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Prof. Dr. med Dr. phil Cristina Granziera

Department of Clinical Research
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INsIDER: ImagiNg the Interplay between Axonal DamagE and Repair in Multiple Sclerosis

Research Project  | 1 Project Members

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS), which affects ~ 2.3 million people worldwide and is associated with substantial economic burden on MS patients, their families and the entire society. Despite significant progress in MS diagnosis and treatment, there remains the need to understand what drives this disease and its clinical progression. Specifically, it is essential to define the interplay between axonal damage - encompassing axonal demyelination, degeneration, loss and disorganization - and axonal repair - namely axonal remyelination and reorganization, which ultimately influence MS evolution and the accrual of disability.Clinical MS categories are quite heterogeneous. Nevertheless, pathology studies have identified some characteristic traits in early-stage patients with active MS (aMS) and in non-active progressive MS patients (naPMS). Early-stage aMS patients - who are subjects with clinical and/or radiological signs of on-going inflammation - exhibit neuropathological signs of substantial acute axonal damage and significant remyelination. On the other end, naPMS patients - who are subjects with clinical deterioration and no clinical or radiological evidence of disease activity - show less acute axonal damage and remyelination but extensive axonal loss. These characteristic neuropathologic traits of aMS and naPMS patients have not yet been demonstrated in living MS patients. The in vivo quantification of axonal damage and repair in MS patients is essential (i) to gain knowledge on MS pathogenesis and its clinical progression as well as (ii) to understand and quantify the effects of current and future neuroprotective and regenerative therapies. To this end, INsIDER will combine advanced MRI techniques sensitive to axonal structure and organization to gain new insights into axonal damage and repair in MS. In fact, MRI metrics derived from models based on diffusion MRI, Magnetization Transfer Imaging, Quantitative Susceptibility Mapping, Myelin Imaging and T1 relaxometry provide complementary and partially redundant information about the axonal structure and axonal organization. Therefore, their combination may increase the sensitivity and specificity to axonal pathology and axonal changes over time.Through classical and modern machine-learning analysis of multiple advanced MRI data combined with demographic and genetic information, INsIDER will quantify in vivo the differences between aMS and non-active progressive MS (naPMS) patients. Furthermore, INsIDER will validate the most discriminative imaging metrics between aMS and naPMS patients with post-mortem measures of axonal damage and remyelination. The specific aims for this proposal are: Aim 1. Quantify differences in axonal integrity and organization in aMS vs naPMS patients. Aim 2. Quantify changes in axonal integrity and organization in aMS vs naPMS patients over a two-year period. Aim 3. Validate the combination of imaging parameters that best differentiate aMS vs naPMS patients using histopathology.INsIDER will provide new knowledge about the contribution of axonal damage and repair to MS progression and will allow to develop novel surrogate biomarkers to assess disease evolution and future neuroprotective and regenerative treatments.