di Donato, Cinzia Gellera, Silvia Genitrini, Caterina Mariotti, Lorenzo Nanetti, Dominga Paridi, Paola Soliveri, Chiara Tomasello, Giuseppe De Michele, Luigi Di Maio, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Elena Salvatore, Pierpaolo Sorrentino, Enrico Amico, Mariagrazia Favellato, Annamaria Griguoli, Irene Mazzante, Martina Petrollini, Ferdinando Squitieri, Barbara D'Alessio, Chiara Esposito, Rita Bentivoglio, Marina Frontali, Arianna Guidubaldi, Tamara Ialongo, Gioia Jacopini, Carla Piano, Silvia Romano, Francesco Soleti, Maria Spadaro, Monique S.E. van Hout, Marloes E. Verhoeven, Jeroen P.P. van Vugt, A. Marit de Weert, J.J.W. Bolwijn, M. Dekker, B. Kremer, K.L. Leenders, J.C.H. van Oostrom, Simon J.A. van den Bogaard, Eve M. Dumas, Ellen P. 't Hart, Berry Kremer, C.C.P. Verstappen, Olaf Aaserud, Jan Frich C, Ragnhild Wehus, Kathrine Bjørgo, Madeleine Fannemel, Per F. Gørvell, Eirin Lorentzen, Lars Retterstøl, Bodil Stokke, Inga Bjørnevoll, Sigrid Botne Sando, Artur Dziadkiewicz, Malgorzata Nowak, Piotr Robowski, Emilia Sitek, Jaroslaw Slawek, Witold Soltan, Michal Szinwelski, Magdalena Blaszcyk, Magdalena Boczarska-Jedynak, Ewelina Ciach-Wysocka, Agnieszka Gorzkowska, Barbara Jasinska-Myga, Gabriela Klodowska-Duda, Gregorz Opala, Daniel Stompel, Krzysztof Banaszkiewicz, Dorota Bocwinska, Kamila Bojakowska-Jaremek, Malgorzata Dec, Malgorzata Krawczyk, Monika Rudzinska, Elzbieta Szczygiel, Andrzej Szczudlik, Anna Wasielewska, Magdalena Wójcik, Anna Bryl, Anna Ciesielska, Aneta Klimberg, Jerzy Marcinkowski, Husam Samara, Justyna Sempolowicz, Anna Gogol, Piotr Janik, Hubert Kwiecinski, Zygmunt Jamrozik, Jakub Antczak, Katarzyna Jachinska, Wioletta Krysa, Maryla Rakowicz, Przemyslaw Richter, Rafal Rola, Danuta Ryglewicz, Halina Sienkiewicz-Jarosz, Iwona Stepniak, Anna Sulek, Elzbieta Zdzienicka, Karolina Zieora-Jakutowicz, Joaquim J Ferreira, Miguel Coelho, Tiago Mendes, Anabela Valadas, Carlos Andrade, Miguel Gago, Carolina Garrett, Maria Rosália Guerra, Carmen Durán Herrera, Patrocinio Moreno Garcia, Miquel Aguilar Barbera, Dolors Badenes Guia, Laura Casas Hernanz, Judit López Catena, Pilar Quiléz Ferrer, Ana Rojo Sebastián, Gemma Tome Carruesco, Jordi Bas, Núria Busquets, Matilde Calopa, Misericordia Floriach Robert, Celia Mareca Viladrich, Jesús Miguel Ruiz Idiago, Antonio Villa Riballo, Esther Cubo, Cecilia Gil Polo, Natividad Mariscal, Perez Jessica Rivadeneyra, Francisco Barrero, Blas Morales, María Fenollar, Rocío García-Ramos García, Paloma Ortega, Clara Villanueva, Javier Alegre, Mónica Bascuñana, Juan Garcia Caldentey, Marta Fatás Ventura, Guillermo García Ribas, Justo García de Yébenes, José Luis López-Sendón Moreno, Fernando Alonso Frech, Pedro J García Ruíz, Asunción Martínez-Descals, Rosa Guerrero, María José Saiz Artiga, Vicenta Sánchez, María Fuensanta Noguera Perea, Lorenza Fortuna, Salvadora Manzanares, Gema Reinante, María Martirio Antequera Torres, Laura Vivancos Moreau, Sonia González González, Luis Menéndez Guisasola, Carlos Salvador, Esther Suaréz San Martín, Inés Legarda Ramirez, Aranzazú Gorospe, Mónica Rodriguez Lopera, Penelope Navas Arques, María José Torres Rodríguez, Barbara Vives Pastor, Itziar Gaston, Maria Dolores Martinez-Jaurrieta, Jose Manuel Garcia Moreno, Carolina Mendez Lucena, Fatima Damas, Hermoso Eva Pacheco Cortegana, José Chacón Peña, Luis Redondo, Fátima Carrillo, María Teresa Cáceres, Pablo Mir, María José Lama Suarez, Laura Vargas-González, Maria E. Bosca, Francisco Castera Brugada, Juan Andres Burguera, Anabel Campos, Garcia Carmen Peiró Vilaplana, Peter Berglund, Radu Constantinescu, Gunnel Fredlund, Ulrika Høsterey-Ugander, Petra Linnsand, Liselotte Neleborn-Lingefjärd, Magnus Wentzel, Ghada Loutfi, Carina Olofsson, Eva-Lena Stattin, Laila Westman, Birgitta Wikström, Yanik Stebler, Alain Kaelin, Irene Romero, Michael Schüpbach, Sabine Weber Zaugg, Maria Hauer, Roman Gonzenbach, Hans H. Jung, Violeta Mihaylova, Jens Petersen, Roisin Jack, Kirsty Matheson, Zosia Miedzybrodzka, Daniela Rae, Sheila A Simpson, Fiona Summers, Alexandra Ure, Vivien Vaughan, Shahbana Akhtar, Jenny Crooks, Adrienne Curtis, Jenny de Souza, John Piedad, Hugh Rickards, Jan Wright, Elizabeth Coulthard, Louise Gethin, Beverley Hayward, Kasia Sieradzan, Matthew Armstrong, Roger A. Barker, Deidre O'Keefe, Anna Di Pietro, Kate Fisher, Anna Goodman, Susan Hill, Ann Kershaw, Sarah Mason, Nicole Paterson, Lucy Raymond, Rachel Swain, Natalie Valle Guzman, Monica Busse, Cynthia Butcher, Catherine Clenaghan, Sarah Hunt, Una Jones, Hanan Khalil, Michael Owen, Kathleen Price, Anne Rosser, Maureen Edwards, Carrie Ho, Teresa Hughes, Marie McGill, Pauline Pearson, Mary Porteous, Paul Smith, Peter Brockie, Jillian Foster, Nicola Johns, Sue McKenzie, Jean Rothery, Gareth Thomas, Shona Yates, Liz Burrows, Carol Chu, Amy Fletcher, Deena Gallantrae, Stephanie Hamer, Alison Harding, Stefan Klöppel, Alison Kraus, Fiona Laver, Monica Lewis, Mandy Longthorpe, Ivana Markova, Ashok Raman, Nicola Robertson, Mark Silva, Aileen Thomson, Sue Wild, Pam Yardumian, Carole Evans, Deena Gallentrae, Emma Hobson, Stuart Jamieson, Hannah Musgrave, Liz Rowett, Jean Toscano, Colin Bourne, Jackie Clapton, Carole Clayton, Heather Dipple, Dawn Freire-Patino, Janet Grant, Diana Gross, Caroline Hallam, Julia Middleton, Ann Murch, Catherine Thompson, Sundus Alusi, Rhys Davies, Kevin Foy, Emily Gerrans, Louise Pate, Thomasin Andrews, Andrew Dougherty, Charlotte Golding, Fred Kavalier, Hana Laing, Alison Lashwood, Dene Robertson, Deborah Ruddy, Alastair Santhouse, Anna Whaite, Stefania Bruno, Karen Doherty, Salman Haider, Davina Hensman, Nayana Lahiri, Marianne Novak, Aakta Patel, Elisabeth Rosser, Rachel Taylor, Thomas Warner, Edward Wild, Natalie Arran, Judith Bek, David Craufurd, Marianne Hare, Liz Howard, Susan Huson, Liz Johnson, Mary Jones, Helen Murphy, Emma Oughton, Lucy Partington-Jones, Dawn Rogers, Andrea Sollom, Julie Snowden, Cheryl Stopford, Jennifer Thompson, Iris Trender-Gerhard, Nichola Verstraelen, Leann Westmoreland, Richard Armstrong, Kathryn Dixon, Andrea H Nemeth, Gill Siuda, Ruth Valentine, David Harrison, Max Hughes, Andrew Parkinson, Beverley Soltysiak, Oliver Bandmann, Alyson Bradbury, Paul Gill, Helen Fairtlough, Kay Fillingham, Isabella Foustanos, Mbombe Kazoka, Kirsty O'Donovan, Cat Taylor, Katherine Tidswell, Oliver Quarrell, Puay Ngoh Lau, Emmanul Pica, Louis Tan, Univ Angers, Okina, Moss, Davina J. Hensman, Tabrizi, Sarah J, Mead, Simon, Kitty, Lo, Pardiã±as, Antonio F, Holmans, Peter, Jones, Lesley, Langbehn, Dougla, Coleman, A., Santos, R. Dar, Decolongon, J., Sturrock, A., Bardinet, E., Ret, C. Jauff, Justo, D., Lehericy, S., Marelli, C., Nigaud, K., Valabrãgue, R., van den Bogaard, S. J. A., Dumas, E. M., van der Grond, J., T'Hart, E. P., Jurgens, C., Witjes-Ane, M. -. N., Arran, N., Callaghan, J., Stopford, C., Frost, C., Jones, R., Hobbs, N., Lahiri, N., Ordidge, R., Owen, G., Pepple, T., Read, J., Say, M., Wild, E., Patel, A., Fox, N. C., Gibbard, C., Malone, I., Crawford, H., Whitehead, D., Keenan, S., Cash, D. M., Berna, C., Bechtel, N., Bohlen, S., Man, A. Hoff, Kraus, P., Axelson, E., Wang, C., Acharya, T., Lee, S., Monaco, W., Campbell, C., Queller, S., Whitlock, K., Campbell, M., Frajman, E., Milchman, C., O'Regan, A., Labuschagne, I., Stout, J., Landwehrmeyer, B., Craufurd, D., Scahill, R., Hicks, S., Kennard, C., Johnson, H., Tobin, A., Rosas, H. D., Reilmann, R., Borowsky, B., Pourchot, C., Andrews, S. C., Bachoud-Lévi, Anne-Catherine, Bentivoglio, Anna Rita, Biunno, Ida, Bonelli, Raphael, Burgunder, Jean-Marc, Dunnett, Stephen, Ferreira, Joaquim, Handley, Olivia, Heiberg, Arvid, Illmann, Torsten, Landwehrmeyer, G. Bernhard, Levey, Jamie, Ramos-Arroyo, Maria A., Nielsen, Jã¸rgen, Koivisto, Susana Pro, Pã¤ivã¤rinta, Markku, Roos, Raymund A. C., Sebastiã¡n, A. Rojo, Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlstrã¶m, Jan, Zaremba, Jacek, Baake, Verena, Barth, Katrin, Garde, Monica Bascuñana, Betz, Sabrina, Bos, Reineke, Callaghan, Jenny, Come, Adrien, Guedes, Leonor Correia, Ecker, Daniel, Finisterra, Ana Maria, Fullam, Ruth, Gilling, Mette, Gustafsson, Lena, Handley, Olivia J, Hvalstedt, Carina, Held, Christine, Koppers, Kerstin, Lamanna, Claudia, Laurã , Matilde, Descals, Asunción Martínez, Martinez-Horta, Saã¼l, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mã¼tze, Lisanne, Oehmen, Martin, Orth, Michael, Padieu, Hã©lãne, Paterski, Laurent, Peppa, Nadia, Di Renzo, Martina, Rialland, Amandine, Rã¸ren, Niini, Å aå¡inkovã¡, Pavla, Timewell, Erika, Townhill, Jenny, Cubillo, Patricia Trigo, da Silva, Wildson Vieira, van Walsem, Marleen R, Whalstedt, Carina, Witjes-Ané, Marie-Noelle, Witkowski, Grzegorz, Wright, Abigail, Zielonka, Daniel, Zielonka, Eugeniusz, Zinzi, Paola, Bonelli, Raphael M., Lilek, Sabine, Hecht, Karen, Herranhof, Brigitte, Holl, Anna, Kapfhammer, Hans-Peter, Koppitz, Michael, Magnet, Marku, Mã¼ller, Nicole, Otti, Daniela, Painold, Annamaria, Reisinger, Karin, Scheibl, Monika, Schã¶ggl, Helmut, Ullah, Jasmin, Braunwarth, Eva-Maria, Brugger, Florian, Buratti, Lisa, Hametner, Eva-Maria, Hepperger, Caroline, Holas, Christiane, Hotter, Anna, Hussl, Anna, Mã¼ller, Christoph, Poewe, Werner, Seppi, Klau, Sprenger, Fabienne, Wenning, Gregor, Boogaerts, Andrea, Calmeyn, Godelinde, Delvaux, Isabelle, Liessens, Dirk, Somers, Nele, Dupuit, Michel, Minet, Cã©cile, van Paemel, Dominique, Ribaã¯, Pascale, van Reijen, Dimphna, Klempã­r, Jirã­, Majerovã¡, Veronika, Roth, Jan, Stã¡rkovã¡, Irena, Hjermind, Lena E., Jacobsen, Oda, Nielsen, Jørgen E., Larsen, Ida Unmack, Vinther-Jensen, Tua, Hiivola, Heli, Hyppã¶nen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau, Dominique, Bost, Marie, Gohier, Bã©nã©dicte, Guã©rid, Marie-Anne, Olivier, Audrey, Prundean, Adriana, Scherer-Gagou, Clarisse, Verny, Christophe, Babiloni, Blandine, Debruxelles, Sabrina, Duchã©, Charlotte, Goizet, Cyril, Jameau, Laetitia, Lafoucriãre, Danielle, Spampinato, Umberto, Barthã©lã©my, Rekha, De Bruycker, Christelle, Carette, Maryline Cabaret Anne-Sophie, Defebvre, Eric Decorte Luc, Delliaux, Marie, Delval, Arnaud, Destee, Alain, Dujardin, Kathy, Lemaire, Marie-HélÃne, Manouvrier, Sylvie, Peter, Mireille, Plomhouse, Lucie, Sablonniãre, Bernard, Simonin, Clã©mence, Thibault-Tanchou, Stã©phanie, Vuillaume, Isabelle, Bellonet, Marcellin, Berrissoul, Hassan, Blin, Stã©phanie, Courtin, Franã§oise, Duru, Cã©cile, Fasquel, Vã©ronique, Godefroy, Olivier, Krystkowiak, Pierre, Mantaux, Bã©atrice, Roussel, Martine, Wannepain, Sandrine, Azulay, Jean-Philippe, Delfini, Marie, Eusebio, Alexandre, Fluchere, Frã©dã©rique, Mundler, Laura, Anheim, Mathieu, Juliã©, Celine, Boukbiza, Ouhaid Lagha, Longato, Nadine, Rudolf, Gabrielle, Tranchant, Christine, Zimmermann, Marie-Agathe, Kosinski, Christoph Michael, Milkereit, Eva, Probst, Daniela, Reetz, Kathrin, Sass, Christian, Schiefer, Johanne, Schlangen, Christiane, Werner, Cornelius J., Gelderblom, Harald, Priller, Josef, Prã¼ã , Harald, Spruth, Eike Jakob, Ellrichmann, Gisa, Herrmann, Lennard, Hoffmann, Rainer, Kaminski, Barbara, Kotz, Peter, Prehn, Christian, Saft, Carsten, Lange, Herwig, Maiwald, Robert, Lã¶hle, Matthia, Maass, Antonia, Schmidt, Simone, Bosredon, Cecile, Storch, Alexander, Wolz, Annett, Wolz, Martin, Capetian, Philipp, Lambeck, Johann, Zucker, Birgit, Boelmans, Kai, Ganos, Christo, Heinicke, Walburgi, Hidding, Ute, Lewerenz, Jan, Mã¼nchau, Alexander, Schmalfeld, Jenny, Stubbe, Lar, Zittel, Simone, Diercks, Gabriele, Dressler, Dirk, Gorzolla, Heike, Schrader, Christoph, Tacik, Pawel, Ribbat, Michael, Longinus, Bernhard, Bã¼rk, Katrin, Mã¶ller, Jens Carsten, Rissling, Ida, Mã¼hlau, Mark, Peinemann, Alexander, Stã¤dtler, Michael, Weindl, Adolf, Winkelmann, Juliane, Ziegler, Cornelia, Bechtel, Natalie, Beckmann, Heike, Bohlen, Stefan, Hã¶lzner, Eva, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Natalia, Dose, Matthia, Leythã¤user, Gabriele, Marquard, Ralf, Raab, Tina, Wiedemann, Alexandra, Buck, Andrea, Connemann, Julia, Geitner, Carolin, Kesse, Andrea, Landwehrmeyer, Bernhard, Lang, Christina, Lezius, Franziska, Nepper, Solveig, Niess, Anke, Schneider, Ariane, Schwenk, Daniela, Sã¼ã muth, Sigurd, Trautmann, Sonja, Weydt, Patrick, Cormio, Claudia, Sciruicchio, Vittorio, Serpino, Claudia, de Tommaso, Marina, Capellari, Sabina, Cortelli, Pietro, Galassi, Roberto, Rizzo, Giovanni, Poda, Roberto, Scaglione, Cesa, Bertini, Elisabetta, Ghelli, Elena, Ginestroni, Andrea, Massaro, Francesca, Mechi, Claudia, Paganini, Marco, Piacentini, Silvia, Pradella, Silvia, Romoli, Anna Maria, Sorbi, Sandro, Abbruzzese, Giovanni, di Poggio, Monica Bandettini, Ferrandes, Giovanna, Mandich, Paola, Roberta, Marchese, Albanese, Alberto, Di Bella, Daniela, Castaldo, Anna, Di Donato, Stefano, Gellera, Cinzia, Genitrini, Silvia, Mariotti, Caterina, Nanetti, Lorenzo, Paridi, Dominga, Soliveri, Paola, Tomasello, Chiara, De Michele, Giuseppe, Di Maio, Luigi, Massarelli, Marco, Peluso, Silvio, Roca, Alessandro, Russo, Cinzia Valeria, Salvatore, Elena, Sorrentino, Pierpaolo, Amico, Enrico, Favellato, Mariagrazia, Griguoli, Annamaria, Mazzante, Irene, Petrollini, Martina, Squitieri, Ferdinando, D'Alessio, Barbara, Esposito, Chiara, Bentivoglio, Rita, Frontali, Marina, Guidubaldi, Arianna, Ialongo, Tamara, Jacopini, Gioia, Piano, Carla, Romano, Silvia, Soleti, Francesco, Spadaro, Maria, van Hout, Monique S. E., Verhoeven, Marloes E., van Vugt, Jeroen P. P., de Weert, A. Marit, Bolwijn, J. J. W., Dekker, M., Kremer, B., Leenders, K. L., van Oostrom, J. C. H., van den Bogaard, Simon J. A., Dumas, Eve M., â t Hart, Ellen P., Kremer, Berry, Verstappen, C. C. P., Aaserud, Olaf, Jan Frich, C., Wehus, Ragnhild, Bjã¸rgo, Kathrine, Fannemel, Madeleine, Gã¸rvell, Per F., Lorentzen, Eirin, Retterstã¸l, Lar, Stokke, Bodil, Bjã¸rnevoll, Inga, Sando, Sigrid Botne, Dziadkiewicz, Artur, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Blaszcyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasinska-Myga, Barbara, Klodowska-Duda, Gabriela, Opala, Gregorz, Stompel, Daniel, Banaszkiewicz, Krzysztof, Bocwinska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Malgorzata, Krawczyk, Malgorzata, Rudzinska, Monika, Szczygiel, Elzbieta, Szczudlik, Andrzej, Wasielewska, Anna, Wã³jcik, Magdalena, Bryl, Anna, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempolowicz, Justyna, Gogol, Anna, Janik, Piotr, Kwiecinski, Hubert, Jamrozik, Zygmunt, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Richter, Przemyslaw, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stepniak, Iwona, Sulek, Anna, Zdzienicka, Elzbieta, Zieora-Jakutowicz, Karolina, Ferreira, Joaquim J, Coelho, Miguel, Mendes, Tiago, Valadas, Anabela, Andrade, Carlo, Gago, Miguel, Garrett, Carolina, Guerra, Maria Rosália, Herrera, Carmen Durán, Garcia, Patrocinio Moreno, Barbera, Miquel Aguilar, Guia, Dolors Badene, Hernanz, Laura Casa, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastiã¡n, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Nãºria, Calopa, Matilde, Robert, Misericordia Floriach, Viladrich, Celia Mareca, Idiago, Jesús Miguel Ruiz, Riballo, Antonio Villa, Cubo, Esther, Polo, Cecilia Gil, Mariscal, Natividad, Rivadeneyra, Perez Jessica, Barrero, Francisco, Morales, Bla, Fenollar, Marã­a, Garcã­a, Rocío García-Ramo, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuã±ana, Mã³nica, Caldentey, Juan Garcia, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Frech, Fernando Alonso, Ruã­z, Pedro J. García, Martínez-Descals, Asunciã³n, Guerrero, Rosa, Artiga, María José Saiz, Sã¡nchez, Vicenta, Perea, María Fuensanta Noguera, Fortuna, Lorenza, Manzanares, Salvadora, Reinante, Gema, Torres, María Martirio Antequera, Moreau, Laura Vivanco, González González, Sonia, Guisasola, Luis Menéndez, Salvador, Carlo, Martã­n, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazãº, Lopera, Mónica Rodriguez, Arques, Penelope Nava, Rodrã­guez, María José Torre, Pastor, Barbara Vive, Gaston, Itziar, Martinez-Jaurrieta, Maria Dolore, Moreno, Jose Manuel Garcia, Lucena, Carolina Mendez, Damas, Fatima, Cortegana, Hermoso Eva Pacheco, Peã±a, José Chacón, Redondo, Lui, Carrillo, Fã¡tima, Teresa Cáceres, Marã­a, Mir, Pablo, Suarez, María José Lama, Vargas-González, Laura, Bosca, Maria E., Brugada, Francisco Castera, Burguera, Juan Andre, Campos, Anabel, Vilaplana, Garcia Carmen Peiró, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, Høsterey-Ugander, Ulrika, Linnsand, Petra, Neleborn-Lingefjärd, Liselotte, Wentzel, Magnu, Loutfi, Ghada, Olofsson, Carina, Stattin, Eva-Lena, Westman, Laila, Wikstrã¶m, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schã¼pbach, Michael, Weber Zaugg, Sabine, Hauer, Maria, Gonzenbach, Roman, Jung, Hans H., Mihaylova, Violeta, Petersen, Jen, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, Simpson, Sheila A, Summers, Fiona, Ure, Alexandra, Vaughan, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Armstrong, Matthew, Barker, Roger A., O'Keefe, Deidre, Di Pietro, Anna, Fisher, Kate, Goodman, Anna, Hill, Susan, Kershaw, Ann, Mason, Sarah, Paterson, Nicole, Raymond, Lucy, Swain, Rachel, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Clenaghan, Catherine, Hunt, Sarah, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Edwards, Maureen, Carrie, Ho, Hughes, Teresa, Mcgill, Marie, Pearson, Pauline, Porteous, Mary, Smith, Paul, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Burrows, Liz, Chu, Carol, Fletcher, Amy, Gallantrae, Deena, Hamer, Stephanie, Harding, Alison, Klã¶ppel, Stefan, Kraus, Alison, Laver, Fiona, Lewis, Monica, Longthorpe, Mandy, Markova, Ivana, Raman, Ashok, Robertson, Nicola, Silva, Mark, Thomson, Aileen, Wild, Sue, Yardumian, Pam, Evans, Carole, Gallentrae, Deena, Hobson, Emma, Jamieson, Stuart, Musgrave, Hannah, Rowett, Liz, Toscano, Jean, Bourne, Colin, Clapton, Jackie, Clayton, Carole, Dipple, Heather, Freire-Patino, Dawn, Grant, Janet, Gross, Diana, Hallam, Caroline, Middleton, Julia, Murch, Ann, Thompson, Catherine, Alusi, Sundu, Davies, Rhy, Foy, Kevin, Gerrans, Emily, Pate, Louise, Andrews, Thomasin, Dougherty, Andrew, Golding, Charlotte, Kavalier, Fred, Laing, Hana, Lashwood, Alison, Robertson, Dene, Ruddy, Deborah, Santhouse, Alastair, Whaite, Anna, Bruno, Stefania, Doherty, Karen, Haider, Salman, Hensman, Davina, Lahiri, Nayana, Novak, Marianne, Patel, Aakta, Rosser, Elisabeth, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Rogers, Dawn, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Armstrong, Richard, Dixon, Kathryn, Nemeth, Andrea H, Siuda, Gill, Valentine, Ruth, David, Harrison, Hughes, Max, Parkinson, Andrew, Soltysiak, Beverley, Bandmann, Oliver, Bradbury, Alyson, Gill, Paul, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Kazoka, Mbombe, O'Donovan, Kirsty, Taylor, Cat, Tidswell, Katherine, Quarrell, Oliver, Lau, Puay Ngoh, Pica, Emmanul, Tan, Louis, Amsterdam Neuroscience - Neurodegeneration, Neurology, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Moss, Davina J Hensman, Lo, Kitty, Pardiñas, Antonio F, Santos, R Dar, Ret, C Jauff, Valabrègue, R., Witjes-Ane, M. -N., Man, A Hoff, Bachoud-Lévi, Anne-Catherine, Nielsen, Jørgen, Päivärinta, Markku, Sebastián, A Rojo, Wahlström, Jan, Garde, Monica Bascuñana, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mütze, Lisanne, Padieu, Hélène, Røren, Niini, Šašinková, Pavla, Witjes-Ané, Marie-Noelle, Müller, Nicole, Schöggl, Helmut, Müller, Christoph, Minet, Cécile, Ribaï, Pascale, Klempír, Jirí, Majerová, Veronika, Stárková, Irena, Nielsen, Jørgen E., Hyppönen, Hannele, Gohier, Bénédicte, Guérid, Marie-Anne, Duché, Charlotte, Lafoucrière, Danielle, Barthélémy, Rekha, Lemaire, Marie-Hélène, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Mantaux, Béatrice, Fluchere, Frédérique, Julié, Celine, Prüß, Harald, Löhle, Matthia, Münchau, Alexander, Bürk, Katrin, Möller, Jens Carsten, Mühlau, Mark, Städtler, Michael, Hölzner, Eva, Leythäuser, Gabriele, Süßmuth, Sigurd, Marchese, Roberta, DI MAIO, Luigi, ’t Hart, Ellen P., Bjørgo, Kathrine, Gørvell, Per F., Retterstøl, Lar, Bjørnevoll, Inga, Wójcik, Magdalena, Guerra, Maria Rosália, Herrera, Carmen Durán, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastián, Ana Rojo, Busquets, Núria, Idiago, Jesús Miguel Ruiz, Fenollar, María, García, Rocío García-Ramo, Bascuñana, Mónica, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Ruíz, Pedro J García, Martínez-Descals, Asunción, Artiga, María José Saiz, Sánchez, Vicenta, Perea, María Fuensanta Noguera, Torres, María Martirio Antequera, González González, Sonia, Guisasola, Luis Menéndez, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Rodríguez, María José Torre, Peña, José Chacón, Carrillo, Fátima, Teresa Cáceres, María, Suarez, María José Lama, Vargas-González, Laura, Vilaplana, Garcia Carmen Peiró, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Wikström, Birgitta, Schüpbach, Michael, Ho, Carrie, Klöppel, Stefan, Harrison, David, Cardiff University, University of Iowa [Iowa City], University of British Columbia (UBC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UCL, Institute of Neurology [London], National Oceanography Centre [Southampton] (NOC), University of Southampton, Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), TRACK-HD investigators, Pardinas, Antonio F, Langbehn, Douglas, Lee, S Hong, TRACK-HD Investigators, and REGISTRY Investigators

Subjects
0301 basic medicine, Oncology, Registrie, Genome-wide association study, Longitudinal Studie, Disease, Bioinformatics, Severity of Illness Index, Principal Component Analysi, Longitudinal Studies, Registries, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Huntington disease, DNA-Binding Proteins, Settore MED/26 - NEUROLOGIA, Adult, Genome-Wide Association Study, Humans, Huntington Disease, MutS Homolog 3 Protein, Principal Component Analysis, Disease Progression, Neurology (clinical), huntingtin gene, age of onest, Huntington’s disease, Human, medicine.medical_specialty, cag repeat, instability, DNA-Binding Protein, Clinical Neurology, Principal component analysis, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Huntington's disease, Internal medicine, medicine, SNP, genome-wide association study, medicine.disease, R1, meta-analysis, Minor allele frequency, 030104 developmental biology, Age of onset, Trinucleotide repeat expansion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Published
2017

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

Author

Mary Jean Stempien, Rajesh Pahwa, Caroline M. Tanner, Stuart Isaacson, Jean-Philippe Azulay, Claudia Trenkwalder, Reinhard Ehret, Larissa Felt, Robert A. Hauser, Karla Eggert, and Wolfgang H. Oertel

Subjects
0301 basic medicine, Levodopa-induced dyskinesia, education.field_of_study, business.industry, Population, Placebo-controlled study, Placebo, Bedtime, Confidence interval, law.invention, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Dyskinesia, Randomized controlled trial, law, Anesthesia, Medicine, Neurology (clinical), medicine.symptom, business, education, 030217 neurology & neurosurgery
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.

Published
2017

44. A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease

Author

Katia Youssov, Christophe Verny, Frédéric Saudou, Jean-Philippe Azulay, Alexandra Durr, Clarisse Scherer, Pascal Reynier, Christine Tranchant, Adriana Prundean, Fabienne Calvas, Philippe Allain, Audrey Olivier, Cyril Goizet, Patrick Maison, Pierre Krystkowiak, Anne-Catherine Bachoud-Lévi, Perrine Charles, Dominique Bonneau, Erica von Studnitz, and Clémence Simonin

Subjects
0301 basic medicine, medicine.medical_specialty, Cysteamine Bitartrate, business.industry, Placebo-controlled study, Repeated measures design, Placebo, medicine.disease, Surgery, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Neurology, chemistry, Huntington's disease, Internal medicine, medicine, Clinical endpoint, Population study, Cysteamine, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease. Methods: Ninety-six patients with early-stage Huntington's disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. Results: At 18 months, the treatment effect was not statistically significant — least-squares mean difference, -1.5 ± 1.71 (P = 0.385) — although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. Conclusions: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society

Published
2017

45. Les signes non moteurs de la maladie de Parkinson

Author

Alexandre Eusebio, Tatiana Witjas, and Jean-Philippe Azulay

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, business.industry, Urination disorder, General Medicine, Disease, Degeneration (medical), medicine.disease, Motor symptoms, REM sleep behavior disorder, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Neuronal circuits, Dopaminergic pathways, medicine, Neuralgia, business, 030217 neurology & neurosurgery
Abstract

In Parkinson's disease, motor signs have long been the main targets of the management of the disease. In recent years, non-motor disorders have elicited increasing interest. These disorders are under diagnosed and managed more difficultly than motor signs and are sometimes perceived as more disturbing by the patients. These signs are polymorphous, sometimes occurring before the motor symptoms but increase with the disease duration and complicating always the late stages. They may fluctuate as the motor signs, while being under the control of dopaminergic pathways, or be linked to the degeneration of other neuronal circuits. These clinical manifestations, whether or not fluctuating are classified into three major categories: psycho-cognitive including sleep disorders, autonomic and sensory.

Published
2017

46. French consensus procedure for assessing cognitive function in Parkinson's disease

Author

Tiphaine Vidal, Fanny Pineau, Nicolas Auzou, François Sellal, Mylène Meyer, Bruno Dubois, Jean-Philippe Azulay, Jean-Christophe Corvol, Franck Durif, Kathy Dujardin, Eugénie Lhommée, François Tison, E. Schmitt, Virginie Czernecki, David Maltête, Olivier Rascol, M-L Welter, and A. Fradet

Subjects
Consensus, Delphi Technique, Delphi method, Neuropsychological Tests, Executive Function, 03 medical and health sciences, Cognition, 0302 clinical medicine, medicine, Humans, Dementia, Neuropsychological assessment, Expert Testimony, Episodic memory, 030214 geriatrics, medicine.diagnostic_test, Working memory, Montreal Cognitive Assessment, Parkinson Disease, medicine.disease, Memory, Short-Term, Neurology, Normative, France, Neurology (clinical), Cognition Disorders, Psychology, 030217 neurology & neurosurgery, Clinical psychology, Cognitive psychology
Abstract

Introduction One of the objectives of the French expert centers for Parkinson's disease (NS-Park) network was to determine a consensus procedure for assessing cognitive function in patients with Parkinson's. This article presents this procedure and briefly describes the selected tests. Methods A group of 13 experts used the Delphi method for consensus building to define the overall structure and components of the assessment procedure. For inclusion in the battery, tests had to be validated in the French language, require little motor participation, have normative data and be recognized by the international community. Experimental tasks and tests requiring specific devices were excluded. Results Two possibilities were identified, depending on whether an abbreviated or comprehensive assessment of cognitive function was necessary. For an abbreviated assessment, the experts recommended the Montreal Cognitive Assessment (MoCA) as a screening test for cognitive impairment or dementia. For a comprehensive neuropsychological assessment, the experts recommended assessing global efficiency plus the five main cognitive domains (attention and working memory, executive function, episodic memory, visuospatial function and language) that may be impaired in Parkinson's disease, using two tests for each domain. Discussion and conclusion A common procedure for assessing cognitive function is now available across the French network dedicated to Parkinson's disease, and is recommended for both research and clinical practice. It will also help to promote standardization of the neuropsychological assessment of Parkinson's disease.

Published
2016

47. Multiple System Atrophy: Phenotypic spectrum approach coupled with brain 18-FDG PET

Author

Mohamed Boucekine, Eric Guedj, Stephan Grimaldi, Mathilde Renaud, Jean-Philippe Azulay, Frédérique Fluchère, Alexandre Eusebio, Tatiana Witjas, Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Service Central de Biophysique et de Médecine Nucléaire, Imagerie MOléculaire pour applications THéranostiques personnalisées (IMOTHEP), Institut FRESNEL (FRESNEL), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Pathology, REM Sleep Behavior Disorder, Hypotension, Orthostatic, 0302 clinical medicine, Retrospective analysis, Cognitive impairment, ComputingMilieux_MISCELLANEOUS, Cognitive Symptoms, medicine.diagnostic_test, Brain, Middle Aged, Phenotype, Latent class model, 3. Good health, Neurology, Positron emission tomography, Latent Class Analysis, Female, medicine.medical_specialty, Spinal Curvatures, Laryngeal Diseases, Muscular Atrophy, Spinal, 03 medical and health sciences, Atrophy, Basal Ganglia Diseases, Cerebellar Diseases, Fluorodeoxyglucose F18, Clinical heterogeneity, medicine, Humans, Cognitive Dysfunction, Gait Disorders, Neurologic, Aged, Retrospective Studies, business.industry, Pharyngeal Diseases, Multiple System Atrophy, medicine.disease, 030104 developmental biology, Urinary Incontinence, nervous system, Positron-Emission Tomography, Accidental Falls, Neurology (clinical), Geriatrics and Gerontology, Radiopharmaceuticals, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

The 2008 diagnostic criteria classify Multiple System Atrophy (MSA) patients in a predominantly parkinsonian (MSA-P) or cerebellar (MSA-C) type. Phenotypic descriptions have since highlighted a clinical heterogeneity among patients (e.g., mixed-type, cognitive impairment, atypical longer survival). This study attempts to identify different phenotypes of patients with MSA and to describe corresponding brain 18-FDG Positron Emission Tomography (PET) patterns.Patients with a "probable" MSA diagnosis for whom a brain 18-FDG PET was performed were included. A retrospective analysis (from 2006 to 2017) was conducted using standardized data collection. We used Latent Class Analysis (LCA), an innovative statistical approach, to identify profiles of patients based on common clinical characteristics. Brain metabolism of different groups was studied at rest.Eighty-five patients were included. Three different profiles were revealed (entropy = 0.835): 1. extrapyramidal, axial, laryngeal-pharyngeal involvement (LPI) and cerebellar symptoms (n = 46, 54.1%); 2. cerebellar and LPI symptoms (n = 30, 35.3%); 3. cerebellar and cognitive symptoms (n = 9, 10.6%). Brain metabolism analyses (k 89; p 0.001) showed hypometabolism of the basal ganglia, frontal/prefrontal, temporal cortices and left posterior cerebellum in profile 1. In profile 2 there was hypometabolism of the medulla, prefrontal, temporal, cingular cortices, putamen and bilateral cerebellar hemispheres. In profile 3 there was hypometabolism of bilateral posterior cerebellar hemispheres and vermis.Beyond the two most common phenotypes of MSA, a third and particularly atypical profile with cerebellar and cognitive symptoms but without LPI involvement is described. These profiles are supported by different brain metabolic abnormalities which could be useful for diagnostic purposes.

Published
2019

48. Metabolic Positron Emission Tomography Response to Gamma Knife of the Ventral Intermediate Nucleus in Essential Tremor

Author

Alexandre Eusebio, Jean Régis, Antoine Verger, Romain Carron, Eric Guedj, Tatiana Witjas, Emmanuelle Boutin, Jean-Philippe Azulay, Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Service de médecine nucléaire [Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Neurochirurgie Fonctionnelle, Institut de Neurosciences des Systèmes (INS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut FRESNEL (FRESNEL), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Service de Médecine Nucléaire [CHRU Nancy], Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Cerebellum, medicine.medical_specialty, Essential Tremor, Thalamus, Gamma knife, Radiosurgery, 03 medical and health sciences, 0302 clinical medicine, Fluorodeoxyglucose F18, Internal medicine, Medical imaging, Humans, Medicine, Aged, Sweden, Ventral Thalamic Nuclei, Ventral intermediate nucleus, medicine.diagnostic_test, Essential tremor, business.industry, Middle Aged, medicine.disease, Glucose, medicine.anatomical_structure, Positron emission tomography, Positron-Emission Tomography, 030220 oncology & carcinogenesis, Cardiology, Female, Surgery, Neurology (clinical), Radiopharmaceuticals, business, Biomarkers, 030217 neurology & neurosurgery, After treatment, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

To understand the substrates of response and nonresponse and to identify potential biomarkers for the selection and follow-up of patients with essential tremor (ET) treated with Gamma Knife (Elekta AB, Stockholm, Sweden) of the ventral intermediate nucleus (GKVIM).To characterize positron emission tomography (PET) changes in the metabolism of glucose and metabolic connectivity in patients with ET treated by GKVIM through observational study.Forty-two patients with right ET were referred to 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET) imaging before and after left GKVIM. Statistical Parametric Mapping T-score map comparisons were performed between pre- and post-GKVIM groups and between clinical responders and nonresponders. Metabolic connectivity was evaluated by the interregional correlation analysis method.After GKVIM, patients with ET exhibited decreased left thalamic metabolism, which was associated with remote metabolic decreases in the right cerebellum, left temporal gyri, and bilateral frontal gyri (P .05, family-wise error-corrected). Additionally, nonresponders (n = 7) showed metabolic decreases in the right temporo-occipital area (P .005 corrected for cluster volume) after GKVIM. The metabolism in this area was already reduced in nonresponders before treatment in comparison to that in responders and was predictive of future response (sensitivity: 89%; specificity: 71%). In nonresponder patients, strong connectivity between the left thalamus and right temporo-occipital area was found before GKVIM and was lost after treatment, whereas this connectivity remained weak and stable in responders.These findings could lead to better knowledge of the variability in the metabolic PET profiles among patients with ET, particularly the integration of 18F-FDG PET imaging in the pretherapeutic evaluation of patients with refractory ET candidates for GKVIM.

Published
2019

50. Psychosocial Impact of dysarthria: the patient-reported outcome as part of the clinical management

Author

Luc Defebvre, Serge Pinto, Joaquim J. Ferreira, Jean-Philippe Azulay, Camille Robieux, Alban Letanneux, Alexandre Eusebio, Danièle Robert, Lauriane Véron-Delor, Guillaume Baille, Manon Berthelot, Marie-Charlotte Cuartero, Cyril Atkinson-Clement, Caroline Moreau, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Cognitions Humaine et ARTificielle (CHART), Université Paris 8 Vincennes-Saint-Denis (UP8)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Nanterre (UPN)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École supérieure du professorat et de l'éducation - Académie de Créteil (UPEC ESPE Créteil), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Aix Marseille Université (AMU), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut de Neurosciences de la Timone (INT), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris 8 Vincennes-Saint-Denis (UP8)-École Pratique des Hautes Études (EPHE), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris 8 Vincennes-Saint-Denis (UP8)-École pratique des hautes études (EPHE)-Université Paris Nanterre (UPN)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Troubles cognitifs dégénératifs et vasculaires (U1171), INSERM-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), CHU Lille, CNRS, Inserm, Université de Lille, Troubles cognitifs dégénératifs et vasculaires - U1171, and Troubles cognitifs dégénératifs et vasculaires - U 1171 [TCDV]

Subjects
Adult, Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Psychometrics, Intelligibility (communication), Audiology, Psychosocial impact, Severity of Illness Index, 050105 experimental psychology, 03 medical and health sciences, Dysarthria, 0302 clinical medicine, medicine, Humans, Psychology, Speech, 0501 psychology and cognitive sciences, Patient Reported Outcome Measures, Voice Handicap Index, Aged, Dystonia, Aged, 80 and over, Cerebellar ataxia, business.industry, 05 social sciences, Communication Barriers, Speech Intelligibility, Discriminant validity, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Neurodegenerative Diseases, Middle Aged, medicine.disease, Mental Status and Dementia Tests, nervous system diseases, Phenotype, Neurology, Self-assessment, Voice, Patient-reported outcome, Female, Neurology (clinical), medicine.symptom, business, Psychosocial, 030217 neurology & neurosurgery
Abstract

Background: Dysarthria in neurological disorders can have psychosocial consequences. The dysarthric speaker’s perspective towards the disorder’s psychosocial impact is essential in its global assessment and management. For such purposes, assessment tools such as the Dysarthria Impact Profile (DIP) are indispensable. Objective: We aimed to confirm the relevance of using the DIP to quantify the psychosocial consequences of dysarthria in neurological diseases. Methods: We studied 120 participants, 15 healthy controls and 105 patients with different kinds of dysarthria induced by several neurological disorders (Parkinson’s disease [PD], Huntington’s disease, dystonia, cerebellar ataxia, progressive supranuclear palsy [PSP], multiple system atrophy, lateral amyotrophic sclerosis). All participants underwent a cognitive evaluation and a speech intelligibility assessment and completed three self-reported questionnaires: the 36-Item Short Form Health Survey, the Voice Handicap Index (VHI), and the DIP. Results: The psychometric properties of the DIP were confirmed, including internal consistency (α = 0.93), concurrent validity (correlation with the VHI: r = –0.77), and discriminant validity (accuracy = 0.93). Psychosocial impact of dysarthria was revealed by the DIP for all patients. Intelligibility loss was found strongly correlated with the psychosocial impact of dysarthria: for a similar level of intelligibility impairment, the DIP total score was similar regardless of the pathological group. However, our findings suggest that the psychosocial impact measured by the DIP could be partially independent from the severity of dysarthria (indirectly addressed here via speech intelligibility): the DIP was able to detect patients without any intelligibility impairment, but with a psychosocial impact. Conclusions: All patients reported a communication complaint, attested by the DIP scores, despite the fact that not all patients, notably PD, ataxic, and PSP patients, had an intelligibility deficit. The DIP should be used in clinical practice to contribute to a holistic evaluation and management of functional communication in patients with dysarthria.

Published
2019

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