Decline In Motor Function Research Articles

Predicting clinical phenotypes of metachromatic leukodystrophy based on the arylsulfatase A activity and the ARSA genotype? - Chances and challenges.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of arylsulfatase A (ARSA). Subsequent accumulation of sulfatides leads to demyelination and neurodegeneration in the central and peripheral nervous system. To date MLD is classified based on the age at onset, however, especially for late onset forms this classification provides only limited projection regarding the clinical disease course. Moreover, evolving newborn screening approaches raise the need to predict the disease onset and course in pre-symptomatic individuals. Here, we correlate the ARSA activity and the ARSA-genotype with clinical parameters in a large cohort of 96 affected individuals. Clinical data of 96 affected individuals with genetically and/or biochemically confirmed MLD were collected from a national database. Leukocyte samples from 69 affected individuals were re-analyzed for the ARSA activity using p-nitrocatecholsulfate as substrate with a refined ARSA assay towards the lower limit of detection. For 84 individuals genetic sequencing was conducted by Sanger or next generation sequencing (NGS). The adapted ARSA assay revealed the discriminatory power to differentiate MLD subtypes as the residual enzyme activity was low in late infantile and early juvenile forms, and clearly higher in late juvenile and adult MLD (p < 0.001). A residual enzyme activity below 1% compared to controls predicted an early onset (late-infantile or early-juvenile) and rapid disease progression. A firm genotype-phenotype correlation was proven as reliable for bi-allelic protein-truncating variants in the ARSA gene resulting in minimal residual ARSA activity, an early onset of the disease and initial decline of motor functions. Although the impact of missense variants was equivocal, few variants with a recognizable clinical spectrum were identified. ARSA activity in leukocytes as well as the ARSA genotype can predict the age of disease onset and the dynamic of disease progression for most of the early onset forms. This knowledge is relevant for patient counseling and to guide treatment decisions, especially when identifying pre-symptomatic individuals, e.g., in newborn screening. However, due to the high cumulative frequency of rare disease-causing missense variants in the ARSA gene that lead to highly variable residual enzyme activity, reiterated biochemical and genetic studies are needed to improve disease course prediction.

Analysis of secular trends in physical fitness of children and adolescents (8-18 years) from Kraków (Poland) between 2010 and 2020.

The aim of the study was to analyze the changes of the motor skills of children and adolescents from Kraków between 2010 and 2020. The group included 4106 children and adolescents (8-18 years of age). The analysis of changes included results of the following fitness tests: backwards overhead medicine ball throw, standing broad jump, dynamometric strength of the hand, flexibility test, as well as shuttle run (10× 5 m). A negative trend in both sexes was observed in the results of overhead medicine ball throw. The girls also had a negative intergenerational changes in the results of the shuttle run and the flexibility test. A positive secular trend was also observed in both sexes in relations to the dynamometric force of the right and left hand. In addition, the boys studied in more contemporary times showed better results in the shuttle run, compared to their peers in 2010. The study reported a decline in overall motor performance in children and adolescents. The observed results may be related to a decrease in the level of physical activity, as well as a higher incidence of overweight and high levels of body fat in the modern population.

Associations of physical activity participation trajectories with subsequent motor function declines and incident frailty: A population-based cohort study

Maintaining physical function and delaying frailty are of significant importance in both quality of life and health longevity for successful aging. The objective of this study is to investigate whether different trajectories of long-term physical activity (PA) participation are associated with subsequent motor function declines and incident frailty in middle-aged and elderly adults. Data from 8,227 aged ≥ 50 years adults enrolled in the English Longitudinal Study of Aging were analyzed. Long-term PA participation trajectories were assessed using group-based trajectory modeling over the first 6-year period from wave 1 (2002-2003) to wave 4 (2008-2009). The longitudinal associations of PA trajectories with motor function declines and incident frailty were evaluated by a linear mixed model and Cox regression model, respectively, with follow-up of 10 years from wave 4 to wave 9 (2018-2019). Five distinct trajectories of long-term PA participation were identified in the aging cohort, including persistently low-active trajectory (N = 2,039), increasing active trajectory (N = 1,711), declining active trajectory (N = 216), persistently moderate-active trajectory (N = 2,254), and persistently high-active trajectory (N = 2,007). Compared with the persistently low-active group, the participants in persistently moderate- and high-active groups experienced significantly decelerated grip strength decline, decreased gait speed decline, and faster chair rises after multiple-adjustment. Similarly, participants maintaining moderate- and high-active PA were also associated with a lower risk of incident frailty (multiple-adjusted hazard ratio: 0.70, 95% confidence interval: 0.62-0.80, and 0.42, 95% CI: 0.36-0.49, respectively), compared with those with persistently low PA. Notably, the participants with the increasing active trajectory got similar health benefits as those with persistently moderate and high levels of PA. In addition to persistent PA, increasing PA was linked to a slower decline in motor function and lower risk of incident frailty in the cohort. Our findings suggest that regular PA is never too late.

Relationship between Testosterone and Sarcopenia in Older-Adult Men: A Narrative Review.

Age-related decline in testosterone is known to be associated with various clinical symptoms among older men and it is possible that the accompanying decline in muscle mass and strength might lead to a decline in motor and physical functions. Sarcopenia is an important pathophysiological factor associated with frailty in older adults and is diagnosed in older adults as a decrease in muscle strength, muscle mass, and walking speed, which can lead to a significant decline in the quality of life and shortened healthy life expectancy. Testosterone directly interacts with the androgen receptor expressed in myonuclei and satellite cells and is also indirectly associated with muscle metabolism through various cytokines and molecules. Currently, significant correlations between testosterone and frailty in men have been confirmed by numerous cross-sectional studies. Many randomized control studies have also supported the beneficial effect of testosterone replacement therapy (TRT) on muscle volume and strength among men with low to normal testosterone levels. In the world’s aging society, TRT can be a tool for preventing the onset of sarcopenia in older-adult men. This narrative review aims to show the relationship between the decline in testosterone with age, sarcopenia, and frailty, as well as the effects of testosterone replacement therapy on muscle mass and strength.

P.67 Development and evaluation of a time to event endpoint for clinical trials in Duchenne muscular dystrophy (DMD)

Event-driven clinical trials, commonly used in oncology, offer several benefits over continuous outcome measures: i) each patient is assessed individually, ii) after the event has occurred, patients can receive therapy without breaking the blind. This study aimed to develop a time-to-event outcome measure for the North Star Ambulatory Assessment (NSAA) corresponding to clinically meaningful disease progression in DMD. Three candidate definitions based on changes in NSAA were investigated: A) Loss of 3 NSAA total score points; B) Loss of 2 distinct NSAA items; C) Loss of 3 NSAA points or loss of 2 NSAA items. To evaluate these definitions, 619 DMD patients with expected decline in motor function (baseline rise from supine ≥5 seconds) were studied from 3 clinical trial placebo arms and 4 natural history studies. At baseline, mean age was 9.3 years (range: 6-18yrs), mean NSAA total score was 22 (range:12-34); 63% were receiving prednisone, 37% deflazacort, and 0.4% no steroids. For each definition, median time to progression was 11.0, 14.0 and 8.3 months, respectively, based on Kaplan-Meier analyses. As a measure of prognostic validity, a progression event during the first year of follow-up was associated with significantly shorter time to loss of ambulation, with hazard ratios of 2.5, 6.5 and 3.2, respectively (all p<0.05), based on landmark analyses. Stability of the progression definitions varied, with approximately 10%, 19% and 12%, respectively, regaining their baseline level of function within a year. Definition A exhibited a favorable combination of event rate, prognostic validity, and stability. A hypothetical, well-powered, randomized, event-driven trial based on endpoint A and enrolling 160 DMD patients over a period of 9 months would require an expected duration of 10, 14, or 25 months to detect treatment effects delaying progression by 13.0, 8.4 or 5.4 months, respectively. Thus, event-driven trials may be viable for drug development in ambulatory DMD.

EFEITO DO EXERCÍCIO AERÓBICO SOBRE A QUALIDADE NEUROMUSCULAR EM IDOSOS

ABSTRACT Introduction: Physical activity has a good effect on improving the health of the elderly, especially in the treatment of chronic diseases of the respiratory, digestive, and cardiovascular systems. Many studies have proven that exercise, especially strength training, can delay and even reverse the decline in neuromuscular and motor function caused by aging, with a safe return to activities of daily living. The elderly generally choose an aerobic exercise for cardiovascular and endocrine benefits, but research on neuromuscular benefits has inconsistent results. Objective: Investigate the effects of aerobic exercise on neuromuscular quality in the elderly. Methods: Medical screening, background information questionnaire, and exercise habits were collected from 80 elderly people aged 65 to 80 years in two nursing homes in a given city. They were randomly divided into four groups without statistical difference. The male and female control groups maintained normal daily activities. In contrast, the male and female experimental groups practiced aerobic training exercises with progressively increasing intensity three times a week for 12 weeks. BMI, lean muscle mass and 6-minute walk test scores were collected. The software SPSS10 approaches t-test and data between groups compared by ANOVA (P&lt;0.05). Results: The 6-minute walking distance of patients in the aerobic exercise group increased by an average of 20%. After aerobic exercise training, the 6-minute walking distance can increase by 10% to 18%. It shows that a certain intensity of aerobic exercise training can improve the submaximal exercise capacity of the patient, thus increasing the walking distance under the same exercise time. Conclusion: The aerobic exercise group is better than the control group at changing the body shape of the elderly by reducing fat and increasing lean body mass, while the control group has apparent effects on increasing muscle mass, strengthening muscle strength, and strengthening muscle function.Evidence Level II; Therapeutic Studies - Investigating the result.

VP.31 10-year course of treatment with enzyme replacement therapy for childhood-onset Pompe disease

Pompe disease is a kind of lysosomal disease and is classified into infantile and late-onset forms, with the late-onset form being divided into pediatric and adult forms. We report the clinical course of childhood-onset Pompe disease that has been treated with enzyme replacement therapy (ERT) for 10 years. Patient: 24-year-old male. At the age of 8 years, he was examined by a pediatrician of a local doctor for motor function decline, gait abnormality, and poor weight gain, but the diagnosis was not made. The patient showed weakness of the cervical and lower limb muscles and an waddling gait. Upper limb muscle strength was preserved. Laboratory findings showed hyperCKemia, elevated liver enzymes, and a %VC of 50%. The diagnosis was confirmed by electromyography, muscle biopsy findings, and GAA gene analysis. 277 ERT sessions have been performed to date. His %VC is currently 34%, but he attends college only on NPPV at night. It has been reported that the need for ventilator and %FVC decrease less in late-onset types, including adult-onset types. In the present case, a decrease in %VC of 1.7%/year was observed. In the untreated group, it was reported to be about 3%/year, which may be due to the effect of ERT on preservation of respiratory function.

Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies.

Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson’s disease, dementia with Lewy body, and multiple system atrophy. Their etiology has not been clarified and multiple pathogenic factors include oxidative stress, mitochondrial dysfunction, impaired protein degradation systems, and neuroinflammation. Current available therapy cannot prevent progressive neurodegeneration and “disease-modifying or neuroprotective” therapy has been proposed. This paper presents the molecular mechanisms of neuroprotection by the inhibitors of type B monoamine oxidase, rasagiline and selegiline. They prevent mitochondrial apoptosis, induce anti-apoptotic Bcl-2 protein family, and pro-survival brain- and glial cell line-derived neurotrophic factors. They also prevent toxic oligomerization and aggregation of α-synuclein. Monoamine oxidase is involved in neurodegeneration and neuroprotection, independently of the catalytic activity. Type A monoamine oxidases mediates rasagiline-activated signaling pathways to induce neuroprotective genes in neuronal cells. Multi-targeting propargylamine derivatives have been developed for therapy in various neurodegenerative diseases. Preclinical studies have presented neuroprotection of rasagiline and selegiline, but beneficial effects have been scarcely presented. Strategy to improve clinical trials is discussed to achieve disease-modification in synucleinopathies.

MAO-B Polymorphism Associated with Progression in a Chinese Parkinson's Disease Cohort but Not in the PPMI Cohort.

Introduction Genetic factors play an important role in Parkinson's disease (PD) risk. However, the genetic contribution to progression in Chinese PD patients has rarely been studied. This study investigated genetic associations with progression based on 30 PD risk loci common in a longitudinal cohort of Chinese PD patients and the Parkinson's Progression Markers Initiative (PPMI) cohort. Methods PD patients from the true world (TW) Chinese PD longitudinal cohort and the PPMI cohort with demographic information and assessment scales were assessed. A panel containing 30 PD risk single nucleotide polymorphisms was tested. Progression rates of each scale were derived from random-effect slope values of mixed-effects regression models. Progression rates of multiple assessments were combined by using principal component analysis (PCA) to derive scores for composite, motor, and nonmotor progression. The association of genetic polymorphism and separate scales or PCA progression was analysed via linear regression. Results In the Chinese PD cohort, MAOB rs1799836 was associated with progression based on the Montreal Cognitive Assessment, the top 3 principal components (PCs) of nonmotor PCA and PC1 of the composite PCA. In the PPMI cohort, both MDS-Unified Parkinson's Disease Rating Scale II and motor PC1 progression were associated with RIT2 rs12456492. The PARK16 haplotype was associated with Geriatric Depression Scale and the State-Trait Anxiety Inventory for Adults progression, and the SNCA haplotype was associated with the Hoehn-Yahr staging progression and motor PC1 progression. Ethnicity-stratified analysis showed that the association between MAOB rs1799836 and PD progression may be specific to Asian or Chinese patients. Conclusion MAOB rs1799836 was associated with the progression of nonmotor symptoms, especially cognitive impairment, and the composite progression of motor and nonmotor symptoms within our Chinese PD cohort. The RIT2 rs12456492 and SNCA haplotypes were associated with motor function decline, and the PARK16 haplotype was associated with progression in mood in the PPMI cohort.

Sensory and motor correlates of frailty: dissociation between frailty phenotype and frailty index

BackgroundFrailty has been associated with a decline in sensory and motor function. However, given that different frailty measures were shown to overlap but also differ in their diagnostic properties, sensory and motor correlates of frailty might be different depending on the operationalization of frailty. Our objective was to identify sensory and motor determinants of frailty and compare the results between frailty phenotype (FP) and frailty index (FI).MethodsData from 44 pre-frail and frail subjects aged 65 and above were used. Frailty was measured using the FP and the FI. Sensory function in the visual, auditory, and tactile domain was assessed using visual acuity, absolute hearing threshold and mechanical detection threshold. Upper extremity motor performance was evaluated by the Purdue Pegboard Test and the Short Physical Performance Battery was used to assess lower extremity motor function. Multiple logistic regression models were employed to determine associations of sensory and motor function with frailty vs. pre-frailty for both frailty measures.ResultsThe frailty measures were moderately correlated (0.497, p ≤ 0.01) and had a Kappa agreement of 0.467 (p = 0.002). Using the FP, frailty was significantly associated with reduced upper extremity motor function only (OR = 0.50, 95% CI 0.29–0.87, p = 0.014). Frailty as assessed by the FI was significantly related to higher hearing thresholds (OR = 1.21, 95% CI 1.02–1.43, p = 0.027) and reduced lower extremity performance (OR = 0.32, 95% CI 0.13–0.77, p = 0.012).ConclusionFrailty is related to reduced performance in measures of sensory and motor function. However, traditional measures of frailty might be differentially sensitive to capture sensory and motor decline, possibly contributing to the much-observed discordance between the diagnostic instruments. This should be taken into account by researchers and clinicians when planning and evaluating therapeutic interventions for frailty.Trial registrationClinicalTrials.gov NCT03666039. Registered 11 September 2018 – Retrospectively registered.

Brain Changes and Fast Cognitive and Motor Decline in Older Adults.

To identify brain magnetic resonance imaging (MRI) signatures characterizing people with different patterns of decline in cognition and motor function. In the Swedish National Study on Aging and Care in Kungsholmen, Stockholm, 385 participants had available repeated brain MRI examinations, where markers of brain volumes and white matter integrity were assessed. The speed of cognitive and motor decline was estimated as the rate of a Mini-Mental State Examination and gait speed decline over 12 years (linear mixed models), and further dichotomized into the upper (25% fastest rate of decline) versus the lower quartiles. Participants were grouped in slow/no decliners (reference), isolated motor decliners, isolated cognitive decliners, and cognitive and motor decliners. We estimated the associations between changes in brain markers (linear mixed models) and baseline diffusion tensor imaging measures (linear regression model) and the 4 decline patterns. Individuals with concurrent cognitive and motor decline (n = 51) experienced the greatest loss in the total brain (β: -12.3; 95% confidence interval [CI]: -18.2; -6.38) and hippocampal (β: -0.25; 95% CI: -0.34; -0.16) volumes, the steepest accumulation of white matter hyperintensities (β: 1.61; 95% CI: 0.54; 2.68), and the greatest ventricular enlargement (β: 2.07; 95% CI: 0.67; 3.47). Compared to the reference, those only experiencing cognitive decline presented with steeper hippocampal volume loss, whereas those exhibiting only motor decline displayed a greater white matter hyperintensities burden. Lower microstructural white matter integrity was associated with concurrent cognitive and motor decline. Concurrent cognitive and motor decline is accompanied by rapidly evolving and complex brain pathology involving both gray and white matter. Isolated cognitive and motor declines seem to exhibit brain damage with different qualitative features.

Relationship between motor cortical and peripheral axonal hyperexcitability in amyotrophic lateral sclerosis

BackgroundPrevious studies have shown that patients with amyotrophic lateral sclerosis (ALS) have hyperexcitability in both the motor cortex and peripheral motor axons, but the relationship between central and peripheral excitability...

A-157 G Syndrome in Adulthood: A Case Report

Abstract Objective: FG syndrome is an X-linked recessive disorder (p.R961W MED12 mutation) affecting phenotypic males and is characterized by intellectual disability, multiple congenital anomalies, hypotonia, constipation, and hyperactivity. Existing literature about syndromic presentations in adulthood is limited. This case study presents an adult with FG syndrome. Method: Patient is a 39-year-old White cisgender male with FG syndrome and confirmed p.R961W mutation. Pertinent history includes agenesis of corpus callosum, moderate intellectual disability, communication disorder, Tourette’s syndrome, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, bipolar disorder not otherwise specified, and posttraumatic stress disorder. Previous neuropsychological assessments found a generalized pattern of impairment. In early adulthood, the patient’s motor skills deteriorated, and he was hospitalized for aggression. At age 37, the patient was “declining” despite a normal CT scan (except for agenesis of corpus callosum) and development of intermittent paranoia and auditory and visual hallucinations. Results: An interdisciplinary evaluation, performed via telehealth, was completed at an academic medical center. Cognitive changes were denied. Hyperactivity, angry outbursts, affability, and talkativeness were reported. Behavioral and psychiatric symptoms decreased since a change in residence and homecare providers. Conclusions: Little is known about adults with FG syndrome. This case suggests that the behavioral phenotype of FG syndrome remains consistent into adulthood. While cognitive changes were not evident, a decline in motor function and the development of psychotic symptoms did occur. This case increases awareness about FG syndrome in adulthood and can inform clinical practice. Adults with FG syndrome can achieve meaningful goals with proper support from community services, supervised living, and therapeutic interventions.

Dying from ALS in Sweden: clinical status, setting, and symptoms

Objectives This retrospective cohort study aims to provide a comprehensive account of death in Swedish patients with ALS, including clinical status preceding death, the death setting, as well as symptoms. Methods The study presents detailed information on a cohort of patients with ALS from Stockholm, Sweden, deceased in 2018–2020. In addition, selected information is presented on a larger complementary cohort of ALS patients from all regions of Sweden deceased in 2011–2020. Data were obtained from patient medical records, the Swedish Motor Neuron Disease Quality Registry, and the Swedish Quality Registry of Palliative Care. Results Ninety-three patients were included in the main cohort and 2224 patients in the complementary cohort. In the main cohort, there was a slow decline in weight and motor function during the 12 months preceding death. Most (93.4%) anticipated/prolonged deaths occurred in a palliative care unit, at home, or in an assisted living facility while 44.8% of precipitous deaths occurred in a hospital ward. Next of kin or health care staff were present at death for most patients (78.7%). In the final week of life, 41.1% experienced at least one symptom (either pain, anxiety, confusion, or dyspnea) that was only partially relieved or not at all. Conclusion The majority of patients died in their own homes or at a palliative unit in the presence of next of kin and most symptoms were adequately managed. This paper might be used in educating patients, next of kin as well as health professionals, decreasing uncertainty surrounding the end of life.

Neuroprotective effects of TRPV1 by targeting GDF11 in the Mpp+/MPTP-induced Parkinson's disease model

Protecting dopaminergic neurons is a key approach in the prevention of Parkinson's disease (PD). Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that is widely distributed in the mammalian nervous system. In this study, we designed experiments to investigate the effect and mechanisms of TRPV1 against DA neurons damage of PD. Our results showed that trpv1-deficient mice showed a significant loss of TH + neurons than PD mice after MPTP intraperitoneal injection, in addition, a significant decline in motor function was observed in trpv1-deficient mice versus the MPTP model. In addition, our study indicated that GDF11 overexpression inhibited MPP + - induced oxidative stress, cell senescence, and apoptosis in neurons. Results also showed that TRPV1 prevented the down-regulation of GDF11 expression in PD model, gdf11 knockdown blocks the effects of TRPV1 on the antioxidant, antiaging, and antiapoptotic activities of dopaminergic neurons. Consequently, our findings indicate that TRPV1 protects dopaminergic neurons from injury by promoting GDF11 expression in PD model.

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Targeting the frontoparietal network using bifocal transcranial alternating current stimulation during a motor sequence learning task in healthy older adults

BackgroundHealthy older adults show a decrease in motor performance and motor learning capacity as well as in working memory (WM) performance. WM has been suggested to be involved in motor learning processes, such as sequence learning. Correlational evidence has shown the involvement of the frontoparietal network (FPN), a network underlying WM processes, in motor sequence learning. However, causal evidence is currently lacking. Non-invasive brain stimulation (NIBS) studies have focused so far predominantly on motor-related areas to enhance motor sequence learning while areas associated with more cognitive aspects of motor learning have not yet been addressed. HypothesisIn this study, we aim to provide causal evidence for the involvement of WM processes and the underlying FPN in the successful performance of a motor sequence learning task by using theta transcranial alternating current stimulation (tACS) targeting the FPN during a motor sequence learning task. MethodsIn a cohort of 20 healthy older adults, we applied bifocal tACS in the theta range to the FPN during a sequence learning task. With the use of a double-blind, cross-over design, we tested the efficacy of active compared to sham stimulation. Two versions of the motor task were used: one with high and one with low WM load, to explore the efficacy of stimulation on tasks differing in WM demand. Additionally, the effects of stimulation on WM performance were addressed using an N-back task. The tACS frequency was personalized by means of EEG measuring the individual theta peak frequency during the N-back task. ResultsThe application of personalized theta tACS to the FPN improved performance during the motor sequence learning task with high WM load (p < .001), but not with low WM load. Active stimulation significantly improved both speed (p < .001), and accuracy (p = .03) during the task with high WM load. In addition, the stimulation paradigm improved performance on the N-back task for the 2-back task (p = .013), but not for 1-back and 3-back. ConclusionThe performance during a motor sequence learning task can be enhanced by means of personalized bifocal theta tACS to the FPN when WM load is high, indicating that the efficacy of this stimulation paradigm is dependent on the cognitive demand during the learning task. These data provide further causal evidence for the critical involvement of WM processes and the FPN during the execution of a motor sequence learning task in healthy older. These findings open new exciting possibilities to counteract the age-related decline in motor performance, learning capacity and WM performance.

Brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington’s disease

Huntington’s disease (HD) is an inherited neurodegenerative disease caused by expansion of cytosine–adenine–guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss and decline in cognitive and motor function. Increasing evidence suggests that blood–brain barrier (BBB) dysfunction may contribute to progression of the disease. Studies in animal models, in vitro models, and post-mortem tissue find that disease progression is associated with increased microvascular density, altered cerebral blood flow, and loss of paracellular and transcellular barrier function. Here, we report on changes in BBB phenotype due to expansion of CAG repeats using an isogenic pair of induced pluripotent stem cells (iPSCs) differentiated into brain microvascular endothelial-like cells (iBMECs). We show that CAG expansion associated with juvenile HD alters the trajectory of iBMEC differentiation, producing cells with ~ two-fold lower percentage of adherent endothelial cells. CAG expansion is associated with diminished transendothelial electrical resistance and reduced tight junction protein expression, but no significant changes in paracellular permeability. While mutant huntingtin protein (mHTT) aggregates were not observed in HD iBMECs, widespread transcriptional dysregulation was observed in iBMECs compared to iPSCs. In addition, CAG expansion in iBMECs results in distinct responses to pathological and therapeutic perturbations including angiogenic factors, oxidative stress, and osmotic stress. In a tissue-engineered BBB model, iBMECs show subtle changes in phenotype, including differences in cell turnover and immune cell adhesion. Our results further support that CAG expansion in BMECs contributes to BBB dysfunction during HD.

Current care practices for patients with Duchenne muscular dystrophy in China

BackgroundThe coronavirus disease (COVID-19) pandemic has presented challenges in the care of patients with chronic diseases. We identified the challenges faced by Chinese patients with Duchenne muscular dystrophy (DMD) during the pandemic. MethodsAn online cross-sectional survey was conducted between March 27 and June 30, 2021. ResultsOf the 2105 valid questionnaire responses, 2,056 patients were from non-lockdown areas. In these areas, 42.8% reduced outside daily activities, 49.4% reduced rehabilitation service use, 39.7% postponed regular follow-ups, and 40.8% reported accelerated motor function decline. These figures generally increased for patients from lockdown areas—67.3% reduced outside daily activities, 44.9% reduced rehabilitation service use, 79.6% postponed regular follow-ups, and 55.1% reported accelerated motor function decline. Ambulation loss was most commonly reported in September and March before 2020; however, this trend was absent in 2020. Regarding the informed prices of disease-modifying drugs in Europe and the United States, 86.7% could afford a maximum of one-twentieth of the prices, 8.0% could afford one-tenth of the prices, and only 0.6% of the patients could afford the full prices. ConclusionsImplementation of standardized care for DMD in China is consistent with global practices, and the COVID-19 pandemic has affected the care of patients with chronic diseases worldwide, particularly in lockdown areas. Telemedicine is an effective model for providing healthcare to such patients. Healthcare workers should assist patients and establish more robust chronic disease management systems. Collaboration between governmental and non-governmental entities could address the cost of disease-modifying drugs in China and other developing countries.

Ability of functional performance assessments to discriminate athletes with and without chronic ankle instability : a case-control study.

BackgroundThe decline in motor function associated with chronic ankle instability (CAI) can be assessed using Functional Performance tests. Ankle muscular strength, endurance and range of motion (ROM) has been assessed in previous studies but functional activities such as sprinting and change of direction are less well studied in athletes with CAI. Hence the aim of this study was to determine how sprint, change of direction, ankle isometric strength, endurance and ROM measures may be associated with discriminate athletes with and without CAI.MethodsOne hundred and six participants (CAI: n = 53 or no CAI: n = 53) provided informed consent to participate in this study. Participants performed three functional performance tests, (30-m sprint test, Modified Illinois change of direction test (MICODT)) and change of direction test. Range of motion for dorsiflexion was measured using weight bearing lunge test and inversion, eversion and plantarflexion using Saunders® digital inclinometer. Strength was assessed using Baseline® hand-held dynamometer for plantarflexors, dorsiflexors, invertors and evertors. Muscular endurance was assessed by single heel raise test and Modified single heel raise test. Between-group comparisons utilised Student’s t-test and Mann-Whitney U-tests, with a number of unique variable and multivariable binomial logistic regression performed to determine which performance measures may discriminate participants with CAI.ResultsThe CAI participants performed significantly worse in the three functional performance tests as well as multiple measures of ankle ROM, isometric strength and muscular endurance (p < 0.008). While several measures of ROM (plantarflexion and dorsiflexion), strength (inversion and eversion) and both muscular endurance tests were significantly associated with CAI in the univariable analysis, the strongest association was the functional performance tests, especially MICDOT time (odds ratio (95% CI): 0.06 [0.02–0.17], sensitivity 94.3%, specificity 88.7%). Multivariable regression analyses indicated that performance across the functional performance tests were more strongly associated with CAI than any ankle ROM, muscular strength or endurance test. Further, the inclusion of the best ankle range of motion, strength or muscular endurance tests did not significantly improve upon the association of the MICDOT with CAI.ConclusionsChronic ankle instability in athletic populations appears to be highly associated with declines in functional performance and to a somewhat lesser extent, ankle range of motion, strength and muscle endurance measures. This may suggest that optimal rehabilitation for athletes with CAI may require a greater focus on improving sprinting speed and change of direction ability in the mid to latter stages of rehabilitation, with regular assessments of these functional performance tests necessary to guide the progression and overload of this training.