Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance

Nuclear magnetic resonance (NMR) imaging is an established diagnostic mediu m to diagnose multiple sclerosis (MS). In clinically stable MS patients, NM R detects silent disease activity, which is the reason why it is being used to monitor treatment trials, in which it serves as a secondary outcome par ameter. The absence of a clear correlation with clinical disability, the so -called 'clinico-radiological' paradox, and the poor predictive value of NM R prohibit the use of NMR as a. primary outcome parameter in clinical trial s. This is-among others-a result of the limited histopathological specifici ty of conventional, or 'T2-weighted' imaging, the most commonly used NMR te chnique. In this paper we review additional NMR techniques with higher tiss ue specificity, most of which show marked heterogeneity within NMR-visible lesions, reflecting histopathological heterogeneity. Gadolinium enhancement identifies the early inflammatory phase of lesion de velopment, with active phagocytosis by macrophages. Persistently hypointens e lesions on T1-weighted images ('black holes') relate to axonal loss and m atrix destruction, and show a better correlation with clinical disability. Marked prolongation of T1 relaxation time correlates with enlargement of th e extracellular space, which occurs as a result of axonal loss or oedema. A xonal viability can also be measured using the concentration of N-acetyl as partate (NAA) using NMR spectroscopy; this technique is also capable of sho wing lactate and mobile lipids in lesions with active: macrophages. The mul tiexponential behaviour of T2 relaxation time in brain white matter provide s a tool to monitor the myelin water component in MS lesions (short T2 comp onent) as well as the expansion of the extracellular space (long T2 compone nt). Chemical exchange with macromolecules (e.g. myelin) can be measured us ing magnetization transfer imaging, and correlates with demyelination, axon al loss and matrix destruction. Increased water diffusion has been found in MS lesions (relating to oedema and an expanded extracellular space) and a loss of anisotropy may indicate a loss of fibre orientation (compatible wit h demyelination). Apart from the histopathological heterogeneity within focal MS lesions, the normal-appearing white matter shows definite abnormalities with all quanti fiable NMR techniques. A decrease in the concentration of NAA, decreased ma gnetization transfer values and prolonged T1 relaxation time values are pro bably all related to microscopic abnormalities, including axonal damage. Th is 'invisible' lesion load may constitute a significant proportion of the t otal lesion load but is not visible on conventional NMR. Similarly, mechani sms for clinical recovery exist, which are not distinguished using MR imagi ng. Therefore, it is highly unlikely that the clinico-radiological paradox will ever be solved completely. However, NMR provides an opportunity to seq uentially measure tissue changes in vivo. Using MR parameters with (presume d) histopathological specificity, the development of(irreversible) tissue d amage can be monitored, which perhaps allows the identification of factors that determine lesional outcome in MS. Since the absence of severe tissue d estruction is prognostically favourable, NMR monitoring of the extent to wh ich such changes can be prevented by treatment will ultimately benefit the selection of future treatment strategies.