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1. Alterations in the LRRK2-Rab pathway in urinary extracellular vesicles as Parkinson’s disease and pharmacodynamic biomarkers

Author

Jean-Marc Taymans, Eugénie Mutez, William Sibran, Laurine Vandewynckel, Claire Deldycke, Séverine Bleuse, Antoine Marchand, Alessia Sarchione, Coline Leghay, Alexandre Kreisler, Clémence Simonin, James Koprich, Guillaume Baille, Luc Defebvre, Kathy Dujardin, Alain Destée, and Marie-Christine Chartier-Harlin

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Expression or phosphorylation levels of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have strong potential as disease or pharmacodynamic biomarkers. The main objective of this study is therefore to assess the LRRK2-Rab pathway for use as biomarkers in human, non-human primate (NHP) and rat urine. With urine collected from human subjects and animals, we applied an ultracentrifugation based fractionation protocol to isolate small urinary extracellular vesicles (uEVs). We used western blot with antibodies directed against total and phosphorylated LRRK2, Rab8, and Rab10 to measure these LRRK2 and Rab epitopes in uEVs. We confirm the presence of LRRK2 and Rab8/10 in human and NHP uEVs, including total LRRK2 as well as phospho-LRRK2, phospho-Rab8 and phospho-Rab10. We also confirm LRRK2 and Rab expression in rodent uEVs. We quantified LRRK2 and Rab epitopes in human cohorts and found in a first cohort that pS1292-LRRK2 levels were elevated in individuals carrying the LRRK2 G2019S mutation, without significant differences between healthy and PD groups, whether for LRRK2 G2019S carriers or not. In a second cohort, we found that PD was associated to increased Rab8 levels and decreased pS910-LRRK2 and pS935-LRRK2. In animals, acute treatment with LRRK2 kinase inhibitors led to decreased pT73-Rab10. The identification of changes in Rab8 and LRRK2 phosphorylation at S910 and S935 heterologous phosphosites in uEVs of PD patients and pT73-Rab10 in inhibitor-dosed animals further reinforces the potential of the LRRK2-Rab pathway as a source of PD and pharmacodynamic biomarkers in uEVs.

Published
2023
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2. Crosstalk between the Hippo Pathway and the Wnt Pathway in Huntington’s Disease and Other Neurodegenerative Disorders

Author

Pasquale Sileo, Clémence Simonin, Patricia Melnyk, Marie-Christine Chartier-Harlin, and Philippe Cotelle

Subjects
Hippo, YAP, Wnt, Huntington’s disease, neurodegeneration, Cytology, QH573-671
Abstract

The Hippo pathway consists of a cascade of kinases that controls the phosphorylation of the co-activators YAP/TAZ. When unphosphorylated, YAP and TAZ translocate into the nucleus, where they mainly bind to the TEAD transcription factor family and activate genes related to cell proliferation and survival. In this way, the inhibition of the Hippo pathway promotes cell survival, proliferation, and stemness fate. Another pathway can modulate these processes, namely the Wnt/β-catenin pathway that is indeed involved in cellular functions such as proliferation and cell survival, as well as apoptosis, growth, and cell renewal. Wnt signaling can act in a canonical or noncanonical way, depending on whether β-catenin is involved in the process. In this review, we will focus only on the canonical Wnt pathway. It has emerged that YAP/TAZ are components of the β-catenin destruction complex and that there is a close relationship between the Hippo pathway and the canonical Wnt pathway. Furthermore, recent data have shown that both of these pathways may play a role in neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, or Amyotrophic Lateral Sclerosis. Thus, this review analyzes the Hippo pathway and the Wnt pathway, their crosstalk, and their involvement in Huntington’s disease, as well as in other neurodegenerative disorders. Altogether, these data suggest possible therapeutic approaches targeting key players of these pathways.

Published
2022
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3. RNA-binding disturbances as a continuum from spinocerebellar ataxia type 2 to Parkinson disease

Author

Aurore Nkiliza, Eugénie Mutez, Clémence Simonin, Frédéric Leprêtre, Aurélie Duflot, Martin Figeac, Céline Villenet, Pierre Semaille, Thomas Comptdaer, Alexandre Genet, Bernard Sablonnière, David Devos, Luc Defebvre, Alain Destée, and Marie-Christine Chartier-Harlin

Subjects
Parkinson's disease, Spinocerebellar ataxia type 2, ATXN2 CAG expansions, RNA metabolism, Translation, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

CAG triplet expansions in Ataxin-2 gene (ATXN2) cause spinocerebellar ataxia type 2 and have a role that remains to be clarified in Parkinson's disease (PD). To study the molecular events associated with these expansions, we sequenced them and analyzed the transcriptome from blood cells of controls and three patient groups diagnosed with spinocerebellar ataxia type 2 (herein referred to as SCA2c) or PD with or without ATXN2 triplet expansions (named SCA2p).The transcriptome profiles of these 40 patients revealed three main observations: i) a specific pattern of pathways related to cellular contacts, proliferation and differentiation associated with SCA2p group, ii) similarities between the SCA2p and sporadic PD groups in genes and pathways known to be altered in PD such as Wnt, Ephrin and Leukocyte extravasation signaling iii) RNA metabolism disturbances with “RNA-binding” and “poly(A) RNA-binding” as a common feature in all groups. Remarkably, disturbances of ALS signaling were shared between SCA2p and sporadic PD suggesting common molecular dysfunctions in PD and ALS including CACNA1, hnRNP, DDX and PABPC gene family perturbations. Interestingly, the transcriptome profiles of patients with parkinsonian phenotypes were prevalently associated with alterations of translation while SCA2c and PD patients presented perturbations of splicing. While ATXN2 RNA expression was not perturbed, its protein expression in immortalized lymphoblastoid cells was significantly decreased in SCA2c and SCA2p versus control groups assuming post-transcriptional biological perturbations.In conclusion, the transcriptome data do not exclude the role of ATXN2 mutated alleles in PD but its decrease protein expression in both SCA2c and SCA2p patients suggest a potential involvement of this gene in PD. The perturbations of “RNA-binding” and “poly(A) RNA-binding” molecular functions in the three patient groups as well as gene deregulations of factors not yet described in PD but known to be deleterious in other neurological conditions, suggest the existence of RNA-binding disturbances as a continuum between spinocerebellar ataxia type 2 and Parkinson's disease.

Published
2016
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4. 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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5. 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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6. Longitudinal study of informed consent in innovative therapy research: experience and provisional recommendations from a multicenter trial of intracerebral grafting.

Author

Laurent Cleret de Langavant, Sophie Sudraud, Christophe Verny, Pierre Krystkowiak, Clémence Simonin, Philippe Damier, Jean-François Demonet, Frédéric Supiot, Amandine Rialland, David Schmitz, Patrick Maison, Katia Youssov, and Anne-Catherine Bachoud-Lévi

Subjects
Medicine, Science
Abstract

There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders.We performed a longitudinal study of the consent of Huntington's disease patients during the Multicenter Fetal Cell Intracerebral Grafting Trial in Huntington's Disease (MIG-HD) in France and Belgium. Patients and their proxies completed a consent questionnaire at inclusion, before signing the consent form and after one year of follow-up, before randomization and transplantation. The questionnaire explored understanding of the protocol, satisfaction with the information delivered, reasons for participating in the trial and expectations regarding the transplant. Forty-six Huntington's disease patients and 27 proxies completed the questionnaire at inclusion, and 27 Huntington's disease patients and 16 proxies one year later.The comprehension score was high and similar for Huntington's disease patients and proxies at inclusion (72.6% vs 77.8%; P > 0.1) but only decreased in HD patients after one year. The information satisfaction score was high (73.5% vs 66.5%; P > 0.1) and correlated with understanding in both patients and proxies. The motivation and expectation profiles were similar in patients and proxies and remained unchanged after one year.Cognitively impaired patients with Huntington's disease were capable of consenting to participation in this trial. This consent procedure has presumably strengthened their understanding and should be proposed before signing the consent form in future gene or cell therapy trials for neurodegenerative disorders. Because of the potential cognitive decline, proxies should be designated as provisional surrogate decision-makers, even in competent patients.

Published
2015
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7. 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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8. 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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11. Alterations in the LRRK2-Rab pathway in urinary extracellular vesicles as Parkinson’s disease and pharmacodynamic biomarkers

Author

Jean-Marc Taymans, Eugenie Mutez, William Sibran, Laurine Vandewynckel, Claire Deldycke, Séverine Bleuse, Antoine Marchand, Alessia Sarchione, Alexandre Kreisler, Clémence Simonin, James Koprich, Guillaume Baille, Luc Defebvre, Kathy Dujardin, Alain Destée, and Marie-Christine Chartier-Harlin

Abstract

Levels of expression or of phosphorylation of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have the potential for use as disease or pharmacodynamic biomarkers. LRRK2 phosphorylation levels at the S910-S935-S955-S973 phosphosites are reduced for most disease mutant forms of LRRK2, while for phospho-S1292, phospho-T72-Rab8 and phospho-T73-Rab10 levels are increased for most mutants. In addition, all of these 5 phosphosites on LRRK2 are rapidly dephosphorylated upon LRRK2 inhibitor treatment, considered potential therapeutics. The main objective of this study is therefore to characterize leucine-rich repeat kinase 2 (LRRK2) and Rab8/10 in human, non-human primate and rat urine for use as potential disease or pharmacodynamic biomarkers. With urine collected from human subjects as well as animals, we have applied an ultracentrifugation based fractionation protocol to isolate small extracellular vesicles (EVs). We used western blot with antibodies directed against LRRK2, LRRK2 phosphorylation sites as well as Rab8 and Rab10 total and phosphorylated proteins in order to measure these LRRK2 and Rab epitopes in urinary EVs (uEVs). We confirm the presence of LRRK2 and Rab8/10 in human and non-human primate (NHP) uEVs, including total LRRK2 as well phosphorylated forms of LRRK2 pS910, pS935, pS955, pS973, pS1292 and phosphorylated Rab8 and Rab10. We also confirm LRRK2 and Rab expression in rodent uEVs. We quantified LRRK2 and Rab epitopes in human cohorts and found in a first cohort that pS1292-LRRK2 levels were elevated in individuals carrying the LRRK2 G2019S mutation, but did not differ significantly between healthy and PD groups, whether for LRRK2 G2019S carriers or not. In a second cohort, we found that PD was associated to an increase in Rab8 levels and a decrease in S910-LRRK2 and S935-LRRK2 phosphorylation rates. In animals, we found that acute treatment with LRRK2 kinase inhibitor led to decreases in Rab10 phosphorylation rates and to a decrease in pS935-LRRK2 rates in uEVs from NHPs. The identification of changes in LRRK2 phosphorylation at heterologous phosphorylation sites in uEVs of PD patients further reinforces the potential of the LRRK2-Rab pathway as a source of PD biomarkers in uEVs.

Published
2022

12. Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients

Author

Alain Destée, Sabine Hilfiker, Elena Fdez, Thomas Comptdaer, Jean-Marc Taymans, Eugénie Mutez, Alexandre Kreisler, Belén Fernández, Laurine Vandewynckel, Marie-Christine Chartier-Harlin, Coline Leghay, Luc Defebvre, Séverine Bleuse, Clémence Simonin, Antonio Ordóñez, Michael J. Fox Foundation for Parkinson's Research, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), and Université de Lille

Subjects
Adult, Male, Parkinson's disease, Cell, Leucine-rich repeat kinase, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Biochemistry, Molecular Bases of Health & Disease, 03 medical and health sciences, Protein phosphorylation, 0302 clinical medicine, Cell Line, Tumor, Rab protein, Centrosome cohesion, medicine, Humans, Phosphorylation, Kinase activity, Molecular Biology, Research Articles, Diagnostics & Biomarkers, Aged, 030304 developmental biology, Centrosome, 0303 health sciences, Post-Translational Modifications, business.industry, Kinase, Parkinson Disease, Cell Biology, Middle Aged, medicine.disease, LRRK2, Signaling, nervous system diseases, medicine.anatomical_structure, Leukocytes, Mononuclear, Cancer research, Biomarker (medicine), Female, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD), and orally bioavailable, brain penetrant and highly potent LRRK2 kinase inhibitors are in early stages of clinical testing. Detection of LRRK2 phosphorylation, as well as phosphorylation of Rab10, a LRRK2 kinase substrate, have been proposed as target engagement biomarkers for LRRK2 inhibitor clinical trials. However, these readouts do not seem able to stratify patients based on enhanced LRRK2 kinase activity. Here, we describe a robust cell biological assay based on centrosomal cohesion alterations which were observed in peripheral blood mononuclear cellderived lymphoblastoid cell lines (LCLs) from patients with G2019S LRRK2 mutations as compared with healthy controls, and could also be detected in a subset of sporadic PD patient samples. We suggest that LCLs may be a valuable resource for LRRK2 research, and that determination of centrosomal cohesion deficits may assist in the stratification of a subset of sporadic PD patients., This work was supported by funding from the Michael J. Fox Foundation for Parkinson's Research (U.S.A.), FEDER, the Spanish Ministry of Science, Innovation and Universities (SAF2017-89402-R), and by the French Ministry of Health's PHRC program (CONVERGENCE 2008-A00219-42), the University of Lille, Inserm and the Lille University Hospital.

Published
2019

13. Anatomy-guided injections of botulinum neurotoxin in neck muscles: how accurate is needle placement?

Author

Alexandre Kreisler, Luc Defebvre, A. Degardin, Eugénie Mutez, and Clémence Simonin

Subjects
medicine.medical_specialty, Injections, Intramuscular, 03 medical and health sciences, 0302 clinical medicine, Neck Muscles, Medicine, Humans, 030212 general & internal medicine, Cervical dystonia, Botulinum Toxins, Type A, Torticollis, Ultrasonography, Dystonia, Splenius capitis muscle, business.industry, Ultrasound, Imaging guidance, medicine.disease, Neck muscles, Botulinum neurotoxin, Neurology, Neuromuscular Agents, Needle placement, Neurology (clinical), Radiology, business, 030217 neurology & neurosurgery
Abstract

BACKGROUND AND PURPOSE In cervical dystonia, the accuracy of botulinum neurotoxin (BoNT) injections may influence the response to the treatment. METHODS We used ultrasound to evaluate the accuracy of anatomy-guided injections of BoNT in the neck muscles. RESULTS A total of 56 consecutive patients and 332 injections were evaluated. The overall accuracy was 76.6%. The lowest accuracy (67.9%) was observed for the splenius capitis muscle. CONCLUSIONS Anatomic guidance of BoNT injections in the neck muscles is often inaccurate. Imaging guidance may improve the accuracy of BoNT injections in cervical dystonia.

Published
2020

14. 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. 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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

15. 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

16. Le traitement par apomorphine en perfusion continue sous-cutanée dans la maladie de Parkinson : analyse rétrospective d’une série de 81 patients

Author

Caroline Moreau, David Devos, Kathy Dujardin, Agnès Annic, M. Rambour, Julia Salleron, Alexandre Kreisler, Clémence Simonin, Eugénie Mutez, Luc Defebvre, and Alain Destée

Subjects
Gynecology, medicine.medical_specialty, Neurology, business.industry, Treatment outcome, Medicine, Neurology (clinical), business
Abstract

Resume Introduction L’apomorphine en perfusion continue sous-cutanee a montre son efficacite dans le traitement des fluctuations motrices de la maladie de Parkinson, mais peu d’etudes ont ete menees a long terme. L’objectif principal etait d’evaluer la qualite de vie des patients. Nous avons egalement evalue l’efficacite sur les fluctuations motrices, les effets indesirables a long terme et les schemas therapeutiques utilises. Methodes Cette etude retrospective a inclus tous les patients parkinsoniens traites par pompe a apomorphine entre avril 2003 et juin 2012 dans notre service. Resultats Quatre-vingt-un patients ont ete inclus dont 27 etaient toujours en cours de traitement a la fin de l’etude (duree moyenne de 28 mois), 46 avaient arrete et 8 etaient perdus de vue. Il n’a pas ete montre de superiorite de l’apomorphine par rapport au traitement dopaminergique per os sur la qualite de vie ni en termes d’efficacite objective ou subjective sur les fluctuations motrices. La tolerance cognitivo-comportementale etait bonne. Le debit moyen d’apomorphine etait de 3,15 mg/h et la diminution du traitement antiparkinsonien per os de 37,8 %. Discussion Le manque d’efficacite sur les fluctuations motrices peut etre du a l’utilisation de posologies trop faibles d’apomorphine. Nous preconisons l’utilisation de posologies plus elevees, afin d’obtenir une stimulation dopaminergique la plus continue possible et une meilleure efficacite sur les fluctuations motrices.

Published
2014

17. RNA-binding disturbances as a continuum from spinocerebellar ataxia type 2 to Parkinson disease

Author

Martin Figeac, Frédéric Leprêtre, Alain Destée, Bernard Sablonnière, Alexandre Genet, A. Duflot, Céline Villenet, Thomas Comptdaer, Luc Defebvre, Marie-Christine Chartier-Harlin, Pierre Semaille, David Devos, Aurore Nkiliza, Eugénie Mutez, and Clémence Simonin

Subjects
0301 basic medicine, Adult, Male, Translation, Parkinson's disease, Nerve Tissue Proteins, Biology, lcsh:RC321-571, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine, Gene family, Humans, Spinocerebellar Ataxias, Allele, Spinocerebellar ataxia type 2, Gene, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Aged, Ataxin-2, Genetics, RNA metabolism, Wnt signaling pathway, RNA-Binding Proteins, Parkinson Disease, ATXN2 CAG expansions, Middle Aged, medicine.disease, Microarray Analysis, Phenotype, 030104 developmental biology, Neurology, Case-Control Studies, Spinocerebellar ataxia, Disease Progression, RNA, Female, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery
Abstract

CAG triplet expansions in Ataxin-2 gene (ATXN2) cause spinocerebellar ataxia type 2 and have a role that remains to be clarified in Parkinson's disease (PD). To study the molecular events associated with these expansions, we sequenced them and analyzed the transcriptome from blood cells of controls and three patient groups diagnosed with spinocerebellar ataxia type 2 (herein referred to as SCA2c) or PD with or without ATXN2 triplet expansions (named SCA2p). The transcriptome profiles of these 40 patients revealed three main observations: i) a specific pattern of pathways related to cellular contacts, proliferation and differentiation associated with SCA2p group, ii) similarities between the SCA2p and sporadic PD groups in genes and pathways known to be altered in PD such as Wnt, Ephrin and Leukocyte extravasation signaling iii) RNA metabolism disturbances with "RNA-binding" and "poly(A) RNA-binding" as a common feature in all groups. Remarkably, disturbances of ALS signaling were shared between SCA2p and sporadic PD suggesting common molecular dysfunctions in PD and ALS including CACNA1, hnRNP, DDX and PABPC gene family perturbations. Interestingly, the transcriptome profiles of patients with parkinsonian phenotypes were prevalently associated with alterations of translation while SCA2c and PD patients presented perturbations of splicing. While ATXN2 RNA expression was not perturbed, its protein expression in immortalized lymphoblastoid cells was significantly decreased in SCA2c and SCA2p versus control groups assuming post-transcriptional biological perturbations. In conclusion, the transcriptome data do not exclude the role of ATXN2 mutated alleles in PD but its decrease protein expression in both SCA2c and SCA2p patients suggest a potential involvement of this gene in PD. The perturbations of "RNA-binding" and "poly(A) RNA-binding" molecular functions in the three patient groups as well as gene deregulations of factors not yet described in PD but known to be deleterious in other neurological conditions, suggest the existence of RNA-binding disturbances as a continuum between spinocerebellar ataxia type 2 and Parkinson's disease.

Published
2016

18. Traitement initial de la maladie de Parkinson : étude sur l’application des règles de consensus de mars 2000 dans la région Nord Pas-de-Calais

Author

Luc Defebvre, Clémence Simonin, and Alain Destée

Subjects
Neurology, Philosophy, Neurology (clinical), Humanities
Abstract

Resume Introduction Dans la maladie de Parkinson, le choix du traitement de premiere intention se fait essentiellement entre la L-Dopa et les agonistes dopaminergiques. La selegiline, les anticholinergiques et l’amantadine s’adressent aux formes peu severes. La premiere conference de consensus francaise, en mars 2000, a permis de definir un arbre decisionnel tenant compte de l’âge et de la severite de la symptomatologie. Le but de ce travail etait d’evaluer, dans la region Nord Pas-de-Calais, l’impact de ces recommandations sur les traitements prescrits aux parkinsoniens de novo, en comparant ceux-ci dans les periodes qui ont precede et suivi cette conference. Methodes Trois groupes de 50 patients dont le diagnostic de la maladie de Parkinson avait ete pose dans les periodes 1985-1992, 1993-1999, et a partir de juillet 2000, date de la publication nationale du consensus, ont ete constitues. Resultats Parmi ces 3 groupes, les traitements etaient conformes aux recommandations de 2000 dans respectivement 58, 84 et 82 p. 100 des cas. Les prescriptions d’agonistes ont progressivement augmente aux depens de la L-Dopa chez les sujets jeunes, en accord avec la conference de consensus, mais aussi pour les patients les plus âges, en opposition aux recommandations, mais sans augmentation de la frequence des effets indesirables. Les traitements non dopaminergiques ont ete presque abandonnes comme traitement initial. Conclusion Les habitudes de prescription se sont progressivement modifiees au cours des 10 dernieres annees en relation avec l’elaboration de la conference nationale de consensus et avec semble-t-il le souci de limiter une prescription trop precoce de L-Dopa.

Published
2004

19. Troubles psychiatriques itératifs révélateurs d’un lupus érythémateux disséminé

Author

Eric Hachulla, P Charpentier, Luc Defebvre, Michel Goudemand, Guillaume Vaiva, Sylvain Dubucquoi, Clémence Simonin, David Devos, J. de Seze, and Alain Destée

Subjects
Systemic disease, medicine.medical_specialty, Systemic lupus erythematosus, Lupus erythematosus, Anti-nuclear antibody, business.industry, Disease, medicine.disease, Dermatology, Connective tissue disease, Neurology, Mood disorders, Immunology, medicine, Neurology (clinical), business, Rheumatism
Abstract

INTRODUCTION: There is a wide range of non-specific symptoms that can reveal neurolupus, sometimes making diagnosis difficult. OBSERVATION: A 29-year-old man presented, from 1996 to 2002, three episodes of mood disorders with hetero-aggression, preceded by seizures, which resolved completely. Repeated investigations were negative except for lymphopenia, an inflammatory cerebrospinal fluid and some rare non-specific areas of high intensity signals in the white matter on the brain MRI. After a six-year course, the patient was considered to have a severe mood disorder related to a schizoid personality. A new dot-blot search for antinuclear antibodies detected anti-Sm antibodies was positive, leading to the diagnosis of neuropsychiatric lupus since the patient's symptoms fulfilling four of the American Rheumatism Association criteria (neuropsychiatric events, lymphopenia, antinuclear and anti-Sm antibodies). The patient was given monthly pulses of cyclophosphamide and remained symptom free one year after the last flare up. CONCLUSIONS: Lupus can rarely be revealed by long-standing isolated psychiatric disorders. Search for auto-antibodies, using highly specialized techniques (western blot, dot blot) should be a routine practice since antibody titres fluctuate during the course of the disease; elevated titres may correlate with exacerbations. Considering the prominence and severity of these behavior disorders, systemic diseases may often be misdiagnosed.

Published
2004

20. Attenuated presentation of ataxia-telangiectasia with familial cancer history

Author

David Devos, Dominique Stoppa-Lyonnet, Bérengère de Martinville, Isabelle Vuillaume, Alain Destée, Bernard Sablonnière, Luc Defebvre, and Clémence Simonin

Subjects
Dystonia, Pediatrics, medicine.medical_specialty, Cerebellar ataxia, business.industry, Limb ataxia, Spasmodic Torticollis, medicine.disease, nervous system diseases, Neurology, Ataxia-telangiectasia, Spinocerebellar ataxia, medicine, Cerebellar atrophy, Neurology (clinical), medicine.symptom, business, Torticollis
Abstract

JO N 2857 ing, generalized choreo-athetoid movements, spasmodic torticollis, writing tremor and myoclonic jerks. Examination also revealed cerebellar ataxia. The IQ was liminal. Neuroleptics, DL-hydroxytryptophan, trihexyphenidyl, and piribedil provided little or no improvement. By the age of 42, the patient was confined to a wheelchair, mainly due to the midline cerebellar disturbances. There was also limb ataxia, dystonia of the legs, torticollis and rest tremor. An ocular apraxia was noted without telangiectasia. Cognitive impairment had appeared with executive, judgement, reasoning and fixation memory troubles. Since age 16 a slowly worsening, predominantly sensory axonal neuropathy was known, whereas cerebral imaging showed global cerebellar atrophy. Standard blood tests, copper balance, vitamin E assay were normal. There was no evidence of metabolic or mitochondrial disorders. Genetic analysis excluded Friedreich’s disease, most frequent spinocerebellar ataxias, dentatorubropallidoluysian atrophy and Huntington’s disease. Igs serum level was normal. There was a slight rise in the serum level of αfetoprotein (AFP) (25.1 μg/L, Clemence Simonin David Devos Isabelle Vuillaume Berengere de Martinville Bernard Sablonniere Alain Destee Dominique Stoppa-Lyonnet Luc Defebvre

Published
2008

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

Author

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

Subjects
medicine.medical_specialty, Drugs and Devices, Epidemiology, medicine.medical_treatment, Tetrabenazine, lcsh:Medicine, law.invention, Cohort Studies, Neuropharmacology, Randomized controlled trial, law, Rating scale, Internal medicine, Drug Psychotherapy, medicine, Genetics, Humans, Antipsychotic, Psychiatry, lcsh:Science, Biology, Depression (differential diagnoses), Multidisciplinary, Risperidone, business.industry, Pharmacoepidemiology, lcsh:R, Clinical Pharmacology, Human Genetics, Neurodegenerative Diseases, Huntington Disease, Mental Health, Neurology, Autosomal Dominant, Therapies, Cohort, Disease Progression, Medicine, lcsh:Q, France, business, medicine.drug, Stroop effect, Antipsychotic Agents, Research Article
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
2013

22. M2 A randomised, double-blind, placebo-controlled trial evaluating cysteamine in huntington’s disease

Author

Christine Tranchant, Fabienne Calvas, Audrey Olivier, Frédéric Saudou, Philippe Allain, Christophe Verny, Clémence Simonin, Dominique Bonneau, Jean-Philippe Azulay, Alexandra Durr, Cyril Goizet, Patrick Maison, Pierre Krystkowiak, and Anne-Catherine Bachoud-Lévi

Subjects
medicine.medical_specialty, Placebo-controlled study, medicine.disease, Placebo, Surgery, Psychiatry and Mental health, chemistry.chemical_compound, Standard error, Huntington's disease, chemistry, Rating scale, Internal medicine, Statistical significance, medicine, Clinical endpoint, Cysteamine, Neurology (clinical), Psychology
Abstract

Background Cysteamine has been demonstrated as potentially neuroprotective in numerous animal models of Huntington’s disease (HD). Methods Ninety-six early-stage HD patients were randomised to a double-blind trial to receive 600 mg delayed-release cysteamine bitartrate (DR-CB) (51) or placebo (45) twice a day for 18 months. The primary endpoint was the change from baseline in the Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor Score (TMS) at 18 months. Key secondary endpoints included other UHDRS scales: total functional capacity, independence, cognition and behaviour. Results are expressed as the least-squares mean (LSM) treatment-effect difference of DR-CB minus placebo; negative values indicating less deterioration relative to placebo. Results The mean baseline TMS (± SD) was 24.2 (10.7) (5 to 53 points). The 18 month treatment-effect (LSM ± standard error [± SE]) was not statistically significant: −1.5 (1.71) points (95% CI: −4.9; 1.9; p = 0.385); representing less mean (± SE) increase (deterioration) from baseline in DR-CB- compared with placebo-treated patients: 4.9 (1.17) versus 6.4 (1.25) points, respectively. No significant treatment-effects were observed for key secondary endpoints. DR-CB was safe and well-tolerated. Post-hoc analyses dichotomized by median baseline TMS ( Interpretation Statistical significance was not observed for the primary endpoint. However, post-hoc analysis indicated statistical significance in patients with more severe baseline motor impairment. Further studies involving a larger number of patients are warranted. Trial registration EudraCT Number: 2010–019444-39

Published
2016

23. External globus pallidus stimulation modulates brain connectivity in Huntington's disease

Author

Luc Defebvre, David Devos, Noémie Ligot, Michel Monclus, Marie Delliaux, Serge Blond, Arnaud Delval, Philippe Peigneux, Clémence Simonin, John Van Naemen, Pierre Krystkowiak, Jérôme Yelnik, Xavier De Tiège, Christine Delmaire, Kathy Dujardin, Alain Destée, Eric Bardinet, Serge Goldman, Simon Lacroix, Service de neurologie [Amiens], CHU Amiens-Picardie, Noyaux gris centraux, Université de Lille, Sciences et Technologies-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Neuropsychology and Functional Neuroimaging Research Unit - UR2NF, Université libre de Bruxelles (ULB), Department of Neurology et Pathologie du Mouvement (IMRT, EA2683), IFR114-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Neurology, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Services de neuroradiologie [Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Neuro-Imagerie de Recherche (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC AP-HP (pitie-Salpetriere)/inserm, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de neurologie [Lille], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille

Subjects
Male, positron emission tomography, medicine.medical_treatment, Deep Brain Stimulation, Stimulation, Cerebrovascular Circulation -- physiology, Oxygen Radioisotopes -- diagnostic use, Basal Ganglia, 0302 clinical medicine, Thalamus, Oxygen Radioisotopes, Basal ganglia, Neural Pathways, default-mode network, Image Processing, Computer-Assisted, Premovement neuronal activity, Huntington Disease -- therapy, Cerebral Cortex, Neurons, 0303 health sciences, musculoskeletal, neural, and ocular physiology, Thalamus -- physiology, Huntington's disease, Sciences bio-médicales et agricoles, Middle Aged, Neural Pathways -- physiology, 3. Good health, medicine.anatomical_structure, Globus pallidus, Huntington Disease, Neurology, Cerebral cortex, Cerebrovascular Circulation, basal ganglia, Female, Cardiology and Cardiovascular Medicine, Psychology, Adult, Deep brain stimulation, Huntington Disease -- radionuclide imaging, Brief Communication, Globus Pallidus, Neurons -- physiology, 03 medical and health sciences, Cerebral Cortex -- physiology, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, 030304 developmental biology, Nerve Net -- physiology, medicine.disease, Globus Pallidus -- physiology, nervous system diseases, nervous system, Positron-Emission Tomography, Neurology (clinical), Nerve Net, Neuroscience, 030217 neurology & neurosurgery, Basal Ganglia -- physiology
Abstract

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2011

24. High insulinlike growth factor I is associated with cognitive decline in Huntington disease

Author

Christine Tranchant, Christophe Verny, Nadine Saleh, N. El Hawajri, Jean-Philippe Azulay, Anne-Catherine Bachoud-Lévi, Patrick Maison, Clémence Simonin, Stéphane Moutereau, Centre de référence maladie de Huntington, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pharmacologie clinique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), Service de Biochimie [Mondor], Service de neurologie et pathologies musculaires, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Noyaux gris centraux, Université de Lille, Sciences et Technologies-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Unité de recherche clinique, the Huntington French Speaking Group, Guellaen, Georges, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], and École normale supérieure - Paris (ENS Paris)

Subjects
Male, medicine.medical_treatment, MESH: Insulin-Like Growth Factor I, Disease, Cohort Studies, 0302 clinical medicine, Degenerative disease, Attention, Prospective Studies, Insulin-Like Growth Factor I, Cognitive decline, MESH: Cohort Studies, 0303 health sciences, MESH: Middle Aged, Cognitive disorder, Huntington's disease, MESH: Follow-Up Studies, Middle Aged, Growth hormone secretion, Huntington Disease, Female, Psychology, Adult, medicine.medical_specialty, Neuroprotection, 03 medical and health sciences, Executive function, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Humans, Growth factor, all cognitive disorders/dementia, MESH: Biological Markers, MESH: Adult, Neuroendocrinology, medicine.disease, MESH: Prospective Studies, MESH: Huntington Disease, MESH: Male, MESH: Cognition Disorders, Endocrinology, Neurology (clinical), Cognition Disorders, MESH: Female, Biomarkers, 030217 neurology & neurosurgery, Follow-Up Studies, Hormone
Abstract

International audience; OBJECTIVE: The somatotropic axis (growth hormone [GH] and insulinlike growth factor I [IGFI]) play a role in the cognitive deficits seen with aging, GH deficiency, and neurodegenerative disorders such as Alzheimer disease. We recently reported elevations in basal plasma GH and IGFI levels in patients with Huntington disease (HD). Here, our objective was to determine whether somatotropic axis abnormalities predicted cognitive dysfunction in HD. METHODS: In this prospective cohort study of 109 patients with genetically documented HD, aged 21 to 85 years, we determined fasting blood levels of total IGFI, GH, and insulinlike factor binding protein 3 at baseline, and we used the cognitive Unified Huntington's Disease Rating Scale to assess cognitive impairment at baseline and for up to 5 years subsequently. Associations were evaluated using mixed linear model analysis. RESULTS: Higher plasma IGFI concentrations were associated with greater cognitive decline (beta Stroop Words, -6.01, p = 0.003; beta Stroop Color, -4.41, p = 0.01; beta Stroop Color/Words, -3.86, p = 0.02; beta Symbol Digit Modalities, -3.69, p = 0.03; and beta verbal fluency, -5.01, p = 0.03). Higher free IGFI concentrations and higher GH concentrations in men also predicted greater cognitive decline. CONCLUSIONS: Our findings in patients with HD suggest that a high IGFI level at baseline may be associated with greater subsequent declines in executive function and attention.

Published
2010

25. [The UHDRS scale]

Author

Clémence Simonin, Delliaux M, and Krystkowiak P

Subjects
Self Care, Behavior, Cognition, Huntington Disease, Personal Autonomy, Disease Progression, Humans, Motor Activity, Severity of Illness Index, Psychomotor Performance, Follow-Up Studies
Published
2010

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

Author

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

Subjects
Adult, Adolescent, Genotype, Receptor, Adenosine A2A, Biology, Polymorphism, Single Nucleotide, lcsh:RC321-571, Cohort Studies, Young Adult, Huntington's disease, Polymorphism (computer science), Genetic variation, medicine, Humans, Polymorphism, Age of Onset, Receptor, Child, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Aged, Genetics, Middle Aged, medicine.disease, Huntington Disease, Neurology, A2A receptors, Linear Models, Population study, Age of onset, Trinucleotide repeat expansion, Trinucleotide Repeat Expansion
Abstract

Based on the pathophysiological role of adenosine A(2A) 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 R(2) 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 A(2A) receptors in Huntington's disease.

Published
2009

27. Reduced levodopa-induced complications after 5 years of subthalamic stimulation in Parkinson's disease: a second honeymoon

Author

Alain Destée, Serge Blond, Arnaud Delval, M. Tir, Kathy Dujardin, Pierre Krystkowiak, Alexandre Kreisler, David Devos, Luc Defebvre, Julia Salleron, and Clémence Simonin

Subjects
Levodopa, medicine.medical_specialty, Dyskinesia, Drug-Induced, Parkinson's disease, Neurology, Deep Brain Stimulation, Neurological disorder, Severity of Illness Index, Central nervous system disease, Antiparkinson Agents, Subthalamic Nucleus, Basal ganglia, medicine, Humans, Dystonia, business.industry, Parkinson Disease, medicine.disease, nervous system diseases, Surgery, Dyskinesia, Anesthesia, Neurology (clinical), medicine.symptom, business, medicine.drug, Follow-Up Studies
Abstract

The purpose of this paper is to describe the effect of 5 years of subthalamic nucleus deep brain stimulation (STN DBS) on levodopa-induced complications, both in everyday life and during an acute challenge with levodopa. Thirty three patients were evaluated during an acute levodopa challenge before surgery and then 1 and 5 years afterwards (both off stim and on stim), using the UPDRS III scale and the CAPSIT-PD scales for dystonia and peak-dose dyskinesia. The UPDRS IV scale was used to assess motor complications in everyday life. The levodopa daily dose and DBS parameters were also recorded. Levodopa-induced complications in everyday life (UPDRS IV) and during an acute levodopa challenge had improved markedly after 1 year (both on and off stim) and still further at 5 years. Peak-dose dyskinesia decreased between the 1- and 5-year measurements. STN DBS decreases levodopa-induced motor complications over the long term. This phenomenon may be explained by (a) overall stabilization of the basal ganglia network and (b) striatal synaptic changes. Our results suggest that DBS leads to both qualitative and quantitative modulations in the corticostriatal loops.

Published
2008

28. Embryonic stem cells: meeting the needs for cell therapy

Author

Maria Teresa Mitjavila-Garcia, Clémence Simonin, and Marc Peschanski

Subjects
Graft Rejection, business.industry, Cellular differentiation, Stem Cells, Teratoma, Pharmaceutical Science, Bioinformatics, medicine.disease, Embryo, Mammalian, Embryonic stem cell, Transplantation, Cell therapy, Haematopoiesis, Degenerative disease, Cell Movement, Cord blood, Immunology, Medicine, Animals, Humans, Stem cell, business, Biological Specimen Banks, Stem Cell Transplantation
Abstract

Cell therapy in diverse organs has bloomed for degenerative diseases over the past decade, following a previous period of development in which haematopoietic stem cells grafts in oncology were its most prominent clinical application. One main limitation that has, however, been encountered on the path for transforming pioneering successes into real therapeutics, that would be applicable to a clinically relevant number of patients, is the difficulty in accessing "therapeutic" cells, such as foetal neurons in neurodegenerative diseases, adult pancreatic beta cells in diabetes or else myoblasts in heart failure and myopathy. The future of cell therapy definitely belongs to cell banks, from which physicians would simply have to draw according to their needs. However, besides haematopoietic stem cells, for which such infrastructures begin to exist for clinical purposes (in particular from cord blood), cell banks are still up to now essentially a scientific concept. This review focuses on the possibility for human ES cells to meet both the requirements of cell banking and the needs for substitutive cell therapy.

Published
2005

29. Acquired hepatocerebral degeneration revealed by neurogenic hyperventilation syndrome and myelitis

Author

Clémence Simonin, Nicolas Carrière, Adeline Rollin, and Pierre Labauge

Subjects
Pathology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Lumbar puncture, Multiple sclerosis, Myelitis, Neurological examination, Macrocytosis, medicine.disease, Nephropathy, Psychiatry and Mental health, Cerebrospinal fluid, Sensory ataxia, medicine, Surgery, Neurology (clinical), medicine.symptom, business
Abstract

A 46-year-old woman with a history of kidney transplant for IgA nephropathy (on tacrolimus and mycophenolate mofetil), type II diabetes and non-alcoholic steatohepatitis was admitted for gait instability. Neurological examination revealed lower limb sensory ataxia and brisk patellar reflexes. Brain/spinal MRI results were normal. Blood tests disclosed macrocytosis (but no vitamin deficiencies) and mild hepatic cytolysis. Lumbar puncture showed the absence of cells, normal protein, hypoglycorrhachia (glycorrhachia: 0.62 g/l; glycaemia: 1.65 g/l) and no oligoclonal bands. Cerebrospinal fluid cultures were negative. Assays for neurotropic viruses, paraneoplastic …

Published
2012

30. 3.074 TRANSCRIPTOME PROFILING OF BLOOD MONONUCLEAR CELLS FROM SCA2 PATIENTS ACCORDING TO CEREBELLAR OR PARKINSONIAN PHENOTYPES

Author

Eugénie Mutez, B. Frigard, Christel Vanbesien-Mailliot, Alain Destée, Alexandre Kreisler, Clémence Simonin, Frédéric Leprêtre, M. Figeac, David Devos, A. Duflot, Marie-Christine Chartier-Harlin, Luc Defebvre, and Bernard Sablonnière

Subjects
Neurology, Transcriptome profiling, Neurology (clinical), Geriatrics and Gerontology, Biology, Peripheral blood mononuclear cell, Phenotype, Molecular biology
Published
2012

31. Mutations du gène EIF4G 1 (Eukaryotic translation initiation factor 4-gamma) et maladie de Parkinson

Author

Clémence Simonin, Marie-Christine Chartier-Harlin, Eugénie Mutez, Matthew J. Farrer, Justus C. Dachsel, Alain Destée, Alexandre Kreisler, E. Le Rhun, A. de Broucker, C. Vanbesien-Maillot, Pierre Semaille, Thomas Comptdaer, Frédéric Leprêtre, and A. Duflot

Subjects
Genetics, chemistry.chemical_compound, Neurology, chemistry, EIF4G, Neurology (clinical), Biology, Gene, Eukaryotic translation initiation factor 4 gamma
Published
2012

32. H02 Behavioural Dysexecutive Disorders In Huntington's Disease

Author

Clémence Simonin, M Roussel, Pierre Krystkowiak, M Tir, Olivier Godefroy, J Doridam, and A Benoist

Subjects
Dysexecutive syndrome, medicine.medical_specialty, Impulsivity, Irritability, medicine.disease, Euphoriant, Psychiatry and Mental health, Huntington's disease, Anticipation (genetics), medicine, Surgery, Apathy, Neurology (clinical), medicine.symptom, Psychology, Psychiatry, Hypoactivity, Clinical psychology
Abstract

Dysexecutive symptoms such as apathy, impulsivity and distractibility have been reported on clinical ground in HD. However previous studies have assessed dysexecutive behavioural disorders using clinical interview or nonspecific questionnaires incorporating other features resulting in highly variable evaluation with poorly defined performance indices. This study aimed to assess dysexecutive behavioural abnormalities in HD, using a validated instrument, the Behavioural Dysexecutive Syndrome Inventory (BDSI). 14 patients (mean age: 55.5 years; SD 12.4; range: 34–73; mean duration: 8.7 years; SD=7; range: 2–30; mean MMSE score: 25; SD=3.4) with clinically diagnosed and genetically confirmed HD, were included. The assessment of depressive symptoms (Montgomery Asberg Depression Scale) showed a mild depression in 7 patients. The BDSI is a highly structured caregiver based interview which rates frequency and severity of 12 dysexecutive disturbances (global hypoactivity with apathy, hyperactivity, irritability-impulsivity, euphoria, perseverative behaviour; environmental dependency, social behaviour disorders). The analysis of individual performance was performed using cutoff scores at the 5% level using normative data obtained in 96 controls 1 . The prevalence of behavioural dysexecutive syndrome was high (50%; 95% CI: 24–76). The behavioural profile was characterised by the prominence of irritability (50%), hyperactivity (43%), apathy (29%), disinterest (22%) and difficulties for anticipation (14%). This study based on the BDSI revealed in HD that behavioural dysexecutive disorders are: 1 frequent with a prevalence of 50%, 2 characterised by a specific profile with the prominence of irritability and hyperactivity-distractibility, 13 whereas the hypoactivity-apathy disorders were less frequent contrary to most other degenerative disorders. 1 Godefroy et al . Ann Neurol. 2010

Published
2014

33. H14 Evaluation Of Impulsivity In Huntington's Disease With A Delay Discounting Task

Author

M Tir, A Benoist, M Roussel, J Doridam, Pierre Krystkowiak, Olivier Godefroy, and Clémence Simonin

Subjects
Dysexecutive syndrome, education.field_of_study, medicine.medical_specialty, Population, Neuropsychology, Cognition, Irritability, Impulsivity, medicine.disease, Psychiatry and Mental health, Huntington's disease, medicine, Surgery, Apathy, Neurology (clinical), medicine.symptom, Psychology, education, Psychiatry, Clinical psychology
Abstract

Background Whereas behavioural disorders, including impulsivity, are frequent and early in Huntington’s disease (HD), their physiopathology remains still poorly understood, especially by lack of validate instrument for their evaluation. Aim The aim objective of this study was to objective that impulsivity is increased in HD by a quantitative evaluation using a delay discouting paradigm, an experimental task specific of impulsive choice. Methods 19 patients with symptomatic MH and 19 healthy and matched controls from the general population were included. Patients underwent a neurological and standardised neuropsychological examination, with an additional assessment exploring behavioural disorders including the delay discounting task (DDT), performed on a computer, and scales of self-report questionnaires to measure impulsivity (Barratt Impulsiveness Scale-11) and apathy (Starkstein scale), and an hetero-report questionnaire, the Behavioural Dysexecutive Syndrome Inventory (BDSI). Results 52.3% of HD patients performances at the DDT were incoherent and could not be interpreted according to the experimental model. Evaluation by BDSI showed significantly impulsivity in HD patients (p = 0.001), as well as irritability and apathy. Statistical analysis did not reveal cognitive factor or factor related to the evolution of HD correlated with the scores at the DDT, BDSI or behavioural scales. Apparent fluctuations between impulsivity and apathy in HD patients could involve inhibitory control disturbances. Conclusion Quantitative evaluation of impulsivity by a delay discounting paradigm seems to be inappropriate in HD. The BDSI is a validate instrument relevant for the qualitative assessment of behavioural disorders in HD, and should be widely used in this pathology.

Published
2014

34. Disease Modifying Strategy Based upon Iron Chelation in Parkinson's Disease: A Translational Study (P02.240)

Author

Maud Pétrault, Gilles Ryckewaert, Alain Destée, Nathalie Rouaix, Patrice Jissendi, Clémence Simonin, David Devos, Régis Bordet, Luc Defebvre, Kathy Dujardin, Alexandre Kreisler, Jerome Kluza, Guillaume Garçon, Philippe Marchetti, Charlotte Laloux, Jean-Christophe Devedjian, and Caroline Moreau

Subjects
Parkinson's disease, business.industry, Medicine, Neurology (clinical), Disease, business, Bioinformatics, medicine.disease, Iron chelation
Published
2012

35. 3.262 DEREGULATION OF GENE EXPRESSION IN PERIPHERAL BLOOD MONONUCLEAR CELLS AT DIFFERENT STAGES OF THE PARKINSON'S DISEASE

Author

Marie-Christine Chartier-Harlin, Alain Destée, R. Blervaque, D. Hot, Clémence Simonin, Eugénie Mutez, Christel Vanbesien-Mailliot, Alexandre Kreisler, Pierre Semaille, A. Duflot, and M. Figeac

Subjects
Parkinson's disease, Neurology, business.industry, Gene expression, Immunology, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, medicine.disease, Peripheral blood mononuclear cell
Published
2012

36. 3.112 TRANSCRIPTOME PROFILING OF BLOOD MONONUCLEAR CELLS FROM RATS EXPOSED TO CUMULATIVE LOW DOSES OF THE PARKINSON'S DISEASE-LINKED PESTICIDE ROTENONE

Author

Christel Vanbesien-Mailliot, Alexandre Kreisler, A. Duflot, Alain Destée, Marie-Christine Chartier-Harlin, Clémence Simonin, Pierre Semaille, Eugénie Mutez, and S. Peckeu

Subjects
Parkinson's disease, Low dose, Rotenone, Pesticide, Biology, Pharmacology, medicine.disease, Peripheral blood mononuclear cell, chemistry.chemical_compound, Neurology, chemistry, medicine, Transcriptome profiling, Neurology (clinical), Geriatrics and Gerontology
Published
2012

37. C08 Caffeine is a modifier of age at onset in Huntington's disease

Author

Olivier Godefroy, Christophe Verny, M Génin, David Blum, Bernard Sablonnière, Katia Youssov, A-C Bachoud-Lévi, Luc Buée, Pierre Krystkowiak, P. Amouyel, P Hincker, Christine Tranchant, Luc Defebvre, Cécile Duru, J-P Azulay, Clémence Simonin, Perrine Charles, Sylvie Burnouf, Alexandra Durr, Cyril Goizet, Florence Richard, and M Rousseau

Subjects
medicine.medical_specialty, Dopaminergic, Antagonist, medicine.disease, Medium spiny neuron, Psychiatry and Mental health, chemistry.chemical_compound, Endocrinology, Huntington's disease, chemistry, Internal medicine, medicine, Clinical endpoint, Surgery, Neurology (clinical), Cognitive decline, Psychiatry, Psychology, Caffeine, Receptor
Abstract

Background Phenotypic expression is variable in Huntington9s disease (HD). Mutation in the IT15/HD1 gene statistically predicts for the age at onset (AAO), but on an individual basis, repeat length accounts for about 60% of its variance supporting the fact that 40% of the remaining variance is due to additional genetic and/or environmental factors. Association of AAO with polymorphisms located in different genes (ex: ADORA2A) has been previously reported. In contrast, whether environmental factors are also able to influence AAO remain unknown. Caffeine is a non-selective antagonist of A2A receptors, selectively localised on striatal medium spiny neurons expressing enkephalin and dopaminergic D2 receptors, known to be the most vulnerable ones in HD. Interestingly, modulation of A2A receptors influence the pathophysiological outcome in experimental models of HD. Aims To determine the impact of caffeine on the AAO (primary endpoint) and the rates of functional, motor and cognitive decline (secondary endpoints) in HD patients. Methods 58 HD patients were included from eight sites over a 6 month period. Information about caffeine consumption was collected with a validated self-questionnaire. All patients were evaluated using the Unified Huntington9s Disease Rating Scale. Factors influencing AAO were examined using a stepwise regression analysis. After adjustment of CAG repeat length, subjects were categorised into three group and we compared the mean of AAO between low end high consumers. Results We found a significant correlation between AAO and caffeine intake (r2=0.041; p=0.016): the highest caffeine intake was associated with the earlier AAO. Also, we demonstrated that caffeine influenced AAO with an advanced AAO of 6.9 years in high consumers compared with low consumers. However, we failed to demonstrate a relation between caffeine intake and the rate of functional, motor and cognitive decline. Conclusion Our findings suggest that caffeine could be the first environmental modifier of AAO in HD. It could have an important therapeutic impact as the modulation of A2A receptors may represent new strategies for treating HD.

Published
2010

38. L03 Use and impact of neuroleptics in Huntington's disease: a prospective cohort study of the Huntington French speaking group

Author

Katia Youssov, R-M Marie, Marc Vérin, Emmanuel Broussolle, Cyril Goizet, Clémence Simonin, Alexandra Durr, J-P Azulay, G. Dolbeau, Christine Tranchant, A-C Bachoud-Lévi, Christophe Verny, J-F Démonet, Perrine Charles, A Lombard, P. Damier, Patrick Maison, Pierre Krystkowiak, and F Supiot

Subjects
Olanzapine, medicine.medical_specialty, Risperidone, business.industry, Tetrabenazine, medicine.disease, Tiapride, Psychiatry and Mental health, chemistry.chemical_compound, chemistry, Huntington's disease, Internal medicine, Cohort, Physical therapy, medicine, Surgery, Neurology (clinical), Prospective cohort study, business, medicine.drug, Cohort study
Abstract

Background Recent reviews of available drug trials and case reports conclude that the guidelines for the treatment of Huntington9s disease (HD) symptoms are scarce. Aims We wanted to better understand the use of neuroleptics and related drugs (NL-R) in HD by observing their use in clinical practice and their impact on disease progression. Methods/techniques We explored and compared the profile and evolution of patients treated by NL-R in the cohort of the Huntington French Speaking Group Cohort. This cohort comparative study included 760 patients with available CAG repeats and medication information, followed for 22.4 (±23.3) months between 2002 and 2010. Results/outcome 63% of patients were treated by a NL-R at least once during the follow up. The main NL-R used by the clinicians were (before and after 2006, respectively): olanzapine (38.8 vs 34.5%, NS), risperidone (15.2 vs 16.0%, NS), tiapride (9.4 vs 8.5%, NS) and tetrabenazine (0.8 vs 18.9%, p Conclusion In our cohort study of 760 HD patients, the four main NL-R used in HD (olanzapine, risperidone, tiapride and tetrabenazine) seem to have different effectiveness on the progression of the disease.

Published
2010

39. O - 25 Transposition bifrontale pour une « HTIC bénigne » compliquée

Author

C. Marmin, Hélène Zéphir, S. Defoort-Dhellemmes, P. Dhellemmes, Clémence Simonin, Pierre Krystkowiak, Alain Destée, Luc Defebvre, and M. Allaoui

Subjects
Neurology, Neurology (clinical)
Abstract

Introduction Les traitements chirurgicaux habituellement proposes dans l’HTIC benigne avec complications ophtalmologiques et resistant au traitement medicamenteux ne sont pas toujours efficaces ou peuvent aggraver les troubles visuels. Observation Une patiente de 26 ans presenta une baisse d’acuite visuelle rapidement progressive sur 3 mois accompagnee de cephalees. Elle etait obese (BMI 42,6), fumeuse et avait 2 antecedents de fausses couches. L’acuite visuelle (AV) fut mesuree : a gauche a 7/10, a droite : perception lumineuse seulement. L’examen ophtamologique etait en faveur d’une neuropathie optique bilaterale, sans œdeme papillaire, malgre une pression du LCR a 300 mmH20. L’IRM cerebrale etait normale. Les etiologies connues d’ordre inflammatoire, genetique et metabolique de neuropathie optique furent eliminees. L’acetazolamide et un regime alimentaire furent prescrits. trois mois plus tard, malgre la prise d’acetazolamide (1 500 mg/j) et la perte de 30 kg, la patiente etait presque aveugle (AV a gauche : 1/20, a droite : 0). Un monitoring de la pression intracrânienne pendant 48 h (sous acetazolamide) montra des pressions elevees en fin de nuit atteignant 600 mmH20. La realisation d’un volet de decompression par transposition bifrontale fut decidee. Une semaine apres l’intervention l’AV etait nettement amelioree (gauche : 6.3/10, droite : 1/32 avec correction), le champ visuel etait elargi et il n’y avait plus de cephalees. La situation restait stable apres 2 mois de suivi. Discussion Le monitoring de la pression intracrânienne, meme s’il est invasif, apporte une grande aide dans les cas d’HTIC benigne de prise en charge diagnostique et therapeutique difficile. La transposition bifrontale a ete decidee en raison du pronostic incertain des techniques chirurgicales habituelles (derivation lombaire, fenestration du nerf optique) chez une patiente ayant une baisse d’acuite visuelle severe handicapante dans la vie quotidienne. Conclusion Cette technique chirurgicale n’est habituellement pas utilisee pour le traitement de l’HTIC benigne mais devant ce bon resultat pourrait etre proposee dans les cas graves.

Published
2007

40. D - 14 Effets de la stimulation électrique du NST sur les complications dopa-induites dans la maladie de Parkinson

Author

Alain Destée, Luc Defebvre, N. Waucquier, Serge Blond, François Cassim, Clémence Simonin, Patrick Devos, Alexandre Kreisler, Mélissa Tir, Pierre Krystkowiak, and David Devos

Subjects
Neurology, Neurology (clinical)
Abstract

Introduction La stimulation du noyau sous-thalamique (NST) semble reduire les fluctuations et les dyskinesies dopa-induites dans la maladie de Parkinson, mais cet effet a ete beaucoup moins etudie que les autres symptomes de la maladie. Objectifs Evaluer precisement l’efficacite a long terme de la stimulation du NST sur les complications motrices dopa-induites. Methodes 36 patients furent evalues avant la chirurgie et 1 et 5 ans apres, avec les echelles du CAPSIT-PD pour la dystonie off drug et les dyskinesies on drug, stimulateur eteint ou allume, avant et apres l’administration de L-dopa dispersible. les echelles UPDRS II, IV et de Schwab et England (SE) furent aussi utilisees. Resultats L’UPDRS IV s’ameliora de 62 % a 1 an et 68 % a 5 ans, l’UPDRS IVA de 72 % a 1 an et 71 % a 5 ans. Les dyskinesies on drug s’ameliorerent a 1 an de 61 % on stim et 60 % off stim, a 5 ans de 85 % on stim et 77 % off stim. Les dystonies off drug s’ameliorerent a 1 an de 45 % on stim et 12 % off stim, a 5 ans de 66 % on stim et 35 % off stim. Pour l’UPDRS II et la SE, il y eut une amelioration significative a 1 et 5 ans. A 5 ans, 1 patient/3 avait le meme score on et off drug a l’UPDRS II (aucun a 1 an), et a la SE (16 % a 1 an). Discussion Il y a un effet positif de la stimulation du NST sur les complications liees a la L-dopa qui persiste et meme augmente a long terme. Les scores de dyskinesie sont ameliores a la fois de maniere chronique et lors d’un test d’administration aigue de L-dopa. De plus cet effet persiste lorsque le stimulateur est eteint. Conclusion La diminution des doses de L-dopa apres stimulation peut expliquer en partie l’amelioration des complications motrices, mais nos resultats sont aussi en faveur du renversement des mecanismes entrainant ces complications.

Published
2007

41. Human Fetal Cell Therapy in Huntington's Disease: A Randomized, Multicenter, Phase <scp>II</scp> Trial

Author

Bachoud-Lévi, Anne-Catherine, Schramm, Catherine, Remy, Philippe, Aubin, Ghislaine, Blond, Serge, Bocket, Laurence, Brugières, Pierre, Calvas, Fabienne, Calvier, Elisabeth, Cassim, François, Challine, Dominique, Gagou, Clarisse Scherer, De Langavant, Laurent Cleret, Collier, Francis, Cottencin, Olivier, David, Philippe, Damier, Philippe, Delliaux, Marie, Delmaire, Christine, Delval, Arnaud, Démonet, Jean‐François, Descamps, Philippe, Gaura, Véronique, Gohier, Bénédicte, Goldman, Serge, Haddad, Bassam, Izopet, Jacques, Jeny, Roland, Kerr-Conte, Julie, Krystowiak, Pierre, Lalanne, Christophe, Lavisse, Sonia, Lefaucheur, Jean‐Pascal, Lemoine, Laurie, Levivier, Marc, Lotterie, Jean‐Albert, Lunel‐Fabiani, Françoise, Maison, Patrick, Massager, Nicolas, Massart, Renaud, Menei, Philippe, Montero‐Menei, Claudia, Neveu, Isabelle, Parant, Olivier, Pautot, Vivien, Payoux, Pierre, Péréon, Yann, Rialland, Amandine, Rosser, Anne, Rouard, Hélène HR, Schmitz, David, Simonetta‐Moreau, Marion, Simonin, Clémence, Slama, Hichem, Sol, Jean‐Christophe, Supiot, Frédéric, Tanguy, Jean‐Yves, Tenenbaum, Liliane, Verny, Christophe, Youssov, Katia, Peschanski, Marc, Audureau, Etienne, Palfi, Stéphane, Hantraye, Philippe, Centre de référence maladie de Huntington, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), IMRB - 'NeuroPsychologie Interventionnelle' [Créteil] (U955 Inserm - UPEC), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris sciences et lettres (PSL), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), AOM00139 and AOM04021 Direction de la Recherche Clinique, Association Française contre les Myopathies., Collaborators : on behalf the Multicentric Intracerebral Grafting in Huntington's Disease Group : Catherine Schramm, Philippe Remy, Ghislaine Aubin, Serge Blond, Laurence Bocket, Pierre Brugières, Fabienne Calvas, Elisabeth Calvier, François Cassim, Dominique Challine, Clarisse Scherer Gagou, Laurent Cleret de Langavant, Francis Collier, Olivier Cottencin, Philippe David, Philippe Damier, Marie Delliaux, Christine Delmaire, Arnaud Delval, Jean-François Démonet, Philippe Descamps, Véronique Gaura, Bénédicte Gohier, Serge Goldman, Bassam Haddad, Jacques Izopet, Roland Jeny, Julie Kerr-Conte, Pierre Krystowiak, Christophe Lalanne, Sonia Lavisse, Jean-Pascal Lefaucheur, Laurie Lemoine, Marc Levivier, Jean-Albert Lotterie, Françoise Lunel-Fabiani, Patrick Maison, Nicolas Massager, Renaud Massart, Philippe Menei, Claudia Montero-Menei, Isabelle Neveu, Olivier Parant, Vivien Pautot, Pierre Payoux, Yann Pereon, Amandine Rialland, Anne Rosser, Hélène Rouard, David Schmitz, Marion Simonetta-Moreau, Clémence Simonin, Hichem Slama, Jean-Christophe Sol, Frédéric Supiot, Jean-Yves Tanguy, Liliane Tenenbaum, Christophe Verny, Katia Youssov, Marc Peschanski, Etienne Audureau, Stéphane Palfi, Philippe Hantraye., and Montero-Menei, claudia

Subjects
0301 basic medicine, medicine.medical_specialty, Neurology, Huntington s disease, MIG-' HD, Cell- and Tissue-Based Therapy, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Disease, law.invention, 03 medical and health sciences, 0302 clinical medicine, Huntington's disease, Randomized controlled trial, law, Internal medicine, medicine, Humans, Stage (cooking), Adverse effect, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, business.industry, phase 2 trial, Neurodegenerative Diseases, Sciences bio-médicales et agricoles, medicine.disease, Confidence interval, Transplantation, Huntington Disease, 030104 developmental biology, Neurology (clinical), cell therapy, business, 030217 neurology & neurosurgery
Abstract

Background\ud Huntington's disease is a rare, severe, inherited neurodegenerative disease in which we assessed the safety and efficacy of grafting human fetal ganglionic eminence intrastriatally.\ud \ud Methods\ud Patients at the early stage of the disease were enrolled in the Multicentric Intracerebral Grafting in Huntington's Disease trial, a delayed‐start phase II randomized study. After a run‐in period of 12 months, patients were randomized at month 12 to either the treatment group (transplanted at month 13–month 14) or the control group and secondarily treated 20 months later (month 33–month 34). The primary outcome was total motor score compared between both groups 20 months postrandomization (month 32). Secondary outcomes included clinical, imaging, and electrophysiological findings and a comparison of pregraft and postgraft total motor score slopes during the entire study period (month 0–month 52) regardless of the time of transplant.\ud \ud Results\ud Of 54 randomized patients, 45 were transplanted; 26 immediately (treatment) and 19 delayed (control). Mean total motor score at month 32 did not differ between groups (treated controls difference in means adjusted for M12: +2.9 [95% confidence interval, −2.8 to 8.6]; P = 0.31). Its rate of decline after transplantation was similar to that before transplantation. A total of 27 severe adverse events were recorded in the randomized patients, 10 of which were related to the transplant procedure. Improvement of procedures during the trial significantly decreased the frequency of surgical events.We found antihuman leucocytes antigen antibodies in 40% of the patients.\ud \ud Conclusion\ud No clinical benefit was found in this trial. This may have been related to graft rejection. Ectopia and high track number negatively influence the graft outcome. Procedural adjustments substantially improved surgical safety. (ClinicalTrials.gov NCT00190450.) © 2020 International Parkinson and Movement Disorder Society

Published
2020

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