Biology subjects

Veleva, E.

Publications and source records attributed to Veleva, E..

5 recordsLinked to original sources

bioRxiv2026

The neuropathy-causing GARS1{triangleup}ETAQ mutation drives pathology in subsets of motor and sensory neurons in mice

Charcot-Marie-Tooth disease type 2D (CMT2D) results from gain-of-function mutations in GARS1, which encodes glycyl-tRNA synthetase (GlyRS), the enzyme responsible for charging transfer RNA (tRNA) with glycine. There are several CMT2D mouse models, but Gars{Delta}ETAQ/+ is the only one that bears a patient-sourced mutation. Created using CRISPR/Cas9 to model a 12-nucleotide de novo GARS1 deletion identified in an unusually severe CMT2D patient, Gars{Delta}ETAQ/+ mice have previously been shown to display several neuromuscular phenotypes; motor axon loss, denervated neuromuscular junctions (NMJs) and reduced muscle function. Here, we extend these analyses to provide a more comprehensive understanding of both motor and sensory nerve deficits across hind- and fore-limbs. At 3 months, Gars{Delta}ETAQ/+ mice possess sex-independent alterations in the levels of neuropathy biomarkers - including decreased NfL and increased periaxin - alongside reduced muscle endurance and strength, and impairments in the sensory modalities of mechanosensation, proprioception and nociception. Underpinning these dysfunctions, we identified site-specific defects comprising altered sensory neuron populations, muscle spindle loss, reduced motor neuron size, disrupted NMJ innervation and maturation, and reduced axonal transport of signalling endosomes in vivo. Together, these experiments show that Gars{Delta}ETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion, priming this CMT2D allele for testing treatments and evaluating mechanisms underlying peripheral nerve vulnerability. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/736541v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@b48a41org.highwire.dtl.DTLVardef@e0c22dorg.highwire.dtl.DTLVardef@1ec2f5forg.highwire.dtl.DTLVardef@11a3311_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Grey matter microstructural alterations distinguish cognitive impairment in Lewy body diseases

INTRODUCTION.Despite widespread cortical involvement in Lewy body diseases, conventional grey matter MRI measures have limited sensitivity. Microstructural measures from diffusion MRI may be more sensitive to early changes. METHODS.We examined grey matter microstructure in 197 participants across the Lewy body diseases spectrum: 88 Lewy body dementia (LBD), 109 Parkinsons normal cognition (PD-NC), and 46 controls. We compared tissue-weighted neurite density (tNDI), orientation dispersion index (tODI), and free water fraction (FWF) cross-sectionally and longitudinally. We examined relationships between microstructure, disease severity and plasma p-tau217. RESULTS.LBD participants showed widespread cortical and subcortical tODI and FWF increases compared to controls and PD-NC, despite minimal atrophy. These changes correlated with cognitive (but not motor severity) and with p-tau217. In 100 Parkinsons patients followed-up over 3 years, cortical FWF increased in those developing cognitive decline. DISCUSSION.Microstructural measures capture early grey matter changes, offering a sensitive marker of grey matter integrity in Lewy body diseases.

neuroscience↗

bioRxiv2025

Neuroimaging and plasma biomarker differences and commonalities in Lewy body dementia subtypes

INTRODUCTIONDespite ongoing debate about whether Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB) are separable diseases or a single Lewy body dementia (LBD) spectrum, there are limited neuroimaging investigations of differences between these conditions. METHODSWe used fixel-based diffusion MRI and plasma measures to examine white matter integrity and burden of amyloid pathology (using tau phosphorylated at theonine-217 (p-tau217) in 47 patients with DLB, 21 PDD, 29 PD and 23 age-matched controls. RESULTSWe show reduced fibre cross-section in LBD versus PD, and increased concentrations of plasma neurofilament light chain and p-tau217; with p-tau217 and fibre cross-section associated with cognition. Fibre density was reduced in PDD versus DLB, but neither plasma measures nor fibre cross-section differed between LBD subtypes. DISCUSSIONOur findings suggest differences in white matter integrity between DLB and PDD that are driven by distinct processes from those causing changes in white matter integrity in LBD compared with PD.

neuroscience↗

bioRxiv2025

Impaired glymphatic clearance independently contributes to poor outcomes in Parkinsons disease

BackgroundImpaired glymphatic clearance may contribute to pathological accumulations in Parkinsons (PD), but how it interacts with other processes causing dementia and poor outcomes remains unclear. ObjectivesClarify how glymphatic clearance impacts cognition in PD and its interaction with established imaging markers. MethodsWe used diffusion tensor image analysis along the perivascular space (DTI-ALPS) as an indirect marker of glymphatic clearance in 98 PD patients (31 PD-poor outcomes: dementia, mild cognitive impairment, frailty or death within 3-year follow-up; 67 PD-good outcomes) and 28 controls. We assessed DTI-ALPS relationship to cognition, white matter (fibre cross-section), cortical thickness, iron accumulation (quantitative susceptibility mapping (QSM)), and plasma markers (phosphorylated tau-181 (p-tau181 and neurofilament light (NFL)) cross-sectionally and longitudinally. ResultsDTI-ALPS was lower in PD-poor outcomes compared to PD-good outcomes and controls (p=0.005) with further longitudinal reductions only in PD-poor outcomes (group*time interaction: {beta}=-0.013, p=0.021). Lower DTI-ALPS was associated with lower fibre cross-section in P, at baseline and longitudinally but with different spatial distribution from white matter changes relating to PD cognition. There was no correlation between baseline DTI-ALPS and plasma ptau-181 (p=0.642), NFL (p=0.448) or baseline cortical thickness. Lower DTI-ALPS was associated with accelerated cortical thinning within left precentral gyrus and changes in brain iron distribution. ConclusionsPD patients who develop poor outcomes show impaired glymphatic clearance at baseline that worsened longitudinally. DTI-ALPS correlated with white matter integrity and brain iron accumulation. However, both showed different spatial distribution than that seen in PD dementia; suggesting impaired glymphatic clearance contributes to cognitive decline in a distinct manner.

neuroscience↗

bioRxiv2023

Neuroimaging and plasma marker evidence for white matter macrostructure loss in Parkinsons disease

Parkinsons disease (PD) is the second commonest neurodegenerative disorder and over half of patients progress to postural instability, dementia or death within 10 years of diagnosis. However, onset and rate of progression to poor outcomes is highly variable, underpinned by heterogeneity in the underlying pathological process. Improved biomarkers of poor outcomes would be helpful for targeted treatment, but most studies to-date have been limited to a single modality or the assessment of patients with established cognitive impairment. Here, we use multimodal neuroimaging and plasma biomarkers in 98 patients with PD and 28 age-matched controls followed-up over 3 years, including: gray matter (cortical thickness), white matter (macrostructure: fibre-cross section and microstructure: fibre density) at whole-brain and tract level, structural and functional connectivity and plasma levels of neurofilament light chain (NFL) and phosphorylated tau (p-tau) 181. We show extensive reductions in fibre cross-section and structural connectivity in PD with poor outcomes, with preserved gray matter and functional connectivity. NFL, but not p-tau181 levels was increased in PD with poor outcomes and correlated with white matter loss. These findings suggest that imaging sensitive to white matter macrostructure and plasma NFL may be useful biomarkers of poor outcomes in PD. As new targeted treatments are emerging, these biomarkers show important potential to aid patient selection for treatments and improve stratification to clinical trials.

neuroscience↗