Magnetic Properties of Normal Appearing White Matter in MS

Magnetic resonance imaging (MRI) has evolved as the most important tool to assess disease related brain tissue changes in multiple sclerosis (MS). Consequently, MRI has significantly contributed to our understanding of brain pathology in MS. However, MRI often fails to detect disease related tissue changes in the so-called normal appearing white matter (NAWM) which looks normal on conventional MRI. This is important because several histological studies have suggested that there is some diffuse disease activity in the NAWM. Consequently, great hope had been put on various quantitative MRI techniques. However, it turned out that the sensitivity and specificity of these techniques do not allow to probe changes in NAWM on an individual level. In this proposal, we aim at assessing MS related tissue changes in NAWM using quantitative susceptibility mapping (QSM). QSM is a new and promising MRI technique which tells us how strong a tissue can be magnetized. QSM allows to map the magnetic susceptibility by making use of local variations of an externally applied magnetic field. There is a lot of evidence, that the magnetic susceptibility is highly sensitive to pathological conditions of MS including inflammation, demyelination, and focal accumulation of iron. We expect that QSM in NAWM could provide further insight into MS pathology and therefore could serve as a new marker for diagnosis and progression of MS. This international cooperation project will be conducted by Graz (Austria) and Jena (Germany) in a collaborative manner. Both centers have the newest 3T facilities in place. Over a period of three years, both centers will recruit in total 60 MS patients and 60 healthy controls and will perform QSM at baseline and after one year with the same MR machinery. Other quantitative MRT techniques will be applied as well to get a more comprehensive picture of disease related changes in NAWM. We expect that the complementary expertise that is provided by Graz and Jena with respect to QSM and quantitative MRI will contribute to a successful project.

Brain tissue is weakly diamagnetic which means that like other biological tissues it cannot be magnetized in a magnetic field. While the magnetic susceptibility, which is a measure of how strong a tissue can be magnetized, is mostly governed by the magnetic properties of tissue water, also the composition and orientation of myelinated fibers in the brain affect the overall susceptibility. This research project employed cutting-edge magnetic resonance imaging (MRI) methods to assess the myelin content and iron content from the magnetic susceptibility of fiber tracts and their orientation with respect to the magnetic field of the MR scanner. The new imaging methods were applied in a large cohort of patients suffering from multiple sclerosis (MS). According to their disease phenotype and disease duration, these patients usually present with damage to the myelin and can also show locally reduced iron levels. Repeated inflammation can affect the integrity of myelin and finally can lead to axonal loss. In parallel, iron-rich oligodendrocytes are also damaged which can result in locally reduce iron levels after clearance by macrophages. This project hypothesized that pathophysiological changes in MS are therefore accompanied by changes in the magnetic susceptibility. This international project was performed in cooperation with the Medical Physics group at Jena University Hospital in Germany. For assessing the magnetic susceptibility, we used high resolution 3D MRI sequences. These allowed to detect even subtle magnetic field changes as induced by the myelinated fibers of the brain. The orientation of theses fibers then was calculated with a diffusion tensor imaging technique. This allowed us to obtain corresponding information on magnetic susceptibility and fiber orientation separately for each fiber tract. While we failed to show an orientation dependence in the vicinity of deep gray matter nuclei with high iron content, several fiber tracts of the brain like the optic radiation or the corpus callosum showed an orientation dependence which was well predicted by electro-dynamical models. When comparing MS patients with healthy controls, we could demonstrate that the magnetic susceptibility in certain fiber tracts of patients lost their orientation dependence already at an early stage of the disease, which also points to a very early damage of the myelin. It should be noted, that these changes remained undetected on conventional MRI. Our results clearly highlight the potential of susceptibility mapping for diagnosing and monitoring MS. However, for a clinical application still further developments are needed including techniques for reducing the acquisition time and mathematical approaches that improve the robustness of susceptibility mapping. It is obvious that also other inflammatory and demyelinating diseases of the brain may benefit from this new technique, but this has to be confirmed by additional clinical studies.