Quantitative Gait and Balance Outcomes for Ataxia Trials: Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers

The Cerebellum, Journal Year: 2023, Volume and Issue: 23(4), P. 1566 - 1592

Published: Nov. 13, 2023

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait balance disturbances most often present as first signs of cerebellar ataxia reported disabling features in disease progression. Thus, gait constitute promising relevant performance outcomes trials.This narrative review with embedded consensus will describe evidence sensitivity evaluating severity progression, propose a protocol establishing metrics natural history studies trials, discuss issues their use outcomes.

Language: Английский

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The cerebellum and the Mirror Neuron System: A matter of inhibition? From neurophysiological evidence to neuromodulatory implications. A narrative review

Neuroscience & Biobehavioral Reviews, Journal Year: 2024, Volume and Issue: 164, P. 105830 - 105830

Published: July 26, 2024

Mirror neurons show activity during both the execution (AE) and observation of actions (AO). The Neuron System (MNS) could be involved motor imagery (MI) as well. Extensive research suggests that cerebellum is interconnected with MNS may critically in its activities. We gathered evidence on cerebellum's role functions, theoretically experimentally. Evidence shows plays a major AO MI lesions impair functions likely because, by modulating cortical inhibitory interneurons mirror properties, contribute to visuomotor matching, which fundamental for shaping properties. Indeed, strengthen sensory-motor patterns minimise discrepancy between predicted actual outcome, AE AO. Furthermore, through connections hippocampus, might internal simulations programs MI. Finally, cerebellar neuromodulation improve impact activity, we explored potential neurophysiological neurorehabilitation implications.

Language: Английский

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Optimizing Rare Disease Gait Classification through Data Balancing and Generative AI: Insights from Hereditary Cerebellar Ataxia

Sensors, Journal Year: 2024, Volume and Issue: 24(11), P. 3613 - 3613

Published: June 3, 2024

The interpretability of gait analysis studies in people with rare diseases, such as those primary hereditary cerebellar ataxia (pwCA), is frequently limited by the small sample sizes and unbalanced datasets. purpose this study was to assess effectiveness data balancing generative artificial intelligence (AI) algorithms generating synthetic reflecting actual abnormalities pwCA. Gait 30 pwCA (age: 51.6 ± 12.2 years; 13 females, 17 males) 100 healthy subjects 57.1 10.4; 60 40 were collected at lumbar level an inertial measurement unit. Subsampling, oversampling, minority adversarial networks, conditional tabular networks (ctGAN) applied generate datasets be input a random forest classifier. Consistency explainability metrics also calculated coherence generated dataset known ctGAN significantly improved classification performance compared original traditional augmentation methods. are effective methods for from populations owing their ability improve diagnostic models consistent explainability.

Language: Английский

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

Movement Disorders, Journal Year: 2024, Volume and Issue: 39(5), P. 788 - 797

Published: Feb. 28, 2024

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

Language: Английский

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Digital Gait Biomarkers Allow to Capture 1‐Year Longitudinal Change in Spinocerebellar Ataxia Type 3

Movement Disorders, Journal Year: 2022, Volume and Issue: 37(11), P. 2295 - 2301

Published: Aug. 31, 2022

ABSTRACT Measures of step variability and body sway during gait have shown to correlate with clinical ataxia severity in several cross‐sectional studies. However, serve as a valid progression biomarker, these measures prove their sensitivity robustly capture longitudinal change, ideally within short time frames (eg, 1 year). We present the first multicenter analysis study spinocerebellar ataxias. performed combined (n = 28) (1‐year interval, n 17) Spinocerebellar Ataxia type 3 subjects (including seven preataxic mutation carriers). Longitudinal showed significant change between baseline 1‐year follow‐up, high effect sizes (stride length variability: P 0.01, size r prb 0.66; lateral sway: 0.007, 0.73). Sample estimation for indicates required cohort 43 detecting 50% reduction natural progression, compared 240 score Scale Assessment Rating (SARA). These thus promising motor biomarkers upcoming interventional © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf International Parkinson Disorder Society

Language: Английский

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Neurophysiology of cerebellar ataxias and gait disorders

Clinical Neurophysiology Practice, Journal Year: 2023, Volume and Issue: 8, P. 143 - 160

Published: Jan. 1, 2023

There are numerous forms of cerebellar disorders from sporadic to genetic diseases. The aim this chapter is provide an overview the advances and emerging techniques during these last 2 decades in neurophysiological tests useful patients for clinical research purposes. Clinically, exhibit various combinations a vestibulocerebellar syndrome, cognitive affective syndrome motor which will be discussed throughout chapter. Cerebellar show abnormal Bereitschaftpotentials (BPs) mismatch negativity. EEG now being applied unravel impaired electrophysiological patterns associated within cortex. Eyeblink conditioning significantly disorders: ability acquire conditioned eyeblink responses reduced hereditary ataxias, stroke after tumor surgery cerebellum. Furthermore, early marker degenerative disease. General rules control suggest that optimal strategies needed execute voluntary movements complex environment daily life. A high degree adaptability required learning procedures underlying as sensorimotor adaptation essential perform accurate goal-directed movements. impairments online visuomotor tasks. Cerebellum-motor cortex inhibition (CBI) biomarker showing inverse association between cerebellothalamocortical tract integrity ataxia severity. Ataxic gait characterized by increased step width, ankle joint range motion, variability, lack intra-limb inter-joint inter-segmental coordination, foot ground placement loss trunk control. Taken together, framework better appraisal disorders.

Language: Английский

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Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach

Molecular Therapy — Nucleic Acids, Journal Year: 2023, Volume and Issue: 33, P. 15 - 27

Published: June 3, 2023

Genetic mutations that disrupt open reading frames and cause translation termination are frequent causes of human disease difficult to treat due protein truncation mRNA degradation by nonsense-mediated decay, leaving few options for traditional drug targeting. Splice-switching antisense oligonucleotides offer a potential therapeutic solution diseases caused disrupted inducing exon skipping correct the frame. We have recently reported on an exon-skipping oligonucleotide has effect in mouse model CLN3 Batten disease, fatal pediatric lysosomal storage disease. To validate this approach, we generated constitutively expresses Cln3 spliced isoform induced molecule. Behavioral pathological analyses these mice demonstrate less severe phenotype compared with model, providing evidence oligonucleotide-induced can efficacy treating This highlights how engineering through RNA splicing modulation be effective approach.

Language: Английский

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Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia

Pharmacological Research, Journal Year: 2023, Volume and Issue: 191, P. 106773 - 106773

Published: April 15, 2023

Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, microglial activation appears be common feature in different types ataxic patients rodent models. However, direct evidence that vivo is sufficient induce ataxia Here, employing chemogenetic approaches manipulate microglia selectively directly, we found specific the vermis directly leads symptoms wild-type mice aggravated motor deficits 3-acetylpyridine (3-AP) mice, classic mouse model ataxia. Mechanistically, proinflammatory induced either M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers Blockade microglia-derived TNF-α, one most important cytokines, attenuates hyperactivity PCs driven microglia. Moreover, inhibition suppression PLX3397 minocycline reduces production including effectively restore overactivation alleviate mice. These results suggest may aggravate neuroinflammatory response subsequently dysfunction PCs, turn deficits. Our findings thus reveal causal relationship between symptoms, offer novel for therapeutic intervention ataxias targeting inflammatory mediators.

Language: Английский

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Step Width Haptic Feedback for Gait Stability in Spinocerebellar Ataxia: Preliminary Results

Movement Disorders, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Background Wider step width and lower step‐to‐step variability are linked to improved gait stability reduced fall risk. It is unclear if patients with spinocerebellar ataxia (SCA) can learn adjust these aspects of reduce Objectives The aims were examine the possibility using wearable haptic biofeedback enhance risk in individuals SCA. Methods Thirteen people SCA type 3 performed training (single session) real‐time feedback. Results Step increased post‐training (19.3 cm, interquartile range [IQR] 16.3–20.2 cm) at retention (16.6 IQR 16.2–21.1 cm), compared baseline (11.0 5.2–15.2 cm; P < 0.001). decreased during (19.7%, 17.4%–26.2%) (22.3%, 18.6%–30.2%), (44.5%, 28.5%–71.2%; Crossover steps, another mark instability, after ( 0.031). Conclusions These pilot results suggest that use a novel, system improve their stability. © 2025 International Parkinson Movement Disorder Society.

Language: Английский

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Biomechanical aspects of gait impairments after stroke: an analytical review

Russian Journal of Physiotherapy Balneology and Rehabilitation, Journal Year: 2025, Volume and Issue: 23(4), P. 205 - 217

Published: Jan. 16, 2025

Restoring gait and balance functions after stroke constitutes a major problem in modern neurology. Post-stroke static locomotor impairments are the most common disabling consequences that critical for patients’ quality of life basic functional independence. This analytical review attempts to comprehensively examine assess biomechanical aspects affecting patients with post-stroke impairments. The outlines multifaceted nature such impairments, including muscle weakness, changes neuromotor coordination, proprioception stability, as well compensatory mechanisms developing patients. A particular focus is on parameters, kinematics kinetics movements, provide deeper understanding order develop more effective treatment strategies. analysis highlights importance personalized rehabilitation approach be based specific each patient. intended enhance further research development innovative approaches rehabilitation. data presented great elaboration medical plans may contribute improving their independence life.

Language: Английский

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