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14. Trial of Deferiprone in Parkinson's Disease

Author

Devos, D., Labreuche, J., Rascol, O., Corvol, J.C., Duhamel, A., Delannoy, P. Guyon, Poewe, W., Compta, Y., Pavese, N., Růžička, E., Dušek, P., Post, B., Bloem, B.R., Berg, D., Maetzler, W., Otto, M., Habert, M.O., Lehericy, S., Ferreira, J., Dodel, R., Tranchant, C., Eusebio, A., Thobois, S., Marques, A.R., Meissner, W.G., Ory-Magne, F., Walter, U., Bie, R.M. de, Gago, M., Vilas, D., Kulisevsky, J., Januario, C., Coelho, M.V.S., Behnke, S., Worth, P., Seppi, K., Ouk, T., Potey, C., Leclercq, C., Viard, R., Kuchcinski, G., Lopes, R., Pruvo, J.P., Pigny, P., Garçon, G., Simonin, O., Carpentier, J., Rolland, A.S., Nyholm, D., Scherfler, C., Mangin, J.F., Chupin, M., Bordet, R., Dexter, D.T., Fradette, C., Spino, M., Tricta, F., Ayton, S., Bush, A.I., Devedjian, J.C., Duce, J.A., Cabantchik, I., Defebvre, L., Deplanque, D., Moreau, C., Devos, D., Labreuche, J., Rascol, O., Corvol, J.C., Duhamel, A., Delannoy, P. Guyon, Poewe, W., Compta, Y., Pavese, N., Růžička, E., Dušek, P., Post, B., Bloem, B.R., Berg, D., Maetzler, W., Otto, M., Habert, M.O., Lehericy, S., Ferreira, J., Dodel, R., Tranchant, C., Eusebio, A., Thobois, S., Marques, A.R., Meissner, W.G., Ory-Magne, F., Walter, U., Bie, R.M. de, Gago, M., Vilas, D., Kulisevsky, J., Januario, C., Coelho, M.V.S., Behnke, S., Worth, P., Seppi, K., Ouk, T., Potey, C., Leclercq, C., Viard, R., Kuchcinski, G., Lopes, R., Pruvo, J.P., Pigny, P., Garçon, G., Simonin, O., Carpentier, J., Rolland, A.S., Nyholm, D., Scherfler, C., Mangin, J.F., Chupin, M., Bordet, R., Dexter, D.T., Fradette, C., Spino, M., Tricta, F., Ayton, S., Bush, A.I., Devedjian, J.C., Duce, J.A., Cabantchik, I., Defebvre, L., Deplanque, D., and Moreau, C.

Abstract

Item does not contain fulltext, BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In parti

Published
2022

24. Motor urgency is mediated by the contralateral cerebellum in Parkinson's disease

Author

Ballanger, B., Baraduc, P., Broussolle, E., Le Bars, D., Desmurget, M., and Thobois, S.

Subjects
Parkinson's disease -- Development and progression, Parkinson's disease -- Research, Motor ability -- Research, Cerebellum -- Physiological aspects, Cerebellum -- Research, Health, Psychology and mental health
Published
2008

26. Manic behaviour induced by deep-brain stimulation in Parkinson's disease: evidence of substantia nigra implication?

Author

Ulla, M., Thobois, S., Lemaire, J.-J., Schmitt, A., Derost, P., Broussolle, E., Llorca, P.-M., and Durif, F.

Subjects
Parkinson's disease -- Development and progression, Parkinson's disease -- Research, Parkinson's disease -- Physiological aspects, Brain stimulation -- Usage, Brain stimulation -- Patient outcomes, Brain stimulation -- Research, Health, Psychology and mental health
Published
2006

29. Neurostimulation for Parkinsonʼs Disease with Early Motor Complications

Author

Schuepbach, W. M.M., Rau, J., Knudsen, K., Volkmann, J., Krack, P., Timmermann, L., Hälbig, T. D., Hesekamp, H., Navarro, S. M., Meier, N., Falk, D., Mehdorn, M., Paschen, S., Maarouf, M., Barbe, M. T., Fink, G. R., Kupsch, A., Gruber, D., Schneider, G. -H., Seigneuret, E., Kistner, A., Chaynes, P., Ory-Magne, F., Courbon, Brefel C., Vesper, J., Schnitzler, A., Wojtecki, L., Houeto, J. -L., Bataille, B., Maltête, D., Damier, P., Raoul, S., Sixel-Doering, F., Hellwig, D., Gharabaghi, A., Krüger, R., Pinsker, M. O., Amtage, F., Régis, J. -M., Witjas, T., Thobois, S., Mertens, P., Kloss, M., Hartmann, A., Oertel, W. H., Post, B., Speelman, H., Agid, Y., Schade-Brittinger, C., and Deuschl, G.

Published
2013
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32. Chronic subthalamic nucleus stimulation and striatal D2 dopamine receptors in Parkinson's disease; A [[.sup.11]C]-raclopride PET study

Author

Thobois, S., Fraix, V., Savasta, M., Costes, N., Pollak, P., Mertens, P., Koudsie, A., Bars, D., Benabid, A. L., and Broussolle, E.

Subjects
Thalamus -- Research, Dopamine -- Dosage and administration, PET imaging -- Usage, Brain stimulation -- Usage, Health
Abstract

Byline: S. Thobois (1,3), V. Fraix (2,5), M. Savasta (5), N. Costes (3), P. Pollak (2,5), P. Mertens (4), A. Koudsie (2), D. Bars (3), A. L. Benabid (2,5), E. Broussolle (1,3) Keywords: Parkinson's disease; subthalamic stimulation; dopamine; raclopride; PET Abstract: Abstract. Context: Subthalamic nucleus (STN) stimulation mechanism of action remains a matter for debate. In animals, an increased striatal dopamine (DA) release due to STN stimulation has been reported. Objective: To determine in Parkinson's disease (PD) patients using positron emission tomography (PET) and [[.sup.11]C]-Raclopride, whether STN stimulation induces a striatal DA release. Methods: Nine PD patients with bilateral STN stimulation were enrolled and underwent two [[.sup.11]C]-Raclopride PET scans. The scans were randomly performed in off and on stimulation conditions. Striatal [[.sup.11]C]-Raclopride binding potential (BP) was calculated using regions of interest and statistical parametric mapping. Results: For PD patients, the mean [[.sup.11]C]-Raclopride BP (+- SD) were, in Off stimulation condition: 1.7 +- 0.3 for the right caudate nucleus, 1.8 +- 0.4 for the left caudate nucleus, 2.6 +- 0.5 for the right putamenand 2.6 +- 0.5 for the left putamen. In On stimulation condition: 1.7 +- 0.4 for the right caudate nucleus, 1.9 +- 0.5 for the left caudate nucleus, 2.8 +- 0.7 for the right putamen and 2.7 +- 0.8 for the left putamen. No significant difference of BP related to the stimulation was noted. Conclusion: STN stimulation does not produce significant variations of striatal DA release as assessed by PET and [[.sup.11]C]-Raclopride. Author Affiliation: (1) Dept. of Neurology D (Pr. G. Chazot) and INSERM U 534, Hopital Neurologique Pierre Wertheimer, 59 Bd Pinel, 69003, Lyon, France (2) Dept. of Neurology and Neurosurgery, CHU, Grenoble, France (3) CERMEP, Cyclotron Unit, Lyon, France (4) Dept. of Neurosurgery A (Pr. M. Sindou), Hopital Neurologique Pierre Wertheimer, Lyon, France (5) INSERM U 318, CHU, Grenoble, France Article History: Received Date: 24/01/2003 Accepted Date: 02/06/2003

Published
2003

33. Multicentre European study of thalamic stimulation in essential tremor: a six year follow up

Author

Sydow, O., Thobois, S., Alesch, F., and Speelman, J.D.

Subjects
Thalamus -- Physiological aspects, Tremor -- Care and treatment -- Management, Disability -- Management -- Care and treatment, Statistics -- Physiological aspects, Health, Psychology and mental health, Company business management, Management, Care and treatment, Physiological aspects
Abstract

J Neurol Neurosurg Psychiatry 2003;74:1387-1391 Background: Thalamic stimulation is an efficient treatment for disabling essential tremor, as previously shown, but follow up has mostly been short term. Objectives: To see [...]

Published
2003

38. P.322 Progression of dopaminergic and serotonergic dysfunction related to neuropsychiatric signs in Parkinson's disease

Author

Prange, S., primary, Metereau, E., additional, Klinger, H., additional, Schmitt, E., additional, Lhommée, E., additional, Bichon, A., additional, Le Bars, D., additional, Maillet, A., additional, Pelissier, P., additional, Meoni, S., additional, Broussolle, E., additional, Castrioto, A., additional, Krack, P., additional, and Thobois, S., additional

Published
2020
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46. Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes

Author

Coutelier, M. Hammer, M.B. Stevanin, G. Monin, M.-L. Davoine, C.-S. Mochel, F. Labauge, P. Ewenczyk, C. Ding, J. Gibbs, J.R. Hannequin, D. Melki, J. Toutain, A. Laugel, V. Forlani, S. Charles, P. Broussolle, E. Thobois, S. Afenjar, A. Anheim, M. Calvas, P. Castelnovo, G. De Broucker, T. Vidailhet, M. Moulignier, A. Ghnassia, R.T. Tallaksen, C. Mignot, C. Goizet, C. Le Ber, I. Ollagnon-Roman, E. Pouget, J. Brice, A. Singleton, A. Durr, A. Belarabi, S. Hamri, A. Tazir, M. Boesch, S. Pandolfo, M. Ullmann, U. Jardim, L. Guergueltcheva, V. Tournev, I. Soong, B.-W. Linarès, O.L.P. Nielsen, J.E. Svenstrup, K. Zaki, M. Azulay, J.-P. Banneau, G. Boesfplug-Tanguy, O. Burgo, A. Cazeneuve, C. Darios, F. Depienne, C. Duyckaerts, C. Fontaine, B. Hazan, J. Koenig, M. Marelli, C. N'guyen, K. Rodriguez, D. Sittler, A. Verny, C. Bauer, P. Schöls, L. Schüle, R. Koutsis, G. Lossos, A. Antenora, A. Bassi, M.T. Basso, M. Bertini, E. Brusco, A. Casali, C. Casari, G. Criscuolo, C. Filla, A. Lieto, M. Orsi, L. Santorelli, F.M. Valente, E.M. Vavla, M. Vazza, G. Megarbane, A. Benomar, A. Roxburgh, R. Erichsen, A.K. Alonso, I. Coutinho, P. Loureiro, J.L. Sequeiros, J. Salih, M. Kostic, V.S. Axpe, I.R. Roumani, S. Kremer, B. Van Roon-Mom, W. Boukhris, A. Mhiri, C. Karabay, A. Nethisinghe, S. Okane, C. Oliva, M. Reid, E. Warner, T. Wood, N. Spastic Paraplegia Ataxia Network

Abstract

IMPORTANCE Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion. OBJECTIVES To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence. DESIGN, SETTING, AND PARTICIPANTS Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations. MAIN OUTCOMES AND MEASURES Identification of variants in genes broadly linked to CA, classified in pathogenicity groups. RESULTS The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants. CONCLUSIONS AND RELEVANCE Exome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease. © 2018 American Medical Association. All rights reserved.

Published
2018

47. Deep brain stimulation as a therapeutic option for obesity: A critical review

Author

Bétry, Cécile, Thobois, S., Laville, M., Disse, Emmanuel, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Service d'Electroneuromyographie et Service de Neurologie C [Hôpital Pierre Wertheimer - HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université de Lyon, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and CarMeN, laboratoire

Subjects
Bariatric surgery, high-calorie foods, Weight loss, long-term, Nutrition & Dietetics, state functional, [SDV]Life Sciences [q-bio], Hypothalamus, Energy metabolism, lateral hypothalamic area, gastric, [SDV] Life Sciences [q-bio], obsessive-compulsive disorder, Endocrinology & Metabolism, connectivity, Nucleus accumbens, high-frequency stimulation, d-2/3 receptor availability, bypass-surgery, subthalamic nucleus stimulation, striatal dopamine release
Abstract

Despite a better understanding of obesity pathophysiology, treating this disease remains a challenge. New therapeutic options are needed. Targeting the brain is a promising way, considering both the brain abnormalities in obesity and the effects of bariatric surgery on the gut-brain axis. Deep brain stimulation could be an alternative treatment for obesity since this safe and reversible neurosurgical procedure modulates neural circuits for therapeutic purposes. We aimed to provide a critical review of published clinical and preclinical studies in this field. Owing to the physiology of eating and brain alterations in people with obesity, two brain areas, namely the hypothalamus and the nucleus accumbens are putative targets. Preclinical studies with animal models of obesity showed that deep brain stimulation of hypothalamus or nucleus accumbens induces weight loss. The mechanisms of action remain to be fully elucidated. Preclinical data suggest that stimulation of nucleus accumbens reduces food intake, while stimulation of hypothalamus could increase resting energy expenditure. Clinical experience with deep brain stimulation for obesity remains limited to six patients with mixed results, but some clinical trials are ongoing. Thus, drawing clear conclusions about the effectiveness of this treatment is not yet possible, even if the results of preclinical studies are encouraging. Future clinical studies should examine its efficacy and safety, while preclinical studies could help understand its mechanisms of action. We hope that our review will provide ways to design further studies. (C) 2018 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Published
2018

48. Microstructural changes in white and grey matter related to apathy, depression and anxiety in de novo Parkinson's disease patients

Author

Prange, S., primary, Metereau, E., additional, Maillet, A., additional, Lhommée, E., additional, Klinger, H., additional, Pellissier, P., additional, Ibarrola, D., additional, Heckemann, R.A., additional, Broussolle, E., additional, Castrioto, A., additional, Tremblay, L., additional, Sgambato, V., additional, Krack, P., additional, and Thobois, S., additional

Published
2019
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