bioRxiv Science⌕ Search

Biology subjects

Day, J. W.

Publications and source records attributed to Day, J. W..

3 recordsLinked to original sources

Deep learning models detect neuromuscular disease and quantify functional impairment from video-derived biomechanics data

Measurements of human movement are critical for evaluating patients with neuromuscular diseases. However, current clinical tools are limited in sensitivity and can fail to detect the full spectrum of movement changes patients may exhibit. These limitations can obscure early signs of decline, delaying interventions that could preserve function and independence. OpenCap, a smartphone application that performs video-based markerless motion capture, can help address this gap by enabling scalable, out-of-lab measurements of human movement. Here, we present a method for both detecting disease and quantifying the severity of impaired movement from smartphone videos of patient motion. We used OpenCap to measure kinematics from 337 individuals with diagnoses spanning 12 rare, genetically-defined neuromuscular diseases and 78 age-matched healthy controls. Our dataset is the largest existing publicly available resource of body segment kinematics for this class of diseases. These data were collected in neuromuscular clinics during regular clinic visits as well as at conferences and community events across the United States. We trained deep learning models on these kinematic time series to differentiate between participants with neuromuscular disease and controls (AUROC = 0.97 [0.93-1.00]). We also developed a movement impairment severity score that correlates with both participant ratings of their own functional abilities ({rho} = -0.81, p < 0.001) and existing clinical tests of movement capabilities such as run speed ({rho} = -0.83, p < 0.001). Our methods for detecting disease and deriving quantitative biomarkers of movement impairment from smartphone videos have the potential to complement clinical assessments, inform screening protocols, and improve clinical trial endpoints.

bioengineering↗

KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

neuroscience↗

Transcriptome Alterations in Myotonic Dystrophy Frontal Cortex

Myotonic dystrophy (dystrophia myotonica, DM) is caused by expanded CTG/CCTG microsatellite repeats, leading to multi-systemic symptoms in skeletal muscle, heart, gastrointestinal, endocrine, and central nervous systems (CNS), among others. For some patients, CNS issues can be as debilitating or more so than muscle symptoms; they include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Although transcriptomes from DM type 1 (DM1) skeletal muscle have provided useful insights into pathomechanisms and biomarkers, limited studies of transcriptomes have been performed in the CNS. To elucidate underlying causes of CNS dysfunction in patients, we have generated and analyzed RNA-seq transcriptomes from the frontal cortex of 21 DM1 patients, 4 DM type 2 (DM2) patients, and 8 unaffected controls. One hundred and thirty high confidence splicing changes were identified, most occurring exclusively in the CNS and not in skeletal muscle or heart. Mis-spliced exons were found in neurotransmitter receptors, ion channels, and synaptic scaffolds, and we identified an alternative exon in GRIP1 that modulates association with kinesins. Splicing changes exhibited a gradient of severity correlating with CTG repeat length, as measured by optical mapping of individual DNA molecules. All individuals studied, including those with modest splicing defects, showed extreme somatic mosaicism, with a subset of alleles having >1000 CTGs. Analyses of gene expression changes showed up-regulation of genes transcribed in microglia and endothelial cells, suggesting neuroinflammation, and downregulation of genes transcribed in neurons. Gene expression of RNAs encoding proteins detectable in cerebrospinal fluid were also found to correlate with mis-splicing, with implications for CNS biomarkers of disease severity. These findings provide a framework for future mechanistic and therapeutic studies of CNS issues in DM.

genetics↗