RNA interference mitigates motor and neuropathological deficits in a cerebellar mouse model of machado-joseph disease.

Machado-Joseph disease or Spinocerebellar ataxia type 3 is a progressive fatal neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Recent studies demonstrate that RNA interference is a promising approach for the treatment of Machado-Joseph disease. However, whether gene silencing at an early time-point is able to prevent the appearance of motor behavior deficits typical of the disease when initiated before onset of the disease had not been explored. Here, using a lentiviral-mediated allele-specific silencing of mutant ataxin-3 in an early pre-symptomatic cerebellar mouse model of Machado-Joseph disease we show that this strategy hampers the development of the motor and neuropathological phenotypic characteristics of the disease. At the histological level, the RNA-specific silencing of mutant ataxin-3 decreased formation of mutant ataxin-3 aggregates, preserved Purkinje cell morphology and expression of neuronal markers while reducing cell death. Importantly, gene silencing prevented the development of impairments in balance, motor coordination, gait and hyperactivity observed in control mice. These data support the therapeutic potential of RNA interference for Machado-Joseph disease and constitute a proof of principle of the beneficial effects of early allele-specific silencing for therapy of this disease.

A structural MRI study of motor conversion disorder: evidence of reduction in thalamic volume.

OBJECTIVE: To investigate potential abnormalities in subcortical brain structures in conversion disorder (CD) compared with controls using a region of interest (ROI) approach. METHODS: Fourteen patients with motor CD were compared with 31 healthy controls using high-resolution MRI scans with an ROI approach focusing on the basal ganglia, thalamus and amygdala. Brain volumes were measured using Freesurfer, a validated segmentation algorithm. RESULTS: Significantly smaller left thalamic volumes were found in patients compared with controls when corrected for intracranial volume. These reductions did not vary with handedness, laterality, duration or severity of symptoms. CONCLUSIONS: These differences may reflect a primary disease process in this area or be secondary effects of the disorder, for example, resulting from limb disuse. Larger, longitudinal structural imaging studies will be required to confirm the findings and explore whether they are primary or secondary to CD.

Recent skin injuries in children with motor disabilities.

OBJECTIVE: To determine the frequency of recent skin injuries in children with neuromotor disabilities and its association with disability. DESIGN: Cross-sectional study of 168 children with neuromotor disabilities aged 2-16 years. SETTING: Two outpatient child rehabilitation centres. MAIN OUTCOME MEASURES: Children were classified as unrestricted walkers, restricted walkers or wheelchair dependent. Each participant's body surface was systematically examined for recent skin injuries with the exception of the anal-genital area. RESULTS: The mean age of our sample was 7.8 (SD 3.7) years with a 3:2 male/female ratio. Overall, 64% had cerebral palsy, 17% a neuromuscular disease and 19% other motor disabilities. Participants had on average 5.3 (SD 4.5) recent skin injuries (max 19), of which 2.5 were bruises (SD 3.3, max 16), 2.4 were abrasions, scratches or cuts (SD 3.0, max 16) and 0.4 were pressure lesions (SD 0.8, max 4). There was a significant decrease in the frequency of recent skin injuries and of bruises with increasing severity of motor disability. Most of this variation was accounted for by injuries to the lower limbs. There were no significant effects of gender, learning disabilities or other comorbidities. CONCLUSIONS: Children with neuromotor disabilities present a progressive reduction in the number of skin injuries with decreasing mobility. Therefore, recent skin injuries in this population which are unusual by their number, appearance or distribution, should raise at least the same level of suspicion for physical abuse as in children without disabilities.

Improvement in gross motor performance between 3 and 5 years of age.

This study examined gross motor performance of 101 typically developing children between 3 and 5 years of age (48 boys, 53 girls, M age = 3.9 yr., SD = 0.5). All children performed 7 different gross motor tasks which were rated on a 5-point scale. Age and sex were assessed by an ordinal-logistic model, and odds ratios were calculated for each task using age and sex as covariates. For standing on one leg, walking on a beam, hopping on one leg, running, and taking stairs, statistically significant age differences were found, while for rising and jumping down, none were apparent. Mean motor performance did not differ between boys and girls on the tasks. The older the children were, the better they performed on the tasks.

A new early and automated MRI-based predictor of motor improvement after stroke.

OBJECTIVES: In this study, we investigated the structural plasticity of the contralesional motor network in ischemic stroke patients using diffusion magnetic resonance imaging (MRI) and explored a model that combines a MRI-based metric of contralesional network integrity and clinical data to predict functional outcome at 6 months after stroke. METHODS: MRI and clinical examinations were performed in 12 patients in the acute phase, at 1 and 6 months after stroke. Twelve age- and gender-matched controls underwent 2 MRIs 1 month apart. Structural remodeling after stroke was assessed using diffusion MRI with an automated measurement of generalized fractional anisotropy (GFA), which was calculated along connections between contralesional cortical motor areas. The predictive model of poststroke functional outcome was computed using a linear regression of acute GFA measures and the clinical assessment. RESULTS: GFA changes in the contralesional motor tracts were found in all patients and differed significantly from controls (0.001 ≤ p < 0.05). GFA changes in intrahemispheric and interhemispheric motor tracts correlated with age (p ≤ 0.01); those in intrahemispheric motor tracts correlated strongly with clinical scores and stroke sizes (p ≤ 0.001). GFA measured in the acute phase together with a routine motor score and age were a strong predictor of motor outcome at 6 months (r(2) = 0.96, p = 0.0002). CONCLUSION: These findings represent a proof of principle that contralesional diffusion MRI measures may provide reliable information for personalized rehabilitation planning after ischemic motor stroke. Neurology® 2012;79:39-46.

Trends in motor vehicle crash mortality in Europe, 1980-2007.

Recent trends (1980-2007) in mortality from road traffic crashes in European countries, and, for comparative purposes, in the USA and Japan were reviewed. Data came from the World Health Organisation database. Age-standardised rates, at all ages and at 15-24, 25-64, >=65 years, were computed. Joinpoint regression analyses to evaluate significant changes in trends were performed. In the European Union as a whole rates declined from 20.2 in 1987 to 13.5/100,000 in 2007 in men, and from 6.3 to 3.7/100,000 in women; European Union rates remained lower than USA, but higher than Japanese ones. In 2007, the highest male rates were in Lithuania (36.7/100,000), the Russian Federation (35.2), Ukraine (29.8), and Latvia (28.5), and the lowest ones in the Netherlands (6.2) and Sweden (6.9); the highest female rates were in the Russian Federation (11.3), Lithuania (9.7), Belarus, Latvia, and Ukraine (around 8), and the lowest ones in Switzerland (1.7), the UK, and Nordic countries (around 2). Mortality from motor vehicle crashes declined in northern and western European countries and - though to a lesser extent - in southern European countries, too. Mortality trends were also favourable in the Czech Republic and Poland since the mid 1990's, whereas they were still upwards in Romania and the Russian Federation. No trend was observed in Hungary and Ukraine. Trends were consistent in various age groups considered. Thus, additional urgent and integrated intervention is required to prevent avoidable deaths from motor vehicle crashes, particularly in selected central and eastern European countries.

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease.

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer's disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick's disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family).

Traitement de la douleur chronique: rôle de la stimulation transcrânienne du cortex moteur [Treatment of chronic pain: transcranial stimulation of the motor cortex?].

Chronic pain refractory to medical therapy poses a therapeutic challenge. The repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS) modulate brain activity offering a new approach. Current evidence suggests a potential therapeutic efficacy of motor cortex stimulation for the treatment of pain, but does not (yet) support their recommendation for clinical practice. These methods allow to deepen our knowledge in the pathophysiology of chronic pain while providing new therapeutic approaches.

Neuromotor development in children. Part 3: motor performance in 3- to 5-year-olds.

AIM: The aim of this cross-sectional study was to provide normative data (ordinal scores and timed performances) for gross and fine motor tasks in typically developing children between 3 and 5 years of age using the Zurich Neuromotor Assessment (ZNA). METHOD: Typically developing children (n=101; 48 males, 53 females) between 3 and 5 years of age were enrolled from day-care centres in the greater Zurich area and tested using a modified version of the ZNA; the tests were recorded digitally on video. Intraobserver reliability was assessed on the videos of 20 children by one examiner. Interobserver reliability was assessed by two examiners. Test-retest reliability was performed on an additional 20 children. The modelling approach summarized the data with a linear age effect and an additive term for sex, while incorporating informative missing data in the normative values. Normative data for adaptive motor tasks, pure motor tasks, and static and dynamic balance were calculated with centile curves (for timed performance) and expected ordinal scores (for ordinal scales). RESULTS: Interobserver, intraobserver, and test-retest reliability of tasks were moderate to good. Nearly all tasks showed significant age effects, whereas sex was significant only for stringing beads and hopping on one leg. INTERPRETATION: These results indicate that timed performance and ordinal scales of neuromotor tasks can be reliably measured in preschool children and are characterized by developmental change and high interindividual variability.

Spatial distribution of motor units recruited during electrical stimulation of the quadriceps muscle versus the femoral nerve.

INTRODUCTION: In this study we investigated differences in the spatial recruitment of motor units (MUs) in the quadriceps when electrical stimulation is applied over the quadriceps belly versus the femoral nerve. METHODS: M-waves and mechanical twitches were evoked using over-the-quadriceps and femoral nerve stimulation of gradually increasing intensity from 22 young, healthy subjects. Spatial recruitment was investigated using recruitment curves of M-waves recorded from the vastus medialis (VM) and vastus lateralis (VL) and of twitches recorded from the quadriceps. RESULTS: At maximal stimulation intensity (Imax), no differences were found between nerve and over-the-quadriceps stimulation. At submaximal intensities, VL M-wave amplitude was higher for over-the-quadriceps stimulation at 40% Imax, and peak twitch force was greater for nerve stimulation at 60% and 80% Imax. CONCLUSIONS: For the VM, MU spatial recruitment during nerve and over-the-quadriceps stimulation of increasing intensity occurred in a similar manner, whereas significant differences were observed for the VL. Muscle Nerve, 2013.