Publications by authors named "Louise-Laure Mariani"

22 Publications

  • Page 1 of 1

Long-term effect of apomorphine infusion in advanced Parkinson's disease: a real-life study.

NPJ Parkinsons Dis 2021 Jun 11;7(1):50. Epub 2021 Jun 11.

Neurology Department, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson's disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson's disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
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http://dx.doi.org/10.1038/s41531-021-00194-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196159PMC
June 2021

Impulse control disorders and related behaviors in Parkinson's disease: risk factors, clinical and genetic aspects, and management.

Curr Opin Neurol 2021 Aug;34(4):547-555

Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS.

Purpose Of Review: To review recent findings and research directions on impulse control disorders and related behaviors (ICDRBs) in Parkinson's disease (PD).

Recent Findings: Longitudinal studies found that prevalence increases during PD progression, incident ICDRBs being around 10% per year in patients treated with dopaminergic therapies. Screening tools and severity scales already developed have been validated and are available in several countries and languages. The main clinical risk factors include young age, male gender, type, doses and duration of dopaminergic therapy, PD motor severity and dyskinesia, depression, anxiety, apathy, sleep disorders, and impulsivity traits. Genetic factors are suspected by a high estimated heritability, but individual genes and variants remain to be replicated. Management of ICDRBs is centered on dopamine agonist decrease, with the risk to develop withdrawal symptoms. Cognitive behavioral therapy and subthalamic nucleus deep brain stimulation also improve ICDRBs. In the perspective of precision medicine, new individual prediction models of these disorders have been proposed, but they need further independent replication.

Summary: Regular monitoring of ICDRB during the course of PD is needed, particularly in the subject at high risk of developing these complications. Precision medicine will require the appropriate use of machine learning to be reached in the clinical setting.
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http://dx.doi.org/10.1097/WCO.0000000000000955DOI Listing
August 2021

Continuous and advanced treatment strategies in old and very old patients with Parkinson's disease.

Geriatr Psychol Neuropsychiatr Vieil 2021 Mar 8. Epub 2021 Mar 8.

Sorbonne Université, Assistance Publique Hôpitaux de Paris, Institut du cerveau, ICM, Inserm, CNRS Neurology Department, Pitié-Salpêtrière University Hospital, Paris, France.

Parkinson's disease (PD) is a neurodegenerative disorder with an incidence and a prevalence increasing with age, predicted to increase drastically in the next 10 years among the geriatric population aged above 80 in France. There are two distinct groups of patients in which therapeutic issues are different. On the one hand, old to very old patients in which PD started at a late age above 80. These patients present with a more severe PD with earlier onsets of cognitive defects and dopa-resistant axial signs, and more comorbidities which need to be taken into account while treating them. Because of their limited life expectancy, these patients would not likely need second-line treatments over their disease course. On the other hand, patients presenting with advanced PD, in which fluctuations and dyskinesia induced by dopamine replacement therapy and dopa-resistant axial symptoms impede patient's daily life. These patients are often treated with multiple anti-Parkinsonian medications, sometimes at high doses. Some patients will also be treated with advanced therapies such as continuous subcutaneous apomorphine infusion, continuous levodopacarbidopa intestinal gel or, more rarely, even subthalamic or pallidal deep brain stimulations. Because of the specificities of the old to very old Parkinsonian patients, tolerance and efficacy of these treatments can be decreased. What is at stake is to aim for the best motor state possible while limiting iatrogenic adverse events. New emerging, potentially less invasive, techniques, such as gamma knife thalamotomy or high-intensity focused ultrasound thalamotomy or sub-thalamotomy, are also discussed here.
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http://dx.doi.org/10.1684/pnv.2020.0906DOI Listing
March 2021

Evaluation of Prescription Practices of Domperidone in Parkinson's Disease: A Cross Sectional Study Among French Neurologists.

CNS Drugs 2020 12 5;34(12):1267-1274. Epub 2020 Dec 5.

Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP.Sorbonne Université, Hôpital Pitié Salpêtrière, Département de Santé Publique, Centre de Pharmacoépidémiologie (Cephepi), CIC-1422, 75013, Paris, France.

Background: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease. Because of an increased risk of cardiac adverse events, the European Medicines Agency has issued recommendations restricting its use mainly in terms of age, dose, and treatment duration.

Objective: The aim of this study was to investigate current prescription practices of domperidone in Parkinson's disease among French neurologists.

Methods: A cross-sectional study based on a questionnaire was conducted among French neurologists from Parkinson's disease expert centers from the French NS-Park/FCRIN network, general hospitals, and private practice.

Results: Among the 253 neurologists who completed the questionnaire, 86 (34%) were physicians from expert centers and 167 (66%) were from other healthcare settings; 209 (83%) were aware of recommendations restricting domperidone use. The majority of neurologists (92%) declared prescribing domperidone regardless of the age of the patients. Sixty-one percent of neurologists prescribed domperidone beyond 7 days in newly diagnosed patients, 33% in patients with orthostatic hypotension, and 79% in patients receiving continuous apomorphine treatment. They did not follow the recommendation on posology in newly diagnosed patients (7% of neurologists), patients with orthostatic hypotension (10%), and patients receiving continuous apomorphine therapy (25%). Finally, only 58% of neurologists declared taking specific precautions before prescribing domperidone.

Conclusions: These findings show most French neurologists who responded to our questionnaire do not fully follow the restrictions on domperidone use, particularly in terms of treatment duration, and in patients receiving continuous apomorphine treatment. This may reflect the unmet need to prevent nausea in patients with Parkinson's disease treated with dopaminergic drugs, particularly continuous apomorphine therapy.
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http://dx.doi.org/10.1007/s40263-020-00774-wDOI Listing
December 2020

Automated Categorization of Parkinsonian Syndromes Using Magnetic Resonance Imaging in a Clinical Setting.

Mov Disord 2021 02 2;36(2):460-470. Epub 2020 Nov 2.

Paris Brain Institute-ICM, INSERM U 1127, CNRS UMR 7225, Sorbonne Université, UMR S 1127, CNRS UMR 7225, Paris, France.

Background: Machine learning algorithms using magnetic resonance imaging (MRI) data can accurately discriminate parkinsonian syndromes. Validation in patients recruited in routine clinical practice is missing.

Objective: The aim of this study was to assess the accuracy of a machine learning algorithm trained on a research cohort and tested on an independent clinical replication cohort for the categorization of parkinsonian syndromes.

Methods: Three hundred twenty-two subjects, including 94 healthy control subjects, 119 patients with Parkinson's disease (PD), 51 patients with progressive supranuclear palsy (PSP) with Richardson's syndrome, 35 with multiple system atrophy (MSA) of the parkinsonian variant (MSA-P), and 23 with MSA of the cerebellar variant (MSA-C), were recruited. They were divided into a training cohort (n = 179) scanned in a research environment and a replication cohort (n = 143) examined in clinical practice on different MRI systems. Volumes and diffusion tensor imaging (DTI) metrics in 13 brain regions were used as input for a supervised machine learning algorithm. To harmonize data across scanners and reduce scanner-dependent effects, we tested two types of normalizations using patient data or healthy control data.

Results: In the replication cohort, high accuracies were achieved using volumetry in the classification of PD-PSP, PD-MSA-C, PSP-MSA-C, and PD-atypical parkinsonism (balanced accuracies: 0.840-0.983, area under the receiver operating characteristic curves: 0.907-0.995). Performances were lower for the classification of PD-MSA-P, MSA-C-MSA-P (balanced accuracies: 0.765-0.784, area under the receiver operating characteristic curve: 0.839-0.871) and PD-PSP-MSA (balanced accuracies: 0.773). Performance using DTI was improved when normalizing by controls, but remained lower than that using volumetry alone or combined with DTI.

Conclusions: A machine learning approach based on volumetry enabled accurate classification of subjects with early-stage parkinsonism, examined on different MRI systems, as part of their clinical assessment. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28348DOI Listing
February 2021

Current challenges in the pathophysiology, diagnosis, and treatment of paroxysmal movement disorders.

Expert Rev Neurother 2021 Jan 8;21(1):81-97. Epub 2020 Nov 8.

Département de Neurologie, AP-HP, Hôpital Pitié-Salpêtrière , Paris, France.

Introduction: Paroxysmal movement disorders mostly comprise paroxysmal dyskinesia and episodic ataxia, and can be the consequence of a genetic disorder or symptomatic of an acquired disease.

Areas Covered: In this review, the authors focused on certain hot-topic issues in the field: the respective contribution of the cerebellum and striatum to the generation of paroxysmal dyskinesia, the importance of striatal cAMP turnover in the pathogenesis of paroxysmal dyskinesia, the treatable causes of paroxysmal movement disorders not to be missed, with a special emphasis on the treatment strategy to bypass the glucose transport defect in paroxysmal movement disorders due to GLUT1 deficiency, and functional paroxysmal movement disorders.

Expert Opinion: Treatment of genetic causes of paroxysmal movement disorders is evolving towards precision medicine with targeted gene-specific therapy. Alteration of the cerebellar output and modulation of the striatal cAMP turnover offer new perspectives for experimental therapeutics, at least for paroxysmal movement disorders due to selected causes. Further characterization of cell-specific molecular pathways or network dysfunctions that are critically involved in the pathogenesis of paroxysmal movement disorders will likely result in the identification of new biomarkers and testing of innovative-targeted therapeutics.
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http://dx.doi.org/10.1080/14737175.2021.1840978DOI Listing
January 2021

Maximizing placebo response in neurological clinical practice.

Int Rev Neurobiol 2020 9;153:71-101. Epub 2020 Jun 9.

Department of Neurology, Pitié-Salpêtrière Hospital, Sorbonne University, Assistance Publique Hôpitaux de Paris, Brain and Spine Institute, ICM, Inserm U 1127, CNRS UMR 7225, Paris, France. Electronic address:

The placebo effect is a widely recognized phenomenon in clinical research, with a negative perception that it could hide the "true" drug effect. In clinical care its positive potential to increase known drug effects has been neglected for too long. The placebo and nocebo responses have been described in many neurologic disorders such as Parkinson's, Huntington's and Alzheimer's diseases, restless leg syndrome, tics, essential tremor, dystonia, functional movement disorders, neuropathic pain, headaches, migraine, amyotrophic lateral sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis and epilepsy. Knowledge regarding placebo mechanisms and their consequences on clinical outcome have greatly improved over the last two decades. This evolution has led to reconsiderations of the importance of placebo response in the clinic and has given several clues on how to improve it in daily practice. In this chapter, we first illustrate "why," e.g. the reasons (relevance to clinical practice, help in differential diagnosis/treatment of psychogenic movements, clinical impact, proven neurobiological grounds, health economic potential), and "how," e.g. the means (increase patients' knowledge, increase learning, improve patient-doctor relationship, increase Hawthorne effect, increase positive/decrease negative expectations (the Rosenthal effect), personalize placebo response), the placebo should be maximized (and nocebo avoided) in neurological clinical practice. Future studies regarding more specific neurobiological mechanisms will allow a finer tuning of placebo response in clinical practice. The use of placebo in clinical practice raises ethical issues, and a recent expert consensus regarding placebo use in the clinic is a first step to future guidelines necessary to this field.
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http://dx.doi.org/10.1016/bs.irn.2020.04.003DOI Listing
June 2020

[Continuous and advanced treatment strategies in the old to very old parkinsonian population].

Geriatr Psychol Neuropsychiatr Vieil 2020 06;18(2):177-186

Sorbonne Université, Assistance Publique Hôpitaux de Paris, Institut du cerveau et de la moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Département de neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France.

Parkinson's disease (PD) is a neurodegenerative disorder with an incidence and a prevalence increasing with age, predicted to increase drastically in the next 10 years among the geriatric population aged above 80 in France. There are two distinct groups of patients in which therapeutic issues are different. On the one hand, old to very old patients in which PD started at a late age above 80. These patients present with a more severe PD with earlier onsets of cognitive defects and dopa-resistant axial signs, and more comorbidities needing to be taken into account while treating them. Because of their limited life expectancy, these patients would not likely need second line treatments over their disease course. On the other hand, patients presenting with advanced PD, in which fluctuations and dyskinesia induced by dopamine replacement therapy and dopa-resistant axial symptoms impede patient's daily life. These patients are often treated with multiple antiparkinsonian medications, sometimes at high doses. Some patients will also be treated with advanced therapies such as continuous subcutaneous apomorphine infusion, continuous levodopa-carbidopa intestinal gel or, more rarely, even subthalamic or pallidal deep brain stimulations. Because of the specificities of the old to very old parkinsonian patients, tolerance and efficacy of these treatments can be decreased. What is at stake is to aim for the best motor state possible while limiting iatrogenic adverse events. New emerging, potentially less invasive, techniques, such as gamma knife thalamotomy or high-intensity focused ultrasound thalamotomy or sub-thalamotomy, are also discussed here.
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http://dx.doi.org/10.1684/pnv.2020.0853DOI Listing
June 2020

Loss-of-Function Mutations in NR4A2 Cause Dopa-Responsive Dystonia Parkinsonism.

Mov Disord 2020 05 10;35(5):880-885. Epub 2020 Jan 10.

Sorbonne Université, Institut du Cerveau et de la Moelle épinière, Inserm U 1127, CNRS UMR 7225, F-75013, Paris, France.

Background: The group of dystonia genes is expanding, and mutations of these genes have been associated with various combined dystonia syndromes. Among the latter, the cause of some dystonia parkinsonism cases remains unknown.

Objective: To report patients with early-onset dystonia parkinsonism as a result of loss-of-function mutations in nuclear receptor subfamily 4 group A member 2.

Methods: Phenotypic characterization and exome sequencing were carried out in 2 families.

Results: The 2 patients reported here both had a history of mild intellectual disability in childhood and subsequently developed dystonia parkinsonism in early adulthood. Brain magnetic resonance imaging was normal, and DATscan suggested bilateral dopaminergic denervation. Two frameshift mutations in NR4A2 were identified: a de novo insertion (NM_006186.3; c.326dupA) in the first case and another small insertion (NM_006186.3; c.881dupA) in the second.

Conclusions: NR4A2 haploinsufficiency mutations have been recently reported in neurodevelopmental phenotypes. Our findings indicate that dystonia and/or parkinsonism may appear years after initial symptoms. Mutations in NR4A2 should be considered in patients with unexplained dystonia parkinsonism. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27982DOI Listing
May 2020

Are PSP patients included in clinical trials representative of the general PSP population?

Parkinsonism Relat Disord 2019 09 10;66:202-206. Epub 2019 Jul 10.

Sorbonne Université, Assistance Publique Hôpitaux de Paris, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Department of Neurology, Hôpital Pitié-Salpêtrière, F-75013, Paris, France. Electronic address:

Background: Progressive supranuclear palsy (PSP) is a rare parkinsonian syndrome with a wide spectrum of clinical presentations. Recently, the MDS published revised diagnosis criteria to provide early and reliable diagnosis of PSP and its variants. Two large randomized clinical trials were initiated in 2017, but the question remains regarding the extrapolation of their results to the general PSP population.

Objective: To determine if PSP patients included in clinical trials are representative of the general PSP population.

Methods: We conducted a single center retrospective study of PSP patients referred to a tertiary department of Neurology (Pitié-Salpêtrière Hospital, Paris) for clinical diagnosis and clinical trial inclusion, over a 12-month period. We collected and analyzed gender, age at examination, age at disease onset, disease duration, and core clinical features regarding oculo-motor dysfunction, postural instability, akinesia and cognitive dysfunction, and inclusion/exclusion criteria of clinical trials to assess eligibility for inclusion. We assessed the relative proportions of different PSP subtypes, as defined by the MDS-PSP criteria, in the whole population compared to patients eligible in trials.

Results: 206 PSP patients were included, among which 175 (85%) were diagnosed with probable PSP-Richardson's syndrome (RS) subtype, with a mean age of 73 and mean disease duration of 5 years. Among those patients, 29 (21%) were eligible (age 71 ± 10.7, disease duration 3.1 ± 1.2 years) and 19 were included in trials, all with a diagnosis of probable PSP-RS. As compared to the whole population, patients included in clinical trials tended to be younger, and showed more PSP-RS subtypes (p < 0.05).

Conclusion: The PSP population included in trials is very similar to the general PSP population, but younger, with shorter disease duration. By definition, only probable PSP subtypes are included in clinical trials. The time window for inclusion is short because of diagnosis delay, fast disease progression and old age of the population.
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http://dx.doi.org/10.1016/j.parkreldis.2019.07.012DOI Listing
September 2019

Differential enhancement of ERK, PKA and Ca signaling in direct and indirect striatal neurons of Parkinsonian mice.

Neurobiol Dis 2019 10 17;130:104506. Epub 2019 Jun 17.

Inserm UMR-S 1270, Paris, France; Sorbonne Université, Science and Engineering Faculty, Paris, France; Institut du Fer à Moulin, Paris, France. Electronic address:

Parkinson's disease (PD) is characterized by severe locomotor deficits due to the disappearance of dopamine (DA) from the dorsal striatum. The development of PD symptoms and treatment-related complications such as dyskinesia have been proposed to result from complex alterations in intracellular signaling in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs, respectively) following loss of DA afferents. To identify cell-specific and dynamical modifications of signaling pathways associated with PD, we used a hemiparkinsonian mouse model with 6-hydroxydopamine (6-OHDA) lesion combined with two-photon fluorescence biosensors imaging in adult corticostriatal slices. After DA lesion, extracellular signal-regulated kinase (ERK) activation was increased in response to DA D1 receptor (D1R) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) stimulation. The cAMP-dependent protein kinase (PKA) pathway contributing to ERK activation displayed supersensitive responses to D1R stimulation after 6-OHDA lesion. This cAMP/PKA supersensitivity was specific of D1R-responding SPNs and resulted from Gα upregulation and deficient phosphodiesterase activity. In lesioned striatum, the number of D1R-SPNs with spontaneous Ca transients augmented while Ca response to AMPA receptor stimulation specifically increased in iSPNs. Our work reveals distinct cell type-specific signaling alterations in the striatum after DA denervation. It suggests that over-activation of ERK pathway, observed in PD striatum, known to contribute to dyskinesia, may be linked to the combined dysregulation of DA and glutamate signaling pathways in the two populations of SPNs. These findings bring new insights into the implication of these respective neuronal populations in PD motor symptoms and the occurrence of PD treatment complications.
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http://dx.doi.org/10.1016/j.nbd.2019.104506DOI Listing
October 2019

Descriptive analysis of the French NS-Park registry: Towards a nation-wide Parkinson's disease cohort?

Parkinsonism Relat Disord 2019 07 25;64:226-234. Epub 2019 Apr 25.

Sorbonne Université, Assistance Publique Hôpitaux de Paris, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Department of Neurology, Hôpital Pitié-Salpêtrière, F-75013, Paris, France; Center for Interdisciplinary Research in Biology, Collège de France, INSERM U1050, CNRS UMR7241, Labex Memolife, Paris Sciences et Lettres, Paris, France; AP-HP, Department of Neurology, Hôpital Avicenne, Hôpitaux Universitaires de Paris - Seine Saint Denis, Bobigny, France. Electronic address:

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's. The French clinical research network for PD (NS-Park) has created a national patient registry to i)report medical activity of Parkinson Expert Centers (PECs) to the Ministry of Health, ii)facilitate PD patients pre-screening for clinical trials, iii) provide a source for pharmaco-epidemiology studies.

Objective: Assess the French Parkinsonian population at a nation-wide level and discover new clinical characteristics.

Methods: In this feasibility study, PECs prospectively collected clinical data in a standardized manner. The population main clinical characteristics are described, focusing on motor and non-motor symptoms and treatments, assessing its representativeness. By using an unbiased clustering with multiple correspondence analysis (MCA), we also investigate potential relationships between multiple variables like symptoms and treatments, as clues for future studies.

Results: Between 2012 and 2016, among 11,157 included parkinsonian syndromes, 9454 (85%) had PD. MCA identified various profiles depending on disease duration. Occurrences of motor complications, axial signs, cognitive disorders and Levodopa use increase over time. Neurovegetative symptoms, psychiatric disorders, sleep disturbances and impulse control disorders (ICDs) seem stable over time. As expected, ICDs were associated to dopaminergic agonist use but other associations, such as ICDs and sleep disturbances for instance, or anxiety and depression, were found.

Conclusions: Our results report one of the biggest PD registries ever reported and demonstrate the feasibility of implementing a nation-wide registry of PD patients in France, a potent tool for future longitudinal studies and clinical trials' population selection, and for pharmaco-epidemiology and cost-effectiveness studies.
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http://dx.doi.org/10.1016/j.parkreldis.2019.04.012DOI Listing
July 2019

[Therapeutic and pharmacologic perspectives in Parkinson's disease].

Rev Prat 2018 May;68(5):515-519

Sorbonne Universités, Assistance publique-Hôpitaux de Paris, Inserm, CNRS, Institut du cerveau et de la moelle, groupe hospitalier La Pitié-Salpêtrière, département de neurologie, Paris, France.

Therapeutic and pharmacologic perspectives in parkinson's disease. Despite the dopaminergic therapy which improves motor symptoms, there are still a lot of challenges to be fulfilled in Parkinson's disease. Dopamine replacement therapy is hampered by motor complications, has no efficacy on non-motor symptoms, and is not neuroprotective so does not change disease progression. Second line therapies, also mainly acting on motor symptoms, such as deep brain stimulation, and continuous administration of levodopa or apomorphine by pumps, can benefit to a limited number of patients but are associated with a high burden for the patients and their caregivers, and a high cost for society. Several therapeutic strategies are currently under evaluation to improve the treatment of motor fluctuations, dyskinesia, and some non-motor symptoms. The recent development of more predictive preclinical models and biomarkers of disease progression should allow fostering the development of innovative neuroprotective strategies. The stratification of patients through the combination of clinical, biological and brain imaging features will help to move towards personalized precision medicine by matching patients care to their individual progression profile.
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May 2018

Naftazone in advanced Parkinson's disease: An acute L-DOPA challenge randomized controlled trial.

Parkinsonism Relat Disord 2019 03 4;60:51-56. Epub 2018 Oct 4.

Clinical Investigation Center CIC-1436, Departments of Clinical Pharmacology and Neurosciences, University Hospital of Toulouse, INSERM, University of Toulouse 3, Toulouse, France; F-CRIN, UMS 015, Toulouse, France.

Introduction: There is an unmet need to better control motor complications in Parkinson's disease (PD). Naftazone, which exhibits glutamate release inhibition properties, has shown antiparkinsonian and antidyskinetic activity in preclinical models of PD and in a clinical proof of concept study.

Methods: We conducted a double-blind randomized placebo-controlled cross-over trial in PD patients with motor fluctuations and dyskinesia testing naftazone 160 mg/day versus placebo for 14 days. The two co-primary endpoints were the area under curve (AUC) of motor (MDS-UPDRS part III) and dyskinesia (AIMS) scores during an acute levodopa challenge performed at the end of each period. Secondary endpoints were UDysRS and axial symptoms scores during the challenge; AIMS, UDysRS, and time spent with or without dyskinesia the day before the challenge. The primary analysis was performed in the per protocol population.

Results: Sixteen patients were included in the analysis. There was no difference between naftazone and placebo for the AUC of MDS-UPDRS III (-89, 95%CI[-1071; 893], p = 0.85), and AIMS (70, 95%CI[-192; 332], p = 0.57). At the end of treatment periods, AIMS score tended to be lower with naftazone than placebo (4.4 ± 3.4 versus 6.7 ± 4.4, p = 0.07), but UDysRS scores and other secondary outcomes were not different. Naftazone was safe and well tolerated.

Conclusions: This study did not confirm previous results on the efficacy of naftazone on dyskinesia nor motor fluctuations highlighting the problem of translating results obtained in preclinical models into clinical trials. Further investigation of naftazone may be conducted in PD with longer treatment duration.
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http://dx.doi.org/10.1016/j.parkreldis.2018.10.005DOI Listing
March 2019

Transthyretin amyloid polyneuropathies mimicking a demyelinating polyneuropathy.

Neurology 2018 07 15;91(2):e143-e152. Epub 2018 Jun 15.

From Service de Physiologie Clinique-Explorations Fonctionnelles (P.L.), AP-HP, Hôpital Lariboisière, Paris; INSERM UMR965 (P.L.), Paris; Université Paris Diderot Sorbonne Paris Cité (P.L., B.A.), Paris; French National Reference Center for FAP (NNERF) (L.-L.M., P.D., G.B., M.T., C.A., D.A.), Le Kremlin-Bicêtre; Service de Neurologie (L.-L.M., P.D., M.T., D.A.) and Service d'anatomopathologie (C.A.), APHP, Hôpital Bicêtre, Le Kremlin-Bicêtre; Unité de Neurophysiologie Clinique et d'épileptologie (G.B.), Hôpital Bicêtre, Le Kremlin-Bicêtre; Immuno-Hematology Department (B.A.), Saint-Louis Hospital, Paris; Université Paris 11 (D.A.); and INSERM UMR1195 (D.A.), Le Kremlin-Bicêtre, France.

Objective: To clearly define transthyretin familial amyloid polyneuropathies (TTR-FAPs) fulfilling definite clinical and electrophysiologic European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy (CIDP).

Methods: From a cohort of 194 patients with FAP, 13 of 84 patients (15%) of French ancestry had late-onset demyelinating TTR-FAP. We compared clinical presentation and electrophysiology to a cohort with CIDP and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome. We assessed nerve histology and the correlation between motor/sensory amplitudes/velocities. Predictors of demyelinating TTR-FAP were identified from clinical and electrophysiologic data.

Results: Pain, dysautonomia, small fiber sensory loss above the wrists, upper limb weakness, and absence of ataxia were predictors of demyelinating TTR-FAP ( < 0.01). The most frequent demyelinating features were prolonged distal motor latency of the median nerve and reduced sensory conduction velocity of the median and ulnar nerves. Motor axonal loss was severe and frequent in the median, ulnar, and tibial nerves ( < 0.05) in demyelinating FAP. Ulnar nerve motor amplitude <5.4 mV and sural nerve amplitude <3.95 μV were distinguishing characteristics of demyelinating TTR-FAP. Nerve biopsy showed severe axonal loss and occasional segmental demyelination-remyelination.

Conclusion: Misleading features of TTR-FAP fulfilling criteria for CIDP are not uncommon in sporadic late-onset TTR-FAP, which highlights the limits of European Federation of Neurological Societies/Peripheral Nerve Society criteria. Specific clinical aspects and marked electrophysiologic axonal loss are red flag symptoms that should alert to this diagnosis and prompt gene sequencing.
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http://dx.doi.org/10.1212/WNL.0000000000005777DOI Listing
July 2018

Molecular basis of dopamine replacement therapy and its side effects in Parkinson's disease.

Cell Tissue Res 2018 07 7;373(1):111-135. Epub 2018 Mar 7.

Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, ICM, Hôpital Pitié-Salpêtrière, Paris, France.

There is currently no cure for Parkinson's disease. The symptomatic therapeutic strategy essentially relies on dopamine replacement whose efficacy was demonstrated more than 50 years ago following the introduction of the dopamine precursor, levodopa. The spectacular antiparkinsonian effect of levodopa is, however, balanced by major limitations including the occurrence of motor complications related to its particular pharmacokinetic and pharmacodynamic properties. Other therapeutic strategies have thus been developed to overcome these problems such as the use of dopamine receptor agonists, dopamine metabolism inhibitors and non-dopaminergic drugs. Here we review the pharmacology and molecular mechanisms of dopamine replacement therapy in Parkinson's disease, both at the presynaptic and postsynaptic levels. The perspectives in terms of novel drug development and prediction of drug response for a more personalised medicine will be discussed.
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http://dx.doi.org/10.1007/s00441-018-2813-2DOI Listing
July 2018

Report of two cases of tocilizumab induced recurrent meningitis or meningoencephalitis.

Joint Bone Spine 2018 10 31;85(5):643-644. Epub 2018 Jan 31.

Rheumatology department, Pitié Salpêtrière Hospital, AP-HP, 75013 Paris, France; UPMC Univ Paris 06, Institut Pierre-Louis d'épidémiologie et de santé publique, Sorbonne Université, 75013 Paris, France.

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http://dx.doi.org/10.1016/j.jbspin.2018.01.002DOI Listing
October 2018

Teaching Video Neuro Hyperekplexia: A syndrome of pathologic startle responses.

Neurology 2017 03;88(13):e126-e127

From APHP, Department of Neurology (L-L.M., E.H., M.M., E.R.), Salpêtrière Hospital, Paris; APHP, Department of Neurophysiology (E.A.), Saint Antoine Hospital, Paris; and Sorbonne Universités (E.H., E.A, E.R.), UPMC Univ Paris 06, INSERM U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France.

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http://dx.doi.org/10.1212/WNL.0000000000003766DOI Listing
March 2017

Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach.

JAMA Neurol 2016 09;73(9):1105-14

Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France3Institut du Cerveau et de la Moelle Epinière, Paris, France4Institut National de la Santé et de la Récherche Médicale Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, Sorbonne Universités, Université Pierre et Marie Curie University Paris 06 Unité Mixte de Recherche S1127, Paris, France.

Importance: Huntington disease (HD), a prototypic monogenic disease, is caused by an expanded CAG repeat in the HTT gene exceeding 35 units. However, not all patients with an HD phenotype carry the pathological expansion in HTT, and the positive diagnosis rate is poor.

Objectives: To examine patients with HD phenotypes to determine the frequency of HD phenocopies with typical features of HD but without pathological CAG repeat expansions in HTT in an attempt to improve the positive diagnosis rate.

Design, Setting, And Participants: Between January 1, 2004, and April 18, 2011, a total of 226 consecutive index patients with an HD phenotype were referred to specialized clinics of the French National Huntington Disease Reference Centre for Rare Diseases. They underwent detailed clinical examination and follow-up, as well as neuropsychological, biological, imaging, and genetic examinations. Nucleotide expansions in JPH3, ATN1, TBP, and C9ORF72 and mutations in PRNP, as well as acquired conditions commonly causing HD phenocopies, were first screened.

Main Outcomes And Measures: The diagnostic rate of HD phenocopies and frequency of other etiologies using deep clinical phenotyping and next generation sequencing. Our goal was to improve the genetic diagnosis of HD phenocopies and to identify new HD related genes.

Results: One hundred ninety-eight patients carried a pathological CAG repeat expansion in HTT, whereas 28 patients (12 women and 16 men) did not. Huntington disease phenocopies accounted for 12.4%, and their mean (SD) age at onset was similar to those of the HD-HTT group (47.3 [12.7] years vs 50.3 [16.4] years, P = .29). We first identified 3 patients with abnormal CTG expansions in JPH3, a fourth patient with an antiphospholipid syndrome, and a fifth patient with B12 avitaminosis. A custom-made 63-gene panel was generated based on clinical evolution and exome sequencing. It contained genes responsible for HD phenocopies and other neurodegenerative conditions, as well as candidate genes from exome sequencing in 3 index cases with imaging features of brain iron accumulation. We identified mutations in genes associated with neurodegeneration, including CACNA1A (n = 2), VPS13A (n = 1), UBQLN2 (n = 1), and VCP (n = 1).

Conclusions And Relevance: Huntington disease phenocopies without CAG repeat expansions in HTT are not rare, occurring in 12.4% (28 of 226) herein, and should be considered in genetic counseling. We used next-generation sequencing combined with clinical data and disease evolution to explore multiple etiologies simultaneously. Our combined clinical and genetic exploration of 28 HD phenocopies identified the underlying cause in 35.7% (10 of 28). In conclusion, the etiologies of HD phenocopies are heterogeneous, and clinical evolution should be taken into account when searching for a genetic cause. The panel of candidate genes to be examined is larger than expected but can be guided by specific imaging and clinical features. Other neurodegenerative diseases with late onset in which variant segregation cannot be verified could be productively explored with the combined approach illustrated herein.
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http://dx.doi.org/10.1001/jamaneurol.2016.2215DOI Listing
September 2016

Genotype-phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France.

Ann Neurol 2015 Dec 7;78(6):901-16. Epub 2015 Oct 7.

Department of Neurology, Bicêtre Hospital, Le Kremlin-Bicêtre;

Objective: To compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP.

Methods: We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression.

Results: By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies.

Interpretation: Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large-fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing).
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http://dx.doi.org/10.1002/ana.24519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738459PMC
December 2015

Exonic deletions of FXN and early-onset Friedreich ataxia.

Arch Neurol 2012 Jul;69(7):912-6

Université Pierre et Marie Curie, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Institut National de la Santé et de la Recherche Médicale, France.

Background: Friedreich ataxia (FA) is the most frequent type of autosomal recessive cerebellar ataxia, occurring at a mean age of 16 years. Nearly 98% of patients with FA present with homozygous GAA expansions in the FXN gene. The remaining patients are compound heterozygous for an expansion and a point mutation. Patients who are compound heterozygous for an exonic deletion and an expansion are exquisitely rare.

Objectives: To describe 6 patients affected with FA due to an exonic deletion mutation (FAexdel) and to compare these 6 patients with FAexdel with 46 patients consecutively diagnosed with typical FA due to homozygous GAA expansion and whose small expansions were within the same range as that of the expansions of the patients with FAexdel.

Design: Description of a series.

Setting: Academic research.

Patients: Six patients with FAexdel and 46 patients with typical FA.

Intervention: FXN gene analysis, including assessments of GAA expansion and exon sequencing and determination of exonic copy numbers using multiplex ligation-dependent probe amplification.

Results: We identified 6 patients with FA who presented with the combination of 1 GAA expansion and 1 FXN exonic deletion. The mean (SD) age at onset of the disease was earlier for patients with FAexdel (7 [4] years [range, 3-12 years]) than for patients with typical FA (15 [5] years [range, 6-30 years]) (P = .001), and the median time to confinement to wheelchair was shorter for patients with FAexdel (20 years) than for patients with typical FA (28 years) (P = .002). There was no difference between the mean (SD) size of the expansion for the patients with FAexdel (780 [256] GAA triplet repeat sequences [range, 340-1070 GAA triplet repeat sequences]) and the mean (SD) size of the short expansion for the patients with typical FA (634 [163] GAA triplet repeat sequences [range, 367-1000 GAA triplet repeat sequences]) (P = .10). The mean disease duration before becoming wheelchair bound was shorter for patients with FAexdel (9 years) than for patients with typical FA (13 years), and the incidence of cardiomyopathy was higher for patients with FAexdel (84%) than for patients with typical FA (68%). However, these differences were not significant, probably owing to the small size of the FAexdel group. The other extraneurological signs, such as scoliosis or diabetes mellitus, were particularly frequently observed in the FAexdel group. One patient presented at 9 years of age with severe angina and marked cardiomyopathy that confined her to a wheelchair. Three patients had disabling autonomic disturbances. It appears that exonic deletion significantly contributes to the clinical picture of patients with FA.

Conclusions: Friedreich ataxia due to an exonic deletion mutation corresponds to an early onset and severe variant of FA. FXN should be investigated for exonic deletion in patients with early-onset FA in which only 1 GAA expansion without a point mutation is found. Patients with FAexdel have to be carefully observed using cardiological, orthopaedic, endocrinological, gastroenterological, and ophthalmological data. Friedreich ataxia due to an exonic deletion mutation should be suspected in young patients presenting with severe scoliosis.
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http://dx.doi.org/10.1001/archneurol.2011.834DOI Listing
July 2012
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