Imaging Tissue Damage Associated With Brain Inflammation

Magnetization transfer imaging

MTI has been used to evaluate the pathological characteristics and the evolution of enhancing MS lesions. Lower MT ratio (MTR) values, which indicate a more pronounced tissue disorganiza-tion,10 were found in: (1) ring-enhancing compared to nodular-enhancing lesions;67,68,81 (2) lesions enhancing only after the injection of a SD of Gd compared to those enhancing after a TD;34 (3) lesions enhancing on at least two consecutive monthly scans compared to those enhancing on a single scan;82 and (4) T1-weighted hypointense lesions at the time of their initial enhancement compared to isointense lesions.34 In addition, two possible evolutions of the MTR of new enhancing lesions have been described.83 In some lesions, a moderate decrease of MTR, with subsequent complete recovery within a few weeks, may reflect early oedema, demyelination and subsequent remyelination.83-84 In other lesions, a marked reduction of MTR with only a partial recovery at follow-up may indicate the formation of lesions with severe pathological destruction and subsequent failure of the reparative mechanisms.32,83,84 A recent, longitudinal study,32 correlating MT and non-contrast T1-weighted images, described two additional patterns of MTR evolution in enhancing lesions, following an initial marked decrease. The first was a rapid restoration of MTR suggesting remyelination, and the second a complete failure of restoration of MTR values, suggesting concomitant destruction of oligodendro-cytes and axons.

Variable changes of MTR may also be detected in the NAWM, which is subsequently involved by enhancement.85-87 MTR reduction may reflect different but not mutually exclusive pathological substrates. These include: (1) increased amounts of NAWM degradation products;33 (2) increased water content in the hyperplastic astrocytes participating in the demyelinating process,33,88 and (3) demyelina-tion and remyelination, which are both known to occur after the early phases of lesion formation.34,89-91 Filippi et al34 observed that the greatest reduction of MTR occurs about 1 month before enhancement. This interval is similar to the time between immune activation and clinical manifestations of the lesions in EAE,92 and it may be the time necessary for immune activation and BBB transmigration of T-cells in the early phase of the pathological evolution of MS lesions.

Magnetic resonance spectroscopy

MRS allows in vivo identification of changes in the chemical composition of brain tissues.93 Reduced N-acetyl aspartate (NAA) levels are associated with axonal dysfunction,93 while changes in inositol, choline and lactate concentrations are correlated with inflammation and demyelination.

MRS studies of enhancing MS lesions94 have shown that, in some lesions during the first 6-10 weeks following the onset of enhancement, elevated lactate levels can be found which might be due to the concomitant presence of inflammation, local ischaemia and neuronal mitochondrial dysfunction. In a recent study95 correlating MRS and pathological findings, high lactate levels were found in MS lesions with marked inflammation and mononuclear cell infiltration. MR spectra from enhancing lesions may also show an elevated choline peak returning to normal over a 4-6-month period, and lipid peaks suggesting increased membrane turnover due to demyelination.94

Data from several MRS studies support the hypothesis that, in MS, perivenous inflammation and demyelination may represent two partially separated pathological processes.93,94,96,97 In enhancing lesions, lipid signal may persist for up to 4-8 months, whereas enhancement usually ceases within 2 months. Moreover, Coles et al44 demonstrated that progressive brain atrophy can be seen in SP MS patients without evidence of ongoing inflammation and that this is associated with decreased NAA levels, thus suggesting axonal degeneration. This process can be conditioned by a previous high inflammatory load, but proceeds even when inflammation has been suppressed.

Recent studies98,99 have demonstrated that MRS can detect transient NAA reductions which occur in the NAWM during a severe MS relapse98 or when a large, solitary lesion develops in the contralateral hemisphere.99 These findings indicate that a generalized and reversible axonal dysfunction may accompany MS relapses, even in the absence of MRI-visible inflammatory changes, and that the effects of damage to axons traversing inflammatory lesions can be transmitted over long distances. A longitudinal study97 using MRS imaging reported that increased lipid peaks can be found both in unenhanced T2 lesions and in the NAWM of RR MS patients. Interestingly, NAWM regions where lipid levels increased subsequently developed macroscopic T2 abnormalities.

Diffusion-weighted imaging

Diffusion-weighted imaging (DWI) is sensitive to the presence of pathological processes which, by modifying the integrity of biological tissues, result in a loss of 'restricting' barriers and lead to an increase of water molecular motion and loss of tissue anisotropy.100

In EAE, DWI signal intensity increased before any detectable change on T2-weighted scans,101 and an increased apparent diffusion coefficient (ADC) was seen in lesions,101 with relatively preserved diffusion anisotropy in chronic compared to acute lesions.102 The first report of water diffusion in MS showed that lesions had increased ADC values compared to NAWM.103 Conflicting results have been achieved when comparing enhancing versus non-enhancing MS lesions: two studies104,105 found a significantly increased mean diffusivity (D) in non-enhancing compared to enhancing lesions, while another,106 which assessed more patients, did not find any significant difference between the two lesion groups. Fractional anisotropy (FA) was found to be lower in enhancing versus non-enhancing lesions.105

All these data again suggest that, although the intrinsic nature of macroscopic MS lesions is heterogeneous, loss and disorganization of structural barriers to water motion can be detected during the early inflammatory phase of lesions. Since inflammatory cells are likely to restrict water molecular motion, demyelination or, less likely, axonal loss might contribute to the increased D and decreased FA in enhancing MS lesions.

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