A new MRI rating scale for progressive supranuclear palsy and multiple system atrophy: validity and reliability

AIM To evaluate a standardised MRI acquisition protocol and a new image rating scale for disease severity in patients with progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA) in a large multicentre study. METHODS The MRI protocol consisted of two-dimensional sagittal and axial T1, axial PD, and axial and coronal T2 weighted acquisitions. The 32 item ordinal scale evaluated abnormalities within the basal ganglia and posterior fossa, blind to diagnosis. Among 760 patients in the study population (PSP = 362, MSA = 398), 627 had per protocol images (PSP = 297, MSA = 330). Intra-rater (n = 60) and inter-rater (n = 555) reliability were assessed through Cohen's statistic, and scale structure through principal component analysis (PCA) (n = 441). Internal consistency and reliability were checked. Discriminant and predictive validity of extracted factors and total scores were tested for disease severity as per clinical diagnosis. RESULTS Intra-rater and inter-rater reliability were acceptable for 25 (78%) of the items scored (≥ 0.41). PCA revealed four meaningful clusters of covarying parameters (factor (F) F1: brainstem and cerebellum; F2: midbrain; F3: putamen; F4: other basal ganglia) with good to excellent internal consistency (Cronbach α 0.75-0.93) and moderate to excellent reliability (intraclass coefficient: F1: 0.92; F2: 0.79; F3: 0.71; F4: 0.49). The total score significantly discriminated for disease severity or diagnosis; factorial scores differentially discriminated for disease severity according to diagnosis (PSP: F1-F2; MSA: F2-F3). The total score was significantly related to survival in PSP (p<0.0007) or MSA (p<0.0005), indicating good predictive validity. CONCLUSIONS The scale is suitable for use in the context of multicentre studies and can reliably and consistently measure MRI abnormalities in PSP and MSA. Clinical Trial Registration Number The study protocol was filed in the open clinical trial registry (http://www.clinicaltrials.gov) with ID No NCT00211224

Role of Basal Ganglia Circuits in Resisting Interference by Distracters: A swLORETA Study

BACKGROUND: The selection of task-relevant information requires both the focalization of attention on the task and resistance to interference from irrelevant stimuli. Both mechanisms rely on a dorsal frontoparietal network, while focalization additionally involves a ventral frontoparietal network. The role of subcortical structures in attention is less clear, despite the fact that the striatum interacts significantly with the frontal cortex via frontostriatal loops. One means of investigating the basal ganglia's contributions to attention is to examine the features of P300 components (i.e. amplitude, latency, and generators) in patients with basal ganglia damage (such as in Parkinson's disease (PD), in which attention is often impaired). Three-stimulus oddball paradigms can be used to study distracter-elicited and target-elicited P300 subcomponents. METHODOLOGY/PRINCIPAL FINDINGS: In order to compare distracter- and target-elicited P300 components, high-density (128-channel) electroencephalograms were recorded during a three-stimulus visual oddball paradigm in 15 patients with early PD and 15 matched healthy controls. For each subject, the P300 sources were localized using standardized weighted low-resolution electromagnetic tomography (swLORETA). Comparative analyses (one-sample and two-sample t-tests) were performed using SPM5® software. The swLORETA analyses showed that PD patients displayed fewer dorsolateral prefrontal (DLPF) distracter-P300 generators but no significant differences in target-elicited P300 sources; this suggests dysfunction of the DLPF cortex when the executive frontostriatal loop is disrupted by basal ganglia damage. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the cortical attention frontoparietal networks (mainly the dorsal one) are modulated by the basal ganglia. Disruption of this network in PD impairs resistance to distracters, which results in attention disorders

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

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

Analyse de la marche dans la maladie de Parkinson par enregistrement baropodométrique à l'aide de semelles embarquées

International audienceIntroduction. The literature reports some studies describing the walking pattern of patients with Parkinson’s disease, its deterioration withdisease severity and the effects of various treatments. Other studies concerned the plantar pressure distribution when walking. The aim ofthis study was to validate the use of baropodometric measurements for gait analysis of parkinsonian patients at various stages of diseaseseverity and in on and off phases. Methods. Fifteen normal control subjects and fifteen parkinsonian patients equipped with a plantarpressure measurement system performed walking tests. The parkinsonian patients performed the walking tests in off phase then in onphase. A clinical examination was performed to score the motor handicap on the UPDRS scale. Results. Analysis of the plantar pressuresof the parkinsonian subjects under various footprint areas detected significant baropodometric differences compared with controls, betweengroups with different UPDRS scores, and before and after L-Dopa treatment. Conclusions. Plantar pressures measurements allow a sufficientlyfine discrimination for using it to detect parkinsonism and monitor patients with Parkinson’s disease.Introduction. De nombreux travaux ont déjà été rapportés sur l'analyse de la marche dans la maladie de Parkinson à différents stades de la maladie ou pour évaluer l'effet de divers traitements. Quelques études ont été consacrées plus spécifiquement à la distribution des pressions plantaires lors de la marche. L'objet de ce travail est de valider l'intérêt des mesures baropodométriques dans l'étude de la marche de sujets parkinsoniens en périodes On et Off à différents stades de sévérité. Méthodes. Quinze sujets valides et quinze sujets parkinsoniens équipés d'un système de mesure des pressions plantaires ont réalisé des tests de marche en période Off, puis en période On. Le niveau de handicap moteur était évalué à partir de l'échelle UPDRS. Résultats. L'analyse des pressions plantaires des sujets parkinsoniens sous différentes zones de l'empreinte a détecté des différences baropodométriques significatives avec les sujets valides, entre des groupes de score UPDRS différents, et aussi avant et après traitement dopaminergique. Conclusions. La mesure des pressions plantaires permet une discrimination suffisamment fine pour que son utilisation soit envisagée dans la détection et le suivi clinique de patients atteints de la maladie de Parkinson

RÉALISATION D'UNE PROTHÈSE D'OREILLE MOYENNE

Nous présentons la conception et la réalisation d'une prothèse complète d'oreille moyenne (remplacement du tympan et de la chaîne ossiculaire). Des considérations de biocompatibilité ont orienté le choix des matériaux. Le tympan artificiel est constitué d'une membrane plane circulaire ou elliptique. Les modes propres de ces membranes sont calculés compte tenu de l'influence des cavités. Les techniques de construction et de caractérisation sont présentées. L'influence de différents paramètres a été étudiée, en particulier le vieillissement et la stérilisation. La réponse des prothèses est comparée à celle de tympans humains. Les résultats cliniques de six implantations sont aussi donnés.We present the design and the realization of a complete middle ear prosthesis (replacement of the eardrum and of the ossicular chain). Biocompatibility considerations have guided the choice of the materials. The artificial eardrum consists of a plane, circular or elliptic membrane. The vibration modes of these membrane have been worked out, considering the influence of the cavities. The characterization and construction technique is detailed. The influence of different parameters has been studied, in particular the aging and the sterilization. The response of the prosthesis is compared to that of the human eardrum. The clinical results of six implantations are also presented