Water-suppressed, proton MR spectra of normal human brain at long echo times reveal four major resonances: one at 3.2 ppm from tetramethylamines (mainly from choline-containing phospholipids [Cho]), one at 3.0 ppm from creatine and phosphocreatine (Cr), one at 2.0 ppm from ^-acetyl groups (mainly NAA), and one at 1.3 ppm from the methyl resonance of lactate (Lac). NAA is a marker of axonal integrity; Cho and Lac are considered as chemical correlates of acute inflammatory/demyelinating changes (Filippi et al., 2001). 1H-MRS studies with shorter echo times can detect additional metabolites, such as lipids and myoinositol (mI), which are also regarded as markers of ongoing myelin damage.
1H-MRS of acute MS lesions reveals increases of metabolites such as Cho and Lac (De Stefano et al., 1995a; Filippi et al., 2001), which reflect the releasing of membrane phospholipids and the metabolism of inflammatory cells, respectively. Short echo time spectra can detect transient increases in visible lipids released during myelin breakdown and mI (Narayana et al., 1998). All these changes are usually followed by a decrease in NAA. Since, NAA is a metabolite detected almost exclusively in neurons and their processes in the normal adult brain, a decrease in NAA is considered to be secondary to neuronal/axonal dysfunction. After the acute phase and over a period of days to weeks, there is a progressive reduction of raised Lac resonance intensities to normal levels. Resonance intensities of Cr also return to normal within a few days. Cho, lipid, and mI resonance intensities return to normal over months. The signal intensity of NAA may remain decreased or show partial recovery, starting soon after the acute phase and lasting for several months (Arnold et al., 1992; De Stefano et al., 1995a). These reversible decreases in NAA are strongly correlated with reversal of functional impairment (De Stefano et al., 1995a). Recovery of NAA may be related to resolution of edema, increases in the diameter of previously shrunken axons secondary to remyelination and clearance of inflammatory factors, and reversible metabolic changes in neurons. In line with the notion that NAA reduction reflects irreversible axonal loss, NAA concentration has been found to be lower in severely T1-hypointense MS lesions than in T1-isointense or hypointense lesions (van Walderveen et al., 1999) and in chronic lesions from patients with SP-MS than in those from patients with benign MS (Falini et al., 1998).
The application of 1H-MRS imaging (MRSI) (De Stefano et al., 1998; Narayana et al., 1998) has enabled spectra from large volumes of interest to be obtained and has improved our ability to interrogate brain NAWM pathology separately. This has led to the demonstration that decreases in NAA are not restricted to MS lesions, but also occur in the NAWM adjacent to or distant from them (Sarchielli et al., 1999; De Stefano et al., 1999, 2002). Although NAA reduction might also reflect transient sublethal axonal injury (Davie et al., 1994; De Stefano et al., 1999), NAA levels of the NAWM tend to decline over time (Fu et al., 1998). Consistent with this finding is the demonstration that NAA reduction is more pronounced in the NAWM of patients with SP-MS and primary progressive (PP)-MS than in those with a RR course (Fu et al., 1998, Suhy et al., 2000). Nevertheless, reduced NAWM-NAA can also be detected in patients with MS in the early phase of the disease (De Stefano et al., 2001; Filippi et al., 2003b) and in patients with very short disease durations and low T2-visible disease burdens (De Stefano et al., 2002).
Metabolite changes, including decrease of NAA and increase of Cho and mI, have also been shown in the cortical gray matter of patients with MS (Kapeller et al., 2001; Sharma et al., 2001; Chard et al., 2002b; Sarchielli et al.,
2002). These abnormalities are more pronounced in patients with SP-MS than in those with RR-MS (Adalsteinsson et al.,
2003). More recently, NAA reductions associated with a considerable amount of tissue loss have also been demonstrated in the thalamus of SP-MS (Cifelli et al., 2002) and RR-MS patients (Wylezinska et al., 2003).
De Stefano and co-workers (1998) found a decrease of NAA/Cr ratio with increasing disability, whereas such a correlation was not found with the amount of T2-visible lesions. Of interest, the relationship between disability and changes of NAA levels has been found to be stronger in patients with RR-MS than in those with SP-MS (Fu et al., 1998), where brain atrophy development progresses at a more rapid pace (De Stefano et al., 2001). These observations have been confirmed by a postmortem study (Bjartmar et al., 2000) where a strong correlation between neurological impairment and both axonal density and NAA reduction in the spinal cord of patients with MS has been found.
NAA levels have also been quantified in specific brain regions, whose damage has been related to the impairment of the corresponding functional systems. Davie et al. (1995)
showed a significant reduction of NAA concentration in the cerebellar white matter of patients with MS and severe ataxia compared with those having little or no cerebellar deficits. Lee et al. (2000a) demonstrated an association between reduction of NAA in the internal capsule and selective motor impairment. Pan et al. (2001) found a relation between cognitive function and NAA levels in the periven-tricular white matter. More recently, Gadea et al. (2003) found a relationship between attentional dysfunction in early RR-MS patients and NAA/Cr values in the locus coeruleus nuclei of the pontine ascending reticular activation system.
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