Biology subjects

Thomas, G. E. C.

Publications and source records attributed to Thomas, G. E. C..

5 recordsLinked to original sources

bioRxiv2025

Mapping the molecular landscape of the living brain: integrating spatial transcriptomics and qMRI

Profiling dynamic molecular processes in neurodegeneration in vivo remains a major clinical challenge. Limited brain tissue accessibility especially limits the development and effective deployment of emerging disease modifying therapies, highlighting the need for non-invasive methods for profiling molecular disease processes. We introduce a non-invasive imaging framework that integrates ultra-high-resolution 7T quantitative MRI (qMRI) with spatially-resolved transcriptomics (SRT) to infer cell-type and pathway-specific molecular features within the cortical grey matter. This proof-of-concept establishes the integration of qMRI and SRT as a scalable, non-invasive platform for molecular profiling in neurodegeneration, with significant potential for precision therapeutic monitoring, drug development and clinical trials.

neuroscience↗

bioRxiv2025

Evidence for divergent cortical organisation in Parkinsons disease and Lewy Body Dementia

Dementia is a defining feature of Lewy body disease: its timing and onset distinguish different clinical diagnoses, and its effect on quality of life is profound. However, it remains unclear whether processes leading to cognitive and motor symptoms in Lewy body disease differ. To clarify this, we used in-vivo neuroimaging to assess spatial gradients of inter-regional differences in structural and functional connectivity in 108 people across the Lewy body disease spectrum (46 Parkinsons with normal cognition (PD-NC), 62 Lewy body dementia (LBD)) and 23 controls. We found divergent structural gradient differences with cognitive impairment: PD-NC showed increased inter-regional differentiation, whilst LBD showed overall gradient distribution similar to controls despite widespread organisational differences at the regional level. We then assessed cellular and molecular underpinnings of these organisational changes. We reveal similarities and also important differences in the drivers of cortical organisation between LBD and PD-NC, particularly in layer 4 excitatory neurons.

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↗

bioRxiv2022

Changes in both top-down and bottom-up effective connectivity drive visual hallucinations in Parkinson's disease

Visual hallucinations are common in Parkinsons disease and are associated with poorer quality of life and higher risk of dementia. An important and influential model that is widely accepted as an explanation for the mechanism of visual hallucinations in Parkinsons disease and other Lewy-body diseases is that these arise due to aberrant hierarchical processing, with impaired bottom-up integration of sensory information and overweighting of top-down perceptual priors within the visual system. This hypothesis has been driven by behavioural data and supported indirectly by observations derived from regional activation and correlational measures using neuroimaging. However, until now, there was no evidence from neuroimaging for differences in causal influences between brain regions measured in patients with Parkinsons hallucinations. This is in part because previous resting-state studies focus on functional connectivity, which is inherently undirected in nature and cannot test hypotheses about directionality of connectivity. Spectral dynamic causal modelling is a Bayesian framework that allows the inference of effective connectivity - defined as the directed (causal) influence that one region exerts on another region - from resting-state functional MRI data. In the current study, we utilise spectral dynamic causal modelling to estimate effective connectivity within the resting-state visual network in our cohort of 15 Parkinsons disease visual hallucinators, and 75 Parkinsons disease non-hallucinators. We find that visual hallucinators display decreased bottom-up effective connectivity from the lateral geniculate nucleus to primary visual cortex and increased top-down effective connectivity from left prefrontal cortex to primary visual cortex and medial thalamus, as compared to non-hallucinators. Importantly, we find that the pattern of effective connectivity is predictive of the presence of visual hallucinations and associated with their severity within the hallucinating group. This is the first study to provide evidence, using resting state effective connectivity, to support a model of aberrant hierarchical predictive processing as the mechanism for visual hallucinations in Parkinsons disease.

neuroscience↗