Biology subjects

White, C. C.

Publications and source records attributed to White, C. C..

12 recordsLinked to original sources

bioRxiv2026

Evaluation of potential serum analytes for individuals at-risk of multiple sclerosis

Circulating proteins have been widely investigated as potential biomarkers in multiple sclerosis (MS), yet findings across studies are often inconsistent, likely reflecting differences in disease stage, treatment exposure, and cohort composition. Studying individuals at elevated risk of MS prior to disease onset offers a unique opportunity to identify immune alterations that precede clinical disease while minimizing confounders. Here, we investigated whether alterations in six previously MS-associated biomarkers are detectable and associate to underlying genetic susceptibility in two independent sample collections comprising people with MS (pwMS), healthy controls, and asymptomatic first-degree relatives of pwMS from the Genes & Environment in MS (GEMS) study cohort. The panel, representing complementary axes of MS immunopathology, included granzyme A (GZMA), MER tyrosine kinase (MERTK), interleukin-2 receptor alpha (IL2RA), osteopontin (SPP1), CD30 (TNFRSF8), and chitinase-3-like protein 1 (CHI3L1). None of the proteins demonstrated associations with MS. A composite score constructed from externally derived effect estimates was not associated with MS status in either collection or in meta-analysis. Among asymptomatic first-degree relatives, the composite score was not significantly associated with group status. In contrast, an inverse correlation between SPP1 and the MS genetic risk score among GEMS participants was found ({beta} = -0.246, p = 0.001). Together, these findings suggest that several circulating proteins recently proposed as MS biomarkers are not robust tools to distinguish MS from healthy individuals. However, SPP1 levels are highlighted for further evaluation among at-risk individuals, and further work is needed to determine whether circulating immune signatures can capture the earliest stages of MS in at-risk individuals.

immunology↗

bioRxiv2025

A Radiomic Approach to Clinical MRI Refines the Thalamus-Cognition Link in Multiple Sclerosis

Background and ObjectivesRadiomics extracts imaging features that may not be detectable through conventional volumetric analyses. Given their role in multiple sclerosis (MS), we applied radiomics to thalamic nuclei and examined their associations with cognitive performance. MethodsA total of 601 individuals were included (342 people with MS-PwMS from two cohorts, and 259 healthy controls-HC). Radiomic features (RF) and volumes were extracted from the whole thalamus, five thalamic nuclei, and the putamen segmented on 3D T1-weighted images. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) in PwMS, and the Digit Symbol Substitution Test (DSST) in HC. In the first MS cohort, multivariate linear regression in a discovery set (N=103) identified thalamus-derived RF associated with SDMT, which were retested in a replication set (N=63). Their associations with PASAT in a second MS cohort (N=176) and DSST in HC were also evaluated. We then tested whether the same RF, when extracted from the putamen, were associated with SDMT. LASSO models assessed the combined predictive value of RF and volumes. Figure 2 presents an overview of the involvement of different cohorts in the study, outlining the specific study objectives and the statistical analysis approaches employed. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/657698v1_fig2.gif" ALT="Figure 2"> View larger version (40K): org.highwire.dtl.DTLVardef@6f1dd8org.highwire.dtl.DTLVardef@11069c6org.highwire.dtl.DTLVardef@905512org.highwire.dtl.DTLVardef@1c12171_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 2.C_FLOATNO Overview of the involvement of different cohorts in the study, specific study objectives and the statistical analysis approaches employed. Abbreviations: SDMT: Symbol Digit Modalities Test, PASAT: Paced Auditory Serial Addition Test, DSST: Digit Symbol Substitution Test, LASSO: Least Absolute Shrinkage and Selection Operator. C_FIG ResultsTwenty-eight RF-ROI pairs were associated with SDMT in the replication set (FDR<0.05). Of these, 24 were also associated with PASAT (FDR[≤]0.03), and 2 with DSST. Only ventral nuclei volume showed replicated associations among volumetrics. Only 4 putamen-derived pairs were associated with SDMT (FDR=0.04). LASSO results confirmed RF outperformed volumes. DiscussionRF extracted from the thalamus are strongly associated with cognitive performance in PwMS, outperforming volumetric measures and supporting their potential as sensitive imaging biomarkers.

neuroscience↗

bioRxiv2024

HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signatures in vitro

Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes1. Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans2-6; however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate7,8. Here, we present a pharmacological approach to mimic human DAM in vitro by exposing different human microglia models to selected histone deacetylase (HDAC) inhibitors. We also provide an initial functional characterization of our model system, showing a specific increase of amyloid beta phagocytosis along with a reduction of MCP-1 secretion. Additionally, we report an increase in MITF expression, a transcription factor previously described to drive expression towards the DAM phenotype. We further identify CADM1, LIPA and SCIN as DAM- marker genes shared across various proposed DAM signatures and in our model systems. Overall, our strategy for targeted microglial polarization bears great potential to further explore human DAM function and biology.

neuroscience↗

bioRxiv2023

Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease

Alzheimers Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brains cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-{beta} proteinopathy while the other mediated the effect of amyloid-{beta} in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.

neuroscience↗

bioRxiv2022

Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

The relationship between genetic variation and gene expression in individual brain cell types and subtypes has remained elusive. Here, we generated single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of 424 individuals of advanced age; analyzing 1.5 million nuclear transcriptomes, we assessed the effect of genetic variants on RNA expression in cis (cis-eQTL) for 7 cell types and 81 cell subtypes. This effort identified 10,004 eGenes at the cell type level and 8,138 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer pathology, accounting for the effect of APOE{varepsilon}4, providing mechanistic insights into both pathologies. While eQTLs are readily detected, only a TMEM106B variant robustly affects the proportion of cell subtypes. Integration of these results with GWAS highlighted the targeted cell type and likely causal gene within susceptibility loci for Alzheimers, Parkinsons, schizophrenia, and educational attainment.

genomics↗

bioRxiv2021

Elamipretide (SS-31) Treatment Attenuates Age-Associated Post-Translational Modifications of Heart Proteins

It has been demonstrated that elamipretide (SS-31) rescues age-related functional deficits in the heart but the full set of mechanisms behind this have yet to be determined. We investigated the hypothesis that elamipretide influences post-translational modifications to heart proteins. The S-glutathionylation and phosphorylation proteomes of mouse hearts were analyzed using shotgun proteomics to assess the effects of aging on these post-translational modifications and the ability of the mitochondria-targeted drug elamipretide to reverse age-related changes. Aging led to an increase in oxidation of protein thiols demonstrated by increased S-glutathionylation of cysteine residues on proteins from Old (24 months old at the start of the study) mouse hearts compared to Young (5-6 months old). This shift in the oxidation state of the proteome was almost completely reversed by 8-weeks of treatment with elamipretide. Many of the significant changes that occurred were in proteins involved in mitochondrial or cardiac function. We also found changes in the mouse heart phosphoproteome that were associated with age, some of which were partially restored with elamipretide treatment. Parallel reaction monitoring of a subset of phosphorylation sites revealed that the unmodified peptide reporting for Myot S231 increased with age, but not its phosphorylated form and that both phosphorylated and unphosphorylated forms of the peptide covering cMyBP-C S307 increased, but that elamipretide treatment did not affect these changes. These results suggest that changes to thiol redox state and phosphorylation status are two ways in which age may affect mouse heart function, which can be restored by treatment with elamipretide.

cell biology↗

bioRxiv2020

Multi-cellular communities are perturbed in the aging human brain and with Alzheimer's disease

The role of different cell types and their interactions in Alzheimers disease (AD) is an open question. Here we pursued it by assembling a high-resolution cellular map of the aging frontal cortex by single nucleus RNA-seq of 24 individuals with different clinicopathologic characteristics. We used the map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA-seq, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including inhibitory neuronal subtypes and oligodendroglial states. We further recovered a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia.

neuroscience↗

bioRxiv2020

Neuroticism alters the transcriptome of the frontal cortex to contribute to the cognitive decline and onset of Alzheimer's disease

Accumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimers disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, {beta}-amyloid (A{beta}) and phosphorylated tangles (TAU). However, it is unknown what is the impact of the AD risk factors, personality characteristics assessed by the NEO Five-Factor Inventory, on the human brains transcriptome. Using postmortem human brain samples from 466 subjects, we found that neuroticism has a significant overall impact on the brain transcriptome (omnibus P=0.005) but not the other 4 personality characteristics. Focused on those cognitive decline related gene co-expressed modules, neuroticism has nominally significant associations (P<0.05) with four neuronal modules, which are more related to PHFtau than A{beta} across all eight brain regions. Furthermore, the effect of neuroticism on cognitive decline and AD might be mediated through the expression of module 7 and TAU pathology (P=0.008). To conclude, neuroticism has overall impact on human brains transcriptome and its effect on cognitive decline and AD might be mediated through TAU pathology related gene transcription mechanism.

neuroscience↗

bioRxiv2018

A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed and belong to a very few prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death for >3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.

cell biology↗

bioRxiv2017

A cortical immune network map identifies a subset of human microglia involved in Tau pathology

Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five gene modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 541 subjects from two cohort studies of brain aging. Two of these transcriptional programs - modules 113 and 114 - relate to the accumulation of {beta}-amyloid, while module 5 relates to tau pathology. These modules are also detectable in the human brain's epigenome, where we replicate these associations. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that VASP, a representative module 5 gene, encodes a protein that is upregulated in activated microglia in AD.

neuroscience↗

bioRxiv2017

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

genetics↗

bioRxiv2017

Brain xQTL Map: Integrating The Genetic Architecture Of The Human Brain Transcriptome And Epigenome

We perform quantitative trait locus (xQTL) analyses on a multi-omic dataset, comprising RNA sequence, DNA methylation, and histone acetylation ChIP sequence data from the dorsolateral prefrontal cortex of 411 older adult individuals. We identify SNPs that are significantly associated with gene expression, DNA methylation, and histone modification levels. Many SNPs influence more than one type of molecular feature, and epigenetic features are shown to mediate eQTLs in a number of (9%) such loci. We illustrate the utility of our new resource, xQTL Serve, in prioritizing the cell type most affected by an xQTL and in enhancing genome wide association studies (GWAS) as we report 18 additional CNS disease susceptibility loci after re-analyzing published studies.

bioinformatics↗