Assessing individualized structural abnormality in multiple sclerosis patients for precision medicine using advanced MRI analysis methods

• Applicant: Dr. Marlene Tahedl
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508174565

Multiple sclerosis (MS) is a debilitating and still incurable disorder of the central nervous system (CNS). The development of novel therapy suffers from the fact that there is no single measure which can assess the long-term effect of that therapy for the individual. One reason for that lack of prognostic value might be the underappreciation of the complexity of the brain, which is crucial especially in MS since it manifests throughout the brain. With magnetic resonance imaging (MRI), however, we have the unique opportunity to assess different properties of the brain and therefore capture this complexity non-invasively in vivo.While MRI-research has proposed a wide range of potential biomarkers in the past, many suffer from two common problems: a) they were developed based on group studies and are therefore difficult to implement for individual clinical treatment, b) single biomarkers hardly capture the complexity of the disease, which is why an integration of different biomarkers seems more promising in terms of validity. This proposal aims to overcome these problems and proposes the integration of novel, imaging-based tools reflecting MS disease burden accurately in individual patients. Of particular importance to this proposal is easy implementation into clinical routine. Furthermore, we focus on the brain as a whole, integrating gray or white matter (GM/WM) pathology, which is especially important in MS given pathology manifests in both WM (inflammation) and GM (neurodegeneration). We investigate and integrate individualized biomarkers for both gray and white matter of the brain. The common idea for both measures is to rate individual patients GM (via cortical thickness) and WM (via anisotropy/diffusivity measures) quality with respect to age- and sex-matched control groups, based on which significance testing is performed to detect abnormality in localized GM / WM regions. The applicant has first developed of both methods during her PhD.To validate these metrics for clinical utility, we will associate them with clinical disability (via EDSS scores, including progression). Also, we will compare our measures to the current MRI-based gold standard of MS disease quantification, i.e. T2 lesion load, to directly investigate potential benefits of our new integrated measures as compared to currently available markers.We plan to achieve this goal in three subprojects, investigating first GM pathology, second WM pathology, third integration. Importantly, we will thoroughly examine our markers for clinical relevance and test their reliability and validity. At the end of this project, we hope to be able to provide a single, integrative measure which accurately reflects disease burden and progression in MS, which can not only release the psychological burden off patients (and their caregivers) in terms of uncertainty of progression, but also serve as a biomarker in clinical trials to probe novel therapeutics targeted at repairing the CNS.

• DFG Programme: WBP Position