Biology subjects

Kiefer, M.

Publications and source records attributed to Kiefer, M..

4 recordsLinked to original sources

bioRxiv2024

The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a slowly progressive, multisystemic disorder caused by a CTG repeat expansion in the DMPK 3UTR that leads to global dysregulation of alternative splicing. Here, we employed a composite RNA splicing biomarker called the Myotonic Dystrophy Splice Index (SI), which incorporates 22 disease-specific splice events that sensitively and robustly assesses transcriptomic dysregulation across the disease spectrum. Targeted RNA sequencing was used to derive the SI in 95 muscle biopsies of the tibialis anterior collected from DM1 individuals with baseline (n = 52) and 3-months (n = 37) outcomes. The SI had significant associations with timepoint matched measures of muscle strength and ambulation, including ankle dorsiflexion strength (ADF) and 10-meter run/fast walk speed (Pearson r = -0.719 and -0.680, respectively). Linear regression modeling showed that the combination of baseline ADF and SI was predictive of strength at 3-months (adjusted R2 = 0.830) in our cohort. These results indicate the SI can reliably capture the association of disease-specific RNA mis-splicing to physical strength and mobility and may be predictive of future function.

molecular biology↗

bioRxiv2024

RNA mis-splicing in children with myotonic dystrophy is associated with physical function

ObjectivesDysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown. Methods82 participants (42 DM1 adults & 40 CDM children) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]inferred in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics. ResultsMyotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]inferred in our cohort of all DM1 individuals and when assessing CDM children independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]inferred from select clinical outcome assessments alone in all subjects (adjusted R2 = 0.6723) or exclusively in CDM children (adjusted R2 = 0.5875). InterpretationOur findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]inferred, in DM1. The strength of these correlations and the development of the predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.

genetics↗

bioRxiv2023

Conceptual representations in the default, control and attention networks are task-dependent and cross-modal

Conceptual knowledge is central to human cognition. Neuroimaging studies suggest that conceptual processing involves modality-specific and multimodal brain regions in a task-dependent fashion. However, it remains unclear (1) to what extent conceptual feature representations are also modulated by the task, (2) whether conceptual representations in multimodal regions are indeed cross-modal, and (3) how the conceptual system relates to the large-scale functional brain networks. To address these issues, we conducted multivariate pattern analyses on fMRI data. 40 participants performed three tasks--lexical decision, sound judgment, and action judgment--on written words. We found that (1) conceptual feature representations are strongly modulated by the task, (2) conceptual representations in several multimodal regions are cross-modal, and (3) conceptual feature retrieval involves the default, frontoparietal control, and dorsal attention networks. Conceptual representations in these large-scale networks are task-dependent and cross-modal. Our findings support theories that assume conceptual processing to rely on a flexible, multi-level architecture.

neuroscience↗

bioRxiv2022

Meta-analytic evidence for a novel hierarchical model of conceptual processing

Conceptual knowledge plays a pivotal role in human cognition. Grounded cognition theories propose that concepts consist of perceptual-motor features represented in modality-specific perceptual-motor cortices. However, it is unclear whether conceptual processing consistently engages modality-specific areas. Here, we performed an activation likelihood estimation (ALE) meta-analysis across 212 neuroimaging experiments on conceptual processing related to 7 perceptual-motor modalities (action, sound, visual shape, motion, color, olfaction-gustation, and emotion). We found that conceptual processing consistently engages brain regions also activated during real perceptual-motor experience of the same modalities. In addition, we identified multimodal convergence zones that are recruited for multiple modalities. In particular, the left inferior parietal lobe (IPL) and posterior middle temporal gyrus (pMTG) are engaged for three modalities: action, motion, and sound. These "trimodal" regions are surrounded by "bimodal" regions engaged for two modalities. Our findings support a novel model of the conceptual system, according to which conceptual processing relies on a hierarchical neural architecture from modality-specific to multimodal areas up to an amodal hub.

neuroscience↗