Gessica Vasco

Robotic and clinical evaluation of upper limb motor performance in patients with Friedreich’s Ataxia: an observational study

BackgroundFriedreich’s ataxia (FRDA) is the most common hereditary autosomal recessive form of ataxia. In this disease there is early manifestation of gait ataxia, and dysmetria of the arms and legs which causes impairment in daily activities that require fine manual dexterity. To date there is no cure for this disease. Some novel therapeutic approaches are ongoing in different steps of clinical trial. Development of sensitive outcome measures is crucial to prove therapeutic effectiveness. The aim of the study was to assess the reliability and sensitivity of quantitative and objective assessment of upper limb performance computed by means of the robotic device and to evaluate the correlation with clinical and functional markers of the disease severity.MethodsHere we assess upper limb performances by means of the InMotion Arm Robot, a robot designed for clinical neurological applications, in a cohort of 14 children and young adults affected by FRDA, matched for age and gender with 18 healthy subjects. We focused on the analysis of kinematics, accuracy, smoothness, and submovements of the upper limb while reaching movements were performed. The robotic evaluation of upper limb performance consisted of planar reaching movements performed with the robotic system. The motors of the robot were turned off, so that the device worked as a measurement tool. The status of the disease was scored using the Scale for the Assessment and Rating of Ataxia (SARA). Relationships between robotic indices and a range of clinical and disease characteristics were examined.ResultsAll our robotic indices were significantly different between the two cohorts except for two, and were highly and reliably discriminative between healthy and subjects with FRDA. In particular, subjects with FRDA exhibited slower movements as well as loss of accuracy and smoothness, which are typical of the disease. Duration of Movement, Normalized Jerk, and Number of Submovements were the best discriminative indices, as they were directly and easily measurable and correlated with the status of the disease, as measured by SARA.ConclusionsOur results suggest that outcome measures obtained by means of robotic devices can improve the sensitivity of clinical evaluations of patients’ dexterity and can accurately and efficiently quantify changes over time in clinical trials, particularly when functional scales appear to be no longer sensitive.

Functional and Gait Assessment in Children and Adolescents Affected by Friedreich's Ataxia: A One-Year Longitudinal Study.

Friedreich’s ataxia is the most common autosomal recessive form of neurodegenerative ataxia. We present a longitudinal study on the gait pattern of children and adolescents affected by Friedreich’s ataxia using Gait Analysis and the Scale for the Assessment and Rating of Ataxia (SARA). We assessed the spectrum of changes over 12 months of the gait characteristics and the relationship between clinical and instrumental evaluations. We enrolled 11 genetically confirmed patients affected by Friedreich’s ataxia in this study together with 13 normally developing age-matched subjects. Eight patients completed a 12-month follow-up under the same protocol. By comparing the gait parameters of Friedreich’s ataxia with the control group, we found significant differences for some relevant indexes. In particular, the increased knee and ankle extension in stance revealed a peculiar biomechanical pattern, which correlated reliably with SARA Total, Gait and Sitting scores. The knee pattern showed its consistency also at the follow-up: Knee extension increased from 6.8±3.5° to -0.5±3.7° and was significantly correlated with the SARA total score. This feature anticipated the loss of the locomotor function in two patients. In conclusion, our findings demonstrate that the selective and segmental analysis of kinetic/kinematic features of ataxic gait, in particular the behavior of the knee, provides sensitive measures to detect specific longitudinal and functional alterations, more than the SARA scale, which however has proved to be a reliable and practical assessment tool. Functional outcomes measures integrated by instrumental evaluation increase their sensitivity, reliability and suitability for the follow-up of the disease progression and for the application in clinical trials and in rehabilitative programs.

Nrf2-Inducers Counteract Neurodegeneration in Frataxin-Silenced Motor Neurons: Disclosing New Therapeutic Targets for Friedreich’s Ataxia

Oxidative stress is actively involved in Friedreich’s Ataxia (FA), thus pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor Nrf2 on frataxin-deficient cultured motor neurons and on fibroblasts of patients. The in vitro treatment of the potent Nrf2 activator sulforaphane increased Nrf2 protein levels and led to the upregulation of phase II antioxidant enzymes. The neuroprotective effects were accompanied by an increase in neurites’ number and extension. Sulforaphane (SFN) is a natural compound of many diets and is now being used in clinical trials for other pathologies. Our results provide morphological and biochemical evidence to endorse a neuroprotective strategy that may have therapeutic relevance for FA. The findings of this work reinforce the crucial importance of Nrf2 in FA and provide a rationale for using Nrf2-inducers as pharmacological agents.

The impact of vision on the dynamic characteristics of the gait: strategies in children with blindness

Visually impaired persons present an atypical gait pattern characterized by slower walking speed, shorter stride length and longer time of stance. Three explanatory hypotheses have been advanced in the literature: balance deficit, lack of an anticipatory mechanisms and foot probing the ground. In the present study, we compared the three hypotheses by applying their predictions to gait analysis and posturography of blind children without neurological impairment and compared their performance with that of an age-matched control group. The gait analysis results documented that blind children presented reduced walking velocity and step length, increased step width and external rotation of the foot progression angle, reduced ground reaction force and ankle maximum angle, moment and power in late stance, increased head flexion, decreased thorax flexion and pelvis anteversion, compared with the control group. The posturographic analysis showed equal skill level between blind children and normally sighted children when they close their eyes. The results are consistent with only one of the three hypotheses: namely, they prove that blind children’s gait is influenced only by the absence of visually driven anticipatory control mechanisms. Finally, rehabilitative recommendations for children with blindness are advanced in discussion.

Non-invasive Focal Mechanical Vibrations Delivered by Wearable Devices: An Open-Label Pilot Study in Childhood Ataxia

Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreichs Ataxia. Although limited by the sample size, the absence of a placebo-controlled group, the poor compliance of enrolled population to the original experimental design and the partial accuracy of outcome measures in pediatric subjects, we suggest that NIFMV by WS could support locomotion of patients with childhood slow/non-progressive cerebellar ataxia with preserved sensory system and no signs of peripheral neuropathy. Future studies are definitely necessary to confirm these preliminary results and define criteria for successful NIFMV-based treatment

Natural history of a cohort of ABCD1 variants female carriers

The therapeutic scenario of X‐linked adrenoleukodystrophy (X‐ALD) is rapidly changing. Whereas the disease is well characterized in men, the condition remains to be fully clarified in women carrying ATP binding cassette subfamily D member 1 (ABCD1) variants. Specifically, data on clinical progression are needed, in order to recommend any appropriate management. The objective of this study was to outline the natural history of a cohort of untreated ABCD1 heterozygous female carriers.

Time to boundary function to assess upright stance in blind children

The goal of this preliminary study was to assess the difference in postural stability between blind and sighted children using the Time to Boundary function (TtB). The experiment was conducted in twelve children (6-12 yrs), six of them had no visual impairment, and other six had congenital blindness. The participants stood on RotoBit force plate maintaining upright stance in static conditions. Each blind subject executed the task three times, each sighted subject executed the task six times, three with eyes closed (EC) and three with eyes open (EO). For all subjects each repetition lasted 30 s. The Centre of Pressure (CoP) coordinates, extracted directly from a force plate, are used to calculate four classical parameters (sway path, sway area, mean amplitude and mean frequency) and a predictive variable called Time to Boundary (TtB). The latter is the time it would take the CoP, given its instantaneous trajectory, to contact a stability boundary. Descriptive statistics were calculated for all parameters. Twoway ANOVA test was done considering the visual condition (EO, EC, BLIND) and the repetitions (RP) as a factor. In the first comparison (BLIND/EO) the results showed significant difference for all the parameters except for TtB. In the second comparison (BLIND/EC) the results showed significant difference only for TtB. In the third comparison (EO/EC) the results showed significant difference for all the calculated parameters. Therefore the TtB would be used to asses the postural control in children with blindness.