Axial symptoms predict mortality in patients with Parkinson disease and subthalamic stimulation.

OBJECTIVE To characterize how disease progression is associated with mortality in a large cohort of patients with Parkinson disease (PD) with long-term follow-up after subthalamic nucleus deep brain stimulation (STN-DBS). METHODS Motor and cognitive disabilities were assessed before and 1, 2, 5, and 10 years after STN-DBS in 143 consecutive patients with PD. We measured motor symptoms "off" and "on" levodopa and STN-DBS and recorded causes of death. We used linear mixed models to characterize symptom progression, including interactions between treatment conditions and time to determine how treatments changed efficacy. We used joint models to link symptom progression to mortality. RESULTS Median observation time was 12 years after surgery, during which akinesia, rigidity, and axial symptoms worsened, with mean increases of 8.8 (SD 6.5), 1.8 (3.1), and 5.4 (4.1) points from year 1-10 after surgery ("on" dopamine/"on" STN-DBS), respectively. Responses to dopaminergic medication and STN-DBS were attenuated with time, but remained effective for all except axial symptoms, for which both treatments and their combination were predicted to be ineffective 20 years after surgery. Cognitive status significantly declined. Forty-one patients died, with a median time to death of 9 years after surgery. The current level of axial disability was the only symptom that significantly predicted death (hazard ratio 4.30 [SE 1.50] per unit of square-root transformed axial score). CONCLUSIONS We quantified long-term symptom progression and attenuation of dopaminergic medication and STN-DBS treatment efficacy in patients with PD and linked symptom progression to mortality. Axial disability significantly predicts individual risk of death after surgery, which may be useful for planning therapeutic strategies in PD

Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with l-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the late

Implication des ganglions de la base dans les troubles comportementaux (approche physiopathologique et thérapeutique chez le primate)

L organisation anatomo-fonctionnelle des ganglions de la base constitue un cadre théorique permettant de rendre compte de l implication de ce système dans certains troubles du comportement observés en pathologie humaine. Nos résultats obtenus chez le primate suggèrent qu un dysfonctionnement dans le territoire associatif du pallidum externe permettait d induire une hyperactivité associée à des troubles de l attention alors qu un dysfonctionnement similaire dans le territoire limbique de cette structure entraînait des comportements stéréotypés. Les circuits sous-tendant ces comportements anormaux, identifiés par traçage des voies axonales, se superposaient largement à ceux impliqués dans l hyperactivité avec déficit attentionnel, la maladie de Gilles de la Tourette (MGDT) et le trouble obsessionnel et compulsif (TOC). Nos résultats permettent donc de poser les bases d un modèle animal de ces pathologies, que nous avons mis à profit pour démontrer, dans une optique pré-clinique, l efficacité de la modulation électrique par stimulation à haute fréquence du noyau subthalamique sur les comportements anormaux répétitifs induits par dysfonctionnement du GPe. La stimulation du noyau subthalamique pourrait donc représenter une piste thérapeutique prometteuse pour traiter la MGDT et le TOC chez l homme.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Dysfonctionnement expérimental du segment externe du Pallidum chez le primate (des troubles du mouvement aux désordres du comportement)

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

The Role of Magnetic Resonance Imaging for the Diagnosis of Atypical Parkinsonism

International audienceThe diagnosis of Parkinson's disease and atypical Parkinsonism remains clinically difficult, especially at the early stage of the disease, since there is a significant overlap of symptoms. Multimodal MRI has significantly improved diagnostic accuracy and understanding of the pathophysiology of Parkinsonian disorders. Structural and quantitative MRI sequences provide biomarkers sensitive to different tissue properties that detect abnormalities specific to each disease and contribute to the diagnosis. Machine learning techniques using these MRI biomarkers can effectively differentiate atypical Parkinsonian syndromes. Such approaches could be implemented in a clinical environment and improve the management of Parkinsonian patients. This review presents different structural and quantitative MRI techniques, their contribution to the differential diagnosis of atypical Parkinsonian disorders and their interest for individual-level diagnosis

De l'intérêt des ontologies modulaires. Application à la modélisation de la prise en charge de la SLA

National audiencePour tenter de comprendre les causes de ruptures de parcours de soins dans le cadre de la prise en charge des patients atteints de Sclérose Latérale Amyotrophique (SLA), dans un réseau de coordination de parcours de soins, nous avons crée une ontologie modulaire. L'objectif de notre travail est d'expliciter les apports et limites d'une ontologie modulaire, dans ce cas d'usage, la méthodologie de construction utilisée et de la comparer d'un point de vue quantitatif à des ontologies monolithiques de domaines connexes. Mots-clés : Ontologie, ontologie modulaire, parcours de soin, Sclérose Latérale Amyotrophique

Explicit Agency in Patients with Cervical Dystonia: Altered Recognition of Temporal Discrepancies between Motor Actions and Their Feedback.

BACKGROUND:Abnormalities in the cognitive processing of movement have been demonstrated in patients with dystonia. The sense of agency, which is the experience of initiating and controlling one's own actions, has never before been studied in these patients. OBJECTIVES:We investigated whether the sense of agency is altered in patients with cervical dystonia. METHODS:We used an explicit metacognitive agency task in which participants had to catch targets with a cursor by moving a computer's mouse. The task included several conditions in which the control over the cursor could be disrupted by adding a spatial or a temporal discrepancy between the mouse and the cursor's movements. Participants had to acknowledge these discrepancies and reflect them in metacognitive judgements of agency. RESULTS:Twenty cervical dystonia patients and 20 matched controls were included in the study. Despite performing equally well as the matched controls, cervical dystonia patients did not fully recognize alterations of agency when a temporal lag was added between their movement and the visual feedback. Moreover, they relied predominantly on their perceived performance to provide judgements of agency and less on their objective degree of controls. There was no correlation between agency scores and clinical severity of dystonia measured by the Toronto Western Spasmodic Torticollis Rating Scale. CONCLUSION:We demonstrated an abnormal processing of agency in cervical dystonia patients, even for motor actions not affected by dystonia. The exact contribution of abnormal agency to dystonia pathophysiology remains to be clarified

A causal role for the pedunculopontine nucleus in human instrumental learning

International audienceA critical mechanism for maximizing reward is instrumental learning. In standard instrumental learning models, action values are updated on the basis of reward prediction errors (RPEs), defined as the discrepancy between expectations and outcomes. A wealth of evidence across species and experimental techniques has established that RPEs are signaled by midbrain dopamine neurons. However, the way dopamine neurons receive information about reward outcomes remains poorly understood. Recent animal studies suggest that the pedunculopontine nucleus (PPN), a small brainstem structure considered as a locomotor center, is sensitive to reward and sends excitatory projection to dopaminergic nuclei. Here, we examined the hypothesis that the PPN could contribute to reward learning in humans. To this aim, we leveraged a clinical protocol that assessed the therapeutic impact of PPN deep-brain stimulation (DBS) in three patients with Parkinson disease. PPN local field potentials (LFPs), recorded while patients performed an instrumental learning task, showed a specific response to reward outcomes in a low-frequency (alpha-beta) band. Moreover, PPN DBS selectively improved learning from rewards but not from punishments, a pattern that is typically observed following dopaminergic treatment. Computational analyses indicated that the effect of PPN DBS on instrumental learning was best captured by an increase in subjective reward sensitivity. Taken together, these results support a causal role for PPN-mediated reward signals in human instrumental learning

Ontologie et TALN: l'anonymisation au service du repérage conceptuel dans le contexte de la SLA.

National audienceL’objectif de notre travail est l’exploitation de la base évènementielle du réseau SLA (Sclérose Latérale Amyotrophique) d’Île-de-France (IDF), pour permettre à long terme, de comprendre les ruptures de parcours de santé. Pour analyser ce corpus une chaine de pré traitement est nécessaire. L’un de ces processus est l’anonymisation, processus consistant à masquer l’ensemble des éléments ne permettant pas l’identification d’une personne. Ce processus de changement de données nominales en catégories sémantiques, permet secondairement une amélioration du repérage des concepts de l’ontologie du domaine, lors de l’utilisation d’outils du traitement automatique de la langue naturelle (TALN)