Biology subjects

Absinta, M.

Publications and source records attributed to Absinta, M..

5 recordsLinked to original sources

bioRxiv2025

Maintenance of chronic neuroinflammation in multiple sclerosis via interferon signaling and CD8 T cell-mediated cytotoxicity

Chronic neuroinflammation and neurodegeneration are critical but unresolved drivers of disability accumulation in progressive multiple sclerosis (MS). Chronic active white matter lesions (CAL), identifiable radiologically as paramagnetic rim lesions (PRL), indicate progression-relevant chronic neuroinflammation. Using single-cell transcriptomics (scRNAseq) and T-cell receptor sequencing (scTCR-seq), we profiled cerebrospinal fluid (CSF) and blood immune cells of 34 radiologically characterized adults with MS (17 untreated, 6 treated with B-cell-depletion) and 5 healthy controls. Coupled with proteomics, we found PRL-associated enrichment of interferon (IFN) signaling and upregulation of TCR signaling in CSF and blood. This was accompanied by clonal expansion of CD8+ T effector memory (TEM) cells, with the highly expanded clonal cells exhibiting T helper type 1 (TH1) and cytotoxic profiles. Validating the cytotoxic immune profile in blood using flow cytometry, we identified a cellular correlate of PRL exhibiting features of CD8+ TEMRA cells. Despite B-cell depletion, PRL-associated neuroinflammation, driven by myeloid activation and CD8+ T-cell cytotoxicity, persisted. Serum and CSF proteomic networks showed PRL-pertinent signatures, including networks unaffected by B-cell depletion. Using in silico perturbation, we nominated therapeutic targets, including MYD88, TNF, MYC, TYK2, JAK2, and BTK, for alleviating chronic neuroinflammation in MS. Our findings highlight mechanisms of chronic neuroinflammation in MS and point to potential biomarkers for monitoring disease progression.

immunology↗

bioRxiv2024

Glia-enriched stem-cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis

The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from hiPSC-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from MS patients, organoids properly mimic macroglia-microglia neuro-degenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally-resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support implementing this organoid model for drug screening to halt inflammatory neurodegeneration.

neuroscience↗

bioRxiv2021

Leptomeningeal Enhancement in Multiple Sclerosis and Other Neurological Diseases: A Systematic Review and Meta-Analysis

BackgroundThe lack of systematic evidence on leptomeningeal enhancement (LME) on MRI in neurological diseases, including multiple sclerosis (MS), hampers its interpretation in clinical routine and research settings. PurposeTo perform a systematic review and meta-analysis of MRI LME in MS and other neurological diseases. Materials and MethodsIn a comprehensive literature search in Medline, Scopus, and Embase, out of 2292 publications, 459 records assessing LME in neurological diseases were eligible for qualitative synthesis. Of these, 135 were included in a random-effects model meta-analysis with subgroup analyses for MS. ResultsOf eligible publications, 161 investigated LME in neoplastic neurological (n=2392), 91 in neuroinfectious (n=1890), and 75 in primary neuroinflammatory diseases (n=4038). The LME-proportions for these disease classes were 0.47 [95%-CI: 0.37-0.57], 0.59 [95%-CI: 0.47-0.69], and 0.26 [95%-CI: 0.20-0.35], respectively. In a subgroup analysis comprising 1605 MS cases, LME proportion was 0.30 [95%-CI 0.21-0.42] with lower proportions in relapsing-remitting (0.19 [95%-CI 0.13-0.27]) compared to progressive MS (0.39 [95%-CI 0.30-0.49], p=0.002) and higher proportions in studies imaging at 7T (0.79 [95%-CI 0.64-0.89]) compared to lower field strengths (0.21 [95%-CI 0.15-0.29], p<0.001). LME in MS was associated with longer disease duration (mean difference 2.2 years [95%-CI 0.2-4.2], p=0.03), higher Expanded Disability Status Scale (mean difference 0.6 points [95%-CI 0.2-1.0], p=0.006), higher T1 (mean difference 1.6ml [95%-CI 0.1-3.0], p=0.04) and T2 lesion load (mean difference 5.9ml [95%-CI 3.2-8.6], p<0.001), and lower cortical volume (mean difference -21.3ml [95%-CI -34.7--7.9], p=0.002). ConclusionsOur study provides high-grade evidence for the substantial presence of LME in MS and a comprehensive panel of other neurological diseases. Our data could facilitate differential diagnosis of LME in clinical settings. Additionally, our meta-analysis corroborates that LME is associated with key clinical and imaging features of MS. PROSPERO No: CRD42021235026. Summary statementOur systematic review and meta-analysis synthesize leptomeningeal enhancement proportions across a comprehensive panel of neurological diseases, including multiple sclerosis, and assesses its prognostic value in multiple sclerosis. Summary dataO_LILeptomeningeal enhancement (LME) is a nonspecific imaging feature present across many neurological disorders, including neoplasm, infection, and primary neuroinflammation. C_LIO_LIThe presence of LME is associated with worse clinical and imaging outcomes in multiple sclerosis, justifying its ascertainment in clinical practice. C_LIO_LINeuroinflammatory animal models can be used to further investigate the pathophysiology of LME, including its pathological tissue signature and/or its association with cortical pathology. C_LI

neuroscience↗

bioRxiv2020

Fully Automated Detection of Paramagnetic Rims in Multiple Sclerosis Lesions on 3T Susceptibility-Based MR Imaging

Background and PurposeThe presence of a paramagnetic rim around a white matter lesion has recently been shown to be a hallmark of a particular pathological type of multiple sclerosis (MS) lesion. Increased prevalence of these paramagnetic rim lesions (PRLs) is associated with a more severe disease course in MS. The identification of these lesions is time-consuming to perform manually. We present a method to automatically detect PRLs on 3T T2*-phase images. MethodsT1-weighted, T2-FLAIR, and T2*-phase MRI of the brain were collected at 3T for 19 subjects with MS. The images were then processed with lesion segmentation, lesion center detection, lesion labelling, and lesion-level radiomic feature extraction. A total of 877 lesions were identified, 118 (13%) of which contained a paramagnetic rim. We divided our data into a training set (15 patients, 673 lesions) and a testing set (4 patients, 204 lesions). We fit a random forest classification model on the training set and assessed our ability to classify lesions as PRL on the test set. ResultsThe number of PRLs per subject identified via our automated lesion labelling method was highly correlated with the gold standard count of PRLs per subject, r = 0.91 (95% CI [0.79, 0.97]). The classification algorithm using radiomic features can classify a lesion as PRL or not with an area under the curve of 0.80 (95% CI [0.67, 0.86]). ConclusionThis study develops a fully automated technique for the detection of paramagnetic rim lesions using standard T1 and FLAIR sequences and a T2*phase sequence obtained on 3T MR images. HighlightsO_LIA fully automated method for both the identification and classification of paramagnetic rim lesions is proposed. C_LIO_LIRadiomic features in conjunction with machine learning algorithms can accurately classify paramagnetic rim lesions. C_LIO_LIChallenges for classification are largely driven by heterogeneity between lesions, including equivocal rim signatures and lesion location. C_LI

neuroscience↗

bioRxiv2020

Imaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition

Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identification of this process in multiple sclerosis patients using post-contrast FLAIR imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 Tesla) MRI to perform post-contrast FLAIR imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced using immunization with proteolipid protein peptide (PLP139-151) and complete Freunds adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time-points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which identified dense cellular infiltrates corresponding to areas of contrast-enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas - presence of peripheral node addressin (PNAd) positive structures, CXCL13 producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib (a Brutons tyrosine kinase inhibitor) for a period of 4 weeks. These mice underwent serial imaging and we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We utilized ultra-high field MRI imaging to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis and then utilized this model to identify Brutons tyrosine kinase inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation.

neuroscience↗