Proton spin relaxation as a means of characterizing the pathology of multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system; the cause(s) of the disease and its pathological progression are at present unknown. Magnetic resonance imaging (MRI), in particular the spin-echo radiofrequency pulse sequence, proved a powerful tool in the study of MS. The question addressed in this thesis, is whether quantitative measurement of the spin-lattice (T₁) and spin-spin (T₂) relaxation times can provide a means of characterizing the pathology of MS in vivo; the final goal being to use these parameters to differentiate acute inflammatory lesions from more chronic demyelinating and gliotic ones. Quantitative MR imaging methods, using two-point determinations of T₁ and T₂, were first used to study post mortem and fixed brain tissue from MS patients. These data demonstrated differences in Ti and T₂ with varying degrees of demyelination and gliosis; however, chronic MS pathology is similar in all cases, and provides little information on the earlier stages of the disease process which are believed to be immune-mediated. The early immune-mediated lesion was then examined by studying experimental allergic encephalomyelitis (EAE), an animal model for MS, in primates. The data obtained from these studies confirmed that the values of T₁ and T₂ obtained from these two-point determinations are sensitive to variable pathology, but cannot be used to distinguish acute from chronic lesions. An in-depth in vitro T₂ study was then carried out on guinea pigs inoculated to produce EAE; this was followed by repeat measurements on the formalin fixed tissue. T₂ measurements were also carried out on samples from the fixed MS tissue already studied using quantitative imaging methods. The relaxation data were analyzed using two different methods; the first assuming a fixed number of exponentials (minuit), and the second a continuous distribution of relaxation times (NNLS). It is clear from these studies that the models currently used to describe the relaxation behaviour of water protons in tissue are inadequate to explain the results observed. Both analysis methods were sensitive to the different types of pathology present; however, assuming a continuous distribution of relaxation times not only provides a better fit to the data, but also represents a more realistic picture of the complex physical system being studied. These results show that T₂ data obtained from tissue are reproducible, and can distinguish differing degrees of inflammation. The same trends observed in vitro were also observed in the fixed tissue; comparison of the fixed tissue data from inflammatory lesions with that from MS tissue showed that T₂ can be used to differentiate acute and chronic lesions. This implies that quantitative MR measurements, together with the sophisticated methods of analysis employed in this thesis, can be used to follow the pathological progression of MS; this would provide insight into the disease process and lead eventually to an understanding of the cause(s) of the disease.Science, Faculty ofChemistry, Department ofGraduat