Decline In Motor Function Research Articles

Microstructure of Brain Nuclei in Early Parkinson's Disease: Longitudinal Diffusion Kurtosis Imaging.

Diffusion kurtosis imaging provides in vivo measurement of microstructural tissue characteristics and could help guide management of Parkinson's disease. To investigate longitudinal diffusion kurtosis imaging changes on magnetic resonance imaging in the deep grey nuclei in people with early Parkinson's disease over two years, and whether they correlate with disease progression. We conducted a longitudinal case-control study of early Parkinson's disease. 262 people (Parkinson's disease: n = 185, aged 67.5±9.1 years; 43% female; healthy controls: n = 77, aged 66.6±8.1 years; 53% female) underwent diffusion kurtosis imaging and clinical assessment at baseline and two-year timepoints. We automatically segmented five nuclei, comparing the mean kurtosis and other diffusion kurtosis imaging indices between groups and over time using repeated-measures analysis of variance, and Pearson correlation with the two-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III. At baseline, mean kurtosis was higher in Parkinson's disease than controls in the substantia nigra, putamen, thalamus and globus pallidus when adjusting for age, sex, and levodopa equivalent daily dose (p < 0.027). These differences grew over two years, with mean kurtosis increasing for the Parkinson's disease group while remaining stable for the control group; evident in significant "group ×time" interaction effects for the putamen, thalamus and globus pallidus (ηp2= 0.08-0.11, p < 0.015). However, we did not detect significant correlations between increasing mean kurtosis and declining motor function in the Parkinson's disease group. Diffusion kurtosis imaging of specific grey matter structures shows abnormal microstructure in PD at baseline and abnormal progression in PD over two years.

Cognitive Decline and Mood Alterations in the Mouse Model of Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is a hereditary disorder, caused by an expansion of polyglutamine in the ataxin-2 protein. Although the mutant protein is expressed throughout all the cell and organ types, the cerebellum is primarily affected. The disease progression is mainly accompanied by a decline in motor functions. However, the disturbances in cognitive abilities and low mental state have also been reported in patients. Recent evidence suggests that the cerebellar functionality expands beyond the motor control. Thus, the cerebellum turned out to be involved into the language, verbal working, and spatial memory; executive functions such as working memory, planning, organizing, and strategy formation; and emotional processing. Here, we used the transgenic SCA2-58Q mice to evaluate their anxiety, cognitive functions, and mood alterations. The expression of the mutant ataxin-2 specifically in the cerebellar Purkinje cells (PCs) in SCA2-58Q mice allowed us to study the direct involvement of the cerebellum into the cognitive and affective control. We determined that SCA2-58Q mice exhibit anxiolytic behavior, decline in spatial memory, and a depressive-like state. Our results support the idea of cerebellar involvement in cognitive control and the handling of emotions.

α-Synuclein and Mechanisms of Epigenetic Regulation.

Synucleinopathies are a group of neurodegenerative diseases with common pathological lesions associated with the excessive accumulation and abnormal intracellular deposition of toxic species of α-synuclein. The shared clinical features are chronic progressive decline of motor, cognitive, and behavioral functions. These disorders include Parkinson's disease, dementia with Lewy body, and multiple system atrophy. Vigorous research in the mechanisms of pathology of these illnesses is currently under way to find disease-modifying treatment and molecular markers for early diagnosis. α-Synuclein is a prone-to-aggregate, small amyloidogenic protein with multiple roles in synaptic vesicle trafficking, neurotransmitter release, and intracellular signaling events. Its expression is controlled by several mechanisms, one of which is epigenetic regulation. When transmitted to the nucleus, α-synuclein binds to DNA and histones and participates in epigenetic regulatory functions controlling specific gene transcription. Here, we discuss the various aspects of α-synuclein involvement in epigenetic regulation in health and diseases.

Optimizing the Effect of tDCS on Motor Sequence Learning in the Elderly.

One of the most visible effects of aging, even in healthy, normal aging, is a decline in motor performance. The range of strategies applicable to counteract this deterioration has increased. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique that can promote neuroplasticity, has recently gained attention. However, knowledge about optimized tDCS parameters in the elderly is limited. Therefore, in this study, we investigated the effect of different anodal tDCS intensities on motor sequence learning in the elderly. Over the course of four sessions, 25 healthy older adults (over 65 years old) completed the Serial Reaction Time Task (SRTT) while receiving 1, 2, or 3 mA of anodal or sham stimulation over the primary motor cortex (M1). Additionally, 24 h after stimulation, motor memory consolidation was assessed. The results confirmed that motor sequence learning in all tDCS conditions was maintained the following day. While increased anodal stimulation intensity over M1 showed longer lasting excitability enhancement in the elderly in a prior study, the combination of higher intensity stimulation with an implicit motor learning task showed no significant effect. Future research should focus on the reason behind this lack of effect and probe alternative stimulation protocols.

Asperuloside, the bioactive compound in the edible Eucommia ulmoides male flower, delays muscle aging by daf-16 mediated improvement in mitochondrial dysfunction.

Muscle aging is accompanied by a progressive decline in motor performance and mitochondrial function, yet fundamental treatments for this disorder remain sparse. The search for active compounds from natural dietary products that promote muscular health has attracted considerable interest. Although the male flowers of Eucommia ulmoides Oliv., an emerging resource of plant-based food, have healthspan-promoting efficacy, it's still unclear whether they or their main active compounds (iridoids) could improve muscle aging. We compared the effects of three iridoids on motion status during different aging processes in Caenorhabditis elegans (C. elegans). Additionally, we further investigated the roles and mechanisms of the iridoid-rich floral extract (EUFE) and the most active monomer on nematode age-related muscle hypofunction exacerbated by high fat. We found that EUFE and asperuloside (Asp) significantly improved motility and muscular health and reduced lipid accumulation at appropriate concentrations. Compared to normal mitochondria against muscle disorder, Asp delayed the deterioration of mitochondrial function, morphology, or related metabolism during aging. Meanwhile, Asp regulated the mitochondrial quality control (MQC) network, mainly activating mitophagy, which was associated with increased mRNA and protein expression of lgg-1 and dct-1. Mechanistically, Asp promoted the expression and nuclear localization of the DAF-16 protein, an upstream regulator of the above two autophagy-related genes. The defective mutant and RNA interference further suggested that daf-16 mediated the ameliorative effects of Asp on muscle aging and mitochondrial dysfunction. These results provide potential evidence for the preventive application and functional food development of E. ulmoides male flowers and asperuloside against muscle aging.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Timed Up and Go Testに着目した新しい運動評価方法の開発

[Purpose] The purpose of this study was to investigate the usefulness of centrifugal acceleration as an indicator for screening early motor function decline using a simple movement measurement system we developed. [Participants and Methods] We measured the Timed Up and Go test (TUG) time using a simple movement measurement system, and investigated frailty in 25 independent healthy elderly people living in the community. [Results] A correlation was found between TUG times and the number of steps taken, and centrifugal accelerations in all subjects. There was no significant difference between the robust and frail groups’ TUG times, but there was a significant difference in centrifugal acceleration. [Conclusion] Centrifugal acceleration may be a more detailed indicator of motor function decline in the elderly.

MR-spectroscopy in metachromatic leukodystrophy: A model free approach and clinical correlation

Background and purposeMetachromatic leukodystrophy (MLD) is a lysosomal enzyme deficiency disorder leading to demyelination and subsequently to a progressive decline in cognitive and motor function. It affects mainly white matter where changes during the course of the disease can be visualized on T2-weighted MRI as hyperintense areas. Associated changes in brain metabolism can be quantified by MR spectroscopy (MRS) and may give complementary information as biomarkers for disease characterisation and progression. Our study aimed to further investigate the correlation of MRS with clinical parameters for motor and cognitive function by using a model free MRS analysis approach that would be precise and straightforward to implement. Materials and methods53 MRS datasets derived from 29 patients (10 late-infantile, 19 juvenile) and 12 controls were acquired using a semi-LASER CSI sequence covering a slice through the centrum semiovale above the corpus callosum. We defined four regions of interest in the white matter (frontal white matter [FWM] and the cortico-spinal tract [CST] area, each left and right) and one in cortical grey matter. Spectra were analysed using a model and fitting free approach by calculating the definite integral of 10 intervals which were distributed along the whole spectrum. These 10 intervals were orientated towards the main peaks of the metabolites N-acetylaspartate (NAA), creatine, myo-inositol, choline, glutamine/glutamate and aspartate to approximately attribute changes in the intervals to corresponding metabolites. Their ratios to the main creatine peak integral were correlated with clinical parameters assessing motor and cognitive abilities. Furthermore, in a post-hoc analysis, NAA levels of a subset of 21 MR datasets were correlated to NAA levels in urine measured by 1H (proton) nuclear magnetic resonance (NMR) spectroscopy.The applied interval integration method was validated in the control cohort against the standard approach, using spectral profile templates of known metabolites (LCModel). Both methods showed good agreement, with coefficients of variance being slightly lower for our approach compared to the related LCModel results. Moreover, the new approach was able to extract information out of the frequency range around the main peaks of aspartate and glutamine where LCModel showed only few usable values for the respective metabolites. ResultsMLD spectra clearly differed from controls. The most pronounced differences were found in white matter (much less in grey matter), with larger values corresponding to main peaks of myo-inositol, choline and aspartate, and smaller values associated with NAA and glutamine. Late-infantile patients had more severe changes compared to later-onset patients, especially in intervals corresponding to NAA, aspartate, myo-inositol, choline and glutamine.There was a high correlation of several intervals in the corticospinal tract region with motor function (with the most relevant interval corresponding to NAA peak with a correlation coefficient of −0.75; p < 0.001), while cognitive function, by means of IQ, was found to be most correlating in frontal white matter corresponding to the NAA peak (r = 0.84, p < 0.001).The post-hoc analysis showed that the main NAA peak interval correlated negatively with the NAA in urine (r = −0.584, p < 0.001). ConclusionThe applied model and fitting free interval integration approach to analyse MRS data of a semi-LASER sequence at 3T suits well to detect and quantify pathological changes in MLD patients through the different courses of the disease and correlates well with clinical symptoms while showing smaller dimensions of variation compared to the more sophisticated single metabolite analysis using LCModel. NAA seems the most clinically meaningful biomarker to use in this context. Its correlation with urine measurements further underlines its potential as a clinically and biologically useful parameter of disease progression in MLD.

Anti-α-synuclein c-terminal antibodies block PFF uptake and accumulation of phospho-synuclein in preclinical models of Parkinson's disease

Parkinson's disease (PD), a neurodegenerative disease affecting dopaminergic (DA) neurons, is characterized by decline of motor function and cognition. Dopaminergic cell loss is associated with accumulation of toxic alpha synuclein aggregates. As DA neuron death occurs late in the disease, therapeutics that block the spread of alpha synuclein may offer functional benefit and delay disease progression. To test this hypothesis, we generated antibodies to the C terminal region of synuclein with high nanomolar affinity and characterized them in in vitro and in vivo models of spread. Interestingly, we found that only antibodies with high affinity to the distal most portion of the C-terminus robustly reduced uptake of alpha synuclein preformed fibrils (PFF) and accumulation of phospho (S129) alpha synuclein in cell culture. Additionally, the antibody treatment blocked the spread of phospho (S129) alpha synuclein associated-pathology in a mouse model of synucleinopathy. Blockade of neuronal PFF uptake by different antibodies was more predictive of in vivo activity than their binding potency to monomeric or oligomeric forms of alpha synuclein. These data demonstrate that antibodies directed to the C-terminus of the alpha synuclein have differential effects on target engagement and efficacy. Furthermore, our data provides additional support for the development of alpha synuclein antibodies as a therapeutic strategy for PD patients.

Characteristics of frailty phenotype in Chinese nursing home population and significance of motor function indicators in frailty assessment.

The objectives of this study were to analyze the distribution characteristics of frailty phenotypes in older adults of Chinese nursing homes, and to compare some motor function characteristics of older adults in nursing homes between frailty and non-frailty, to determine which motor function and frailty are related. This cross-sectional study included 177 older adults living in nursing homes. Frailty was diagnosed by Fried's phenotype, and motor function assessment characteristics (including muscle tone, ROM, and balance) were also evaluated. Chi-square and logistic regression analyses were performed. Frailty prevalence was 53% in nursing homes in big Chinese cities (average age 82.0 ± 6.1). Low levels of physical activity (90.4% in frail elder), decreased handgrip strength (98.9% in frail elder) and slowed walking speed (100% in frail elder) were the 3 main components of the frailty phenotype of frail adults in nursing homes in China. It is worth noting that 74.7% of the non-frail elders also had reduced handgrip strength. Further analysis showed that balance (P < .001), muscle tone (upper, P = .028, lower, P = .001) and the range of motion (P < .001) were associated with frailty in older adults. The frailty of the elders in Chinese nursing homes was characterized by the decline of motor function. And surprisingly, both frail and non-frail elders were found to have poor strength. Frail nursing home seniors also have body muscle tone, range of motion and balance problems. The elderly of China should focus on strength, stretch and balance training to improve motor function, especially strength training, which is important for prevention frailty.

A longitudinal study of creatine kinase and creatinine levels in Duchenne muscular dystrophy.

Management of Duchenne muscular dystrophy (DMD) has entered an era featuring novel treatments. Trackable noninvasive biomarkers could improve disease progression monitoring and drug effect detection. Our aim in this study was to measure changes in selected noninvasive biomarkers and assess their relationship to age and motor function. We retrospectively studied 555 patients with DMD who had at least 12 months of treatment of glucocorticoids and were not enrolled in trials of potential disease-modifying therapies. We extracted biomarker data of serum creatine kinase (CK), serum creatinine (Cr), urine Cr, and urine Cr/urine osmolality (osm), as well as functional data for age at loss of ambulation and Functional Motor Scale (FMS) values from patients' clinical records. Data were analyzed using linear mixed-model analyses. CK, serum Cr, urine Cr, and urine Cr/urine osm all decreased with declining motor function. CK consistently decreased and FMS score consistently worsened with age without clear inflection points. There was an increased odds ratio for LOA with lower values of CK, serum Cr, urine Cr, and urine Cr/urine osm, most notably for urine Cr. Although individual biomarker values are challenging to directly apply clinically, our study has demonstrated that trends over time may complement functional measures in the assessment of individuals with DMD. Future studies could elucidate predictive utility of these biomarkers in assessing motor function changes in DMD.

At Crossroads in a Virtual City: Effect of Spatial Disorientation on Gait Variability and Psychophysiological Response among Healthy Older Adults

Introduction: Aging has been associated with a decline in cognitive and motor performance, often expressed in multitasking situations, which could include wayfinding. A major challenge to successful wayfinding is spatial disorientation, occurring mostly at crossings. Although gait changes have been observed in various dual-task conditions, little is known about the effect of disorientation on gait and psychophysiological response among older adults during wayfinding. The study aimed at identifying the effect of spatial disorientation on gait variability and psychophysiological response among healthy older adults during wayfinding in a controlled environment. Method: We analyzed data of 28 participants (age 70.8 ± 4.6, 18 female), 14 experimental and 14 controls. Participants performed a wayfinding task consisting of 14 major decision points (7 intersections) within a virtual environment (VE) projected on a 180° screen while walking on a self-paced treadmill equipped with a marker-based optical motion-capture system. The VE was held constant for the controls and manipulated for the experimental participants. Disorientation was identified based on a customized annotation scheme. Variability in gait, including the coefficient of variation (CV), was measured as the primary endpoint. Psychophysiological response measures, including heart rate variability (RMSSD) and skin conductance response (SCR), were continuously monitored as secondary endpoints and estimates of cognitive effort. Linear Mixed Effects models were applied to hypothesis-driven outcome measures extracted from decision points. Results: Walking speed and step length decreased when disoriented (p < 0.05), while stride time, stance time, walking speed CV, stance time CV, SCR amplitude, and SCR count increased when disoriented (p < 0.05). A higher RMSSD was associated with being disoriented at crossings (p < 0.05). SCR count was greater in the older experimental group (p < 0.001), including when disoriented (p < 0.001). Discussion/Conclusion: The results provide evidence for the impact of spatial disorientation on changes in gait pattern and psychophysiological response among older adults during wayfinding. Location also had implications for the effect of disorientation on gait and cognitive effort. This gives further insight into the substrates of real-world navigation challenges among older adults, with an emphasis on viable features for designing situation-adaptive interventional devices aiding independent mobility.

Poorer dexterity is associated with underlying Alzheimer’s disease brain pathology

AbstractBackgroundThere has been increasing recognition for the decline of motor function in Alzheimer’s disease (AD) progression and its substantial role in disease morbidity. However, less is known about regional pathology burden—including amyloid‐β and tau protein deposition and cortical trophy—and its relationship to motor performance. Here investigate this relationship using standardized motor function assessment tools.MethodParticipants along a control‐to‐impaired continuum were enrolled in the Alzheimer’s Disease Connectome Project and underwent T1‐weighted MRI (N=206), with a subset undergoing [C‐11]PiB (N=61) and [F‐18 ]Flortaucipir PET (N=58) (Table 1) imaging for amyloid and tau pathology, respectively. T1‐weighted scans were processed using Freesurfer to estimate regional cortical thickness. [C‐11]PiB distribution volume ratios (DVR; cerebellar GM reference region) and [F‐18] Flortaucipir standardized uptake value ratios (SUVr; inferior cerebellar GM reference region) were assessed. Regions of interest (ROI) for analysis included the parahippocampal, entorhinal, motor, and frontal regions. Motor function was assessed utilizing NIH toolbox tests including the 2‐minute walking, 9‐hole pegboard dexterity, and dynamometer grip strength assessments. Motor performance was analyzed using participants uncorrected standardized scores. Scores were collected from participant‐reported dominant hand assessments. Multiple linear regression models tested relationships between AD biomarker burden and motor performance while controlling for age and sex of participants.ResultIncreased amyloid‐β (β‐0.42, p‐value: &lt;0.05) and tau (β: ‐0.53, p‐value: &lt;0.05) burden in primary motor cortices were associated with worse dexterity scores independent of age and sex. Grip strength did not show a significant correlation to cortical amyloid‐β (β: ‐0.14, p‐value 0.33) or tau burden (β: 0.23, p‐value: 0.36). Higher cortical thickness in primary motor regions were associated with higher dexterity (β: 0.21, p‐value &lt;0.0001) and 2‐minute walking scores (β: 0.24, p‐value &lt;0.001). When controlling for age and sex, grip strength predicted decreasing cortical thickness (β: 0.01, p‐value: &lt;0.001) (Table 2).ConclusionLower dexterity performance may be driven by elevated AD pathological burden and cortical thinning in cortical motor regions. Further research into motor performance and clinical disease manifestation is needed to determine the diagnostic utility of fine motor assessment as a predictor of motor decline in individuals with Alzheimer’s disease pathology.

The association of gabapentin initiation and neurocognitive changes in older adults with normal cognition.

Background: Gabapentin is increasingly prescribed to older adults, which raises concerns about its potential to cause neurocognitive changes. Therefore, we aimed to examine the association of gabapentin use with neurocognitive changes (i.e., cognitive decline, functional status decline, and motor function change) in older adults. Methods: We conducted a retrospective cohort study using the National Alzheimer's Coordinating Center Uniform Data Set (UDS; September 2005-March 2021 data freeze). From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index visit). Initiators were matched to randomly selected nonusers on year of UDS enrollment and visit number from enrollment to index. Cognitive decline was defined as any increase in the Clinical Dementia Rating global score (CDRGLOB) and as a 1-point increase in CDR sum of boxes (CDR-SB). Functional status decline was defined as a 3-point increase in the sum of the Functional Activities Questionnaire (FAQ) and as 0.3-point increase in mean FAQ. Decline in motor function was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, we used joint stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights. All analyses were conducted comparing index to index+1 and index+2 visits. Results: From the eligible UDS participants (N = 23,059), we included 480 initiators (mean age [SD]: 78.7 [6.9]; male 34.4%); 4,320 nonusers (78.3 [7.0]; 34.4%). Gabapentin initiation was significantly associated with cognitive/functional status decline: worsening CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.55 [1.07, 2.25]); CDR-SB at index+1 visit (1.94 [1.22, 3.09]); and mean of FAQ at index+2 visit (1.78 [1.12, 2.83]). After excluding initiators with extant motor dysfunction (n = 21), we identified 459 initiators (78.7 [6.9]; 34.0%) and 4,131 nonusers (78.2 [6.9]; 34.7%); in this sample, gabapentin initiation was associated with increased falls at the index+2 visit (2.51 [1.19, 5.31]). Conclusion: Gabapentin initiation was significantly associated with deleterious neurocognitive changes among older adults with initially normal cognition. Further studies are needed to examine the risk/benefit of prescribing gabapentin in older adults.

The importance of early diagnosis and views on newborn screening in metachromatic leukodystrophy: results of a Caregiver Survey in the UK and Republic of Ireland

Metachromatic Leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). MLD causes progressive loss of motor function and severe decline in cognitive function, leading to premature death. Early diagnosis of MLD provides the opportunity to begin treatment before the disease progresses and causes severe disability. MLD is not currently included in newborn screening (NBS) in the UK.This study consisted of an online survey, and follow-up semi-structured interviews open to MLD patients or caregivers, aged 18 years and over. The aims of the study were to understand the importance of early diagnosis and to establish the views of families and caregivers of patients with MLD on NBS.A total of 24 patients took part in the survey, representing 20 families (two families had two children with MLD, one family had three children with MLD). Following on from the survey, six parents participated in the interviews. Our data showed diagnostic delay from first symptoms was between 0 and 3 years, with a median of 1 year (n = 18); during this time deterioration was rapid, especially in earlier onset MLD. In patients with late infantile MLD (n = 10), 50% were wheelchair dependent, 30% were unable to speak, and 50% were tube fed when a diagnosis of MLD was confirmed. In patients with early juvenile MLD (n = 5), over half used a wheelchair some of the time, had uncontrollable crying, and difficulty speaking (all 60%) before or at the time of diagnosis. A high degree of support was expressed for NBS among caregivers, 95% described it as very or extremely important and 86% believed detection of MLD at birth would have changed their child’s future. One parent expressed their gratitude for an early diagnosis as a result of familial MLD screening offered at birth and how it had changed their child’s future: “It did and it absolutely has I will be forever grateful for his early diagnosis thanks to his older sister.”The rapid rate of deterioration in MLD makes it an essential candidate for NBS, particularly now the first gene therapy (Libmeldy™) has been approved by the European Medicines Agency. Libmeldy™ has also been recommended as a treatment option in England and Wales by the National Institute for Health and Care Excellence (NICE) and is being made available to patients in Scotland via the Scottish Medicines Consortium’s ultra-orphan pathway.

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 &lt; 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.