Single Systemic Administration of a Gene Therapy Leading to Disease Treatment in Metachromatic Leukodystrophy Arsa Knock-Out Mice.

Metachromatic leukodystrophy (MLD) is a rare, inherited, demyelinating lysosomal storage disorder caused by mutations in the arylsulfatase-A gene (ARSA). In patients, levels of functional ARSA enzyme are diminished and lead to deleterious accumulation of sulfatides. Herein, we demonstrate that intravenous administration of HSC15/ARSA restored the endogenous murine biodistribution of the corresponding enzyme, and overexpression of ARSA corrected disease biomarkers and ameliorated motor deficits in Arsa KO mice of either sex. In treated Arsa KO mice, when compared with intravenously administered AAV9/ARSA, significant increases in brain ARSA activity, transcript levels, and vector genomes were observed with HSC15/ARSA Durability of transgene expression was established in neonate and adult mice out to 12 and 52 weeks, respectively. Levels and correlation between changes in biomarkers and ARSA activity required to achieve functional motor benefit was also defined. Finally, we demonstrated blood-nerve, blood-spinal and blood-brain barrier crossing as well as the presence of circulating ARSA enzyme activity in the serum of healthy nonhuman primates of either sex. Together, these findings support the use of intravenous delivery of HSC15/ARSA-mediated gene therapy for the treatment of MLD.SIGNIFICANCE STATEMENT Herein, we describe the method of gene therapy adeno-associated virus (AAV) capsid and route of administration selection leading to an efficacious gene therapy in a mouse model of metachromatic leukodystrophy. We demonstrate the therapeutic outcome of a new naturally derived clade F AAV capsid (AAVHSC15) in a disease model and the importance of triangulating multiple end points to increase the translation into higher species via ARSA enzyme activity and biodistribution profile (with a focus on the CNS) with that of a key clinically relevant biomarker.

Constraint-induced movement therapy alleviates motor impairment by inhibiting the accumulation of neutrophil extracellular traps in ischemic cortex.

Stroke is a major cause of mortality and morbidity and most acute strokes are ischemic. Evidence-based medicine has demonstrated the effectiveness of constraint-induced movement therapy (CIMT) in the recovery of motor function in patients after ischemic stroke, but the specific treatment mechanism remains unclear. Herein, our integrated transcriptomics and multiple enrichment analysis studies, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) studies show that CIMT conduction broadly curtails immune response, neutrophil chemotaxis, and chemokine-mediated signaling pathway, CCR chemokine receptor binding. Those suggest the potential effect of CIMT on neutrophils in ischemic mice brain parenchyma. Recent studies have found that accumulating granulocytes release extracellular web-like structures composed of DNA and proteins called neutrophil extracellular traps (NETs), which destruct neurological function primarily by disrupting the blood-brain barrier and promoting thrombosis. However, the temporal and spatial distribution of neutrophils and their released NETs in parenchyma and their damaging effects on nerve cells remain unclear. Thus, utilizing immunofluorescence and flow cytometry, our analyses uncovered that NETs erode multiple regions such as primary motor cortex (M1), striatum (Str), nucleus of the vertical limb of the diagonal band (VDB), nucleus of the horizontal limb of the diagonal band (HDB) and medial septal nucleus (MS), and persist in the brain parenchyma for at least 14 days, while CIMT can reduce the content of NETs and chemokines CCL2 and CCL5 in M1. Intriguingly, CIMT failed to further reduce neurological deficits after inhibiting the NET formation by pharmacologic inhibition of peptidylarginine deiminase 4 (PAD4). Collectively, these results demonstrate that CIMT could alleviate cerebral ischemic injury induced locomotor deficits by modulating the activation of neutrophils. These data are expected to provide direct evidence for the expression of NETs in ischemic brain parenchyma and novel insights into the mechanisms of CIMT protecting against ischemic brain injury.

Broad Therapeutic Time Window for Driving Motor Recovery After TBI Using Activity-Dependent Stimulation.

BACKGROUND: After an acquired injury to the motor cortex, the ability to generate skilled movements is impaired, leading to long-term motor impairment and disability. While rehabilitative therapy can improve outcomes in some individuals, there are no treatments currently available that are able to fully restore lost function. OBJECTIVE: We previously used activity-dependent stimulation (ADS), initiated immediately after an injury, to drive motor recovery. The objective of this study was to determine if delayed application of ADS would still lead to recovery and if the recovery would persist after treatment was stopped. METHODS: Rats received a controlled cortical impact over primary motor cortex, microelectrode arrays were implanted in ipsilesional premotor and somatosensory areas, and a custom brain-machine interface was attached to perform the ADS. Stimulation was initiated either 1, 2, or 3 weeks after injury and delivered constantly over a 4-week period. An additional group was monitored for 8 weeks after terminating ADS to assess persistence of effect. Results were compared to rats receiving no stimulation. RESULTS: ADS was delayed up to 3 weeks from injury onset and still resulted in significant motor recovery, with maximal recovery occurring in the 1-week delay group. The improvements in motor performance persisted for at least 8 weeks following the end of treatment. CONCLUSIONS: ADS is an effective method to treat motor impairments following acquired brain injury in rats. This study demonstrates the clinical relevance of this technique as it could be initiated in the post-acute period and could be explanted/ceased once recovery has occurred.

Dynamic Standing Exercise using the Innowalk Device in Patients with Genetic and Acquired Motor Impairments.

OBJECTIVE: For individuals with motor impairments, dynamic standing has been proposed as an opportunity for regular daily physical activity. The aim of this study was to analyse patient characteristics, indications, intensity of usage, desired objectives and outcomes of dynamic standing in daily clinical practice in order to form the basis for research regarding this treatment option. SETTING: Data were analysed from standardized questionnaires completed prospectively before supply of a home-based medical device for dynamic standing (Innowalk; Made for Movement GmbH, Langenhagen, Germany) and at the time of individual adaptations. PARTICIPANTS: In a retrospective chart analysis, records of 46 patients (50% cerebral palsy; 50% diverse syndromes) were evaluated. INTERVENTION: The Innowalk had been prescribed for either home-based use (n = 31), in therapeutic institutions (n = 8), or other settings (n = 7). Dynamic standing was performed for 10-30 min as a single session (n = 8) or for 20-60 min 11 [4-21] weeks in 36 patients. RESULTS: Improvements were found for: passive assisted motion (79%), stimulation of intestinal functions (71%), body stability (64%), joint mobility (56%), secure means of allowing supine position (52%), and revision of abnormal motion patterns (48%). CONCLUSION: Thus, this systematic approach shows usage patterns, indications, desired goals and clinical outcome of dynamic standing in daily clinical practice and forms the basis for the design of a prospective, randomized controlled trial.

Murine glial progenitor cells transplantation and synthetic PreImplantation Factor (sPIF) reduces inflammation and early motor impairment in ALS mice.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuronal disorder characterized by neuronal degeneration and currently no effective cure is available to stop or delay the disease from progression. Transplantation of murine glial-restricted precursors (mGRPs) is an attractive strategy to modulate ALS development and advancements such as the use of immune modulators could potentially extend graft survival and function. Using a well-established ALS transgenic mouse model (SOD1G93A), we tested mGRPs in combination with the immune modulators synthetic PreImplantation Factor (sPIF), Tacrolimus (Tac), and Costimulatory Blockade (CB). We report that transplantation of mGRPs into the cisterna magna did not result in increased mice survival. The addition of immunomodulatory regimes again did not increase mice lifespan but improved motor functions and sPIF was superior compared to other immune modulators. Immune modulators did not affect mGRPs engraftment significantly but reduced pro-inflammatory cytokine production. Finally, sPIF and CB reduced the number of microglial cells and prevented neuronal number loss. Given the safety profile and a neuroprotective potential of sPIF, we envision its clinical application in near future.

Motor symptom asymmetry predicts non-motor outcome and quality of life following STN DBS in Parkinson's disease.

Risk factors for long-term non-motor symptoms and quality of life following subthalamic nucleus deep brain stimulation (STN DBS) have not yet been fully identified. In the present study, we investigated the impact of motor symptom asymmetry in Parkinson's disease. Data were extracted for 52 patients with Parkinson's disease (half with predominantly left-sided motor symptoms and half with predominantly right-sided ones) who underwent bilateral STN and a matched healthy control group. Performances for cognitive tests, apathy and depression symptoms, as well as quality-of-life questionnaires at 12 months post-DBS were compared with a pre-DBS baseline. Results indicated a deterioration in cognitive performance post-DBS in patients with predominantly left-sided motor symptoms. Performances of patients with predominantly right-sided motor symptoms were maintained, except for a verbal executive task. These differential effects had an impact on patients' quality of life. The results highlight the existence of two distinct cognitive profiles of Parkinson's disease, depending on motor symptom asymmetry. This asymmetry is a potential risk factor for non-motor adverse effects following STN DBS.

Neonatal arterial stroke location is associated with outcome at 2 years: a voxel-based lesion-symptom mapping study.

OBJECTIVE: In contrast to motor impairments, the association between lesion location and cognitive or language deficits in patients with neonatal arterial ischaemic stroke remains largely unknown. We conducted a voxel-based lesion-symptom mapping cross-sectional study aiming to reveal neonatal arterial stroke location correlates of language, motor and cognitive outcomes at 2 years of age. DESIGN: Prospective observational multicentre study. SETTING: Six paediatric university hospitals in Spain. PARTICIPANTS: We included 53 patients who had a neonatal arterial ischaemic stroke with neonatal MRI and who were followed up till 2 years of age. MAIN OUTCOME MEASURES: We analysed five dichotomous clinical variables: speech therapy (defined as the need for speech therapy as established by therapists), gross motor function impairment, and the language, motor and cognitive Bayley scales. All the analyses were controlled for total lesion volume. RESULTS: We found that three of the clinical variables analysed significantly correlated with neonatal stroke location. Speech therapy was associated with lesions located mainly at the left supramarginal gyrus (p=0.007), gross motor function impairment correlated with lesions at the left external capsule (p=0.044) and cognitive impairment was associated with frontal lesions, particularly located at the left inferior and middle frontal gyri (p=0.012). CONCLUSIONS: The identification of these susceptible brain areas will allow for more precise prediction of neurological impairments on the basis of neonatal brain MRI.

[Effectiveness of respiratory physiotherapy combined with postural education in children with chronic neurological diseases].

BACKGROUND: Children with chronic neurological diseases present motor disability and increased respiratory morbidity and mortality. The aim of this study was to assess whether children with chronic neurological impairment benefit from respiratory physiotherapy and postural hygiene. METHODS: Quasi-experimental study in which six fortnightly respiratory physiotherapy sessions and workshops on postural hygiene were carried out on children aged 0 to 6 years with chronic neurological disease and respiratory impairment. A PedsQL questionnaire assessed respiratory clinical variables, expectorated secretions, respiratory exacerbations and quality of life. Assessments were performed at baseline, post-intervention, and at a 3-month follow-up. RESULTS: After physiotherapy sessions, all participants (n=30) experienced a significant (p<0.001) improvement in average oxygen saturation (94.37 to 98.3%), heart rate (126.03 to 103.6 beats/minute) and respiratory rate (42.13 to 34.27 breaths/minute), as well as a decrease in secretions (from 45.33 to 28.17 mL). This improvement was maintained after a 3-month follow-up. The average respiratory exacerbations decreased (p<0.001) compared to the previous six months: hospitalizations (from 1.6 to 0.5), visits to the emergency department (from 2.59 to 1.53) and to primary care Pediatric consultations (from 7 to 5.03). The mean score on the PedsQL questionnaire demonstrated a significant increase (p<0.001) in the quality of life after the intervention for physical (27%, to 73.4) and mental health (12%, to 70.09%). CONCLUSION: Respiratory physiotherapy combined with postural hygiene is effective for the clinical status and quality of life in children with chronic neurological diseases, and therefore could be introduced in habitual clinical practice.

Subthalamic dynamic neural states correlate with motor symptoms in Parkinson's Disease.

OBJECTIVE: This study aims to discriminate the dynamic synchronization states from the subthalamic local field potentials and investigate their correlations with the motor symptoms in Parkinson's Disease (PD). METHODS: The resting-state local field potentials of 10 patients with PD were recorded from the subthalamic nucleus. The dynamic neural states of multiple oscillations were discriminated and analyzed. The Spearman correlation was used to investigate the correlations between occurrence rate or duration of dynamic neural states and the severity of motor symptoms. RESULTS: The proportion of long low-beta and theta synchronized state was significantly correlated with the general motor symptom and tremor, respectively. The duration of combined low/high-beta state was significantly correlated with rigidity, and the duration of combined alpha/high-beta state was significantly correlated with bradykinesia. CONCLUSIONS: This study provides evidence that motor symptoms are associated with the neural states coded with multiple oscillations in PD. SIGNIFICANCE: This study may advance the understanding of the neurophysiological mechanisms of the motor symptoms and provide potential biomarkers for closed-loop deep brain stimulation in PD.

Intranasal delivery of exosomes from human adipose derived stem cells at forty-eight hours post injury reduces motor and cognitive impairments following traumatic brain injury.

The neuroprotective role of human adipose-derived stems cells (hASCs) has raised great interest in regenerative medicine due to their ability to modulate their surrounding environment. Our group has demonstrated that exosomes derived from hASC (hASCexo) are a cell-free regenerative approach to long term recovery following traumatic brain injury (TBI). Previously, we demonstrated the efficacy of exosome treatment with intravenous delivery at 3 h post TBI in rats. Here, we show efficacy of exosomes through intranasal delivery at 48 h post TBI in mice lengthening the therapeutic window of treatment and therefore increasing possible translation to clinical studies. Our findings demonstrate significant recovery of motor impairment assessed by an elevated body swing test in mice treated with exosomes containing MALAT1 compared to both TBI mice without exosomes and exosomes depleted of MALAT1. Significant cognitive improvement was seen in the reversal trial of 8 arm radial arm water maze in mice treated with exosomes containing MALAT1. Furthermore, cortical damage was significantly reduced in mice treated with exosomes containing MALAT1 as well as decreased MHCII+ staining of microglial cells. Mice without exosomes or treated with exosomes depleted of MALAT1 did not show similar recovery. Results demonstrate both inflammation related genes and NRTK3 (TrkC) are target genes modulated by hASC exosomes and further that MALAT1 in hASC exosomes regulates expression of full length TrkC thereby activating the MAPK pathway and promoting recovery. Exosomes are a promising therapeutic approach following TBI with a therapeutic window of at least 48 h and contain long noncoding RNA's, specifically MALAT1 that play a vital role in the mechanism of action.

Characterizing upper limb function in the context of activities of daily living in CLN3 disease.

In CLN3 disease, impairments in motor function are frequently reported to have later onset compared to visual and cognitive decline, but upper limb motor function has yet to be explored in this population. In a cohort of 22 individuals with CLN3, we used a novel application of multiple measures to (1) characterize motor function, particularly of the upper limbs, in activities of daily living (ADLs), and (2) explore associations between motor function and age as well as visual ability, disease severity, and cognitive function, as evaluated by the Unified Batten Disease Rating Scale (UBDRS), a validated CLN3 disease measure. ADLs that required coordination, speed, and fine motor control were particularly challenging for children with CLN3 based on item-level performance across direct assessments (Jebsen-Taylor Hand Function Test [JTHFT] and MyoSet Tools) and caregiver reports (Pediatric Evaluation of Disability Inventory-Computer Adaptive Testing [PEDI-CAT] and Patient-Reported Outcomes Measurement Information System [PROMIS] Pediatric Upper Extremity). Poorer visual ability, disease severity, and cognitive function were associated with worse performance on these measures, whereas age had limited impact. These findings support the need for children with CLN3 to receive skilled clinical evaluation and treatment tailored to their individual needs, particularly in the context of ADLs, as their symptom profile progresses.

Earlier Acupuncture Enhancing Long-Term Effects on Motor Dysfunction in Acute Ischemic Stroke: Retrospective Cohort Study.

Stroke is the leading fatal disease in China. This retrospective study aimed to explore the optimal acupuncture intervention time for long-term efficacy on motor dysfunction in patients suffering from acute ischemic stroke through 1-year of follow-up. Three hundred and nine patients collected at Longhua Hospital from January 2016 to December 2017 were classified into 3 groups based on the acupuncture intervention time, including groups A (within 2 days), B (within 3-7 days) and C (within 8-14 days). All patients had received standard treatment combined with acupuncture therapy. Specifically, acupuncture was performed at the acupoints including LI4 (Hegu), ST40 (Fenglong), DU20 (Baihui), and motor area of the scalp, followed by 2 electroacupuncture protocols based on different muscle tensions once a day for 5 days consecutively. The time-effect relationship was assessed using both the Fugl-Meyer Assessment (FMA) and the modified Barthel index (MBI) on the 90th day and 1st year, respectively. Meanwhile, the modified Rankin scale (mRS), high-sensitivity C-reactive protein (hs-CRP), and fibrinogen (FIB) were also measured during the 1-year follow-up. The favorable outcome rate was 74.4%. One-way univariate analysis of variance (ANOVA) revealed significant differences in FMA and MBI on the 90th day among the 3 groups ([Formula: see text] < 0.05), while no significant differences were observed in FMA, MBI or mRS at the 1st year between groups A and B. The levels of hs-CRP and FIB ([Formula: see text] < 0.05) were markedly reduced. Binary logistic regression analysis suggested that patients with atrial fibrillation (AF) (odds ratio (OR): 3.156), chronic kidney disease (CKD) (OR: 2.563), diabetes mellitus (DM) (OR: 2.174) or stroke history (OR: 1.883) were more inclined to recover poorly from nerve function deficit ([Formula: see text] < 0.05). Earlier acupuncture intervention may have a better long-term effect on motor dysfunction and inflammation during the 1-year follow-up. Moreover, acupuncture within 2 days is probably the optimal treatment time for early recovery on the 90th day.

Modulation of the human sensorimotor system by afferent somatosensory input: evidence from experimental pressure stimulation and physiotherapy.

Peripheral afferent input is critical for human motor control and motor learning. Both skin and deep muscle mechanoreceptors can affect motor behaviour when stimulated. Whereas some modalities such as vibration have been employed for decades to alter cutaneous and proprioceptive input, both experimentally and therapeutically, the central effects of mechanical pressure stimulation have been studied less frequently. This discrepancy is especially striking when considering the limited knowledge of the neurobiological principles of frequently used physiotherapeutic techniques that utilise peripheral stimulation, such as reflex locomotion therapy. Our review of the available literature pertaining to pressure stimulation focused on transcranial magnetic stimulation (TMS) and neuroimaging studies, including both experimental studies in healthy subjects and clinical trials. Our search revealed a limited number of neuroimaging papers related to peripheral pressure stimulation and no evidence of effects on cortical excitability. In general, the majority of imaging studies agreed on the significant involvement of cortical motor areas during the processing of pressure stimulation. Recent data also point to the specific role of subcortical structures, such as putamen or brainstem reticular formation. A thorough comparison of the published results often demonstrated, however, major inconsistencies which are thought to be due to variable stimulation protocols and statistical power. In conclusion, localised peripheral sustained pressure is a potent stimulus inducing changes in cortical activation within sensory and motor areas. Despite historical evidence for modulation of motor behaviour, no direct link can be established based on available fMRI and electrophysiological data. We highlight the limited amount of research devoted to this stimulus modality, emphasise current knowledge gaps, present recent developments in the field and accentuate evidence awaiting replication or confirmation in future neuroimaging and electrophysiological studies.

Effect of Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) on balance performance in Parkinson's disease.

PURPOSE: To study the effect of STN-DBS on balance performance of Parkinson's disease. METHOD: 16 idiopathic PD patients treated with bilateral STN-DBS (DBS Group) and 20 PD patients treated with Levodopa (Medicine group) were included in the study. Clinical material including Levodopa Equivalent Daily Dose (LEDD, mg/day), life quality (PDQ-39) were collected. For DBS group and Medicine group, The motor disability (Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale Ⅲ, MDS-UPDRSIII) and balance performance (MDS-UPDRS 3.12, Berg Balance Scale BBS) and the Limits of Stability (LoS) (target acquisition percentage, trunk swing angle standard deviation, time) in state of Med-Off/Med-On at preoperation, postoperation, 6 months postoperation and 12 months postoperation were evaluated. Repeated ANOVA was used to analyze the effect of STN-DBS on balance performance. RESULT: The Clinical material (age, gender, duration, LEDD preoperation, PDQ39), motor disability (Med-on/Med-Off), balance performance (Med-on/Med-Off) and LoS preoperation had no differences in DBS-group and Medical-group (P>0.05). During the follow up, LEDD, PDQ39, Motor disability (MDS-UPDRSIII), balance performance (MDS-UPDRS 3.12, BBS) in Medicine-group had no significant changes in both Med-Off and Med-On. For DBS-group, immediately improvement of motor disability (MDS-UPDRSIII), LoS (target acquisition percentage, trunk swing angle standard deviation, time) and LEDD were observed postoperation (P<0.05); PDQ39, balance performance (MDS-UPDRS 3.12, BBS) began to improve at 6 months and 12 months postoperation. Repeated ANOVA showed that DBS could significantly improve the motor disability, balance performance and LoS in PD. CONCLUSION: STN-DBS could improve the balance performance of PD patients in H&Y3.

Therapy of Parkinson's Disease Subtypes.

Early descriptions of subtypes of Parkinson's disease (PD) are dominated by the approach of predetermined groups. Experts defined, from clinical observation, groups based on clinical or demographic features that appeared to divide PD into clinically distinct subsets. Common bases on which to define subtypes have been motor phenotype (tremor dominant vs akinetic-rigid or postural instability gait disorder types), age, nonmotor dominant symptoms, and genetic forms. Recently, data-driven approaches have been used to define PD subtypes, taking an unbiased statistical approach to the identification of PD subgroups. The vast majority of data-driven subtyping has been done based on clinical features. Biomarker-based subtyping is an emerging but still quite undeveloped field. Not all of the subtyping methods have established therapeutic implications. This may not be surprising given that they were born largely from clinical observations of phenotype and not in observations regarding treatment response or biological hypotheses. The next frontier for subtypes research as it applies to personalized medicine in PD is the development of genotype-specific therapies. Therapies for GBA-PD and LRRK2-PD are already under development. This review discusses each of the major subtyping systems/methods in terms of its applicability to therapy in PD, and the opportunities and challenges designing clinical trials to develop the evidence base for personalized medicine based on subtypes.

Effects of infant motor problems and treatment with physiotherapy on child outcomes at school-age.

BACKGROUND: Early motor coordination problems have previously been associated with various developmental outcomes at school-age. AIMS: Investigate whether and how treatment with physiotherapy may alter associations between early motor problems and subsequent developmental outcomes. STUDY DESIGN: A prospective whole-population study. SUBJECTS: 1374 children were followed from birth to 8 years. OUTCOME MEASURES: Early motor functioning was determined with standard neurological examinations at birth and at 5 months. Information on receipt of physiotherapy was collected through parent interviews at 5, 20 and 56 months. Developmental outcomes at 6 and 8 years included motor skills, mental health, cognitive function, and attention regulation and were determined through standard tests, parent reports and observed behavior ratings. RESULTS: Early motor problems were associated with lower motor skills, cognitive function, and attention regulation at school-age, but not with mental health. In addition to early motor problems, receipt of physiotherapy was independently and negatively related to outcomes at school-age. Accounting for imbalances in covariates, including initial motor scores, via propensity score matching attenuated the adverse effects of receipt of physiotherapy on school-aged outcomes. CONCLUSIONS: Infant motor problems are associated with motor and cognitive outcomes at school-age. Early motor problems may represent a starting point of a trajectory of difficulties that may lead to a higher risk of problems in multiple developmental domains. No evidence for a beneficial effect of treatment with physiotherapy was found.

Four-Repeat Tauopathies: Current Management and Future Treatments.

Four-repeat tauopathies are a neurodegenerative disease characterized by brain parenchymal accumulation of a specific isoform of the protein tau, which gives rise to a wide breadth of clinical syndromes encompassing diverse symptomatology, with the most common syndromes being progressive supranuclear palsy-Richardson's and corticobasal syndrome. Despite the lack of effective disease-modifying therapies, targeted treatment of symptoms can improve quality of life for patients with 4-repeat tauopathies. However, managing these symptoms can be a daunting task, even for those familiar with the diseases, as they span motor, sensory, cognitive, affective, autonomic, and behavioral domains. This review describes current approaches to symptomatic management of common clinical symptoms in 4-repeat tauopathies with a focus on practical patient management, including pharmacologic and nonpharmacologic strategies, and concludes with a discussion of the history and future of disease-modifying therapeutics and clinical trials in this population.

Minimum Clinically Important Difference of Gross Motor Function and Gait Endurance in Children with Motor Impairment: A Comparison of Distribution-Based Approaches.

OBJECTIVE: The minimum clinically important difference (MCID) is a standard way of measuring clinical relevance. The objective of this work was to establish the MCID for the 6-minute walking test (6minWT) and the Gross Motor Function Measure (GMFM-88) in pediatric gait disorders. METHODS: A cohort, pretest-posttest study was conducted in a hospitalized care setting. A total of 182 patients with acquired brain injury (ABI) or cerebral palsy (CP) performed 20 robot-assisted gait training sessions complemented with 20 sessions of physical therapy over 4 weeks. Separate MCIDs were calculated using 5 distribution-based approaches, complemented with an anonymized survey completed by clinical professionals. RESULTS: The MCID range for the 6minWT was 20-38 m in the ABI cohort, with subgroup ranges of 20-36 m for GMFCS I-II, 23-46 m for GMFCS III, and 24-46 m for GMFCS IV. MCIDs for the CP population were 6-23 m, with subgroup ranges of 4-28 m for GMFCS I-II, 9-19 m for GMFCS III, and 10-27 m for GMFCS IV. For GMFM-88 total score, MCID values were 1.1%-5.3% for the ABI cohort and 0.1%-3.0% for the CP population. For dimension "D" of the GMFM, MCID ranges were 2.3%-6.5% and 0.8%-5.2% for ABI and CP populations, respectively. For dimension "E," MCID ranges were 2.8%-6.5% and 0.3%-4.9% for ABI and CP cohorts, respectively. The survey showed a large interquartile range, but the results well mimicked the distribution-based methods. CONCLUSIONS: This study identified for the first time MCID ranges for 6minWT and GMFM-88 in pediatric patients with neurological impairments, offering useful insights for clinicians to evaluate the impact of treatments. Distribution-based methods should be used with caution: methods based on pre-post correlation may underestimate MCID when applied to patients with small improvements over the treatment period. Our results should be complemented with estimates obtained using consensus- and anchor-based approaches.

Dance PREEMIE, a Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age: an Australian feasibility trial protocol.

INTRODUCTION: Children born extremely preterm (EP: <28 weeks gestation) and/or extremely low birth weight (ELBW: <1000 g) are at increased risk of motor impairment compared with children born at term. Children with motor impairment have lower rates of physical activity (PA) participation compared with their typically developing peers. PA participation is an important outcome for children with motor impairment, however, there is limited evidence available to support interventions that improve PA participation in this population. The aim of this study is to assess the feasibility, including the recruitment and retention, acceptability and fidelity, of a preschool dance participation intervention for children born EP/EBLW with motor impairment called Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age. METHODS AND ANALYSIS: This feasibility case series trial will recruit EP/ELBW children with motor impairment (n=10) from the Victorian Infant Collaborative Study 2016/2017 cohort, a prospective longitudinal cohort study. Up to 10 community-based dance teachers will be recruited and provided with physiotherapy-led training and support to facilitate the participation of EP/ELBW children in community dance classes. A mixed-methods approach (quantitative and qualitative) will be used to analyse the primary aim, to determine the feasibility of the intervention from the perspectives of families and dance teachers. ETHICS AND DISSEMINATION: This study is approved by the Human Research Ethics Committees of The Royal Children's Hospital and The Royal Women's Hospital, Melbourne. Study outcomes will be disseminated through conference presentations, peer-reviewed publications and social media. TRIAL REGISTRATION NUMBER: ACTRN12619001266156.