Muscle & Nerve

Introduction Spinal muscular atrophy (SMA) is a monogenic neuromuscular disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Onasemnogene abeparvovec is a U.S. FDA-approved single-dose gene therapy for SMA. Both its intravenous formulation (Zolgensma, approximately USD 2.13 million per patient) and intrathecal formulation (Itvisma, around USD 2.59 million per patient) are prohibitively expensive, substantially limiting accessibility in low- and middle-income countries (LMICs). We conducted a clinical study of vesemnogene lantuparvovec, an alternative to onasemnogene abeparvovec developed for use in LMIC settings. Methods Sixteen patients with SMA, including 8 with type 1 SMA and 8 with type 2 SMA, received a single intrathecal administration of vesemnogene lantuparvovec. Eleven patients were treated with a low dose (1.5 * 10^14 vg) and five with a high dose (3.0 * 10^14 vg). The primary endpoints were safety and efficacy, assessed by changes from baseline in developmental gross motor milestones according to the World Health Organization criteria. Overall survival was primarily evaluated in type 1 SMA patients. This trial was registered with ClinicalTrials.gov NCT06288230. Results As of the March 2026 cutoff date, 15 of 16 treated patients had completed at least 12 months of follow-up after treatment, while the remaining one type 1 SMA patient died of disease progression at month 6 post-treatment. At 12 months post-treatment, among the surviving 7 patient with type 1 SMA, the median age was 21.6 months (range, 16.1 to 32.3 months). Among the 16 treated patients, the median age at diagnosis was 4.4 months (range, 0.0 to 18.0 months), and the median age at dosing was 10.7 months (range, 2.8 to 22.5 months). All patients experienced at least one AE. Thirty-one AESIs were reported in 13 patients, including hepatotoxicity, thrombocypenia-related events and cardiac events. No patient required prolonged prednisolone prophylaxis. SAEs, including pneumonia, lower respiratory tract infection, upper respiratory tract infection, and haemorrhagic diarrhoea, occurred in 5 of 8 (63%) patients with type 1 SMA and 2 of 8 (25%) patients with type 2 SMA. Two patients with type 1 SMA required invasive ventilation, and one of whom subsequently died. At 12 months post-treatment, 11 of 16 treated patients (69%) gained at least one new WHO motor milestone versus baseline, including 3 type 1 and 8 type 2 SMA patients; one type 2 patient gained six WHO motor milestones and achieved independent walking. Conclusions In patients younger than 24 months of age with type 1 or type 2 SMA, a single intrathecal dose of vesemnogene lantuparvovec was safe and generally well tolerated and was associated with improvements in developmental gross motor milestones compared with outcomes observed among referred but untreated patients. Additional studies are required to further evaluate the long-term safety and efficacy of this gene therapy.

Abstract Purpose: MyotonPRO (MTP) and time-harmonic elastography (THE) are increasingly used to assess muscle mechanical properties, yet they operate on fundamentally different physical principles. MTP measures composite MTP stiffness (N/m) through surface oscillations, while THE quantifies intrinsic shear modulus (THE stiffness, kPa) via propagating shear waves. This study aimed at systematically compare MTP and THE measurements in the vastus lateralis muscle across different contraction intensities and examine how the skin layer and subcutaneous fat (SLSF) thickness influence their relationship. Methods: Twenty-six healthy adults (15 males, 11 females; age 25 [SD 4] years) underwent MTP and THE measurements of the vastus lateralis at rest and during isometric contractions at 15% and 30% maximal voluntary contraction (MVC). Effects of contraction intensities on tissue properties were assessed using univariate analyses of variance with repeated measures. Associations between the different outcomes of THE and MTP technologies were explored using Pearson's correlations and partial correlation coefficients separately for each contraction intensity with adjustment of the SLSF thickness of participants. Results: Both technologies detected contraction intensity-dependent stiffening across all outcomes (p < 0.001). THE stiffness increased from 5.3 [1.2] kPa at rest to 15.6 [6.1] kPa at 30% MVC; THE wave attenuation increased from 0.83 [0.19] to 1.42 [0.36] s/m while MTP stiffness increased from 337.3 [49.3] N/m at rest to 529.4 [160.7] N/m at 30% MVC. Correlations between modalities were weak and condition-dependent. THE wave attenuation did not significantly correlate with any MTP outcome across conditions. Conclusion: MTP and THE detect contraction-induced stiffening through fundamentally different physical mechanisms and should not be regarded as interchangeable. Their correlation is modest at rest and breaks down (or reverses) during active contraction, with subcutaneous fat as a key modifying factor. Clinical trial number: Not applicable.

Wearable digital health technologies may complement traditional gait assessments in amyotrophic lateral sclerosis (ALS) by sensitively capturing real-world mobility changes. In this study, we validated six digital gait metrics derived from ankle-worn sensors in a natural history cohort of 182 individuals with ALS. Investigated metrics correspond to various aspects of gait, including volume, speed, intensity, similarity, variability, and fragmentation. Longitudinal analyses showed significant declines in step count, peak cadence, stride intensity, and stride similarity, with increasing stride duration variability and walking fragmentation over 52 weeks. Many participants exhibited greater relative change in the gait metrics than the self-reported ALS Functional Rating Scale-Revised (ALSFRS-RSE). Stratified analyses revealed that digital metrics captured significant functional decline even in participants with stable walking scores on the ALSFRS-RSE. These findings support the potential utility of these metrics for disease monitoring in ALS clinical care and trials.

Background: Biallelic variants in GFM2, encoding mitochondrial elongation factor G2 (mtEFG2), a GTPase involved in the termination stage of mitochondrial translation, cause autosomal recessive combined oxidative phosphorylation deficiency. Noncoding structural variants may be missed by exome sequencing but can disrupt splicing and provide opportunities for variant-specific therapeutic rescue. We investigated the molecular mechanism underlying suspected Leigh syndrome in an infant with mitochondrial disease and evaluated whether splice-switching oligonucleotide (SSO) treatment could correct the pathogenic splicing defect. Methods: The proband underwent exome sequencing followed by short-read and long-read whole genome sequencing. RNA sequencing, reverse-transcription PCR, quantitative PCR, and cycloheximide treatment were used to characterize the effect of the identified intronic duplication on GFM2 splicing and transcript stability. Patient-derived fibroblasts were treated with SSOs targeting the aberrant splice junction. Rescue was assessed by RNA studies, western blotting, and spectrophotometric measurement of cytochrome c oxidase (COX). Results: Whole genome sequencing identified a paternally-inherited GFM2 missense variant, NM_032380.5:c.2195C>T p.(Pro732Leu), in trans to a maternally-inherited 221-nucleotide intronic duplication, NM_032380.5:c.2029-741_2029-521dup. RNA studies revealed a 87-nucleotide pseudoexon, generated by activation of a cryptic acceptor splice site within the duplicated sequence. The resulting transcript harbored a premature termination codon (PTC) and underwent nonsense-mediated decay, as confirmed by cycloheximide rescue. Together with reduced mtEFG2 protein levels on western blot, the findings supported a loss-of-function mechanism. Enzymatic analysis of affected fibroblasts showed reduced activity of the mtDNA-dependent complex IV subunit COX, with preservation of the nuclear-encoded complex II enzyme succinate dehydrogenase and the control enzyme citrate synthase, consistent with impaired mitochondrial translation. A SSO targeting the aberrant intron-pseudoexon junction nearly abolished pseudoexon inclusion, restored correctly spliced GFM2 transcript from the duplication-containing allele, increased mtEFG2 protein levels, and significantly improved COX activity. Conclusions: This study identifies a pathogenic intronic GFM2 duplication that causes mitochondrial disease through pseudoexon activation and nonsense-mediated decay. The findings demonstrate the value of integrated genome and transcriptome analysis for exome-negative mitochondrial disease and provide in-vitro proof of concept that SSOs can restore transcript processing, protein expression, and mitochondrial respiratory-chain function in patient-derived cells.

Purpose: To identify, through iterative user-centered design, the auditory biofeedback requirements and sound preferences supporting gait training in children with cerebral palsy (CP), and to determine which feedback variables, sound mappings, and sound types yield clinically viable and movement-interpretable paradigms. Methods: The iterative process spanned two prototype phases. Prototype A comprised seven paradigms demonstrated to two experienced physiotherapists (Workshop 1A). Two of these were subsequently discarded owing to poor sound-movement interpretability and two were modified. Six paradigms were added to Prototype B, demonstrated to four children, five parents, and one therapist (Workshop 1B) and two therapists (Workshop 2B). Data were analyzed using systematic text condensation. Results: Within-child sound preferences varied with energy level and sensory state on a given day. Sound-movement interpretability tended to suffer for paradigms with greater acoustic complexity (e.g. computer-generated music). Therapists endorsed a repertoire spanning both movement quality and movement quantity targets. Participants independently proposed paradigms rewarding restrained and controlled movement, a feedback category absent from the current prototype. Conclusions: Session-level calibration is preferable to fixed sound profiles, requiring real-time interface support for paradigm adjustment. Acoustic complexity must remain subordinate to movement-sound interpretability. Paradigms targeting movement restraint are a development priority unaddressed in the literature.

Objectives: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder with predominant striatal pathology in affected males, who frequently show hyperechogenicity of the lentiform nucleus on transcranial sonography. We aim to investigate female mutation carriers and female healthy controls using transcranial sonography to identify potential abnormalities in the striatum, substantia nigra, and ventricular system. Methods: We examined 81 participants (35 female mutation carriers and 46 female controls) using transcranial sonography to assess the presence of hyperechogenicity of the lentiform nucleus, the area of substantia nigra hyperechogenicity, and the widths of the lateral and third ventricles. Clinical evaluation focused on dystonic and parkinsonian symptoms, and we determined genotypes relevant for four X-linked dystonia-parkinsonism genetic modifiers. Results: Female mutation carriers showed more subtle parkinsonian signs compared with controls. The prevalence of hyperechogenicity of the lentiform nucleus was higher in female mutation carriers and was associated with a more unfavorable genetic modifier profile. No relevant abnormalities were observed in the substantia nigra or the ventricular system. Imbalanced X-chromosome inactivation in favor of the wildtype allele expression was not significantly associated with clinical severity or hyperechogenicity of the lentiform nucleus frequency, although female mutation carriers with such an imbalance showed no parkinsonian signs and only rarely hyperechogenicity of the lentiform nucleus (1/8, 13%). Conclusions: Women carrying the X-linked dystonia-parkinsonism-causing variant display subtle parkinsonian signs and frequently exhibit hyperechogenicity of the lentiform nucleus, supporting hyperechogenicity of the lentiform nucleus as a sensitive imaging marker of early neurodegenerative change, especially in those with higher genetic risk.

Background: Accurate evaluation of fine motor abilities is a key aspect of neurological rehabilitation. However, conventional approaches like goniometry are limited by variations among raters and their difficulty in detecting active movement. On the other hand, computer vision-based software delivers non-invasive and quantitative analysis of hand movements. An innovative computer-vision-based software tool, F.A.I.R. Chance(C), was developed to track and analyze individual finger joint movements on a camera-equipped laptop and give real-time numerical feedback. However, its metrics require validation in a healthy population before the tool can be used for clinical purposes. Objective: To assess the reliability and validity of finger movement assessment by the F.A.I.R. Chance computer vision-based tool in healthy adult participants. Methods: An observational cross-sectional study was done at MGM School of Physiotherapy, comprising 30 healthy participants between 18 and 60 years of age. Finger movements like flexion, extension, abduction, and adduction were measured with a standard handheld goniometer. These same finger movements were then measured with the tool at two time points separated by a 30-minute interval to determine the test-retest reliability. The tool's measurements were compared with the goniometric measurements to determine its concurrent validity. Test retest reliability was checked by the Intra-class Correlation Coefficient ICC (2,1), while concurrent validity was tested through Pearson's correlation coefficients. Results: Metacarpophalangeal and proximal interphalangeal joint motions demonstrated moderate to good test-retest reliability (ICC: 0.716-0.953) for the F.A.I.R. Chance tool. However, distal interphalangeal joint movements had lower consistency. Good reliability (ICC: 0.754-0.908) was seen for movements of abduction and adduction in the fingers. Strong concurrent validity for extension movements of the metacarpophalangeal joints (r=0.760-0.914) and moderate concurrent validity for flexion movements of the metacarpophalangeal joints (r=0.427-0.604) was demonstrated for all fingers for the F.A.I.R. Chance tool. Concurrent validity for adduction and abduction movements demonstrated a low to fair correlation with goniometric measurements (r=0.210-0.440). This is consistent with previous research showing poor agreement between goniometry and adduction-abduction movements of the fingers. Conclusion: The F.A.I.R. Chance tool shows good reliability and acceptable concurrent validity to assess fine motor movements in the healthy adult population. This sets a basis for further clinical study of the tool in the target population with fine motor impairments. Keywords: artificial intelligence; assistive technology; computer vision; fine motor evaluation; hand function;

Background Gait impairment is a central sign of cervical spondylotic myelopathy (CSM) that is typically evaluated through subjective patient-reported questionnaires or objective in-clinic measures. These systems require substantial resources to administer and are poorly suited for longitudinal monitoring, however, emerging smartphone applications present an efficient alternative. We developed and assessed the validity of a data processing framework based on the SynapTrack smartphone application to assess gait function in individuals with CSM. Methods Participants completed walking tasks which were recorded on both the SynapTrack app and a gold standard gait mat. Acceleration data extracted from the smartphone by the app were filtered and processed to produce gait cycle features including velocity, step time, waveform features and frequency domain features. Standard gait features were compared across the two methods by correlation and Bland-Altman plots to assess validity. App-based gait features were then compared to the standard modified Japanese Orthopedic Assessment (mJOA) assessment to determine construct validity through correlation and ability to discriminate between individuals with CSM and healthy controls. Finally, intraclass correlation coefficients and coefficients of variation were used to measure test-retest reliability and standard variation across app features. Results A total of 110 participants were included in this study, of which 55 (50%) had CSM, 24 (22%) had peripheral neuropathy, and 31 (28%) were healthy controls. SynapTrack gait measures including velocity, step time, and double support showed strong validity as indicated through Bland-Altman plots and high correlation (>0.8) with mat features. In addition to the gait features, acceleration root mean square, acceleration crest, spectral entropy, and dominant frequency showed strong construct validity compared to the mJOA across correlation (0.2-0.54), trend test (p < 0.001), and AUROC (0.62-0.79) analyses. ICCs showed moderate test-retest reliability (0.52-0.67). Discussion The proposed framework for processing gait data showed strong validity compared to the gold standard mat and high construct validity compared to the mJOA suggesting the utility of the SynapTrack app as an efficient alternative to existing methods. The confirmation of gait metrics related to CSM severity and identification of relevant waveform and frequency domain features present opportunities to use smartphone apps to develop ecologically valid data driven markers of CSM severity.

Background: RNA sequencing (RNA-seq) is increasingly recognized as a complementary tool to DNA-based sequencing for improving the diagnostic yield in Mendelian disorders. However, how the diagnostic performance of RNA-seq varies across molecularly and phenotypically distinct patient subgroups remains poorly defined. This study aimed to evaluate and compare the diagnostic utility of RNA-seq across three stratified groups of patients with non-diagnostic exome sequencing. Methods: We performed RNA-seq on whole blood samples from 90 patients with suspected Mendelian disease in whom clinical exome or whole-exome sequencing had failed to establish a molecular diagnosis. Patients were prospectively stratified into three groups of 30: (i) patients with a candidate variant of uncertain significance (VUS) with predicted splicing impact (Group 1), (ii) patients with a specific clinical pre-diagnosis but no identified pathogenic variant (Group 2), and (iii) patients without a specific pre-diagnosis or candidate variant (Group 3). Aberrant splicing, gene expression outliers, and allele-specific expression were analyzed using multiple bioinformatic tools and compared against a GTEx-derived control cohort. Results: RNA-seq contributed to a molecular diagnosis in 29 of 88 evaluable patients (32.9%). Diagnostic yield differed substantially across groups: 82.8% (24/29) in Group 1, 6.9% (2/29) in Group 2, and 10% (3/30) in Group 3. In Group 1, RNA-seq enabled reclassification of candidate VUS through direct demonstration of aberrant splicing events. In Group 2, RNA-seq identified a somatic mosaic ACTB variant missed by exome sequencing and reclassified a previously deprioritized APPL1 VUS. In Group 3, a deep intronic pseudoexon-activating variant in IGBP1 was identified in two siblings with severe microcephaly, providing evidence for a candidate X-linked microcephaly gene, and a pathogenic RNU4-2 variant was detected in a patient with ReNU syndrome, a non-protein-coding gene not captured by standard exome sequencing. Conclusions: RNA-seq has the highest diagnostic utility when applied to evaluate candidate splice variants identified by prior DNA testing but also provides independent diagnostic value in patients without candidate variants. The systematic comparison across stratified patient groups supports the integration of RNA-seq into clinical genomic workflows and highlights the need for standardized analytic frameworks.

Introduction: Incomplete recovery from relapses contributes to long-term disability accumulation in relapsing remitting multiple sclerosis (RRMS), yet the relationship between immune regulation and relapse recovery remains poorly defined. Objective: To longitudinally characterize regulatory/effector immune cell dynamics in untreated RRMS patients and assess their association with immune balance and relapse recovery. Methods: Monocytic myeloid-derived suppressor cells (M MDSCs), regulatory T cells (Treg), and effector CD4 T cell subsets were measured in blood from 69 untreated RRMS patients sampled during relapse or remission and reevaluated after 12 months. Associations with clinical recovery after relapse were examined. Results: During relapse, patients exhibited higher M MDSC and Treg frequencies than in remission, while effector T cell subsets remained unchanged. Over one year, M-MDSCs increased consistently regardless of baseline clinical status, whereas Treg frequencies remained stable. Effector to M MDSC ratios were markedly elevated during relapse and declined over time, while effector-to-Treg ratios showed minimal variation. M MDSC levels during relapse were associated with sustained regulatory features at 12 month follow up. Importantly, higher baseline M MDSC levels, but not Treg frequencies, were associated with complete relapse recovery at one year. Conclusion: These findings suggest that circulating M-MDSCs, but not Treg, reflect interindividual differences in immune regulation and clinical recovery after relapse in early RRMS.

Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a genetic disease characterized by spasticity and ataxia which reflects involvement of the corticospinal tracts (CST) and cerebellum. The primary involvement of the middle cerebellar peduncles (MCP) and transverse pontine fibers (TPF) at the crossing with the CST, and their role in the pathophysiology of the disease, is currently debated. Objectives: Advanced MRI techniques capable of isolating sub-voxel microstructural parameters can test the hypothesis that the MCP and TPF are abnormally large, compressing the CST at their crossing, and potentially impairing CST development. Methods: Tract macro- and micro-structural properties, including axon and tract caliber, axon density and geometry, and myelin content were estimated from diffusion-relaxometry and magnetization transfer imaging. These features were analyzed along segments of the CST, MCP, and TPF of 9 patients and 9 age-matched controls. Results: While the CST showed significant decreases in tract size, axon caliber, and myelination throughout its length compared to controls (p<0.01), the MCP and TPF were relatively unaffected. In our group, neither the MCP nor the pons were enlarged. The proximal MCP showed an increase in axon caliber. Conclusions: The increase in fractional anisotropy and axon density towards the center of the TPF could be driven by geometric confounds related to differences in the relative sizes of the CST and TPF compared to controls. This highlights the importance of investigating tract-specific microstructural profiles, particularly in regions of geometric complexity. The findings confirm the involvement of the CST, with a relatively limited involvement of the MCP and TPF.

Amitriptyline is commonly prescribed for chronic pain, yet treatment response and tolerability vary substantially. Genetic variation in CYP2C19 and CYP2D6 influences amitriptyline metabolism, but evidence linking pharmacogene status to clinical outcomes in chronic pain is limited. Amitriptyline is typically prescribed for chronic pain at lower doses than for depression, which may reduce pharmacogenomic effects on clinical outcomes. We analysed 1,146 participants with chronic pain from the Australian Genetics of Depression Study who reported amitriptyline use, treatment outcomes, and genotype data. Metaboliser phenotypes were assigned using PharmCAT. Associations with self-reported effectiveness and discontinuation due to side effects were examined using regression models adjusted for age and sex. Only CYP2C19 intermediate metabolisers showed nominally lower odds of discontinuation and reduced likelihood of reporting moderate effectiveness. Overall, pharmacogenetic phenotypes were not significantly associated with patient-reported amitriptyline outcomes in chronic pain, potentially reflecting the lower doses typically prescribed for pain management.

Background: Quadriceps strength and landing mechanics are two modifiable factors associated with anterior cruciate ligament (ACL) injury risk. Collecting detailed biomechanical data is an arduous task. Identifying a relationship using more easily measured variables, such as quadriceps strength, would offer value for athlete counseling and injury prevention programs. Although quadriceps weakness has been associated with altered landing strategies in ACL-reconstructed (ACLR) individuals, this relationship is less clear in healthy athletes. Purpose: To investigate the association between isokinetic quadriceps strength and peak knee flexion angle during a vertical drop jump in healthy adolescent athletes. Study Design: Secondary analysis of previously collected data. Methods: Healthy adolescent athletes had their dominant leg quadriceps strength measured using an isokinetic dynamometer at 60{degrees}/s from 0-90{degrees} of knee flexion. Landing mechanics were assessed during a vertical drop jump using three-dimensional motion capture synchronized with force plates. Pearson correlation was used to evaluate the association between quadriceps strength and peak knee flexion angle during landing, with statistical significance defined as p < .05. Results: There was a weak negative correlation between quadriceps strength and peak knee flexion angle (p = .017, R = -.22 [-.04, -.38]), suggesting that stronger athletes achieved greater knee flexion angles. Discussion: Greater quadriceps strength was associated with increased peak knee flexion angles during landing; however, the weak correlation suggests that strength explains only a small portion of the variability in landing mechanics. These findings deviate slightly from prior literature in healthy populations but are consistent with studies demonstrating that greater quadriceps strength is associated with achieving greater peak knee flexion in ACLR patients. Accordingly, quadriceps strengthening should remain a key component of multifactorial ACL injury prevention programs.

Background. Poor sleep quality is common in people with multiple sclerosis (pwMS) and reduces quality of life. Objectives. To examine associations between modifiable factors and sleep quality in pwMS. Methods. In a prospective clinic cohort (2017-2023), we evaluated whether baseline measures of disability, depression, fatigue, and pain were associated with poor sleep quality (Pittsburgh Sleep Quality Index, PSQI) cross-sectionally using covariate-adjusted linear regression, structural equation modeling (SEM), and LASSO logistic regression, and longitudinally using mixed-effects models. Results. In this cohort (n=750; mean age 48.9 years; 80.3% women, 88.7% relapsing type), higher body mass index ({beta} [95% CI]: 0.06 [0.01, 0.12], p=.001) and area deprivation index (6.78 [2.17, 11.39], p<.001) were associated with worse baseline PSQI scores. In adjusted analyses (n=730), disability, depression, fatigue, and pain were each associated with worse sleep. In SEM, pain had a moderate direct effect on sleep ({beta} [95% CI]: 0.56 [0.48, 0.64], p<.001). LASSO models that included pain outperformed the benchmark (AUROC 0.741 vs 0.517). Longitudinally (n=382), time and higher baseline pain predicted worse sleep ({beta} [95% CI]: time in months 0.04 [0.02, 0.06], p<.001; pain 0.36 [0.31, 0.41], p<.001). Conclusion. Pain is a key, potentially modifiable driver of poor sleep quality in pwMS.

Background and Objectives: Cervical spondylotic myelopathy (CSM) is a leading cause of neurological disability in older adults. However, validated, scalable tools to quantify disease severity and changes over time are lacking. Recent advances in smartphone technology have opened new avenues for longitudinal, objective, and remote monitoring of neurological conditions. We performed a preliminary evaluation of the reliability and validity of SynapTrack, a smartphone-based digital platform for objective remote CSM assessments. Methods: In this single-center prospective cohort study, 265 participants (151 with CSM, 114 healthy controls) completed in-person SynapTrack assessments related to tapping, pinching, and vibratory detection, along with reference laboratory measures of dexterity (Box and Block Test, 9-Hole Peg Test) and vibratory sensation (tuning fork). A subset completed repeated home-based testing to assess test-retest reliability. We evaluated convergent validity, construct validity against the modified Japanese Orthopedic Association (mJOA) score, known-groups validity, and test-retest reliability (intraclass correlation coefficient, ICC). Results: Smartphone-derived metrics demonstrated good-to-excellent test-retest reliability, with the strongest stability for vibratory detection threshold (ICC = 0.92), overall and non-dominant tapping speed (ICC = 0.90 each), and pinching successful targets (ICC = 0.90). Convergent validity was supported by moderate-to-strong correlations between digital metrics and reference laboratory dexterity tests ({rho} up to 0.60 for tapping speed; up to -0.65 for the vibratory threshold). Construct validity against the mJOA was strongest for the vibratory threshold ({rho} = -0.53 to -0.54) and Level 2 non-dominant pinching errors ({rho} = -0.45). Selected metrics distinguished CSM patients from controls with good discrimination, including non-dominant tapping speed (AUROC = 0.76, 95% CI 0.68-0.85), Level 2 dominant pinching successful targets (AUROC = 0.78, 95% CI 0.62-0.94), and the non-dominant vibratory threshold (AUROC = 0.77, 95% CI 0.64-0.90). Conclusions and Relevance: A smartphone-based battery of upper-extremity sensorimotor tasks demonstrated preliminary reliability and validity in CSM. Furthermore, to our knowledge, the novel vibratory detection task represents the first smartphone-based sensory assessment used for CSM. Collectively, these findings position SynapTrack as a scalable platform for objective, remote neurological monitoring of CSM.

Background: Comorbidities are common in multiple sclerosis (MS) and may influence disability outcomes, but their dynamic impact on bidirectional disability transitions and long-term disability remains incompletely understood. Better understanding of this longitudinal relationship could inform personalized disability management strategies for people with MS. Methods: We leveraged two large electronic health record (EHR)-linked MS registries and applied multi-state Markov models (MSMs) to examine the extent to which individual comorbidities and overall comorbidity burden were associated with short-term disability transitions, long-term disability transition probabilities, and expected time spent in each disability state. We additionally compared MSM-based predictions of confirmed disability worsening (CDW) with Cox proportional hazards (CoxPH) model-based predictions using the integrated Brier score with bootstrap validation. Results: Among 3,723 patients with MS (74.6% female; 86.2% non-Hispanic White; mean age=41.9 years; mean disease duration=5.4 years) contributing 41,860 disability assessments over a mean follow-up of 7.3 years, higher cardiometabolic and psychiatric comorbidity burden was associated with increased transition intensity toward worse disability states and decreased transition intensity toward improvement, with a stepwise gradient across burden levels. Compared with patients without comorbidities, those with [&ge;]4 comorbidities had a 28% higher risk of worsening (HR=1.28 [1.06, 1.55]) and a 20% lower risk of improvement (HR=0.80 [0.67, 0.95]). Each individual comorbidity was significantly associated with worse disability transitions. Long-term estimates indicated a higher 5-year probability of severe disability and fewer years spent in the no-disability state among patients with greater comorbidity burden. CoxPH models showed directionally consistent associations but lower predictive accuracy for CDW compared with MSMs. Conclusion: Cardiometabolic and psychiatric comorbidities are associated with worse disability trajectories in MS, reducing improvement and accelerating progression. By providing a nuanced framework to quantify short-term disability transitions and long-term disability patterns, MSMs may have real-world clinical utility in disability prediction.

Objective Astrocyte activation is increasingly recognized as an important component of multiple sclerosis (MS) pathology. Natalizumab (NTZ), a highly effective therapy for relapsing-remitting MS (RRMS), primarily blocks leukocyte trafficking into the central nervous system. However, its effects on astrocytic metabolism remain unclear. We investigated astrocyte-associated metabolic changes after NTZ treatment using quantitative 1-11C-acetate positron emission tomography (PET). Methods Seven patients with RRMS underwent quantitative 1-11C-acetate PET before and after NTZ treatment. PET-derived k2, an index of oxidative acetate metabolism, was analyzed voxel-wise and within GM and white-matter volumes of interest. Clinical status and brain magnetic resonance imaging (MRI) findings were assessed, and cognitive performance was evaluated using Rao's Brief Repeatable Battery of Neuropsychological Tests. Results After NTZ treatment, k2 decreased in all patients compared with pretreatment levels. Both gray and white matter showed significant reductions, and voxel-based analysis demonstrated widespread decreases across cortical and subcortical regions of the cerebrum and cerebellum, with no regions showing significant posttreatment increases. MRI showed no worsening; Expanded Disability Status Scale scores were stable or improved, and cognitive performance was generally stable, with improvements in selected subtests. Interpretation Quantitative 1-11C-acetate PET demonstrated a whole-brain reduction in astrocyte-associated metabolism after NTZ treatment in RRMS, most prominently in gray matter. NTZ may modulate astrocyte activity, in addition to its established effects on peripheral immune cell trafficking.

Background and Aims: Clinical interpretation of the precordial leads V1-V6 assumes that Wilson's central terminal (WCT) has a fixed anatomical location. Consequently, a positive signal corresponds to electrical activation spreading from WCT towards the respective electrode, and vice versa. However, the location of WCT has never been systematically investigated. Yet, a better understanding of WCT location could improve the interpretation of the precordial leads. This work aims to characterize the spatial expansion and location of the physical WCT i.e., the electrical potential defined by the WCT, during the P-wave on the body surface. Methods: An intensive analysis of body surface potential maps (BSPMs) during atrial depolarization in an in silico patient cohort and clinical data was conducted. Results: During the P-wave, the location of WCT was not stationary but the spatial extent and location varied across time as well as across individuals. Four distinct spatial patterns of WCT distribution on the body surface were identified in silico, and three of these were found in the clinical cohort. WCT signals agreed with BSPM signals at commonly assumed positions of WCT only for a small fraction of the P-wave. Conclusion: The spatial extension and location of WCT changes during the P-wave and thus should be considered when interpreting the precordial leads.

Background: Citrin deficiency, caused by biallelic pathogenic variants in SLC25A13, must be identified early to prevent serious complications such as hyperammonemia and liver failure. However, clinical diagnosis is often delayed due to its nonspecific presentation and limited sensitivity of amino acid-based newborn screening methods. Although genome-based evaluations are being investigated to address these issues, concerns about their cost, turnaround time, variant interpretation ability, and data handling highlight the need for a more practical yet reliable alternative. We investigated the feasibility of applying proteomic approach on dried blood spots (DBS), which are routinely used in newborn screening. Methods: We performed untargeted liquid chromatography-tandem mass spectrometry to analyze the proteome of DBS using a previously developed "non-targeted analysis of non-specifically DBS-absorbed proteins" (NANDA) workflow. SLC25A13 protein abundance was quantified in individuals with biallelic loss-of-function mutations, compound loss-of-function/missense mutations, and heterozygous carriers; this was also evaluated in healthy and diseased controls representing relevant differential diagnoses. To leverage proteomic information, we derived a multivariate proteomic signature using feature selection and evaluated its performance with leave-one-out cross-validation. Biological relevance was assessed by enrichment analysis, and complementary transcriptomics was performed using RNA sequencing. Results: A total of 7,474 proteins, including SLC25A13, were consistently detected in DBS. SLC25A13 was undetectable in individuals with biallelic loss-of-function mutations. However, individuals with compound loss-of-function/missense genotypes showed reduced but measurable SLC25A13 levels, comparable to those observed in heterozygous carriers. In contrast, a compact 15-protein signature accurately identified individuals with compound loss-of-function/missense genotypes (AUC, 0.99; sensitivity, 1.00; specificity, 0.95). The signature was enriched for Ca2+-response, and transcriptomics showed downregulation of genes related to multimodal ion channels in affected individuals compared to controls. Conclusions: DBS-based proteomic profiling may assist in the diagnosis of citrin deficiency through SLC25A13-quantification and a biologically plausible multivariate signature. More broadly, this strategy offers a promising new diagnostic layer for protein disorders, providing a proteomic readout in a clinically practical DBS format with potential utility for future diagnostic and screening applications.

Background: The Functional Outcome in Patients with Primary Intracerebral Hemorrhage (FUNC) score was initially validated for prediction of functional independence on the Glasgow Outcome Scale (GOS) 90 days after intracerebral hemorrhage (ICH), but recovery often extends beyond three months. Aims: Our objective was to extend the FUNC score for prediction of 12-month functional independence to strengthen its utility for family counseling and research methodology. Methods: We conducted a single-center prospective cohort study enrolling adult patients with primary ICH between February 2009 and January 2018. We calculated FUNC scores at admission and assessed GOS 12 months after ICH. The primary outcome was 12-month functional independence, defined as a GOS score [&ge;]4. We calculated the area under the receiver operating characteristic curve (AUC) of the FUNC score using logistic regression, handling missing GOS with multiple imputation by chained equations. We evaluated score calibration using a calibration curve and the Brier score, and we assessed clinical utility using decision curve analysis. We explored the statistical efficiency gains of using FUNC-based sliding dichotomy thresholds for favorable outcome definitions by running simulations of a clinical trial with 1:1 randomization. We ran 5000 simulations for each sample size (100 to 1000, in increments of 10) and treatment effect (odds ratio of 1.5, 2.0 and 2.5) combination and calculated efficiency gains for each respective treatment effect as the percentage reduction in sample size required to have 80% power using sliding versus fixed dichotomy thresholds. Results: A total of 535 patients were included (median [IQR] age 68 [54-79], 237 [44%] female, median [IQR] NIHSS 16 [6-25], median [IQR] FUNC 8 [6-9]). Overall, 99 of 445 (22%) patients with known 12-month GOS achieved functional independence. The FUNC score had an AUC of 0.79 (95%-CI: 0.75-0.84) for 12-month functional independence. The calibration plot was reasonable, with modest evidence of overestimation at low predicted probabilities, and the Brier score was 0.15. A net benefit was observed across 5-50% threshold probabilities. Sliding dichotomy had an efficiency gain of 27% for a treatment effect of OR=2.0, and a gain of 22% for a treatment effect of OR=2.5. The efficiency gain for a treatment effect of OR=1.5 could not be calculated because the fixed dichotomy did not reach 80% power despite a sample size of 1000 patients. Conclusions: The FUNC score's predictive performance for 12-month functional independence was comparable to its originally validated 3-month discrimination. Following external validation across centers, the FUNC score may be leveraged to counsel families on global measures of long-term functional independence and to implement sliding dichotomy methodology in ICH research.