Integrative CSF profiling identifies disease-specific immune responses in leptomeningeal disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE286518 | GEO | 2026/01/20
REPOSITORIES: GEO
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2014-12-07 | E-GEOD-60990 | biostudies-arrayexpress
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Project description:Background. COVID-19-induced neurological disease is a growing concern. Here we provide a comprehensive clinical, molecular, and neuroimaging investigation of patients presenting neurological symptoms to investigate underlying processes. Methods. We performed a detailed systematized clinical, laboratory, and neuroimaging (CT/MRI) data analysis from 35 mild to severe Brazilian COVID-19 hospitalised patients with clinical indications for cerebrospinal fluid (CSF) exam. In patients' CSF, we measured interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and the Alzheimer's disease-associated biomarkers amyloid-beta (Aβ)1-40, Aβ1-42, Tau and pTau181 levels (n=31-35). In addition, CSF proteomics and the search for SARS-CoV-2 spike protein presence using shotgun and targeted multiple reaction monitoring liquid-chromatography/mass-spectrometry were performed (n=16). We further evaluated a 29-cytokine panel in patients’ blood (n=16). An electronic questionnaire was conducted one-year post-hospitalisation (n=19, 63.3%). Findings. COVID-19 patients presented heterogeneous clinical and neurological features, including encephalopathy, encephalitis, and neuromuscular syndromes, despite low pulmonary burden. Patients showed increased circulating cytokines and CSF IL-6 and TNF-α levels compared to controls. Alzheimer’s disease-related biomarkers were unaltered compared to controls. COVID-19 altered CSF proteomic pathways associated to complement and coagulation cascades, immune-inflammatory, metabolism and amyloidosis. We found no traces of spike protein in patients’ CSF. Severe patients presented more pronounced neuroimaging alterations, altered CSF levels of IL-6, Tau, and Aβ-species compared to mild patients. Peripheral inflammation markers correlated with CSF IL-6 and Tau-species levels. Finally, in a one-year post-COVID survey, survivors were not recovered entirely (12/19) and reported confusion or memory/attention deficits (13/19). Interpretation. COVID-19 induces a broad spectrum of neurological presentations associated with changes in central nervous system (CNS) inflammatory and neurodegenerative molecular and structural biomarkers that correlate with systemic inflammation and disease severity. Given that neurological symptoms persist up to one-year post-COVID, our results urge us to investigate whether systemic, and CNS molecular changes are permanent or alleviated so that COVID-19 patients with lingering symptoms are adequately treated.
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Project description:Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4-restricted plasma cells in a variety of organs. Clinical presentation is heterogeneous and pathophysiological mechanisms of IgG4-related autoimmunity remain elusive. Secondary parenchymal lesions of IgG4-RD in the central nervous system (CNS) are rare and there are very few cases of IgG4-RD with isolated CNS manifestation. Patients suffering from IgG4-RD frequently require prolonged treatment with glucocorticoids and are often unable to taper these medications. By leveraging single-cell sequencing of the cerebrospinal fluid (CSF) of a patient with an unusual inflammatory intracranial pseudotumor we provide novel insights into the immuno-pathophysiology of IgG4-RD by illustrating an IgG4-RD-associated polyclonal T cell response in the CSF and multifaceted cell-cell interaction between immune cell subsets and pathogenic B cells.
2021-06-19 | E-MTAB-10479 | biostudies-arrayexpress
Project description:Several proteomics studies have been conducted to identify new cerebrospinal fluid (CSF) biomarkers in Multiple Sclerosis (MuS). However, the complexity of CSF and its invasive collection, limits its use. Therefore, the goal of biomarker research in MuS is to identify novel distinctive targets in CSF or in easily accessible biofluids. Tears represent an interesting matrix for this purpose, because (1) tears are related to the central nervous system (CNS) and (2) the CNS contains Extracellular Vesicles (EVs) derived from brain cells. These EVs are emerging new biomarkers associated to several neurological disorders. Here we applied an optimized flow cytometer for the identification and subtyping of EVs from CSF and tears. We found, for the first time, microglia-derived and neural-derived EVs in tears. The flow cytometer was used to sort and purify 106 EVs from untouched CSF and tears of MuS patients and healthy subjects. Purified EVs were analysed with shotgun proteomics analysis, revealing that EVs from both CSF and tears of MuS patients conveyed similar proteins. Our data demonstrated a specific EVs-mediated molecular cross talk between CSF and tears, which opens the door to new diagnostic perspectives for MuS.
2019-06-06 | PXD013794 | Pride
Project description:C9orf72-linked amyotrophic lateral sclerosis (c9ALS) is driven by an intronic G4C2 repeat expansion, leading to the production of toxic RNA transcripts and dipeptide repeat proteins (DPRs). A clinical trial using the antisense oligonucleotide (ASO), BIIB078, to target these transcripts was discontinued after failing to meet secondary efficacy endpoints, despite a reduction in DPRs in cerebrospinal fluid (CSF). The extent of target engagement in the central nervous system (CNS) and the relevance of pharmacodynamic CSF biomarkers following BIIB078 treatment remain unclear. Post-mortem analysis of CNS tissue from six BIIB078-treated c9ALS patients revealed widespread intracellular BIIB078 distribution in the spinal cord and brain regions, persisting for over a year after the last dose. C9orf72 mRNA levels were inversely correlated with BIIB078 concentration, indicating partial target engagement. Despite reductions in CSF DPRs, these proteins and phosphorylated TDP-43 remained abundant in the brain and spinal cord, suggesting that CSF biomarkers may not fully reflect CNS target engagement. Additionally, sustained increases in inflammation biomarkers, including CCL26, GDF15, and other cytokines, were observed. Global proteomic analysis of spinal cord tissue revealed significant changes in c9ALS cases that were not normalized in BIIIB078 treated cases. Notably, proteome-wide correlations with BIIB078 concentration in the spinal cord identified hydrolytic nucleases, including RNASET2 and DNASE2, to be increased in BIIB078 treated cases. Thus, while BIIB078 demonstrated widespread and sustained distribution and partial target engagement, it did not significantly impact key proteomic and pathological features in the CNS of c9ALS patients. Consequently, ceasing strategies that target the G4C2 sense strand may be premature.
2025-08-27 | PXD055796 | Pride
Project description:Objectives: Central nervous system (CNS) infections are common causes of morbidity and mortality worldwide. We aimed to discover protein biomarkers that could rapidly and accurately identify the likely cause of the infections, essential for clinical management and improving outcome. Methods: We applied liquid chromatography tandem mass-spectrometry on 45 cerebrospinal fluid (CSF) samples from a cohort of adults with/without CNS infections to discover potential diagnostic biomarkers. We then validated the diagnostic performance of a selected biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS infections admitted to a referral hospital in Vietnam. Results: In the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of bacterial meningitis (BM) other than tuberculous meningitis. The analysis of the validation cohort showed that LCN2 could discriminate BM from other CNS infections (including tuberculous meningitis, cryptococcal meningitis and viral/antibody-mediated encephalitis), with the sensitivity: 0.88 (95% confident interval (CI): 0.77-0.94), the specificity: 0.91 (95%CI: 0.88-0.94) and the diagnostic odd ratio: 73.8 (95%CI: 31.8-171.4)). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) commonly used in routine care worldwide. The combination of LCN2, CSF leukocytes, glucose, protein and lactate resulted in the highest diagnostic performance for BM (area under receiver-operating-characteristic-curve 0.96; 95%CI: 0.93-0.99). Conclusions: Our results suggest that LCN2 is a sensitive and specific biomarker for discriminating BM from a broad spectrum of other CNS infections. A prospective study is needed to assess the diagnostic utility of LCN2 in the diagnosis and management of CNS infections..
2020-08-20 | PXD020510 | Pride