Contribution of Myelin to the Diamagnetic Susceptibility

Multiple Sclerosis (MS) is the most frequent chronic disorder of the central nervous system (CNS) in young adults. MS is an inflammatory disease, damaging the myelin sheath of the nerve fibers. The myelin sheaths are wrapped around the nerve fibers and responsible for fast signal conduction. In MS, the myelin sheaths are damaged, leading to a slowed signal conduction and further to neurological symptoms. Although there is a wide spectrum of magnetic resonance imaging (MRI) techniques to assess the density and integrity of myelin, the detailed contribution of its different constituents in relation to the magnetic susceptibility is still fragmentary understood. A novel technique called quantitative susceptibility mapping (QSM) allows to assess the magnetic susceptibility of biological tissue using MRI. The strongest contributors to the magnetic susceptibility of the human brain are iron and myelin. The main goal of this project is to uncover the influence of myelin and its different components on the magnetic susceptibility in healthy and MS brain tissue. This will be achieved by separating the influence of iron and myelin by performing post-mortem QSM of brain tissue at different temperatures in combination with a technique to assess the myelin content called myelin water imaging (MWI). Subsequent to the MRI investigations, histological and biochemical analysis of the brain tissue will be performed to assess the chemical composition of myelin. This project will increase the fundamental understanding of the effect of myelin on the magnetic susceptibility which will allow to better characterize disease induced changes in MS using MRI. This will further allow to relate changes of the magnetic susceptibility to changes in myelin content or composition which could serve as marker to diagnose or monitor MS.

The steady development of quantitative imaging techniques in health and disease is of high importance. The use of imaging techniques, such as magnetic resonance imaging (MRI), especially, in disorders affecting the brain represents a standard application nowadays. Various disease related changes are displayable including morphological and structural changes triggered by alterations on the cellular level. These cellular alterations include, for example, protein and lipid content modifications of cells and their surrounding area. In the human nervous system, myelin is a protein which is crucial for the fast transmission of nerve impulses from one neuron to another, whereas the white matter component of the brain contains the major myelin proportion produced in oligodendrocytes. These cells form extensions wrapping around neuronal axons allowing the fast transmission in the nervous system. Disturbances in myelin content and structure can adversely affect signal transmission. Several disorders and their symptoms, such as in multiple sclerosis, are due to such myelin lesions occurring in different brain and spinal cord regions. In general, myelin can be assessed with different MRI techniques. Today, the gold standard is the myelin water imaging approach. This MRI technique includes the acquisition of multiple weighted images to measure the so called T2 signal decay. This signal decay can be decomposed into a component related to myelin water and to a component related to intra- and extracellular water. However, imaging techniques detect with a certain probability additional signals resulting in biased image acquisition. These interfering signals can be identified using interdisciplinary experimental approaches with human brain tissue. Such experiments allow the direct determination of MRI-influencing factors on the cellular level. In this project, we could identify the biasing role of iron in myelin water imaging. In the white matter, iron and myelin are closely linked, as iron is located in the myelin-producing oligodendrocytes. In MRI, iron is known to induce strong signals due to its magnetic properties. We could identify that iron content is strongly influencing the myelin content signal. In total, 25% of the presumed myelin content signal could be attributed to the iron content. Furthermore, we could observe that the orientation of the myelin structure can affect the estimation of the myelin content. Myelinated nerve fibers with the same amount of myelin, but with a different orientation in the MRI, are differentially expressed in myelin water images. This could lead to an inaccurate myelin content estimation, which is crucial for the assessment of myelin content in the developing brain and in various neurological disorders. Overall, several factors influencing the gold standard of myelin content imaging were detected during this project leading to the suggestion that MRI techniques have to be constantly redeveloped, updated and adjusted to improve their validity in clinical application.