Myo-Inositol –a new imaging biomarker for Multiple Sclerosis

Magnetic resonance imaging (MRI) has become an important tool for the assessment of patients with Multiple Sclerosis (MS) involved in the diagnostic workup, monitoring of treatment response, and to elucidate the mechanisms of MS pathogenesis and progression. However, clinically established MRI is unable to sufficiently explain the severity or nature of many clinical signs and symptoms. Recently, we have developed a new spectroscopic MRI method that - for the first time - allows a high-resolution mapping of a chemical compounds termed myo-inositol (mIns) in the brain. First pilot data in MS patients show that mIns mapping may be a powerful imaging biomarker for microglia activation (inflammation), which is highly relevant already in the early formation of MS. We hypothesize that: (a) increased mIns concentration is primarily a marker for microglia activation; (b) locally increased mIns will allow a more accurate and earlier diagnosis of MS; (c) mIns increase will predict MS progression; (d) successful treatment will affect mIns levels; and (e) a new technique termed chemical exchange saturation transfer (CEST) will allow a further improved mapping of mIns levels. In this project we will: (a) perform a longitudinal observation of mIns and other MRI as well as clinical measures in three MS patient groups and one matched control group to elucidate the diagnostic power and possibility of mIns mapping to predict disease progression and treatment response; (b) investigate the origin of this mIns increase via correlation with histology; and (c) develop and validate a further improved MRI technique for mIns imaging. This new mIns-sensitive MRI method could constitute a powerful imaging biomarker for future scientific studies as well as clinical practice. This might ultimately be helpful in the selection of patients who will benefit from expensive and potentially harmful treatments.

In this study we have evaluated Magnetic Resonance Spectroscopic Imaging (MRSI) as an imaging tool to longitudinally monitor the metabolic changes in the brain of Multiple Sclerosis patients over more than five years. We have specifically targeted two main metabolites, namely myo-inositol as a tentative marker of neuroinflammation and N-acetyl aspartate as a marker of neuronal integrity/loss. In this project we have also compared these biomarkers with clinically established alternatives and state-of-the-art MR imaging techniques such as iron-sensitive MRI, which is able to visualize iron-deposition in the periphery of some, but not all MS lesions. However, because MRSI is limited with respect to its spatial resolution, we have in parallel developed an alternative method to provide similar metabolic information, but using a technique termed Chemical Exchange Saturation Transfer (CEST). Indeed, CEST turned out to provide superior spatial resolution, but was less robust and specific to the biomarkers provided by MRSI. Comparing all these multi-parametric MRI data with clinical development over time has brought valuable insights into MS lesion development potentially leading to improved prognostic markers for disease development and treatment monitoring.