Comparative analysis of gait and speech in Parkinson's disease: hypokinetic or dysrhythmic disorders?

International audienceGait and speech are automatic motor activities which are frequently impaired in Parkinson's disease (PD). Obvious clinical similarities exist between these disorders but were never investigated. We propose to determine whether there exist any common features in PD between spatiotemporal gait disorders and temporal speech disorders. Gait and speech were analyzed on eleven PP undergoing deep-brain-stimulation of the sub-thalamic-nucleus (STN-DBS) and eleven control subjects (CS) under 3 conditions of velocity (natural, slow and speed). The patients were tested with and without L-Dopa and stimulator ON or OFF. Locomotor parameters were recorded using an optoelectronic system. Speech parameters were recorded with a headphone while subjects were reading a short paragraph. The results confirmed that PP walk and read more slowly than controls. Patient's difficulties in modulating walking and speech velocities seem to be due mainly to an inability to internally control the step length and the interpause-speech duration ISD. STN-DBS and levodopa increased patients' walking velocity by increasing the step length. STN-DBS and levodopa had no effect on speech velocity but restored the patients' ability to modulate the ISD. The walking cadence and speech index of rythmicity (SPIR) tended to be lower in patients and were not significantly improved by STN-DBS or levodopa. Speech and walking velocity as well as ISD and step length were correlated in both groups. Negative correlations between SPIR and walking cadence were observed in both groups Similar fundamental hypokinetic impairment and probably a similar rhythmic factor affected similarly the patients' speech and gait. These results suggest a similar physiopathological process in both walking and speaking dysfunction

Neuroendocrine Disturbances in Huntington's Disease

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

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

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

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

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.Identification of new causative genes in spinocerebellar degenerations by combination of whole genome scan, next-generation sequencing and biological validation in vitro and in vivoInfrastructure de Recherche Translationnelle pour les Biothérapies en NeurosciencesEuropean Union’s Horizon 2020 research and innovation programm

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

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

Role of sensory information in the control of postural orientation in Parkinson's disease

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Analyse comparative des troubles rythmiques de la marche et de la parole chez le patient parkinsonien stimulé

Si l expression motrice des symptômes de la maladie de Parkinson se traduit principalement au niveau des membres, le clinicien constate souvent l émergence, au fur et à mesure de l évolution de la maladie, de signes axiaux caractéristiques. Ainsi, marche et parole sont souvent touchées par le syndrome akinéto-rigide de la maladie mais aussi par une dysrégulation du rythme de ces activités motrices automatisées se manifestant sur le plan clinique pour l une par des phénomènes de festination et de freezing de la marche et pour l autre par des phénomènes de répétitions et de blocage de la parole. C est à la relation qu il peut exister entre akinésie et rythme au cours de la marche et de la parole que nous nous sommes intéressés au cours de ce travail. Pour cela, nous avons comparé les performances de marche et de parole en lecture et en répétition de syllabes de 11 sujets témoins et de 11 patients parkinsoniens porteurs d une stimulation cérébrale profonde bilatérale du noyau sous-thalamique, dans les quatre conditions de traitement et dans cinq situations expérimentales. Nos résultats montrent une augmentation de la cadence de marche compensatoire à l akinésie de la marche chez le patient parkinsonien. Par l existence de corrélations positives entre cadence de marche et vitesse de parole d une part et longueur du pas et durée des suites sonores d autre part nos résultats suggèrent que l accélération du rythme de parole observée dans la maladie de Parkinson pourrait, de la même façon, être compensatoire à l akinésie de la parole. Cette première approche des corrélations entre marche et parole dans la maladie de Parkinson n a pu prouver avec certitude l hypothèse de déficits similaires sur l axe temporel entre ces deux activités motrices mais nos résultats prometteurs soulèvent l existence de processus physiopathologiques proches. Ainsi, si le dysfonctionnement des noyaux gris centraux explique l akinésie de la marche et de la parole et que le trouble du rythme de la marche trouve son origine dans un dysfonctionnement du noyau pédonculopontin, notre étude ouvre de nouvelle perspectives expérimentales qui peut être permettront de déterminer avec certitude la structure impliquée dans la dysrégulation du rythme de la parole chez le patient parkinsonien.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Les anomalies d'excitabilité du cortex moteur primaire et leurs relations avec les troubles locomoteurs dans la maladie de Parkinson

Les travaux réalisés lors de cette thèse ont porté sur le cortex moteur et les troubles de la marche de patients atteints de la maladie de Parkinson (MP). L atteinte fonctionnelle des aires motrices corticales dans la MP et leur implication dans la physiopathologie des désordres moteurs a surtout été établie à partir de données issues des aires corticales des membres supérieurs. L analyse électrophysiologique par stimulation magnétique transcranienne réalisée dans ces travaux de thèse a exploré les aires motrices corticales des membres inférieurs et révélé des troubles d excitabilité différents de ceux classiquement décrits dans les aires corticales des membres supérieurs. En effet, il ressort principalement de l étude sur le membre inférieur une diminution de la facilitation intracorticale (FIC) alors que la littérature décrit essentiellement pour les aires motrices corticales des membres supérieurs une altération des mécanismes inhibiteurs intracorticaux. Les anomalies corticales mises en évidence sont corrélées avec les paramètres locomoteurs affectés par la maladie, longueur d enjambée et vitesse de marche. L analyse des patients avec et sans traitement a permis de montrer que la supplémentation dopaminergique agit à la fois au niveau cortical et locomoteur normalisant partiellement les déficits observés. Les anomalies de FIC des aires corticales motrices des membres inférieurs paraissent donc être impliquées dans la physiopathologie des troubles de la marche dans la MP et pourraient de ce fait constituer un paramètre d évaluation et un objectif thérapeutique de choix. L utilisation de la stimulation magnétique transcranienne répétitive couplée à la neuronavigation permettrait d explorer cette dernière piste.This thesis aims to study the relationships between motor cortex impairment and locomotor disorders in Parkinsonian patients (PP). Most of the previous studies have focused on the upper limb cortical areas showing the existence of an imbalance in cortical excitability, which mainly evolves towards a state of impaired intracortical inhibition. However, just a few studies have been devoted so far to the exact cortical abnormalities responsible for Parkinsonians gait disorders. The transcranial magnetic stimulation (TMS) studies presented here demonstrate that the excitability abnormalities occurring in PP differ between the cortical areas associated with the lower and upper limbs, since defective intracortical facilitation (ICF) processes were mainly detected in the lower limbs cortical areas. Furthermore, these specific excitability abnormalities identified seem to be involve in the genesis of the hypokinetic locomotor component since correlations were established between the ICF level and the shortened stride length (and by correlates, with the reduced velocity). Patients were assessed with and without dopaminergic substitution treatment (DST). We found that DST modified significantly both the cortical excitability abnormalities and the defective locomotor parameters. Impaired facilitatory processes in lower limbs cortical areas may be involved in the pathophysiology of gait disorders in PD. This hypothesis should be addressed in an experiment coupling repetitive TMS and neuronavigation.AIX-MARSEILLE2-Bib.electronique (130559901) / SudocSudocFranceF

Apport de l'étude de la voie motrice au diagnostic de l'atrophie multisystématisée

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Locomotion : physiologie, méthodes d'analyse et classification des principaux troubles

International audienceDepuis son acquisition au cours du développement jusqu'à la sénescence, les troubles de la marche, ainsi que ceux de l'équilibre et de la posture, sont des motifs de consultation fréquents en médecine, et tout spécialement auprès du neurologue, du rhumatologue et du médecin rééducateur. L'approche de ces troubles repose essentiellement sur une analyse clinique systématique associée à un examen neurologique global. La classification proposée dans cet article dans un but très pratique de diagnostic repose sur le déficit cardinal du trouble : équilibre, déficit moteur, trouble hyper- ou hypokinétique, ce qui nécessite de connaître les principaux fondements physiopathologiques de la locomotion. Certains troubles étiquetés complexes intègrent plusieurs dysfonctions dont une dimension cognitive. L'identification du trouble spécifique de la marche peut dans certains cas déboucher sur une conduite thérapeutique adaptée : rééducation fonctionnelle, traitement chimique (lévodopa), chirurgical (dérivation ventriculopéritonéale). Les innovations dans ce domaine sont nombreuses ; il faut en particulier souligner la place que prend la stimulation cérébrale profonde qui donne déjà dans les cibles classiques des résultats dans de nombreux domaines de la pathologie du mouvement (pallidum interne et dystonie, noyau sous-thalamique et maladie de Parkinson), mais qui connaît un développement propre aux troubles posturolocomoteurs avec le ciblage du noyau pédonculopontin en relation directe avec les études les plus récentes en neurosciences chez l'animal et chez l'homme sur les centres locomoteurs