Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia

Background: Animal models are essential for understanding etiology and pathophysiology of movement disorders. Previously, we have found that mice transgenic for the human CYP2C19 gene, expressed in the liver and developing brain, exhibit altered neurodevelopment associated with impairments of their motor function and emotionality. Objectives: To characterize motoric phenotype of the CYP2C19 transgenic mice and validate its usefulness as an animal model of ataxia. Methods: The rotarod and beam-walking tests were utilized to quantify the functional alterations induced by motoric phenotype. Dopaminergic system was assessed by tyrosine hydroxylase immunohistochemistry and by chromatographic quantification of the whole-brain dopamine levels. Beam-walking test was also repeated after the treatment with the dopamine receptor antagonists, ecopipam and raclopride. The volumes of 20 brain regions in the CYP2C19 transgenic mice and controls were quantified by 9.4T gadolinium-enhanced postmortem structural neuroimaging. Results: CYP2C19 transgenic mice were found to exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips using the beam-walking test (p<0.0001, n=89); the phenotype was more pronounced in younger animals. Hyperdopaminergism was observed in the CYP2C19 mice; however, the motoric impairment was not ameliorated by dopamine receptor antagonists and there was also no midbrain dopamine neuron loss in CYP2C19 mice. However, in these mice, cerebellar volume was drastically decreased (-11.8% [95%CI: -14.7, -9.0], q<0.0001, n=59), whereas a moderate decrease in hippocampal volume was observed (-4.2% [95%CI: -6.4%, -1.9%], q=0.015, n=59). Conclusions: Humanized CYP2C19 transgenic mice exhibit altered motoric function and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.

ASSOCIATION BETWEEN BALANCE SELF-EFFICACY AND WALKING ABILITY IN THOSE WITH NEW LOWER LIMB AMPUTATIONS

BACKGROUND: A relationship between walking ability and self-efficacy has been demonstrated in various rehabilitation patient populations. In experienced prosthetic ambulators, walking ability is related to self-efficacy of balance, however, this relationship has not been quantified for those with newly acquired lower limb amputations (LLA). OBJECTIVE(S): To investigate the association between walking performance (objective) and self-reported walking abilities (subjective) on balance self-efficacy in those with LLA. METHODOLOGY: Cross-sectional study of 27 people (17 men; mean age=63.57±9.33) at discharge from inpatient prosthetic rehabilitation for first major unilateral LLA. Individuals completed 6m straight path walking and the L-Test under single- and dual-task conditions. The Prosthesis Evaluation Questionnaire (PEQ) was administered, and the Ambulation subscale provided subjective measures of walking ability. A single PEQ question on satisfaction with walking (16B) was also used as a proxy for subjective walking ability. The Activities-specific Balance Confidence Scale measured balance self-efficacy. Multivariable linear regression was used to evaluate the strength of association between walking ability (objective and subjective) and balance self-efficacy (dependent variable). FINDINGS: Walking velocity on the 6m straight path under single-task (p=0.011) and dual-task conditions (p=0.039), the single-task L-Test (p=0.035) and self-reported satisfaction with walking (p=0.019) were associated with self-efficacy of balance. CONCLUSION: Objective measures of walking ability that were independently associated with balance self-efficacy included straight path walking velocity under single and dual-task conditions and the single-task L-Test. Satisfaction with walking was also associated with balance self-efficacy. This highlights the interplay between physical and psychological factors during rehabilitation. More research in the area of self-efficacy and walking ability is needed to establish self-efficacy as a target during prosthetic rehabilitation for those with LLA. Layman's Abstract Self-efficacy is a person’s belief in their ability to do a certain task well. Improving self-efficacy can be done by watching others complete a task, by getting praise from experts, or by doing the task yourself. There is a link between how well some people walk and their confidence with walking, however this has not been studied in people learning to use a lower limb prosthesis. The goal of this paper was to study the link between balance self-efficacy, scores on walking tests and self-reported walking ability in those with lower limb amputations (LLA) when they leave rehabilitation. To do this, two walking tests were done (straight path and complex path) in two settings (walking only and walking with distraction). A survey about walking ability and a questionnaire on balance self-efficacy were also done. Results showed that self-efficacy of balance was related to the straight path walking test under both settings and the complex walking test during walking alone. A person’s satisfaction with walking ability was also linked. The only test not related was the complex walking test under distracting conditions. It might be that more time is needed for people with LLA to confidently do this task. This shows the link between physical and mental factors during rehabilitation. More research is needed to find other factors that might impact self-efficacy and walking ability in people with LLA when they leave rehabilitation. Article PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/36695/28904 How To Cite: Frengopoulos C, Zia Z, Payne M.W.C, Viana R, Hunter S.W. Association between balance self-efficacy and walking ability in those with new lower limb amputations. Canadian Prosthetics & Orthotics Journal. 2022; Volume 5, Issue 1, No.4. https://doi.org/10.33137/cpoj.v5i1.36695 Corresponding Author: Courtney Frengopoulos,University of Western Ontario, Room 1408, Elborn College, London, Ontario, Canada, N6G 1H1.E-Mail: [email protected] ID: https://orcid.org/0000-0002-4131-2727

Distance to first symptoms measured by the 6-min walking test differentiates between treatment success and failure in patients with degenerative lumbar disorders

Purpose The smartphone-based 6-min walking test (6WT) is an established digital outcome measure in patients undergoing surgery for degenerative lumbar disorders (DLD). In addition to the 6WTs primary outcome measure, the 6-min walking distance (6WD), the patient’s distance to first symptoms (DTFS) and time to first symptoms (TTFS) can be recorded. This is the first study to analyse the psychometric properties of the DTFS and TTFS. Methods Forty-nine consecutive patients (55 ± 15.8 years) completed the 6WT pre- and 6 weeks (W6) postoperative. DTFS and TTFS were assessed for reliability and content validity using disease-specific patient-reported outcome measures. The Zurich Claudication Questionnaire patient satisfaction subscale was used as external criterion for treatment success. Internal and external responsiveness for both measures at W6 was evaluated. Results There was a significant improvement in DTFS and TTFS from baseline to W6 (p < 0.001). Both measures demonstrated a good test–retest reliability (β = 0.86, 95% CI 0.81–0.90 and β = 0.83, 95% CI 0.76–0.87, both p < 0.001). The DTFS exceeded the 6WD capability to differentiate between satisfied (82%) and unsatisfied patients (18%) with an AUC of 0.75 (95% CI 0.53–0.98) vs. 0.70 (95% CI 0.52–0.90). The TTFS did not demonstrate meaningful discriminative abilities. Conclusion Change in DTFS can differentiate between satisfied and unsatisfied patients after spine surgery. Digital outcome measures on the 6WT metric provide spine surgeons and researchers with a mean to assess their patient’s functional disability and response to surgical treatment in DLD.

Yoga Versus Physical Therapy In Multiple Sclerosis: Randomized Controlled Trial

Background. Yoga originated in the territory of modern India more than 3000 years ago and uses techniques for working with the musculoskeletal system, cardiorespiratory system and attention. Currently, the effectiveness and safety of yoga in patients with various neurological disorders, including MS, is of interest to many scientists and clinicians. The main aim of this study is to examine the effect of yoga on symptoms and quality of life in patients with MS versus physical therapy (exercise therapy) and no exercise.Methods. The patients were randomly assigned to 3 groups (yoga, PT, or waiting list), patients from the waiting list had an opportunity to enter the yoga program after the end of the trial period. After 12 weeks of regular exercises (or absence of them), the effect of yoga and PT on the functional status and quality of life of patients were evaluated. The MS treatment was a part of routine practice, as prescribed by the treating neurologist. The data was collected during the patients’ two visits to the study center - before the start of the study and at the end of the 12-week period. The in-person examination included a doctor's assessment of the EDSS, the SF-36 quality of life questionnaire, the fatigue scale, the Berg balance scale, the 6-minute walking test.Results. A total of 36 patients finished the clinical study: 30 women and 6 men. There was no statistically significant difference between the groups in terms of improvement in MS symptoms as measured by the balance, walking test and fatigue scales. However, in the analysis of the 8 criteria of SF-36 quality-of-life questionnaire the covariation analysis statistically significant differences were found in favor of the yoga group in terms of physical functioning (PF) (p=0.003), life activity (VT) (p<0.001), mental health (MH) (p=013), social functioning (SF) (p=0.028). Conclusions. Thus, regular yoga classes under the guidance of qualified staff are a promising method of non-drug rehabilitation of patients with MS with motor disorders. More research is needed to examine the impact of yoga on clinical patient improvement and quality of life indicators.Trial registration. ISRCTN15486200 https://doi.org/10.1186/ISRCTN15486200

Effects of Combining Online Anodal Transcranial Direct Current Stimulation and Gait Training in Stroke Patients: A Systematic Review and Meta-Analysis

Objective: Combining transcranial direct current stimulation (tDCS) and repetitive gait training may be effective for gait performance recovery after stroke; however, the timing of stimulation to obtain the best outcomes remains unclear. We performed a systematic review and meta-analysis to establish evidence for changes in gait performance between online stimulation (tDCS and repetitive gait training simultaneously) and offline stimulation (gait training after tDCS).Methods: We comprehensively searched the electronic databases Medline, Cochrane Central Register of Controlled Trials, Physiotherapy Evidence Database, and Cumulative Index to Nursing and Allied Health Literature, and included studies that combined cases of anodal tDCS with motor-related areas of the lower limbs and gait training. Nine studies fulfilled the inclusion criteria and were included in the systematic review, of which six were included in the meta-analysis.Result: The pooled effect estimate showed that anodal tDCS significantly improved the 10-m walking test (p = 0.04; I2 = 0%) and 6-min walking test (p = 0.001; I2 = 0%) in online stimulation compared to sham tDCS.Conclusion: Our findings suggested that simultaneous interventions may effectively improve walking ability. However, we cannot draw definitive conclusions because of the small sample size. More high-quality studies are needed on the effects of online stimulation, including various stimulation parameters.

Cardiometabolic risk factors predict executive function scores in high-risk individuals

Alzheimer’s disease (AD) is expected to triple by 2050, affecting 16 million Americans. As a result, it is essential to combat this alarming increase in cognitive impairment through early detection. Cardiometabolic risk factors have shown to be associated with higher risk of AD. The purpose of this study was to determine if cardiometabolic risk factors could predict executive function scores in a high-risk population. Fifty (60.9±8.8 years) high-risk adults (classified by the Australian National University Alzheimer’s Disease Risk Index) were enrolled in this study. Participants completed a 6-minute walking test, venous blood draw, blood pressure measurement, and the digit coding symbol test (DCS). Results were examined through a multiple linear regression with DCS as the dependent variable and age, sex, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), glucose, 6-minute walking test, systolic blood pressure (SBP), and diastolic blood pressure (DBP) as predictor variables. The model explained 42% of the variance of DCS (p = .04) with SBP (45%; p = .003) as a significant predictor. LDL (p = .087) and DBP (p = .123) accounted for 24% and 22% of the variance for this model, respectively. These results suggest cardiometabolic risk factors predict executive function values in high-risk individuals. Higher SBP was significantly associated with lower DCS scores indicating SBP as a valuable tool for practitioners when evaluating cognitive decline. Further research should expand sample size and track values longitudinally to substantiate these claims.

782 Cardiopulmonary exercise testing in patients with COVID-19 at 3 months from hospital discharge

Aims The long-term COVID-19 effects are currently unknown. Whether and for how long symptoms extend beyond the acute phase of the disease is unresolved. Aim of this study was to determine the functional capacity of COVID-19 survivors by cardiopulmonary exercise testing (CPET) and describe its association with dyspnoea, the most frequent symptom after discharge from a tertiary care hospital. Methods and results All COVID-19 patients discharged from our tertiary care institution were enrolled in a prospective follow-up study which would assess clinical, instrumental and laboratory characteristics of COVID-19 survivors at 3 months from hospital discharge (i.e. long-covid). To limit bias in dyspnoea quantification, patients hospitalized in residential care facilities with severe cognitive impairment/disability, ischaemic cardiopathy, and/or heart failure and severe respiratory disease (i.e. chronic obstructive pulmonary disease) were excluded. Clinical evaluation included: peripheral blood samples including inflammatory cytokines, pulmonary function testing (functional respiratory and 6 min-walking test), lung ultrasound, ECG recording, and a comprehensive echocardiographic exam. All patients with peripheral oxygen desaturation at 6 min-walking test (SpO2 &lt; 92%), dyspnoea and with a history of hospitalization in critical care settings were referred for CPET. Dyspnoea was classified with the Medical Research Council (MRC) scale. From June 2020 to May 2021, 198 patients were enrolled; overall, 42% of patients presented with dyspnoea at 3 months from hospital discharge with no difference according to disease severity on hospital admission (P = 0.233). Clinical, laboratory, and echocardiographic parameters were similar between patients with and without dyspnoea. At CPET, 61% of patients complaining dyspnoea showed a %peak VO2 lower than 85% of the predicted value, associated with a lower exercising tolerance and duration and with a globally reduced equivalent metabolic load (METS: 5.3 ± 1.2 vs. 6.6 ± 1.6, P = 0.003). Mean anaerobic threshold was lower for symptomatic patients (46 + 13 vs. 50 + 10, P = 0.03). At multivariable logistic regression analysis, after adjustment for age, number of comorbidities, and body mass index, only %peak VO2 (HR: 0.973; 95% CI: 0.948–0.998) and male gender (HR: 0.548; 95% CI: 0.328–0.999) were associated with dyspnoea. Conclusions At 3-months, almost 1-in-2 patients discharged for COVID-19 pneumonia presented with dyspnoea, irrespective of disease severity. Among patients undergoing CPET, only %peak VO2 and gender were associated with symptoms suggesting a potential systemic inflammatory-mediated response and important gender related differences for the long-covid.

Methods and Rationale for Using GPS-Derived Objective Technologies to Examine Community Mobility in Older Adults

Objective measures of community mobility are advantageous for capturing life-space activity. In contrast to subjective, self-reported approaches, GPS-derived objective measures leverage passive, real-time data collection techniques to mitigate recall bias and minimize participant burden. We present methods to quantify community mobility among a sample of 164 community-dwelling older adults (Mean age=77.3±6.5) from a physical therapy intervention aimed at improving walking ability. We characterized community mobility using activity space metrics (e.g., standard deviation ellipse (SDE) area), timing (e.g., time outside home), and shape (e.g., SDE compactness). We will discuss challenges and solutions to generating these metrics as well as their associations with physical and cognitive performance. Time outside of home and SDE area, but not SDE compactness, were correlated with better performance on the 6-Minute Walking Test and Trail-Making Test (Part B) (ρ=.20-.23, p’s&lt;.05). These findings will aid in understanding which community mobility measures are associated with functional capacity.

55 Brisk walking can be a maximal effort in heart failure patients. A comparison of cardiopulmonary exercise and 6-min walking test cardiorespiratory data

Aims Cardiopulmonary exercise test (CPET) and 6-min walking test (6MWT) are frequently used in heart failure (HF). CPET is a maximal exercise, whereas 6MWT is a self-selected constant load test usually considered a submaximal, and therefore safer, exercise but this has not been tested previously. The aim of this study was to compare the cardiorespiratory parameters collected during CPET and 6MWT in a large group of healthy subjects and patients with HF of different severity. Methods and results Subjects performed a standard maximal CPET and a 6MWT wearing a portable device allowing breath-by-breath measurement of cardiorespiratory parameters. HF Patients were grouped according to their CPET peak oxygen uptake (peakṼO2). One-hundred and fifty-five subjects were enrolled, of whom 40 were healthy (59 ± 8 years; male 67%) and 115 were HF patients (69 ± 10 years; male 80%; left ventricular ejection fraction 34.6 ± 12.0%). CPET peakṼO2 was 13.5 ± 3.5 ml/kg/min in HF patients and 28.1 ± 7.4 ml/kg/min in healthy (P &lt; 0.001). 6MWT-ṼO2 was 98 ± 20% of the CPET peakṼO2 values in HF patients, while 72 ± 20% in healthy subjects (P &lt; 0.001). 6MWT-ṼO2 was &gt;110% of CPET peakṼO2 in 42% of more severe HF patients (peakṼO2 &lt;12 ml/kg/min). Similar results have been found for ventilation and heart rate. Of note, the slope of the relationship between ṼO2 at 6MWT, reported as percentage of CPET peakṼO2 vs. 6MWT ṼO2 reported as absolute value, progressively increased as exercise limitation did. Conclusions 6MWT must be perceived as a maximal or even supra-maximal exercise activity at least in patients with severe exercise limitation from HF. Our findings should influence the safety procedures needed for the 6MWT in HF.