Cagol, A. | bioRxiv Science

bioRxiv2024

Towards Longitudinal Characterization of Multiple Sclerosis Atrophy Employing SynthSeg Framework and Normative Modeling

Multiple Sclerosis (MS) is a complex neurodegenerative disease characterized by heterogeneous progression patterns. Traditional clinical measures like the Expanded Disability Status Scale (EDSS) inadequately capture the full spectrum of disease progression, highlighting the need for advanced Disease Progression Modeling (DPM) approaches. This study harnesses cutting-edge neuroimaging and deep learning techniques to investigate deviations in subcortical volumes in MS patients. We analyze T1-weighted and Fluid-attenuated inversion recovery (FLAIR) Magnetic Resonance Imaging (MRI) data using advanced DL segmentation models, SynthSeg+ and SynthSeg-WMH, which address the challenges of conventional methods in the presence of white matter lesions. By comparing subcortical volumes of 326 MS patients to a normative model from 37,407 healthy individuals, we identify significant deviations that enhance our understanding of MS progression. This study highlights the potential of integrating DL with normative modeling to refine MS progression characterization, automate informative MRI contrasts, and contribute to data-driven DPM in neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Cell-binding IgM in CSF is distinctive of multiple sclerosis and targets the iron transporter SCARA5

Intrathecal IgM production in multiple sclerosis (MS) is associated with a worse disease course. To investigate pathogenic relevance of autoreactive IgM in MS, CSF from two independent cohorts, including MS patients and controls, were screened for antibody binding to induced pluripotent stem cell-derived neurons and astrocytes, and a panel of CNS-related cell lines. IgM binding to a primitive neuro-ectodermal tumour cell line discriminated 10% of MS donors from controls. Transcriptomes of single IgM producing CSF B cells from patients with cell-binding IgM were sequenced and used to produce recombinant monoclonal antibodies for characterisation and antigen identification. We produced 5 cell-binding recombinant IgM antibodies, of which one, cloned from an HLA-DR+ plasma-like B cell, mediated antigen-dependent complement activation. Immunoprecipitation and mass spectrometry, and biochemical and transcriptome analysis of the target cells identified the iron transport scavenger protein SCARA5 as the antigen target of this antibody. Intrathecal injection of a SCARA5 antibody led to an increased T cell infiltration in an EAE model. CSF IgM might contribute to CNS inflammation in MS by binding to cell surface antigens like SCARA5 and activating complement, or by facilitating immune cell migration into the brain.

immunology↗