Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia.

Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a splicing mutation in elongator acetyltransferase complex subunit 1 (ELP1). This mutation leads to the skipping of exon 20 and a tissue-specific reduction of ELP1, mainly in the central and peripheral nervous systems. FD is a complex neurological disorder accompanied by severe gait ataxia and retinal degeneration. There is currently no effective treatment to restore ELP1 production in individuals with FD, and the disease is ultimately fatal. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked on its optimization to generate novel splicing modulator compounds (SMCs) that can be used in individuals with FD. Here, we optimize the potency, efficacy, and bio-distribution of second-generation kinetin derivatives to develop an oral treatment for FD that can efficiently pass the blood-brain barrier and correct the ELP1 splicing defect in the nervous system. We demonstrate that the novel compound PTC258 efficiently restores correct ELP1 splicing in mouse tissues, including brain, and most importantly, prevents the progressive neuronal degeneration that is characteristic of FD. Postnatal oral administration of PTC258 to the phenotypic mouse model TgFD9;Elp1Δ20/flox increases full-length ELP1 transcript in a dose-dependent manner and leads to a 2-fold increase in functional ELP1 in the brain. Remarkably, PTC258 treatment improves survival, gait ataxia, and retinal degeneration in the phenotypic FD mice. Our findings highlight the great therapeutic potential of this novel class of small molecules as an oral treatment for FD.

Closing the Loop: From Motor Neuroscience to Neurorehabilitation.

The fields of human motor control, motor learning, and neurorehabilitation have long been linked by the intuition that understanding how we move (and learn to move) leads to better rehabilitation. In reality, these fields have remained largely separate. Our knowledge of the neural control of movement has expanded, but principles that can directly impact rehabilitation efficacy remain somewhat sparse. This raises two important questions: What can basic studies of motor learning really tell us about rehabilitation, and are we asking the right questions to improve the lives of patients? This review aims to contextualize recent advances in computational and behavioral studies of human motor learning within the framework of neurorehabilitation. We also discuss our views of the current challenges facing rehabilitation and outline potential clinical applications from recent theoretical and basic studies of motor learning and control.

Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is known to contribute to cognitive impairment, apathy, and gait dysfunction. Although associations between cognitive impairment and either apathy or gait dysfunction have been shown in SVD, the inter-relations among these three clinical features and their potential common neural basis remains unexplored. The dopaminergic meso-cortical and meso-limbic pathways have been known as the important brain circuits for both cognitive control, emotion regulation and motor function. Here, we investigated the potential inter-relations between cognitive impairment, apathy, and gait dysfunction, with a specific focus on determining whether these clinical features are associated with damage to the meso-cortical and meso-limbic pathways in SVD. In this cross-sectional study, we included 213 participants with SVD in whom MRI scans and comprehensive neurobehavioral assessments were administered. These assessments comprised of six clinical measures: processing speed, executive function, memory, apathy (based on the Apathy Evaluation Scale), and gait function (based on the time and steps in Timed Up and Go test). We reconstructed five tracts connecting ventral tegmental area (VTA) and the dorsolateral prefrontal cortex (dlPFC), ventral lateral PFC (vlPFC), medial orbitofrontal cortex (mOFC), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) within meso-cortical and meso-limbic pathways using diffusion weighted imaging. The damage along the five tracts was quantified using the free water (FW) and FW-corrected mean diffusivity (MD-t) indices. Furthermore, we explored the inter-correlations among the six clinical measures and identified their common components using principal component analysis (PCA). Linear regression analyses showed that higher FW values of tracts within meso-cortical pathways were related to these clinical measures in cognition, apathy, and gait (all P-corrected values < 0.05). PCA showed strong inter-associations among these clinical measures and identified a common component wherein all six clinical measures loaded on. Higher FW values of tracts within meso-cortical pathways were related to the PCA-derived common component (all P-corrected values < 0.05). Moreover, FW values of VTA-ACC tract showed the strongest contribution to the PCA-derived common component over all other neuroimaging features. In conclusion, our study showed that the three clinical features (cognitive impairment, apathy, and gait dysfunction) of SVD are strongly inter-related and that the damage in meso-cortical pathway could be the common neural basis underlying the three features in SVD. These findings advance our understanding of the mechanisms behind these clinical features of SVD and have the potential to inform novel management and intervention strategies for SVD.

Vertebral level specific modulation of paraspinal muscle activity based on vestibular signals during walking.

Evoking muscle responses by electrical vestibular stimulation (EVS) may help to understand the contribution of the vestibular system to postural control. Although paraspinal muscles play a role in postural stability, the vestibulo-muscular coupling of these muscles during walking has rarely been studied. This study aimed to investigate how vestibular signals affect paraspinal muscle activity at different vertebral levels during walking with preferred and narrow step width. Sixteen healthy participants were recruited. Participants walked on a treadmill for 8 min at 78 steps/min and 2.8 km/h, at two different step width, either with or without EVS. Bipolar electromyography was recorded bilaterally from the paraspinal muscles at eight vertebral levels from cervical to lumbar. Coherence, gain, and delay of EVS and EMG responses were determined. Significant EVS-EMG coupling (P < 0.01) was found at ipsilateral and/or contralateral heel strikes. This coupling was mirrored between left and right relative to the midline of the trunk and between the higher and lower vertebral levels, i.e. a peak occurred at ipsilateral heel strike at lower levels, whereas it occurred at contralateral heel strike at higher levels. EVS-EMG coupling only partially coincided with peak muscle activity. EVS-EMG coherence slightly, but not significantly, increased when walking with narrow steps. No significant differences were found in gain and phase between the vertebral levels or step width conditions. In summary, vertebral level specific modulation of paraspinal muscle activity based on vestibular signals might allow a fast, synchronized, and spatially co-ordinated response along the trunk during walking. KEY POINTS: Mediolateral stabilization of gait requires an estimate of the state of the body, which is affected by vestibular afference. During gait, the heavy trunk segment is controlled by phasic paraspinal muscle activity and in rodents the medial and lateral vestibulospinal tracts activate these muscles. To gain insight in vestibulospinal connections in humans and their role in gait, we recorded paraspinal surface EMG of cervical to lumbar paraspinal muscles, and characterized coherence, gain and delay between EMG and electrical vestibular stimulation, during slow walking. Vestibular stimulation caused phasic, vertebral level specific modulation of paraspinal muscle activity at delays of around 40 ms, which was mirrored between left, lower and right, upper vertebral levels. Our results indicate that vestibular afference causes fast, synchronized, and spatially co-ordinated responses of the paraspinal muscles along the trunk, that simultaneously contribute to stabilizing the centre of mass trajectory and to keeping the head upright.

Polypharmacy Is Associated With Slow Gait Speed and Recurrent Falls in Older People With HIV.

BACKGROUND: Older people with human immunodeficiency virus (HIV, PWH) are prone to using multiple medications due to higher rates of medical comorbidities and the use of antiretroviral therapy (ART). We assessed the prevalence and clinical impact of polypharmacy among PWH. METHODS: We leveraged clinical data from the AIDS Clinical Trials Group A5322 study "Long-Term Follow-up of Older HIV-infected Adults: Addressing Issues of Aging, HIV Infection and Inflammation" (HAILO). We included PWH aged ≥40 years with plasma HIV RNA levels <200 copies/µL. We assessed the relationship between polypharmacy (defined as the use of 5 or more prescription medications, excluding ART) and hyperpolypharmacy (defined as the use of 10 or more prescription medications, excluding ART) with slow gait speed (less than 1 meter/second) and falls, including recurrent falls. RESULTS: Excluding ART, 24% of study participants had polypharmacy and 4% had hyperpolypharmacy. Polypharmacy was more common in women (30%) than men (23%). Participants with polypharmacy had a higher risk of slow gait speed (odds ratio [OR] = 1.78; 95% confidence interval [CI] = 1.27-2.50) and increased risk of recurrent falls (OR = 2.12; 95% CI = 1.06-4.23). The risk for recurrent falls was further increased in those with hyperpolypharmacy compared with those without polypharmacy (OR = 3.46; 95% CI = 1.32-9.12). CONCLUSIONS: In this large, mixed-sex cohort of PWH aged ≥40 years, polypharmacy was associated with slow gait speed and recurrent falls, even after accounting for medical comorbidities, alcohol use, substance use, and other factors. These results highlight the need for increased focus on identifying and managing polypharmacy and hyperpolypharmacy in PWH.

Developing a novel dual-injection FDG-PET imaging methodology to study the functional neuroanatomy of gait.

Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, we used a hybrid PET/MR system and measured glucose metabolism related to both walking and standing with a dual-injection paradigm in a single study session. For this study, 15 healthy older adults (10 females, age range: 60.5-70.7 years) with normal cognition were recruited from the community. Each participant received an intravenous injection of [18F]-2-fluoro-2-deoxyglucose (FDG) before engaging in two distinct tasks, a static postural control task (standing) and a walking task. After each task, participants were imaged. To discern independent neural functions related to walking compared to standing, we applied a bespoke dose correction to remove the residual 18F signal of the first scan (PETSTAND) from the second scan (PETWALK) and proportional scaling to the global mean, cerebellum, or white matter (WM). Whole-brain differences in walking-elicited neural activity measured with FDG-PET were assessed using a one-sample t-test. In this study, we show that a dual-injection paradigm in healthy older adults is feasible with biologically valid findings. Our results with a dose correction and scaling to the global mean showed that walking, compared to standing, increased glucose consumption in the cuneus (Z = 7.03), the temporal gyrus (Z = 6.91) and the orbital frontal cortex (Z = 6.71). Subcortically, we observed increased glucose metabolism in the supraspinal locomotor network including the thalamus (Z = 6.55), cerebellar vermis and the brainstem (pedunculopontine/mesencephalic locomotor region). Exploratory analyses using proportional scaling to the cerebellum and WM returned similar findings. Here, we have established the feasibility and tolerability of a novel method capable of capturing neural activations related to actual walking and extended previous knowledge including the recruitment of brain regions involved in sensory processing. Our paradigm could be used to explore pathological alterations in various gait disorders.

Impact of visual rotations on heading direction and center of mass control during steady-state gait.

Visual information is essential to navigate the environment and maintain postural stability during gait. Visual field rotations alter the perceived heading direction, resulting in gait trajectory deviations, known as visual coupling. It is unclear how center of mass (CoM) control relative to a continuously changing base of support (BoS) is adapted to facilitate visual coupling. This study aimed to characterize mediolateral (ML) balance control during visual coupling in steady-state gait. Sixteen healthy participants walked on an instrumented treadmill, naive to sinusoidal low-frequency (0.1 Hz) rotations of the virtual environment around the vertical axis. Rotations were continuous with 1) high or 2) low amplitude or were 3) periodic with 10-s intervals. Visual coupling was characterized with cross-correlations between CoM trajectory and visual rotations. Balance control was characterized with the ML margin of stability (MoSML) and by quantifying foot placement control as the relation between CoM dynamics and lateral foot placement. Visual coupling was strong on a group level (continuous low: 0.88, continuous high: 0.91, periodic: 0.95) and moderate to strong on an individual level. Higher rotation amplitudes induced stronger gait trajectory deviations. The MoSML decreased toward the deviation direction and increased at the opposite side. Foot placement control was similar compared with regular gait. Furthermore, pelvis and foot reorientation toward the rotation direction was observed. We concluded that visual coupling was facilitated by reorientating the body and shifting the extrapolated CoMML closer to the lateral BoS boundary toward the adjusted heading direction while preserving CoM excursion and foot placement control.NEW & NOTEWORTHY Healthy, naive participants were unaware of subtle, low-frequency rotations of the visual field but still coupled their gait trajectory to a rotating virtual environment. In response, participants decreased their margin of stability toward the new heading direction, without changing the center of mass excursion magnitude and foot placement strategy.

The effects of P2 segment of posterior cerebral artery to thalamus blood supply pattern on gait in cerebral small vessel disease: A 7 T MRI based study.

Gait disturbance is a manifestation of cerebral small vessel disease (CSVD). The posterolateral thalamus (PL), whose blood is mainly supplied by the P2 segment of posterior cerebral artery (P2-PCA), plays pivotal roles in gait regulation. We investigated the influence of the distance between P2-PCA and PL on gait with varying CSVD burden. 71 participants were divided into low and high CSVD burden groups. The distance from P2-PCA to PL was measured using 7 T TOF-MRA and categorized into an immediate or distant PCA-to-thalamus pattern. Functional connectivity (FC) and voxel-based morphometry were assessed to evaluate functional and structural alterations. In the low CSVD burden group, immediate PCA-to-thalamus supply strongly correlates with longer step length and higher wave phase time percent, and exhibited enhanced FCs in left supplementary motor area, right precentral cortex (PreCG.R). While in the high CSVD burden group, no association between PCA-to-thalamus pattern and gait was found, and we observed reduced FC in PreCG.R with immediate PCA-to-thalamus pattern. Higher CSVD burden was associated with decreased gray matter density in bilateral thalamus. However, no significant structural thalamic change was observed between the two types of PCA-to-thalamus patterns in all patients. Our study demonstrated patients with immediate PCA-to-thalamus supply exhibited better gait performance in low CSVD burden populations, which also correlated with enhanced FCs in motor-related cortex, indicating the beneficial effects of the immediate PCA-to-thalamus supply pattern. In the higher burden CSVD populations, the effects of PCA-to-thalamus pattern on gait are void, attributable to the CSVD-related thalamic destruction and impairment of thalamus-related FC.

Low and high-order topological disruption of functional networks in multiple system atrophy with freezing of gait: A resting-state study.

OBJECTIVE: Freezing of gait (FOG), a specific survival-threatening gait impairment, needs to be urgently explored in patients with multiple system atrophy (MSA), which is characterized by rapid progression and death within 10 years of symptom onset. The objective of this study was to explore the topological organisation of both low- and high-order functional networks in patients with MAS and FOG. METHOD: Low-order functional connectivity (LOFC) and high-order functional connectivity FC (HOFC) networks were calculated and further analysed using the graph theory approach in 24 patients with MSA without FOG, 20 patients with FOG, and 25 healthy controls. The relationship between brain activity and the severity of freezing symptoms was investigated in patients with FOG. RESULTS: Regarding global topological properties, patients with FOG exhibited alterations in the whole-brain network, dorsal attention network (DAN), frontoparietal network (FPN), and default network (DMN), compared with patients without FOG. At the node level, patients with FOG showed decreased nodal centralities in sensorimotor network (SMN), DAN, ventral attention network (VAN), FPN, limbic regions, hippocampal network and basal ganglia network (BG), and increased nodal centralities in the FPN, DMN, visual network (VIN) and, cerebellar network. The nodal centralities of the right inferior frontal sulcus, left lateral amygdala and left nucleus accumbens (NAC) were negatively correlated with the FOG severity. CONCLUSION: This study identified a disrupted topology of functional interactions at both low and high levels with extensive alterations in topological properties in MSA patients with FOG, especially those associated with damage to the FPN. These findings offer new insights into the dysfunctional mechanisms of complex networks and suggest potential neuroimaging biomarkers for FOG in patients with MSA.

Cortical modulations before lower limb motor blocks are associated with freezing of gait in Parkinson's disease: an EEG source localization study.

BACKGROUND: Freezing of gait (FOG) is a debilitating symptom of Parkinson's disease (PD) characterized by paroxysmal episodes in which patients are unable to step forward. A research priority is identifying cortical changes before freezing in PD-FOG. METHODS: We tested 19 patients with PD who had been assessed for FOG (n=14 with FOG and 5 without FOG). While seated, patients stepped bilaterally on pedals to progress forward through a virtual hallway while 64-channel EEG was recorded. We assessed cortical activities before and during lower limb motor blocks (LLMB), defined as a break in rhythmic pedaling, and stops, defined as movement cessation following an auditory stop cue. This task was selected because LLMB correlates with FOG severity in PD and allows recording of high-quality EEG. Patients were tested after overnight withdrawal from dopaminergic medications ("off" state) and in the "on" medications state. EEG source activities were evaluated using individual MRI and standardized low resolution brain electromagnetic tomography (sLORETA). Functional connectivity was evaluated by phase lag index between seeds and pre-defined cortical regions of interest. RESULTS: EEG source activities for LLMB vs. cued stops localized to right posterior parietal area (Brodmann area 39), lateral premotor area (Brodmann area 6), and inferior frontal gyrus (Brodmann area 47). In these areas, PD-FOG (n=14) increased alpha rhythms (8-12 Hz) before LLMB vs. typical stepping, whereas PD without FOG (n=5) decreased alpha power. Alpha rhythms were linearly correlated with LLMB severity, and the relationship became an inverted U-shape when assessing alpha rhythms as a function of percent time in LLMB in the "off" medication state. Right inferior frontal gyrus and supplementary motor area connectivity was observed before LLMB in the beta band (13-30 Hz). This same pattern of connectivity was seen before stops. Dopaminergic medication improved FOG and led to less alpha synchronization and increased functional connections between frontal and parietal areas. CONCLUSIONS: Right inferior parietofrontal structures are implicated in PD-FOG. The predominant changes were in the alpha rhythm, which increased before LLMB and with LLMB severity. Similar connectivity was observed for LLMB and stops between the right inferior frontal gyrus and supplementary motor area, suggesting that FOG may be a form of "unintended stopping." These findings may inform approaches to neurorehabilitation of PD-FOG.

Biochemical, biomechanical and imaging biomarkers of ischemic stroke: Time for integrative thinking.

Stroke is one of the leading causes of adult disability affecting millions of people worldwide. Post-stroke cognitive and motor impairments diminish quality of life and functional independence. There is an increased risk of having a second stroke and developing secondary conditions with long-term social and economic impacts. With increasing number of stroke incidents, shortage of medical professionals and limited budgets, health services are struggling to provide a care that can break the vicious cycle of stroke. Effective post-stroke recovery hinges on holistic, integrative and personalized care starting from improved diagnosis and treatment in clinics to continuous rehabilitation and support in the community. To improve stroke care pathways, there have been growing efforts in discovering biomarkers that can provide valuable insights into the neural, physiological and biomechanical consequences of stroke and how patients respond to new interventions. In this review paper, we aim to summarize recent biomarker discovery research focusing on three modalities (brain imaging, blood sampling and gait assessments), look at some established and forthcoming biomarkers, and discuss their usefulness and complementarity within the context of comprehensive stroke care. We also emphasize the importance of biomarker guided personalized interventions to enhance stroke treatment and post-stroke recovery.

Distributional data analysis via quantile functions and its application to modeling digital biomarkers of gait in Alzheimer's Disease.

With the advent of continuous health monitoring with wearable devices, users now generate their unique streams of continuous data such as minute-level step counts or heartbeats. Summarizing these streams via scalar summaries often ignores the distributional nature of wearable data and almost unavoidably leads to the loss of critical information. We propose to capture the distributional nature of wearable data via user-specific quantile functions (QF) and use these QFs as predictors in scalar-on-quantile-function-regression (SOQFR). As an alternative approach, we also propose to represent QFs via user-specific L-moments, robust rank-based analogs of traditional moments, and use L-moments as predictors in SOQFR (SOQFR-L). These two approaches provide two mutually consistent interpretations: in terms of quantile levels by SOQFR and in terms of L-moments by SOQFR-L. We also demonstrate how to deal with multi-modal distributional data via Joint and Individual Variation Explained using L-moments. The proposed methods are illustrated in a study of association of digital gait biomarkers with cognitive function in Alzheimers disease. Our analysis shows that the proposed methods demonstrate higher predictive performance and attain much stronger associations with clinical cognitive scales compared to simple distributional summaries.

Osteoarthritis year in review 2023: Biomechanics.

Biomechanics plays a significant yet complex role in osteoarthritis (OA) onset and progression. Identifying alterations in biomechanical factors and their complex interactions is critical for gaining new insights into OA pathophysiology and identification of clearly defined and modifiable mechanical treatment targets. This review synthesized biomechanics studies from March 2022 to April 2023, from which three themes relating to human gait emerged: (1) new insights into the pathogenesis of OA using computational modeling and machine learning, (2) technology-enhanced biomechanical interventions for OA, and (3) out-of-lab biomechanical assessments of OA. We further highlighted future-focused areas which may continue to advance the field of biomechanics in OA, with a particular emphasis on exploiting technology to understand and treat biomechanical mechanisms of OA outside the laboratory. The breadth of studies included in this review highlights the complex role of biomechanics in OA and showcase numerous innovative and outstanding contributions to the field. Exciting cross-disciplinary efforts integrating computational modeling, mobile sensors, and machine learning methods show great promise for streamlining in vivo multi-scale biomechanics workflows and are expected to underpin future breakthroughs in the understanding and treatment of biomechanics in OA.

Hip contact forces can be predicted with a neural network using only synthesised key points and electromyography in people with hip osteoarthritis.

OBJECTIVE: To develop and validate a neural network to estimate hip contact forces (HCF), and lower body kinematics and kinetics during walking in individuals with hip osteoarthritis (OA) using synthesised anatomical key points and electromyography. To assess the capability of the neural network to detect directional changes in HCF resulting from prescribed gait modifications. DESIGN: A calibrated electromyography-informed neuromusculoskeletal model was used to compute lower body joint angles, moments, and HCF for 17 participants with mild-to-moderate hip OA. Anatomical key points (e.g., joint centres) were synthesised from marker trajectories and augmented with bias and noise expected from computer vision-based pose estimation systems. Temporal convolutional and long short-term memory neural networks (NN) were trained using leave-one-subject-out validation to predict neuromusculoskeletal modelling outputs from the synthesised key points and measured electromyography data from 5 hip-spanning muscles. RESULTS: HCF was predicted with an average error of 13.4 ± 7.1% of peak force. Joint angles and moments were predicted with an average root-mean-square-error of 5.3 degrees and 0.10 Nm/kg, respectively. The NN could detect changes in peak HCF that occur due to gait modifications with good agreement with neuromusculoskeletal modelling (r2 = 0.72) and a minimum detectable change of 9.5%. CONCLUSION: The developed neural network predicted HCF and lower body joint angles and moments in individuals with hip OA using noisy synthesised key point locations with acceptable errors. Changes in HCF magnitude due to gait modifications were predicted with high accuracy. These findings have important implications for implementation of load-modification based gait retraining interventions for people with hip OA in a natural environment (i.e., home, clinic).

CAMTA1-related disorder: Phenotypic and molecular characterization of 26 new individuals and literature review.

Calmodulin-binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long-term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift-7, nonsense-6, splicing-1, initiation codon-1, missense-5, and intragenic deletions-3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait, hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under-reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals.

Evaluation of mobility recovery after hip fracture: a scoping review of randomized controlled studies.

Few older adults regain their pre-fracture mobility after a hip fracture. Intervention studies evaluating effects on gait typically use short clinical tests or in-lab parameters that are often limited to gait speed only. Measurements of mobility in daily life settings exist and should be considered to a greater extent than today. Less than half of hip fracture patients regain their pre-fracture mobility. Mobility recovery is closely linked to health status and quality of life, but there is no comprehensive overview of how gait has been evaluated in intervention studies on hip fracture patients. The purpose was to identify what gait parameters have been used in randomized controlled trials to assess intervention effects on older people's mobility recovery after hip fracture. This scoping review is a secondary paper that identified relevant peer-reviewed and grey literature from 11 databases. After abstract and full-text screening, 24 papers from the original review and 8 from an updated search and manual screening were included. Records were eligible if they included gait parameters in RCTs on hip fracture patients. We included 32 papers from 29 trials (2754 unique participants). Gait parameters were primary endpoint in six studies only. Gait was predominantly evaluated as short walking, with gait speed being most frequently studied. Only five studies reported gait parameters from wearable sensors. Evidence on mobility improvement after interventions in hip fracture patients is largely limited to gait speed as assessed in a controlled setting. The transition from traditional clinical and in-lab to out-of-lab gait assessment is needed to assess effects of interventions on mobility recovery after hip fracture at higher granularity in all aspects of patients' lives, so that optimal care pathways can be defined.

Noradrenergic cardiac denervation is associated with gait velocity in Parkinson disease: a dual ligand PET study.

PURPOSE: Preliminary data suggest that gait abnormalities in Parkinson disease (PD) may be associated with sympathetic cardiac denervation. No kinematic gait studies were performed to confirm this observation. We aimed to correlate spatiotemporal kinematic gait parameters with cardiac sympathetic denervation as determined by cardiac [11C]HED PET in PD. METHODS: Retrospective database analysis of 27 PD patients with cardiac sympathetic denervation. All patients underwent spatiotemporal kinematic gait assessment (medication 'off' state), cardiac [11C]HED and dopaminergic brain [11C]DTBZ PET scans. We employed a hierarchical regression approach to examine associations between the extent of cardiac denervation, dopaminergic nigrostriatal neurodegeneration, and three gait parameters - velocity, step length and cadence. RESULTS: More extensive cardiac denervation was associated with slower velocity (estimate: -1.034, 95% CI [-1.65, -0.42], p = 0.002), shorter step length (estimate: -0.818, 95% CI [-1.43, -0.21], p = 0.011) and lower cadence (estimate: -0.752, 95% CI [-1.28, -0.23], p = 0.007) explaining alone 30% (Adjusted-R²: 0.297), 20% (Adjusted-R²: 0.202) and 23% (Adjusted-R²: 0.227) of the variability, respecivetly. These associations remained independent of striatal dopaminergic impairment and confounding factors such as age, Hoehn and Yahr (HY) stages, peripheral neuropathy, cognition, and autonomic symptoms. In contrast, striatal dopaminergic denervation was significantly associated with step length (estimate: 0.883, 95% CI [0.29, 1.48], p = 0.005), explaining about 24% of the variability but was dependent of HY stage. CONCLUSIONS: More severe cardiac noradrenergic denervation was associated with lower gait velocity, independent of striatal dopaminergic denervation and HY stage, impacting both step length and cadence. These results suggest independent contributions of the peripheral autonomic system degeneration on gait dynsfunction in PD.

The Effect of taVNS at 25 Hz and 100 Hz on Parkinson's Disease Gait-A Randomized Motion Sensor Study.

BACKGROUND: Transcutaneous electrostimulation of the auricular branch of the vagal nerve (taVNS) has the propensity to reach diffuse neuromodulatory networks, which are dysfunctional in Parkinson's disease (PD). Previous studies support the use of taVNS as an add-on treatment for gait in PD. OBJECTIVES: We assessed the effect of taVNS at 25 Hz (taVNS25), taVNS at 100 Hz (taVNS100), and sham earlobe stimulation (sVNS) on levodopa responsive (arm swing velocity, arm range of motion, stride length, gait speed) and non-responsive gait characteristics (arm range of motion asymmetry, anticipatory postural adjustment [APA] duration, APA first step duration, APA first step range of motion), and turns (first turn duration, double 360° turn duration, steps per turn) in advanced PD. METHODS: In our double blind sham controlled within-subject randomized trial, we included 30 PD patients (modified Hoehn and Yahr stage, 2.5-4) to assess the effect of taVNS25, taVNS100, and sVNS on gait characteristics measured with inertial motion sensors during the instrumented stand and walk test and a double 360° turn. Separate generalized mixed models were built for each gait characteristic. RESULTS: During taVNS100 compared to sVNS arm swing velocity (P = 0.030) and stride length increased (P = 0.027), and APA duration decreased (P = 0.050). During taVNS25 compared to sVNS stride length (P = 0.024) and gait speed (P = 0.021) increased and double 360° turn duration decreased (P = 0.039). CONCLUSIONS: We have found that taVNS has a frequency specific propensity to improve stride length, arm swing velocity, and gait speed and double 360° turn duration in PD patients. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Trans-Spinal Theta Burst Magnetic Stimulation in Parkinson's Disease and Gait Disorders.

BACKGROUND: Gait disorders in patients with Parkinson's disease (PD) can become disabling with disease progression without effective treatment. OBJECTIVES: To investigate the efficacy of intermittent θ burst trans-spinal magnetic stimulation (TsMS) in PD patients with gait and balance disorders. METHODS: This was a randomized, parallel, double-blind, controlled trial. Active or sham TsMS was applied at third thoracic vertebra with 100% of the trans-spinal motor threshold, during 5 consecutive days. Participants were evaluated at baseline, immediately after last session, 1 and 4 weeks after last session. Primary outcome was Total Timed Up and Go (TUG) values comparing active versus sham phases 1 week after intervention. The secondary outcome measurements consisted of motor, gait and balance scales, and questionnaires for quality of life and cognition. RESULTS: Thirty-three patients were included, average age 68.5 (6.4) years in active group and 70.3 (6.3) years in sham group. In active group, Total TUG mean baseline was 107.18 (95% CI, 52.1-116.1), and 1 week after stimulation was 93.0 (95% CI, 50.7-135.3); sham group, Total TUG mean baseline was 101.2 (95% CI, 47.1-155.3) and 1 week after stimulation 75.2 (95% CI 34.0-116.4), P = 0.54. Similarly, intervention had no significant effects on secondary outcome measurements. During stimulation period, five patients presented with mild side effects (three in active group and two in sham group). DISCUSSION: TsMS did not significantly improve gait or balance analysis in patients with PD and gait disorders. The protocol was safe and well tolerated. © 2024 International Parkinson and Movement Disorder Society.

Digital Gait Measures Capture 1-Year Progression in Early-Stage Spinocerebellar Ataxia Type 2.

BACKGROUND: With disease-modifying drugs in reach for cerebellar ataxias, fine-grained digital health measures are highly warranted to complement clinical and patient-reported outcome measures in upcoming treatment trials and treatment monitoring. These measures need to demonstrate sensitivity to capture change, in particular in the early stages of the disease. OBJECTIVE: Our aim is to unravel gait measures sensitive to longitudinal change in the-particularly trial-relevant-early stage of spinocerebellar ataxia type 2 (SCA2). METHODS: We performed a multicenter longitudinal study with combined cross-sectional and 1-year interval longitudinal analysis in early-stage SCA2 participants (n = 23, including nine pre-ataxic expansion carriers; median, ATXN2 CAG repeat expansion 38 ± 2; median, Scale for the Assessment and Rating of Ataxia [SARA] score 4.8 ± 4.3). Gait was assessed using three wearable motion sensors during a 2-minute walk, with analyses focused on gait measures of spatio-temporal variability that have shown sensitivity to ataxia severity (eg, lateral step deviation). RESULTS: We found significant changes for gait measures between baseline and 1-year follow-up with large effect sizes (lateral step deviation P = 0.0001, effect size rprb = 0.78), whereas the SARA score showed no change (P = 0.67). Sample size estimation indicates a required cohort size of n = 43 to detect a 50% reduction in natural progression. Test-retest reliability and minimal detectable change analysis confirm the accuracy of detecting 50% of the identified 1-year change. CONCLUSIONS: Gait measures assessed by wearable sensors can capture natural progression in early-stage SCA2 within just 1 year-in contrast to a clinical ataxia outcome. Lateral step deviation represents a promising outcome measure for upcoming multicenter interventional trials, particularly in the early stages of cerebellar ataxia. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.