Biology subjects

Rudko, D. A.

Publications and source records attributed to Rudko, D. A..

6 recordsLinked to original sources

bioRxiv2025

A unified imaging-histology framework for superficial white matter architecture studies in the human brain

The superficial white matter (SWM), immediately beneath the cortical mantle, is thought to play a major role in cortico-cortical connectivity as well as large-scale brain function. Yet, this compartment remains rarely studied due to its complex organization. Our objectives were to develop and disseminate a robust computational framework to study SWM organization based on 3D histology and high-field 7T MRI. Using data from the BigBrain and Ahead 3D histology initiatives, we first interrogated variations in cell staining intensities across different cortical regions and different SWM depths. These findings were then translated to in-vivo 7T quantitative myelin-sensitive MRI, including T1 relaxometry (T1 map) and magnetization transfer saturation (MTsat). As indicated by the statistical moments of the SWM intensity profiles, the first 2 mm below the cortico-subcortical boundary were characterized by high structural complexity. We quantified SWM microstructural variation using a non-linear dimensionality reduction method and examined the relationship of the resulting microstructural gradients with indices of cortical geometry, as well as structural and functional connectivity. Our results showed correlations between SWM microstructural gradients, as well as curvature and cortico-cortical functional connectivity. Our study provides novel insights into the organization of SWM in the human brain and underscores the potential of SWM mapping to advance fundamental and applied neuroscience research. HighlightsO_LIDeveloped an anatomy-based open science framework to study SWM organization based on 3D post-mortem histology and/or in-vivo high-field MRI C_LIO_LIThe first 2 mm into the white matter are characterized by high structural complexity C_LIO_LIInter-regional trends in SWM microstructural variation, which related to cortical geometry, as well as cortico-cortical connectivity C_LI

neuroscience↗

bioRxiv2025

An MRI-informed histo-molecular analysis implicates ependymal cells in the pathogenesis of periventricular pathology in multiple sclerosis

It is now widely recognized that the cerebrospinal fluid (CSF)-adjacent brain surfaces - namely the subpial cortical region and the ependyma-adjacent periventricular region - are uniquely susceptible to a distinct, diffuse form of pathology in multiple sclerosis. So-called surface-in gradients of pathology predict future disease relapses independent of classical white matter lesions and are thought to occur as a result of cytotoxic factors in the CSF. Given the underlying mechanisms driving surface-in gradients appear to be distinct, they represent a novel treatment target. However, exactly how cytotoxic factor entry into the brain is regulated at these CSF-facing borders is not understood, particularly at the ventricular interface. Indeed, although studies have indicated that ependymal cells may be damaged in MS, there has yet to be a comprehensive assessment of cell health in the disease. We employed ultra-high-field MRI-guided immunohistochemistry, electron microscopy, and multiomic single nucleus RNA/ATAC sequencing to deeply phenotype human ependymal cells in MS. Our data revealed that ependymal cell pathology is a direct correlate of periventricular surface-in gradients of pathology in MS, and that the immune-responsive, reactive state assumed by ependymal cells is associated with widespread transporter and junctional protein gene dysregulation. We then further defined the gene regulatory networks underpinning the MS ependymal state, predicted ligands known to be enriched in MS CSF that could drive the emergence of this state, and tested one candidate in vivo. We found that IFN{gamma} increased murine ependymal permeability and that conditional knockout of ependymal interferon gamma receptor 1 (Ifngr1) was sufficient to reverse this effect. Our data directly implicate ependymal cell dysregulation in the emergence of periventricular pathology in MS. More widely, we denote the modulatory capacity of CSF ligands on ependymal cell function and how this may influence the inflammatory status of the periventricular region. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/633055v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@d76aadorg.highwire.dtl.DTLVardef@9cb480org.highwire.dtl.DTLVardef@e4805org.highwire.dtl.DTLVardef@19a50b4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

A single Citrobacter rodentium infection in Pink1 knockout and wild type mice leads to regional blood-brain-barrier perturbation and glial activation without dopamine neuron axon terminal loss

A growing body of research suggests a link between immune system activation and the development of Parkinsons disease (PD). Previous work showed that repeated gastrointestinal infection with Citrobacter rodentium can induce PD-like motor dysfunction in Pink1 knockout (KO) mice, along with immune cell infiltration into the brain. To better understand mechanisms underlying immune-mediated brain attack in this model, we tested whether mild infections are sufficient to increase blood-brain barrier (BBB) permeability and trigger brain inflammation. Pink1 wild-type (WT) and KO mice were infected with C. rodentium, and gadolinium-enhanced magnetic resonance imaging (MRI) was performed at days 13 and 26 post-infection to assess BBB integrity. Quantitative MRI analysis revealed increased BBB permeability at day 26 in both WT and KO mice, particularly in the striatum, dentate gyrus, somatosensory cortex, and thalamus. Notably, this permeability was not associated with changes in tight junction protein expression or dopamine system markers in the striatum at either time point. However, persistent microglial activation was observed at day 26 post-infection, along with elevated levels of inflammatory mediators such as eotaxin, IFN-{gamma}, CXCL9, IL-17, and MIP-2 in the striatum. Additionally, serum levels of IL-17 and CXCL1 were increased in infected Pink1 KO mice. Flow cytometry revealed neutrophil infiltration in the brain at day 26 post-infection. Finally, a bulk RNA-seq transcriptome analysis revealed that gene sets related to synaptic function were particularly influenced by the infection and that inflammation-related genes were upregulated by the infection in the Pink1 KO mice. These findings support the hypothesis that even mild gastrointestinal infections can increase BBB permeability, disrupt brain homeostasis, and promote chronic neuroinflammation. In genetically susceptible individuals, such as those with Pink1 deficiency, this may represent a first hit that contributes to subsequent induction of PD pathology with aging. Author summaryWe hypothesize that immune system activation is linked to the development of Parkinsons disease (PD). Previous work revealed that repeated gastrointestinal infections with Citrobacter rodentium causes PD-like symptoms and immune cell invasion in the brain of Pink1 knockout (KO) mice. In the current study, we tested whether a single mild gut infection alters blood-brain barrier (BBB) permeability and causes brain inflammation. We infected Pink1 WT and KO mice with Citrobacter rodentium and used gadolinium-enhanced MRI to detect BBB permeability changes at 13- and 26-days post-infection. Results showed increased BBB permeability in specific brain regions at 26 days. While tight-junction and dopamine (DA)-related proteins remained unchanged, we observed altered expression of synaptic genes, chronic microglial activation, elevated inflammatory markers, and neutrophil infiltration in the brain. Our findings suggest that even mild gastrointestinal infections can increase BBB permeability, potentially enabling immune cell infiltration into the brain and exacerbating pathways implicated in the development of PD, particularly among individuals with genetic risk factors.

neuroscience↗

bioRxiv2024

Brain Charts for the Rhesus Macaque Lifespan

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

neuroscience↗

bioRxiv2024

Age-Related Cerebral Ventriculomegaly occurs in Patients with Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a genetic disorder causing motile ciliary dysfunction primarily affecting the respiratory and reproductive systems. However, the impact of PCD on the central nervous system, through dysfunction of motile cilia in multiciliated ependymal cells, remains poorly understood. We hypothesized that patients with PCD exhibit sub-clinical ventriculomegaly due to ependymal ciliary dysfunction, which may influence neuropsychiatric diagnoses. We demonstrated highly specific expression levels of known PCD-related genes in human brain ependymal cells (p<0.0001), supporting their potential role in regulating ependymal ciliary function. Computed tomography sinus images from patients with PCD (n=33) and age/sex-matched controls (n=64) were analysed. Patients with PCD displayed significantly larger ventricular areas (p<0.0001) and Evans index (p<0.01), indicating ventriculomegaly that was consistent across all genetic subgroups. Ventricular enlargement correlated positively with increasing age in patients with PCD compared to controls (p<0.001). Chart review demonstrated a high prevalence (39%) of neuropsychiatric/neurological disorders in adult PCD patients that did not correlate with degree of ventriculomegaly. Our findings suggest that patients with PCD may have unrecognized, mild ventriculomegaly potentially due to ependymal ciliary dysfunction which correlates with ageing. Further study is required to determine if ventricular enlargement contributes to neuropsychiatric/neurological or other morbidity in PCD.

neuroscience↗

bioRxiv2024

MULTIMODAL GRADIENTS UNIFY LOCAL AND GLOBAL CORTICAL ORGANIZATION

AO_SCPLOWBSTRACTC_SCPLOWSpecialization of brain areas and subregions, as well as their integration into large-scale networks are key principles in neuroscience. Consolidating both local and global cortical organization, however, remains challenging. Our study developed a new approach to map global cortex-wise similarities of microstructure, structural connectivity, and functional interactions, and integrate these patterns with maps of cortical arealization. Our analysis combined repeated high-field in-vivo 7 tesla (7T) Magnetic Resonance Imaging (MRI) data collected in 10 healthy adults with a recently introduced probabilistic post-mortem atlas of cortical cytoarchitecture. We obtained multimodal eigenvectors describing cortex-wide gradients at the level of microstructural covariance, structural connectivity, and intrinsic functional interactions, and then assessed inter- and intra-area differences in cortex-wide embedding based on these multimodal eigenvectors. Inter-area similarities followed a canonical sensory-fugal gradient, with primary sensorimotor cortex being the most distinctive from all other areas, while paralimbic regions were least distinctive. This pattern largely corresponded to functional connectivity variations across different tasks collected in the same participants, suggesting that the degree of global cortical integration mirrors the functional diversity of brain areas across contexts. When studying heterogeneity within areas, we did not observe a similar relationship, despite overall higher heterogeneity in association cortices relative to paralimbic and idiotypic cortices. The results were replicated in a different dataset. Our findings highlight a close coupling between cortical arealization and global cortical motifs in shaping specialized versus integrative human brain function. SO_SCPLOWIGNIFICANCEC_SCPLOWOur work situates cytoarchitecture-derived cortical areas within multimodal gradients of cortical microstructure, connectivity, and function derived from high-definition multimodal neuroimaging. We demonstrated that primary sensory and motor areas show most distinctive gradient profiles while paralimbic areas were least distinctive, overall recapitulating a sensory-fugal axis. This axis was shown to relate to the diversity of cortical areas across different functional contexts, and findings could be replicated across an independent dataset. Overall, our work shows how frameworks of cortical arealization and macroscale gradients converge in shaping functional specialization versus integration in the human brain.

neuroscience↗