Fluid Biomarkers of Diffuse Pathology in Multiple Sclerosis

• Applicant: Dr. Adrian Minh Schumacher
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568249057

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system (CNS) and a leading cause for disability in young adults. The disease is driven by both focal and diffuse CNS pathology. Focal pathology, like the development of inflammatory, demyelinating lesions in the white matter, is the basis for clinical relapses. It is detectable by magnetic resonance imaging (MRI) and responds well to the many available immunotherapies. Diffuse pathology is happening on a more continuous scale. It plays a key role in disability accrual independent of clinical relapses, also known as silent progression. Diffuse damage to neurons and their axons as well as widespread microglial activation throughout the CNS are being highlighted as the main drivers of progression. Specifically, my colleagues and I have shown microglia-mediated synaptic loss, even in the normal-appearing grey matter. However, despite pathological insights there are only few clinically useful diagnostic tools to assess diffuse pathology. Cellular or molecular processes cannot be captured with MRI and molecular imaging (PET) is costly and exposes to radiation. In contrast, fluid biomarkers are easy to obtain, cost-efficient and can potentially capture diffuse pathology. Yet, the most studied protein biomarker, serum neurofilament light chain, lacks specificity for tracking silent progression. My aim is to fill this gap with novel fluid biomarkers in MS patients. I will utilise known pathways of diffuse pathology, like microglia-mediated synaptic damage, to identify candidate proteins. In previous work we were able to identify a multitude of synaptic proteins in the cerebrospinal fluid (CSF) of an animal model of MS. I will now investigate human MS samples at the hosting institution, a leading laboratory in neurological biomarker research. Using an orthogonal approach, I will identify the most promising biomarker candidates within four available proteomic datasets. They contain ~1,500 or ~5,400 distinct proteins detected by a Proximity Extension Assays (PEA, Olink) in n=96 cerebrospinal fluid und n=617 serum samples of n=287 MS patients. Subsequently, I will develop targeted immunoassays (i.e. Simoa) for the top 2 biomarker candidates identified in the proteomic analysis and run a method validation. Lastly, I will clinically validate the assay in another longitudinal patient cohort at the hosting institution with n=352 MS patients, where three serum samples per patient, in-depth clinical data, neuropsychological testing as well as MRIs are available. By the end of the funding period, I aim to have a novel biomarker ready for further validation in other clinical MS cohorts. I will use the new expertise to start my own research group.

• DFG Programme: WBP Fellowship
• International Connection: Netherlands
• Host: Professorin Charlotte Teunissen, Ph.D.