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PubMed2022

Biological correlates of elevated soluble TREM2 in cerebrospinal fluid.

Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells-2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer's disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. While associations between sTREM2 and tau in CSF are established, we sought to determine additional biological correlates of CSF sTREM2 during the prodromal stages of AD by evaluating CSF Aβ species (Aβx-40), a fluid biomarker of blood-brain barrier integrity (CSF/plasma albumin ratio), and CSF biomarkers of neurodegeneration measured in 155 participants from the Vanderbilt Memory and Aging Project. A novel association between high CSF levels of both sTREM2 and Aβx-40 was observed and replicated in an independent dataset. Aβx-40 levels, as well as the CSF/plasma albumin ratio, explained additional and unique variance in sTREM2 levels above and beyond that of CSF biomarkers of neurodegeneration. The component of sTREM2 levels correlated with Aβx-40 levels best predicted future cognitive performance. We highlight potential contributions of Aβ homeostasis and blood-brain barrier integrity to elevated CSF sTREM2, underscoring novel biomarker associations relevant to disease progression and clinical outcome measures.

Alzheimer Disease↗

PubMed2025

Sex differences in cerebrospinal fluid proteomics of patients with restless legs syndrome.

STUDY OBJECTIVES: The pathobiology of restless legs syndrome (RLS) remains poorly understood, complicating effective treatment. This observational cross-sectional study aimed to identify a cerebrospinal fluid proteomic signature of RLS and to explore sex-specific differences in cerebrospinal fluid proteomics. METHODS: Cerebrospinal fluid samples were collected from 22 untreated RLS patients and 18 controls, matched for age, body mass index, and sex. Proteomic analysis was conducted using the SOMAscan platform, assessing over 7000 peptides. RESULTS: Eight proteins were differentially abundant between patients and controls, with CRP and JAML increased, and TAPBPL and IL1RL1 decreased. Pathway analysis highlighted significant involvement in immune response, coagulation, and cytoskeletal regulation. Analyses were then carried out using sex stratification, comparing men and women separately. Sex-specific analyses revealed more pronounced proteomic alterations in males (68 differentially abundant proteins vs. control males) than in females (17 proteins). Gene enrichment analysis revealed that men with RLS had more involvement in gene regulation and epigenetic factors than control males and women with restless legs syndrome had greater involvement in systemic inflammatory and vascular processes than control females. CONCLUSIONS: This study identified a cerebrospinal fluid proteomic signature in RLS, implicating immune and inflammatory pathways in the disease's pathophysiology. Significant sex differences in protein level suggest potential sex-specific mechanisms in RLS, warranting further investigation. These findings contribute to the current understanding of RLS and could inform future therapeutic strategies.

Humans↗

PubMed2025

Cerebrospinal fluid microbiome revisited: no evidence of resident bacteria in archived samples.

UNLABELLED: DNA from oral bacteria has been detected in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease and related dementias (AD/ADRD). We hypothesized that examination of archived CSF samples from donors with variable cognitive status would reveal evidence of a resident microbiome. 176 CSF samples harvested from community-dwelling individuals (77% between 61 and 80 years old) were analyzed; 57% originated from donors with impaired cognitive status. DNA was extracted after adding microbial spike-in controls, and libraries were prepared and sequenced on an Illumina-MiSeq platform. 16S rRNA sequences were processed, and a taxonomic classification was performed. Spike-in bacteria were consistently detected, and Streptococcus pneumoniae was found in a positive control sample from a patient with bacterial meningitis. However, very few reads mapping to other bacterial taxa were detected across samples, suggesting a negligible bacterial content consistent with occasional contamination or sequencing errors. CSF is a privileged, sterile environment that does not harbor a resident microbiome in elderly people with various morbidities, including AD/ADRD. IMPORTANCE: Recent reports have suggested that DNA from oral bacteria has been found in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease and related dementias (AD/ADRD). We hypothesized that examination of archived CSF samples from donors with variable cognitive status would reveal evidence of a resident microbiome. We thus analyzed 176 CSF samples harvested from community-dwelling individuals including donors with impaired cognitive status. While our findings suggested the presence of occasional bacterial contamination, they provided no evidence of a resident microbiome. We thus conclude that the CSF is indeed a privileged, sterile environment that does not harbor a resident microbiome in elderly people with various morbidities including AD/ADRD.

Humans↗

PubMed2026

Cerebrospinal fluid infection caused by Mixta calida in a patient with sarcoma: Case report with whole-genome sequencing.

Mixta calida is a rare environmental Erwiniaceae organism with limited evidence of invasive human infection. We report cerebrospinal fluid infection in a 6-year-old girl with recurrent CIC-rearranged central nervous system sarcoma after neurosurgery, chemotherapy, stem-cell transplantation, and Ommaya reservoir access. Turbid cerebrospinal fluid showed severe neutrophilic inflammation and Gram-negative bacilli with leukocyte phagocytosis. Pure culture yielded an isolate identified by MALDI-TOF mass spectrometry. Four genomic 16S rRNA sequences showed 99.93% identity to the M. calida type strain, and whole-genome ANI was 99.59%. These findings support M. calida as a clinically significant opportunistic pathogen in immunocompromised patients.

Meningitis↗

PubMed2026

Essence: A benchmarking-validated transformer framework for early diagnosis of Parkinson's disease using cerebrospinal fluid protein biomarkers.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. The lack of objective molecular biomarkers limits early diagnosis and personalized treatment. Here, we propose Essence, a benchmarking-validated framework integrating cerebrospinal fluid (CSF) proteomics with traditional and deep learning models to identify robust protein signatures for PD. Using data from two independent cohorts, 1266 high-confidence proteins are quantified, among which 178 exhibit differential abundance between PD and healthy controls (HC). Through systematic benchmarking of ten machine learning algorithms and four neural architectures, the Transformer model consistently outperforms alternatives across multiple feature selection strategies, achieving an area under the receiver operating characteristic curve (AUC) of 1.0000 with only 35 features. Functional analyses of the top-ranked 35 proteins reveal enrichment in neuroinflammatory, synaptic, and oxidative stress-related pathways. Importantly, spatial transcriptomic profiling based on the Allen Brain Atlas shows region-specific expression of these biomarkers in PD-relevant brain structures, including the striatum, subthalamic nucleus, hippocampus, and white matter tracts. This anatomical alignment supports the functional relevance of the identified markers and highlights their potential utility in early-stage diagnosis and mechanistic understanding of PD.

Benchmarking↗

PubMed2026

Metagenomic next-generation sequencing of cerebrospinal fluid reveals pathogen spectrum and mortality predictors among patients with advanced HIV-1 disease at a tertiary hospital in China.

BACKGROUND: Central nervous system (CNS) infections remain the major causes of morbidity and mortality among people living with HIV-1 (PLWH), particularly in resource-limited settings. However, the clinical characteristics and prognostic indicators of PLWH with suspected CNS infections are not well defined. In this study, we aim to characterize the spectrum of CNS pathogens, clinical characteristics, in-hospital mortality, and factors associated with death among people with advanced HIV-1 disease (AHD) in Guangxi, China. METHODS: Metagenomic next-generation sequencing (mNGS) was performed to analyze types of infection in cerebrospinal fluid (CSF) from 61 treatment-naive PLWH with suspected CNS infections. Clinical data, routine laboratory tests, and biochemical tests were collected and analyzed. RESULTS: Among the 61 CSF samples, primarily with AHD, a total of 206 pathogens were identified. Viral pathogens predominated, with Epstein-Barr virus being the most frequently identified, followed by cytomegalovirus. Compared with patients with single-pathogen infection, those with multiple infections (viral, bacterial, and fungal) exhibited significantly lower CD4 T cell counts, higher C-reactive protein levels, and markedly reduced lipid metabolism parameters. However, infection types were not significantly associated with in-hospital death. Multivariate logistic regression analysis identified plasma low density lipoprotein (LDL) and CSF lactate dehydrogenase (LDH) as independent predictors of in-hospital death. CONCLUSION: In PLWH with AHD and suspected CNS infections, multiple pathogens frequently coexist in the CSF. Plasma LDL and CSF LDH levels were independent predictors of death, indicating their potential value as early risk stratification in AHD.

Humans↗

PubMed2026

First isolation and characterisation of human Rotavirus alphagastroenteritidis from cerebrospinal fluid in Malaysia.

Rotavirus infection is a major cause of paediatric gastroenteritis and has increasingly been associated with neurological complications, although direct evidence of central nervous system involvement remains limited. In this study, Rotavirus A was detected in both cerebrospinal fluid and stool samples from a child presenting with encephalopathy and seizures, and infectious virus was successfully propagated in mammalian cell lines. Genomic analysis revealed a Wa-like genotype constellation, G1-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. Although lateral flow immunoassay yielded negative results, molecular diagnostic approaches proved valuable for identifying atypical RVA infections.

Cerebrospinal fluid↗

PubMed2025

Proteome Profiling in Cerebrospinal Fluid Reveals Increased Levels of Peroxiredoxin 2 Discriminating Japanese Encephalitis Virus and Scrub Typhus Infection.

Japanese encephalitis virus (JEV) and scrub typhus (ST) are major etiological agents of acute encephalitis syndrome (AES) in India and South Asia. The pathophysiological changes at the molecular level caused by JEV and ST have yet to be studied in detail. The cerebrospinal fluid (CSF) proteomic landscape is a critical indicator of CNS pathology. Here, we conducted label-free quantitative proteomics on CSF from AES patients (n = 15) to identify etiology-specific differentially expressed proteins (DEPs) linked to encephalitis. The key DEPs were validated via ELISA in CSF (n = 49) and serum (n = 33). Our findings revealed 50 proteins exhibited differential expression across JEV and ST groups, with a notable subset of three proteins, PRDX2, KLK6, and TTR. PRDX2 and KLK6 were markedly elevated in JEV CSF (AUC: 0.8933 and 0.9689) but not in ST or non-JEV AES, while TTR was reduced in JEV yet elevated in ST (AUC: 0.5619 vs. 0.8238). Further, PRDX2 upregulation was validated in JEV-infected mouse brains and cortical neurons. Overexpression of PRDX2 in human neuroblastoma cells correlated with enhanced antiviral gene expression, p-STAT1, p-AKT (ser473), and viral replication. Thus, our comprehensive proteomic analysis of CSF identifies PRDX2 as an important circulatory protein, differentially expressed between JEV and ST, with high specificity and enhancing viral propagation, underscoring its role in viral propagation and pathogenesis.

Humans↗

PubMed2026

Comparison of Proteomic Analysis of Cerebrospinal Fluid From Neurological Patients With and Without Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symptoms. Approximately 85% of ALS cases are sporadic (sALS), while the remaining 10%-15% are familial (fALS). Biological biomarkers of sporadic ALS remain poorly understood, hindering precise patient screening, delaying diagnosis and negatively affecting prognosis. This study aims to identify potential proteomic biomarkers by comparing the cerebrospinal fluid (CSF) of sALS patients with that of patients suffering from other neurological diseases. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic profiling of CSF samples from 24 sALS patients and 26 patients with other neurological diseases. The complete protein expression profiles were compared using a two-tailed Student's t-test, with a p < 0.05 considered statistically significant with additional FDR correction at the 0.1 level. Proteomic analysis of CSF samples identified significant quantitative changes in 96 proteins with threshold p < 0.05 and 74 proteins with FDR < 0.1 between sALS and non-ALS patients, including alterations in proteins associated with neurodegenerative processes, such as amyloid precursor proteins and inflammatory markers. CSF proteomic analysis reveals altered inflammatory and neurodegenerative metabolic pathways, providing valuable insights into the proteomic landscape of sALS. Several dysregulated proteins were consistent with the disease mechanisms highlighted in previous studies. These findings represent a step forward in developing personalised approaches for diagnosing and managing the disease.

Humans↗

PubMed2025

Untargeted metabolomics in a prospective cross-sectional observational study reveals differences in plasma and cerebrospinal fluid between asymptomatic neurosyphilis and serofast syphilis.

Asymptomatic neurosyphilis (ANS), a diagnostically elusive complication of Treponema pallidum infection, necessitates invasive cerebrospinal fluid (CSF) analysis for detection. This study investigated metabolic differences between patients with ANS and those with serofast syphilis. Using untargeted metabolomics, we analyzed plasma and CSF from 15 patients with ANS, 15 patients with serofast syphilis, and 16 healthy controls via liquid chromatography-mass spectrometry. Univariate statistical analyses identified differential metabolites, followed by pathway enrichment through Kyoto encyclopedia of genes and genomes enrichment analysis and biomarker evaluation. Plasma analysis identified dysregulated tryptophan metabolism as a central feature in ANS, with key alterations in 4-(2-aminophenyl)-2,4-dioxobutanoic acid and 2-formylaminobezaldehyde. Comparative analysis further distinguished ANS through perturbations in inositol phosphate metabolism in both plasma and CSF. Spearman correlation analysis identified positive associations of the plasma biomarkers 1D-myo-inositol-1,3,4,6-tetrakisphosphate, inositol-1,3-bisphosphate, 4-(2-aminophenyl)-2,4-dioxobutanoic acid, and 2-formylaminobezaldehyde with CSF total protein. Our findings suggest that dysregulation in tryptophan and inositol phosphate metabolism may play an important role in ANS pathogenesis, warranting further confirmatory studies.

Humans↗

PubMed2025

Elevated Cerebrospinal Fluid Total Tau in Niemann-Pick Disease Type C1: Correlation With Clinical Severity and Response to Therapeutic Interventions.

Niemann-Pick disease, type C1 (NPC1) is an inborn error of intracellular cholesterol transport. Impaired function of NPC1 leads to endolysosomal accumulation of unesterified cholesterol, which results in progressive neurodegeneration. Although the age of onset is variable, classical NPC1 is a pediatric disease. Identification of biomarkers that correlate with clinical phenotype and respond to therapeutic interventions will be essential for developing effective therapeutic interventions. Aβ peptides and Tau protein are primary components of amyloid plaques and neurofibrillary tangles, respectively, which are major pathological features in neurodegenerative disorders. Cerebrospinal fluid (CSF) levels of total Tau, a biomarker of axonal damage, were elevated ~3-fold (p < 0.0001) in 106 individuals with Niemann-Pick disease, type C1, relative to age-appropriate comparison samples. Baseline CSF total Tau levels correlated with clinical measures of disease severity. Specifically, CSF total Tau levels decreased with increased age of neurological onset (rs = -0.42, FDR adj. p < 0.0001) and increased with increased Annual Severity Increment Score (rs = 0.52, FDR adj. p < 0.0001). Baseline CSF total Tau levels were decreased 40% (p = 0.0066) in individuals being treated with miglustat, and longitudinal analysis substantiated this observation with a 40% decrease (p < 0.0001, 95% CI 32%-47.4%). Longitudinal analysis also showed a significant (p = 0.004) decrease of 19% (95% CI 7%-30%) in total Tau levels associated with intrathecal 2-hydroxypropyl-β-cyclodextrin therapy. These data show that CSF total Tau levels are significantly increased in individuals with NPC1, positively correlated with increased disease severity, and respond to therapeutic interventions.

Humans↗

PubMed2026

The investigation of human cerebrospinal fluid exosome in spinal cord injury.

Spinal cord injury (SCI) leads to severe neurological and functional impairments, yet reliable biomarkers for assessing injury severity and predicting recovery remain limited. Cerebrospinal fluid (CSF) is in direct contact with the central nervous system and provides a valuable source for detecting molecular changes after SCI. Although exosomal microRNAs (miRNAs) and proteins are increasingly recognized as mediators of intercellular communication, the role of human CSF exosomes in SCI has not been systematically investigated. To identify exosome-based biomarkers and potential therapeutic targets, we analyzed CSF and serum exosomes from patients with acute SCI using RNA sequencing and proteomic profiling. Weighted gene co-expression network analysis identified 6 gene modules significantly associated with injury severity and neurological recovery at 3 months. Proteomic analysis revealed a 5-protein panel that distinguished complete from incomplete SCI and a 4-protein panel that predicted neurological improvement. Additionally, 15 CSF-specific and 9 serum-specific exosomal miRNAs were identified independent of injury severity. Among 10 tested miRNAs associated with neurological recovery, 7 regulated astrocyte proliferation, and 6 promoted neurite extension and synapse formation. Overall, this study provides a comprehensive characterization of CSF exosomal miRNAs and proteins in human SCI and identifies molecular signatures associated with injury severity and recovery.

Humans↗

PubMed2025

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72, 38 GRN, and 25 MAPT) and 55 symptomatic (27 C9orf72, 17 GRN, and 11 MAPT) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer's disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.

Humans↗

PubMed2025

Differential DNA methylation in blood as potential mediator of the association between ambient PM 2.5 and cerebrospinal fluid biomarkers of Alzheimer's disease among a cognitively normal population-based cohort.

INTRODUCTION: Fine particulate matter (PM 2.5 ) is a known risk factor for Alzheimer's disease (AD), with emerging evidence linking PM 2.5 exposure to cerebrospinal fluid (CSF) biomarkers in pre-clinical stages. However, the role of DNA methylation (DNAm) as potential mediator in this relationship among cognitively normal individuals remains largely unexplored. METHODS: In 535 cognitively normal individuals, we assessed genome-wide blood DNAm, CSF Aβ 42 concentrations, and residential PM 2.5 exposure in the year preceding blood collection. Multi-stage comprehensive mediation analyses were conducted. RESULTS: Nine CpG sites mediated the PM 2.5 -Aβ42 association, with significant natural indirect effects (NIEs) for eight CpGs, mediating 14-43% of the effect. The joint NIE for all nine CpGs was -0.115 (95% CI: -0.215, -0.101) per 1 ug/m 3 increase in PM 2.5 exposure. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. DISCUSSION: Our findings suggest that differential DNAm, particularly in neuroinflammation-related genes, mediates PM 2.5 toxicity in AD's pre-clinical stage.

Journal Article↗

PubMed2026

Multi-omics profiling of cerebrospinal fluid in autoimmune encephalitis: insights into pathogenesis and therapeutic targets.

BACKGROUND: Autoimmune encephalitis (AIE) is a rare, severe inflammatory brain disease, with its pathogenesis not yet fully elucidated. This study aimed to characterize proteomic and metabolomic alterations in the cerebrospinal fluid (CSF) of AIE patients and identify potential therapeutic targets. METHODS: 65 consecutive AIE patients and age-matched concurrent controls were enrolled, respectively. Clinical characteristics, including blood and CSF laboratory findings, were compared between the two groups, and CSF samples were collected for multi-omics analysis. Differentially expressed proteins (DEPs) and metabolites (DEMs) between AIE patients and controls were identified using data-independent acquisition-based proteomics and targeted liquid chromatography-mass spectrometry-based metabolomics, followed by integrated multi-omics analysis. RESULTS: Compared with controls, AIE patients had lower levels of triglyceride and C1q, but higher HDL-CH levels, neutrophil counts, and eosinophil counts in blood. CSF leukocyte, erythrocyte, lymphocyte, and mononuclear cell counts were also elevated in AIE patients. Proteomic analysis identified 163 DEPs, with enrichment of 87 canonical pathways primarily associated with immune-inflammatory responses, neuronal-synaptic dysfunction, and cell signaling and metabolic pathways. Metabolomic analysis recognized 21 DEMs, predominantly amino acids, lipids, and carbohydrates, which were involved in lipid-carbohydrate metabolism and immune regulation. Integrated multi-omics analysis validated these findings and identified several potential therapeutic targets for AIE, including the IL6-STAT3 axis. CONCLUSIONS: Integrated multi-omics analysis systematically delineates cellular and molecular alterations underlying AIE. Immune-inflammatory response and lipid metabolism are pivotal in AIE progression and the IL6-STAT3 axis holds promise as a potential therapeutic target.

Humans↗

PubMed2026

Differential DNA methylation in blood as potential mediator of the association between ambient PM2.5 and cerebrospinal fluid biomarkers of Alzheimer's disease among a cognitively normal population-based cohort.

Fine particulate matter (PM2.5) is a known risk factor for Alzheimer's disease (AD), with emerging evidence showing its effects detectable in the pre-clinical stage through cerebrospinal fluid (CSF) biomarkers of AD. While studies have linked PM2.5 exposure and AD to DNA methylation (DNAm) alterations, the role of DNAm as potential mediator in the association between PM2.5 and AD biomarkers in cognitively normal individuals remains largely unexplored, and formal mediation analyses addressing this question are scarce. Genome-wide DNAm profiles (Illumina EPIC BeadChips) in whole blood and CSF Aβ42 concentrations were assessed in 536 cognitively normal individuals from the Emory Healthy Brain Study (EHBS). Residential PM2.5 exposure for the year preceding participants' blood collection was estimated. A multi-stage analytical pipeline, incorporating single-mediator analysis, high-dimensional mediation analysis, and causal mediation analysis, was applied. Nine CpG sites were identified as noteworthy mediators of the relationship between PM2.5 and decreased CSF Aβ42 concentrations. Causal mediation analysis confirmed significant natural indirect effects (NIE) for eight CpGs, with effect estimates ranging from -0.015--0.029 per 1 ug/m3 increase in PM2.5 exposure. The proportion mediated ranging from 14-43%. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. These findings suggest that differential DNAm, particularly in genes related to neuroinflammation, mediates the association between PM2.5 exposure and CSF Aβ42 concentrations, highlighting the utility of blood DNAm in detecting and studying biological pathways underlying PM2.5 toxicity in the pre-clinical stages of AD.

Humans↗

PubMed2026

DNA methylation landscape of cerebrospinal fluid cells in multiple sclerosis: an epigenome-wide association study.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which DNA methylation may link genetic and environmental risk factors. METHODS: We profiled genome-wide DNA methylation in cerebrospinal fluid (CSF) cells from people with MS (pwMS) and matched controls. Differentially methylated positions (DMPs) and regions (DMRs) were integrated with transcriptomic data, T-cell chromatin annotations, and pathway analyses. Protocadherin gamma (PCDHγ) expression was assessed in primary CD4+ T-cell subsets and confirmed by flow cytometry. FINDINGS: We identified 2710 DMPs and 4330 DMRs associating with genes that were enriched in immune signalling, adhesion and migration processes, and were accompanied by corresponding RNA changes. MS-associated methylation changes enriched in the cohesin chromatin-regulation pathway localised to T-cell regulatory regions, and this pathway included multiple protocadherin (PCDH) genes, which displayed consistent methylation and expression changes in CSF cells of pwMS compared to controls. PCDHγ cluster gene expression was detected in CD4+ T-cell subsets, and flow cytometry confirmed PCDHγ protein expression in peripheral blood T cells. Moreover, co-expression analysis suggests a role of PCDH genes in aryl hydrocarbon receptor (AHR) signalling. Protein-level validation showed fewer PCDHγ-positive CD4+ T cells in pwMS and activation-induced PCDHγ upregulation after T-cell stimulation. INTERPRETATION: DNA methylation changes in CSF resident cells reflect dysregulated T cell activation and migration in pwMS and suggest involvement of protocadherin molecules in MS pathogenesis. FUNDING: European Research Council, Swedish Research Council, Swedish Brain Foundation, Swedish MS Foundation, Knut and Alice Wallenberg Foundation, European Union and others.

Humans↗

PubMed2025

Causal effect of three autoimmune diseases on brain functional networks and cerebrospinal fluid metabolites to underlie the pathogenesis of autoimmune psychosis: a two-sample mendelian randomization analysis.

BACKGROUND: Autoimmune diseases such as Systemic Lupus Erythematosus (SLE), Sjögren's Syndrome (SS), and Hashimoto's Thyroiditis (HT) frequently exhibit neuropsychiatric manifestations, including cognitive impairment, depression, anxiety, and so on, yet the exact pathogenesis underlying this association remain incompletely understood. Dysfunction of brain resting-state functional networks and cerebrospinal fluid (CSF) metabolite disturbances have been widely reported in psychiatric disorders. However, the application of resting-state functional magnetic resonance imaging (rsfMRI) and CSF metabolomics in the diagnosis and monitoring of autoimmune psychosis is still limited. METHODS: A two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationships between three autoimmune diseases (SLE, SS, and HT, n = 14,267 to 402,090 individuals) and 191 rsfMRI phenotypes (n = 47,276 individuals), as well as 338 CSF metabolites. The genome-wide association study (GWAS) of three autoimmune diseases was used as the exposure, whereas rsfMRI phenotypes and 338 CSF metabolites were treated as the outcome. Inverse variance weighted (IVW) with P value < 0.05 was regarded as the primary approach for calculating causal estimates. Additionally, the false discovery rate (FDR)-adjusted P value (PFDR) < 0.05 was utilized to account for multiple testing. MR Egger method, weighted median method, simple mode method and weighted mode method were used for sensitive analysis. RESULTS: Our analyses identified 5 causal relationships between SLE and the 191 rsfMRI phenotypes, 48 between SS and the 191 rsfMRI phenotypes, and 4 between HT and the 191 rsfMRI phenotypes. Additionally, we found 8 causal relationships between HT and CSF metabolites. Furthermore, all three diseases were significantly associated with the temporal lobe and triple networks (default mode network (DMN), salience network (SN), and central executive network (CEN)), which are the core brain regions and functional networks for cognition. Following FDR correction, 6 causal relationships between SS and the 191 rsfMRI phenotypes were further validated. CONCLUSIONS: Our study pinpoints important brain functional networks and CSF metabolites potentially implicated in the pathogenesis of psychiatric disorders associated with autoimmune diseases and highlights critical brain regions for the development of novel therapeutics.

Humans↗