Biology subjects

Sinclair, B.

Publications and source records attributed to Sinclair, B..

9 recordsLinked to original sources

bioRxiv2025

Factor Analysis of Multimodal MRI, Biofluid and Vascular Health Biomarkers Reveals Latent Constructs of Brain Health

Individual imaging and fluid biomarkers provide insights into specific components of brain health, but integrated multimodal approaches are necessary to capture the complex, interrelated biological systems that contribute to brain homeostasis and neurodegenerative disease. Using data from the Brain and Cognitive Health (BACH) cohort study (N=127; mean age=67 years, 68% women), we performed an exploratory factor analysis to identify latent constructs of brain health. We included multimodal neurovascular imaging markers, brain atrophy metrics, plasma Alzheimers disease (AD) biomarkers and cardiovascular risk factors. Five constructs emerged: "Brain & Vascular Health" (greater hippocampal volume, basal ganglia enlarged perivascular spaces [ePVS], cerebral blood flow and HDL cholesterol; lower ventricle volume and BMI); "Structural Integrity" (greater cortical thickness, fractional anisotropy and basal ganglia ePVS); "Fluid Transport" (greater white matter ePVS and Free Water); "AD Biomarkers" (higher phosphorylated tau [pTau]181 and pTau217; lower amyloid-beta 42/40 ratio); and "Neuronal Injury" (higher glial fibrillary acidic protein and neurofilament light chain). All constructs were associated with age ({beta}=-0.70-0.39, p[≤].014), except for Fluid Transport (p>.05). Brain & Vascular Health and Structural Integrity (partial r=.305, p<.001), and AD Biomarkers and Neuronal Injury (partial r=.248, p=.005) were positively correlated. Only Brain & Vascular Health was associated with global cognition ({beta}=0.27, SE=0.13, p=.043). These findings provide a data-driven framework for examining distinct constructs underlying vascular health, fluid regulation and neurodegenerative pathology. We demonstrate the utility of using multiple biomarkers to probe these biological systems, paving the way for future research to explore how these systems change across diverse neurodegenerative conditions.

neuroscience↗

bioRxiv2025

Associations between epilepsy-related polygenic risk and brain morphology in childhood

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is associated with a complex genetic architecture, but the translation from genetic risk factors to brain vulnerability remains unclear. Here, we examined associations between epilepsy-related polygenic risk scores for HS (PRS-HS) and brain structure in a large sample of neurotypical children, and correlated these signatures with case-control findings in in multicentric cohorts of patients with TLE-HS. Imaging-genetic analyses revealed PRS-related cortical thinning in temporo-parietal and fronto-central regions, strongly anchored to distinct functional and structural network epicentres. Compared to disease-related effects derived from epilepsy case-control cohorts, structural correlates of PRS-HS mirrored atrophy and epicentre patterns in patients with TLE-HS. By identifying a potential pathway between genetic vulnerability and disease mechanisms, our findings provide new insights into the genetic underpinnings of structural alterations in TLE-HS and highlight potential imaging-genetic biomarkers for early risk stratification and personalized interventions.

neuroscience↗

bioRxiv2024

Relationships between measures of neurovascular integrity and fluid transport in aging: a multi-modal neuroimaging study

Fluid transport in the neurovascular unit (NVU) is essential for maintaining brain health through nutrient delivery and waste clearance. NVU integrity and fluid regulation can be assessed through MRI measures, including water exchange rate through the NVU (BBB kw), enlarged perivascular spaces (ePVS), cerebral blood flow (CBF), free water (FW), and white matter hyperintensities (WMH). This study investigated relationships between these MRI measures using Bayesian mixed models, and their variation with chronological age or biological brain age (brainageR) using linear regression in 132 non-clinical older adults (mean age=67 years; 68% female). BBB kw positively associated with CBF ({beta}^=0.08, 95% credible interval (CI)=[0.02,0.15]). FW positively associated with both ePVS ({beta}^=0.44, CI=[0.30,0.63]) and WMH ({beta}^=0.13, CI=[0.04,0.21]). BBB kw, CBF and ePVS decreased with age, while FW and WMH increased (all p<.05). There were no associations with brain age (all p>.05). Relationships between FW, ePVS and WMH likely reflect interconnectivity of fluid regulation within different compartments, while the relationship between BBB kw and CBF indicates a link between NVU fluid flow and vessel function. While individual metrics of NVU integrity are associated with age, their inter-relationships appear stable, providing a baseline for future research in fluid transport and vascular health in neurodegenerative disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/622194v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@df1273org.highwire.dtl.DTLVardef@1343e84org.highwire.dtl.DTLVardef@f475c2org.highwire.dtl.DTLVardef@15f32d1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Neurovascular function and the fluid transport system. The brains fluid transport system comprises the neurovascular unit, interstitial fluid exchange in the parenchyma and venous outflow. a. The flow of water molecules from the vessel to the perivascular space through the blood-brain barrier, and subsequently into the brain (facilitated by aquaporin-4 (AQP4) channels) in quantified by BBB kw. b. Greater cerebral blood flow rate (CBF) is associated with greater BBB kw, possibly due to vessel pulsations increasing osmotic pressure. c. Enlarged perivascular spaces (ePVS) may indicate reduced fluid flow within the NVU and are associated with (d.) increased extracellular free water (FW) in the parenchyma, suggesting a link between fluid regulation within the vasculature and the surrounding brain tissue. Greater white matter hyperintensity (WMH) volume also occurs alongside increase FW, in line with WMH reflecting more severe fluid flow stagnation occurring in concert with neuroinflammation and/or neuronal demyelination. C_FIG

neuroscience↗

bioRxiv2024

Automated segmentation of epilepsy surgical resection cavities: comparison of four methods to manual segmentation

Accurate resection cavity segmentation on MRI is important for neuroimaging research involving epilepsy surgical outcomes. Manual segmentation, the gold standard, is highly labour intensive. Automated pipelines are an efficient potential solution; however, most have been developed for use following temporal epilepsy surgery. Our aim was to compare the accuracy of four automated segmentation pipelines following surgical resection in a mixed cohort of subjects following temporal or extra temporal epilepsy surgery. We identified 4 open-source automated segmentation pipelines. Epic-CHOP and ResectVol utilise SPM-12 within MATLAB, while Resseg and Deep Resection utilise 3D U-net convolutional neural networks. We manually segmented the resection cavity of 50 consecutive subjects who underwent epilepsy surgery (30 temporal, 20 extratemporal). We calculated Dice similarity coefficient (DSC) for each algorithm compared to the manual segmentation. No algorithm identified all resection cavities. ResectVol (n=44, 88%) and Epic-CHOP (n=43, 86%) were able to detect more resection cavities than Resseg (n=22, 44%, P<0.001) and Deep Resection (n=21, 42%, P<0.001). The SPM-based pipelines (Epic-CHOP and ResectVol) performed better than the deep learning-based pipelines in the overall and extratemporal surgery cohorts, however there was no difference between methods in the temporal surgery cohort. These pipelines could be applied to machine learning studies of outcome prediction to improve efficiency in pre-processing data, however human quality control is still required.

neuroscience↗

bioRxiv2024

A worldwide ENIGMA study on epilepsy-related gray and white matter compromise across the adult lifespan

ObjectivesTemporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. MethodsWe studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. ResultsIn TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. ConclusionsThis study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.

neuroscience↗

bioRxiv2021

Structural network alterations in focal and generalized epilepsy follow axes of epilepsy risk gene expression: An ENIGMA study

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem co-expression patterns of epilepsy risk genes. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1,328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-genetic signatures could guide diagnosis, and ultimately, tailor therapeutic approaches to specific epilepsy syndromes.

neuroscience↗

bioRxiv2021

FindZX: an automated pipeline for detecting and visualising sex chromosomes using whole-genome sequencing data

Sex chromosomes have evolved numerous times, as revealed by recent genomic studies. However, large gaps in our knowledge of sex chromosome diversity across the tree of life remain. Filling these gaps, through the study of novel species, is crucial for improved understanding of why and how sex chromosomes evolve. Characterization of sex chromosomes in already well-studied organisms is also important to avoid misinterpretations of population genomic patterns caused by undetected sex chromosome variation. Here we present findZX, an automated Snakemake-based computational pipeline for detecting and visualizing sex chromosomes through differences in genome coverage and heterozygosity between males and females. FindZX is user-friendly and scalable to suit different computational platforms and works with any number of male and female samples. An option to perform a genome coordinate lift-over to a reference genome of another species allows users to inspect sex-linked regions over larger contiguous chromosome regions, while also providing important between-species synteny information. To demonstrate its effectiveness, we applied findZX to publicly available genomic data from species belonging to widely different taxonomic groups (mammals, birds, reptiles, fish, and insects), with sex chromosome systems of different ages, sizes, and levels of differentiation. We also demonstrate that the lift-over method is robust over large phylogenetic distances (>80 million years of evolution).

bioinformatics↗

bioRxiv2021

Topographic divergence of atypical cortical asymmetry and regional atrophy patterns in temporal lobe epilepsy: a worldwide enigma study

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy (TLE), a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter pathology in TLE relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multi-site ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 TLE patients and 1,418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in TLE, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity, and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of TLE-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of TLE and may inform future discovery and validation of complementary MRI biomarkers in TLE.

neuroscience↗

bioRxiv2020

Network-based atrophy modelling in the common epilepsies: a worldwide ENIGMA study

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1,021 adults with epilepsy compared to 1,564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy co-localized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Indices of progressive atrophy further revealed a strong influence of connectome architecture on disease progression in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients, and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided novel insights into the macroscale features that shape the pathophysiology of common epilepsies.

neuroscience↗