White matter involvement in young non-demented Down's syndrome subjects: a tract-based spatial statistic analysis.

PURPOSE: Cognitive decline in Down syndrome generally shows neurodegenerative aspects similar to what is observed in Alzheimer's disease. Few studies reported information on white matter integrity. The aim of this study was to evaluate white matter alterations in a cohort of young Down subjects, without dementia, by means of DTI technique, compared to a normal control group. METHODS: The study group consisted of 17 right-handed subjects with DS and many control subjects. All individuals participating in this study were examined by MR exam including DTI acquisition (32 non-coplanar directions); image processing and analysis were performed using FMRIB Software Library (FSL version 4.1.9, http://www.fmrib.ox.ac.uk/fsl )) software package. Finally, the diffusion tensor was estimated voxel by voxel and the FA map derived from the tensor. A two-sample t test was performed to assess differences between DS and control subjects. RESULTS: The FA is decreased in DS subjects, compared to control subjects, in the region of the anterior thalamic radiation, the inferior fronto-occipital fasciculum, the inferior longitudinal fasciculum, and the cortico-spinal tract, bilaterally. CONCLUSIONS: The early white matter damage visible in our DS subjects could have great impact in the therapeutic management, in particular in better adapting the timing of therapies to counteract the toxic effect of the deposition of amyloid that leads to oxidative stress.

Age effects on cortical thickness in young Down's syndrome subjects: a cross-sectional gender study.

INTRODUCTION: The aim of this study was to determine differences in the characteristic pattern of age-related cortical thinning in men and women with Down's syndrome (DS) by means of MRI and automatic cortical thickness measurements and a cross-sectional design, in a large cohort of young subjects. METHODS: Eighty-four subjects with DS, 30 females (11-35 years, mean age ± SD = 22.8 ± 5.9) and 54 males (11-35 years, mean age ± SD = 21.5 ± 6.5), were examined using a 1.5-T scanner. MRI-based quantification of cortical thickness was performed using FreeSurfer software package. For all subjects participating in the study, the Pearson product-moment correlation coefficient between age and mean cortical thickness values has been evaluated. RESULTS: A significant negative correlation between cortical thickness and age was found in female DS subjects, predominantly in frontal and parietal lobes, bilaterally. In male DS subjects, a significant negative correlation between cortical thickness and age was found in the right fronto-temporal lobes and cingulate regions. Whole brain mean cortical thickness values were significantly negative correlated with age only in female DS subjects. CONCLUSIONS: Females with Down's syndrome showed a strong correlation between cortical thickness and age, already in early age. We suggest that the cognitive impairment due to hormonal deficit in the postmenopausal period could be emphasized by the early structural decline of gray matter in female DS subjects.

Intracellular distribution of differentially phosphorylated dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A).

The gene encoding dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is located within the Down syndrome (DS) critical region of chromosome 21. DYRK1A interacts with a plethora of substrates in the cytosol, cytoskeleton, and nucleus. Its overexpression is a contributing factor to the developmental alterations and age-associated pathology observed in DS. We hypothesized that the intracellular distribution of DYRK1A and cell-compartment-specific functions are associated with DYRK1A posttranslational modifications. Fractionation showed that, in both human and mouse brain, almost 80% of DYRK1A was associated with the cytoskeleton, and the remaining DYRK1A was present in the cytosolic and nuclear fractions. Coimmunoprecipitation revealed that DYRK1A in the brain cytoskeleton fraction forms complexes with filamentous actin, neurofilaments, and tubulin. Two-dimensional gel analysis of the fractions revealed DYRK1A with distinct isoelectric points: 5.5-6.5 in the nucleus, 7.2-8.2 in the cytoskeleton, and 8.7 in the cytosol. Phosphate-affinity gel electrophoresis demonstrated several bands of DYRK1A with different mobility shifts for nuclear, cytoskeletal, and cytosolic DYRK1A, indicating modification by phosphorylation. Mass spectrometry analysis disclosed one phosphorylated site in the cytosolic DYRK1A and multiple phosphorylated residues in the cytoskeletal DYRK1A, including two not previously described. This study supports the hypothesis that intracellular distribution and compartment-specific functions of DYRK1A may depend on its phosphorylation pattern.

Robot-assisted walking training for individuals with Parkinson's disease: a pilot randomized controlled trial.

BACKGROUND: Over the last years, the introduction of robotic technologies into Parkinson's disease rehabilitation settings has progressed from concept to reality. However, the benefit of robotic training remains elusive. This pilot randomized controlled observer trial is aimed at investigating the feasibility, the effectiveness and the efficacy of new end-effector robot training in people with mild Parkinson's disease. METHODS: Design. Pilot randomized controlled trial. RESULTS: Robot training was feasible, acceptable, safe, and the participants completed 100% of the prescribed training sessions. A statistically significant improvement in gait index was found in favour of the EG (T0 versus T1). In particular, the statistical analysis of primary outcome (gait speed) using the Friedman test showed statistically significant improvements for the EG (p = 0,0195). The statistical analysis performed by Friedman test of Step length left (p = 0,0195) and right (p = 0,0195) and Stride length left (p = 0,0078) and right (p = 0,0195) showed a significant statistical gain. No statistically significant improvements on the CG were found. CONCLUSIONS: Robot training is a feasible and safe form of rehabilitative exercise for cognitively intact people with mild PD. This original approach can contribute to increase a short time lower limb motor recovery in idiopathic PD patients. The focus on the gait recovery is a further characteristic that makes this research relevant to clinical practice. On the whole, the simplicity of treatment, the lack of side effects, and the positive results from patients support the recommendation to extend the use of this treatment. Further investigation regarding the long-time effectiveness of robot training is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01668407.

Feedback reliance during an arm-tapping task with obstacle avoidance in adults with Down syndrome.

Optimal movement control reflects a combination of both feedback and feedforward processes. However, as motor control evolves, feedforward mechanisms become prevailing respect to feedback-based movements, and less reliance on sensory information leads to a decreased number of corrections in the trajectory. In subjects with Down syndrome (DS), the study of the wrist's trajectory during an arm-tapping task revealed feedback-based corrections designed to reduce the degree of discrepancy between the position of the limb and the target, leading to the assumption that performers with DS have problems with movement planning and feedforward control. The present study was aimed at expanding the evidence about motor control in DS by evaluating the influence of a perturbing factor (an obstacle) on motor control strategies during an arm-tapping task and to clarify if the presence of an obstacle elicited a higher reliance on feedback control in controls and in DS. Sixteen right-handed adults with DS and 21 right-handed, age-matched control subjects (N) were evaluated by means of quantitative motion analysis. The results suggest that the presence of an obstacle elicited changes in the motor strategies of both DS and N, with a destabilizing effect that led subjects to rely more on feedback control. DS showed some aspects of movement efficiency that were in accordance with N strategies, but the prevailing factor of optimization in these subjects remained safety. A focused rehabilitation could help DS subjects to develop more efficient motor strategies in the presence of motor uncertainty and perturbations.

Motor strategies and motor programs during an arm tapping task in adults with Down Syndrome.

Slow movements and atypical patterns of muscle activation are well-known features of Down Syndrome (DS). Some studies attribute these features to a deficit in voluntary motor commands and preprogramming of actions, that lead subjects with DS to be more reliant on feedback control. In the present study, we evaluated the movement strategies of 13 adult subjects with DS and of 22 age-matched controls (N) during an arm tapping task. By means of quantitative motion analysis, our aim was to describe movement differences in DS respect to typical population and provide a means of interpreting such differences in terms of the underlying different control processes. The results highlighted distinct motor strategies for the tapping task in the two groups, with DS relying more on the trunk motion and N relying on the elbow motion to accomplish the task. Furthermore, DS corrected their wrist trajectory more than N subjects, giving shape to multi-peaked velocity profiles. Longer duration of the trials and a higher index of curvature were found in DS. The results suggest that subjects with DS rely more on feedback control, whereas they have problems with movement planning and feed-forward control. The different strategy operated by subjects with DS leads to a different task performance.

Whole-brain voxel-based morphometry study of children and adolescents with Down syndrome.

In order to investigate alterations in brain morphology and a possible temporal pattern of neuroanatomical abnormalities in the gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) of young patients with Down syndrome (DS), high-resolution magnetic resonance imaging (MRI) voxel-based morphometry (VBM) was performed on 21 children and adolescents with this chromosomal aberration and 27 age-matched participants as controls. In comparison with control subjects, children and adolescents with DS showed not only an overall smaller whole-brain volume, but also volume reductions of the GM in the cerebellum, frontal lobes, frontal region of the limbic lobe, parahippocampal gyri and hippocampi and of the WM in the cerebellum, frontal and parietal lobes, sub-lobar regions and brainstem. By contrast, volume preservation was observed in the GM of the parietal lobes, temporal lobe and sub-lobar regions and in the WM of the temporal lobe and temporal regions of the limbic lobe. A lower volume of CSF was also detected in the frontal lobes. This study is the first to use the high-resolution MRI VBM method to describe a whole-brain pattern of abnormalities in young DS patients falling within such a narrow age range and it provides new information on the neuroanatomically specific regional changes that occur during development in these patients.

Movement analysis and EEG recordings in children with hemiplegic cerebral palsy.

Impaired hand function is often the most disabling symptom in children with hemiplegic cerebral palsy (CP). Literature provides a wide number of studies dealing either with the kinematics or the cerebral correlates of the impairment. Nevertheless, few studies exist merging both aspects together. The aim of this study is the integrated analyses of time and spatial parameters of both the affected and less-affected sides and of the EEG signal, recorded during the movement execution, for the quantitative description of the pointing gesture in children with CP. The participants (pathological and control subjects) were asked to execute a pointing task simultaneously with the recording by an optoelectronic system and an electroencephalographer. Kinematic data were processed for the extraction of several synthetic indexes, to be correlated with parameters derived from frequency analysis of the electroencephalographic signal. Kinematic results showed statistical differences (1) between the affected and the less-affected arms in patients and (2) between the less-affected arm in patients and the normal arm in controls. Further differences were found in kinematics with respect to bilateral or ipsilateral motor control, extracted from EEG. Given the different behavior evidenced by either ipsilateral or contralateral reorganization, and considering the role of feedback and feed-forward contributions to motor programming, some hypotheses emerged about the motor control during pointing task in CP.

Quantitative evaluation of facial movement and morphology.

OBJECTIVES: The aim of our study was to quantitatively analyze facial motion kinematics by means of an optoelectronic system. In particular, we defined a set of easily recognizable reference points for markerization, and tested the applicability of our markerization method for an exhaustive characterization of the subjects' facial motion through the definition of some kinematic parameters. METHODS: Thirty healthy subjects (mean age, 24.6 +/- 1.0 years; 15 female and 15 male) participated in the study. A set of markers (diameter, 3 mm) was positioned on several reference points of the face, and some parameters were computed for the characterization of facial morphology and movement, such as ranges of motion, angles, times, and distances. RESULTS: The protocol was tested for inter-rater and intra-rater reliability by use of intraclass correlation, of which the results were good (between 0.4 and 0.75) to excellent (greater than 0.75). The parameters were useful for characterizing the resting position, mimicry, and speaking movements, and highlighted some distinctions between men and women in facial morphology. CONCLUSIONS: The protocol can be applied to a variety of facial movements, including speaking. Future works could address the use of the protocol in subjects with disorders and the integrated analysis of kinematic parameters and voice spectrography.

Spatiotemporal and kinematic aspects of obstacle avoidance in subjects with Down syndrome.

Obstacle avoidance studies have been extensively performed in normally developed subjects (N), but little work has been done on the characterization of this task in subjects with Down syndrome (DS). The aim of this study was to describe the management of walking with obstacle avoidance in adults with DS and in age-matched N subjects, considering both the lower and upper limbs. Ten subjects with DS and 16 N subjects were evaluated. The subjects walked along a walkway in two conditions: level, unobstructed walking and walking with an obstacle. The tasks were acquired using three-dimensional quantitative movement analysis. Spatiotemporal and kinematic parameters for the trunk, upper limbs and lower limbs were analyzed. The results demonstrated that the presence of a destabilizing element, the obstacle, enhanced different motor strategies in DS compared with N subjects, as shown by the parameters of the lower limbs, with a stabilization and safety strategy adopted at the upper limbs in DS.

Long-term voluntary running modifies the levels of proteins of the excitatory/inhibitory system and reduces reactive astrogliosis in the brain of Ts65Dn mouse model for Down syndrome.

We showed previously that voluntary long-term running improved cognition and motor skills, but in an age-dependent manner, in the Ts65Dn mouse model for Down syndrome (DS). Presently, we investigated the effect of running on the levels of some key proteins of the excitatory/inhibitory system, which is impaired in the trisomic brain, and on astroglia, a vital component of this system. Ts65Dn mice had free access to a running wheel for 9-13 months either from weaning or from the age of 7 months. Sedentary Ts65Dn mice served as controls. We found that running modified the levels of four of the seven proteins we tested that are associated with the glutamatergic/GABA-ergic system. Thus, Ts65Dn runners demonstrated increased levels of glutamine synthetase and metabotropic glutamate receptor 1 and decreased levels of glutamate transporter 1 and glutamic acid decarboxylase 65 (GAD65) versus sedentary mice, but of metabotropic glutamate receptor 1 and GAD65 only in the post-weaning cohort. GAD67, ionotropic N-methyl-D-aspartate type receptor subunit 1, and GABAAα5 receptors' levels were similar in runners and sedentary animals. The number of glial fibrillary acidic protein (GFAP)-positive astrocytes and the levels of GFAP were significantly reduced in runners relative to sedentary mice. Our study provides new insight into the mechanisms underlying the beneficial effect of voluntary, sustained running on function of the trisomic brain by identifying the involvement of proteins associated with glutamatergic and GABAergic systems and reduction in reactive astrogliosis.

Gait patterns in Prader-Willi and Down syndrome patients.

BACKGROUND: Prader-Willi (PWS) and Down Syndrome (DS) are two genetic disorders characterised by some common clinical and functional features. A quantitative description and comparison of their patterns would contribute to a deeper understanding of the determinants of motor disability in these two syndromes. The aim of this study was to measure gait pattern in PWS and DS in order to provide data for developing evidence-based deficit-specific or common rehabilitation strategies. METHODS: 19 PWS patients (17.7-40 yr) and 21 DS patients (18-39 yr) were evaluated with an optoelectronic system and force platforms for measuring kinematic and kinetic parameters during walking. The results were compared with those obtained in a group of normal-weight controls (Control Group: CG; 33.4 + 9.6 yr). RESULTS AND DISCUSSION: The results show that PWS and DS are characterised by different gait strategies. Spatio-temporal parameters indicated a cautious, abnormal gait in both groups, but DS walked with a less stable strategy than PWS. As for kinematics, DS showed a significantly reduced hip and knee flexion, especially at initial contact and ankle range of motion than PWS. DS were characterised by lower ranges of motion (p < 0.05) in all joints than CG and PWS. As for ankle kinetics, both PWS and DS showed a significantly lower push-off during terminal stance than CG, with DS yielding the lowest values. Stiffness at hip and ankle level was increased in DS. PWS showed hip stiffness values close to normal. At ankle level, stiffness was significantly decreased in both groups. CONCLUSIONS: Our data show that DS walk with a less physiological gait pattern than PWS. Based on our results, PWS and DS patients need targeted rehabilitation and exercise prescription. Common to both groups is the aim to improve hypotonia, muscle strength and motor control during gait. In DS, improving pelvis and hip range of motion should represent a major specific goal to optimize gait pattern.

Increased levels of carbonic anhydrase II in the developing Down syndrome brain.

By using a proteomic approach, we found increased levels of carbonic anhydrase II (CA II) in the brain of Ts65Dn mice, a mouse model for Down syndrome (DS). Further immunoblot analyses showed that the levels of CA II are increased not only in the brain of adult Ts65Dn mice but also in the brain of infants and young children with DS. Cellular localization of the enzyme in human brain, predominantly in the oligodendroglia and primitive vessels in fetal brain and in the oligodendroglia and some GABAergic neurons postnatally, was similar in DS subjects and controls. Given the role of CA II in regulation of electrolyte and water balance and pH homeostasis, up-regulation of CA II may reflect a compensatory mechanism mobilized in response to structural/functional abnormalities in the developing DS brain. However, this up-regulation may also have an unfavorable effect by increasing susceptibility to seizures of children with DS.

Management of pathologic laughter and crying in patients with locked-in syndrome: a report of 4 cases.

Emotional lability and pathologic laughter and crying (PLC) have been frequently mentioned in patients with locked-in syndrome (LIS) without giving any detail about the clinical characteristics and possible consequences in terms of symptoms burden, functional impact, and recovery. In the present report, we describe our approach and management of 4 patients with LIS and PLC. PLC caused discomfort to the patients and hindered the different components of their rehabilitation program, limiting communication, the execution of swallowing testing and training, and the improvement of any residual motor function. PLC was unrelated to depression, did not ameliorate after pharmacologic treatment, and improved with cognitive-behavior treatment. Our findings suggest that, in LIS patients, laughter and crying alterations do not represent symptoms of a mood disorder but are the result of the same pontine lesion that causes LIS. In relation to the complex pathway regulating laughter and crying, we hypothesized that, in patients with LIS, PLC may be the result of a direct damage to the pontine center or of an alteration in the ponto-cerebellar pathway linking emotional behavior to contextual information. Presence of PLC in patients with LIS severely affects their intelligent adaptation to the environment. Direct explanation to the patients of the origin of PLC may be helpful as a cognitive-behavior treatment, with resulting benefits to the entire rehabilitation program.

Postural control in patients with Down syndrome.

PURPOSE: To assess postural control in individuals with Down syndrome. METHOD: Sixty young adults with Down syndrome were assessed and compared to 10 non-handicapped young. The subjects were asked to stay on a force platform for 30 seconds. Postural control was evaluated in two conditions: open and closed eyes. The kinetic data carried out from the force platform (i.e., ground reaction forces and Center of Pression (COP) displacements) were both evaluated in time domain and in frequency domain. RESULTS: Patients with Down syndrome are characterized by instable postural control. In particular the data evaluation in frequency domain underlined for Down syndrome subjects versus control group an increase in frequency oscillation both in anterior-posterior and in medio-lateral direction, that are confirmed in time domain analysis only for medio-lateral direction. In DS no changes are evident between eyes open and eyes closed condition. CONCLUSION: This study finds that subjects with Down syndrome included in this research demonstrate that deficits in postural control system that may provide a partial explanation for function balance problems that are common in these subjects.

Cognitive level and adaptive behaviour in the Klippel-Trenaunay-Weber Syndrome. An example of the potentials of an early intervention model applied to a complex pathology.

PURPOSE: The Klippel-Trenaunay-Weber syndrome is a rare, congenital disorder characterized by benign excessive growth of blood vessels on the skin. Little is still known about its cognitive development and adaptive behaviour functioning. CASE STUDY: This case study describes the clinical history of a female child suffering from this rare syndrome and admitted to our Pediatric Unit in order to provide motor rehabilitation, speech therapy and psychoanalytic psychotherapy following an early intervention model program. After five years of treatment her clinical picture witnessed a considerable improvement. CONCLUSIONS: Patients with Klippel-Trenaunay-Weber Syndrome are best served by a multidisciplinary approach, and this case study shows the effectiveness of an early intervention program on the cognitive development and adaptive behaviour functioning.

Computerized gait analysis of botulinum toxin treatment in children with cerebral palsy.

PURPOSE: Intramuscular botulinum toxin A (BTA) injection is a local reversible treatment with a wide range of therapeutic applications, including temporary reduction of spasticity. The aim of this work was a quantitative, computerized objective evaluation of BTA-induced improvement of the walking functional ability in a group of children with cerebral palsy (CP). METHODS: Fifteen children with CP and 20 healthy children were evaluated. All patients were equinus walkers without fixed contractures of triceps surae muscles and they were evaluated before and after about 1.5 months from BTA injections into the calf muscles. The effectiveness of treatment was evaluated by 3D computerized gait analysis. RESULTS: Data analysis revealed a significant improvement of equinus foot and ankle range of motion during gait after BTA injection. Positive effects were evident also at the knee joint as documented by the improvement of kinetics characteristics (moment and power). CONCLUSIONS: Computerized gait analysis is a valid method for quantification of BTA effect on walking in children with CP, allowing a detailed evaluation of improvement at each joint and a quantitative evaluation of treatment outcome.

Are patients with hereditary spastic paraplegia different from patients with spastic diplegia during walking? Gait evaluation using 3D gait analysis.

Patients with hereditary spastic paraplegia (HSP) often resemble patients with mild spastic diplegia (SD), although their motor limitations differ. The aim of this study was to analyse quantitatively the gait of HSP and SD subjects in order to define the gait pattern in HSP and the differences between the two conditions. Fifteen subjects with HSP, 40 patients with SD and 20 healthy subjects underwent gait analysis (GA). The spatio-temporal and kinematic parameters at the proximal joints were found to be similar in HSP and SD, whereas the most significant differences were found at the knee and ankle joints. Both groups displayed a tendency for knee hyperextension in the midstance phase, but the duration of this hyperextension was longer in the HSP patients. This study shows that GA complements traditional clinical evaluations, making it possible to distinguish, clearly, between motor ability in HSP and in SD patients; the duration of the knee hyperextension during midstance was found to discriminate between the two gait patterns.

Gait alteration of a teenager with Down's syndrome: a 5-year follow-up before and after surgery.

Aim of this study is to evaluate kinematic and kinetic aspects of gait alteration in a teenager with Down's syndrome before and after surgery. The gait pattern of the participant was evaluated quantitatively by gait analysis at different ages. In the interval between 14 and 16 years, a patella surgery was performed on the right knee joint. A worsening of gait ability in kinematic and kinetic patterns was highlighted before surgical treatment. After surgery, a significant improvement was observed. The 5-year follow-up showed an improvement in the gait ability after the surgery and allowed quantitative evaluation of treatment outcomes.

Three dimensional motion capture applied to violin playing: A study on feasibility and characterization of the motor strategy.

BACKGROUND AND OBJECTIVE: Playing string instruments requires advanced motor skills and a long training that is often spent in uncomfortable postures that may lead to injuries or musculoskeletal disorders. Thus, it is interesting to objectively characterize the motor strategy adopted by the players. In this work, we implemented a method for the quantitative analysis of the motor performance of a violin player. METHODS: The proposed protocol takes advantage of an optoelectronic system and some infra-red reflecting markers in order to track player's motion. The method was tested on a professional violin player performing a legato bowing task. The biomechanical strategy of the upper limb and bow positioning were described by means of quantitative parameters and motion profiles. Measured quantities were: bow trajectory, angles, tracks, velocity, acceleration and jerk. RESULTS: A good repeatability of the bowing motion (CV < 2%) and high smoothness (jerk < 5 m/s3) were observed. Motion profiles of shoulder, elbow and wrist were repeatable (CV < 7%) and comparable to the curves observed in other studies. Jerk and acceleration profiles demonstrated high smoothness in the ascending and descending phases of bowing. High variability was instead observed for the neck angle (CV ∼56%). CONCLUSIONS: "Quantitative" measurements, instead of "qualitative" observation, can support the diagnosis of motor disorders and the accurate evaluation of musicians' skills. The proposed protocol is a powerful tool for the description of musician's performance, that may be useful to document improvements in playing abilities and to adjust training strategies.