Proton magnetic resonance spectroscopy of human brain <i>in vivo</i> in the evaluation of multiple sclerosis: Assessment of the load of disease

Arnold, Douglas L.; Matthews, Paul M.; Francis, Gordon; Antel, Jack P.

doi:10.1002/mrm.1910140115

Cited by 256 publications

(112 citation statements)

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“…Further, active lesions show increased levels of lactate (indicating the invasion of macrophages), mobile lipid peaks (myelin breakdown products) and increased levels of Cho (demyelination) (Davie et al 1994;Landtblom et al 1996;De Stefano et al 1995), in contrast to`stable' lesions with reduced Cho levels. In established MS lesions, decreased levels of NAA are observed, which is in agreement with the observation of a decrease in axonal density observed histopathologically (Matthews et al 1991;Arnold et al 1990Arnold et al , 1992Davie et al 1995;Van Walderveen et al 1999b) (¢gure 4). The concentration of NAA correlates strongly with T1 relaxation time (Van Walderveen et al 1999b) (table 2).…”

Section: Magnetic Resonance Spectroscopy: In Vivo Metabolic Tissue Chsupporting

confidence: 88%

Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance

Barkhof

Walderveen²

1999

Phil. Trans. R. Soc. Lond. B

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Nuclear magnetic resonance (NMR) imaging is an established diagnostic medium to diagnose multiple sclerosis (MS). In clinically stable MS patients, NMR 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 parameter. The absence of a clear correlation with clinical disability, the so-called`clinico-radiological' paradox, and the poor predictive value of NMR prohibit the use of NMR as a primary outcome parameter in clinical trials. This isöamong othersöa result of the limited histopathological speci¢city of conventional, or T2-weighted' imaging, the most commonly used NMR technique. In this paper we review additional NMR techniques with higher tissue speci¢city, most of which show marked heterogeneity within NMRvisible lesions, re£ecting histopathological heterogeneity.Gadolinium enhancement identi¢es the early in£ammatory phase of lesion development, with active phagocytosis by macrophages. Persistently hypointense lesions on T1-weighted images (`black holes') relate to axonal loss and matrix destruction, and show a better correlation with clinical disability. Marked prolongation of T1 relaxation time correlates with enlargement of the extracellular space, which occurs as a result of axonal loss or oedema. Axonal viability can also be measured using the concentration of N-acetyl aspartate (NAA) using NMR spectroscopy; this technique is also capable of showing lactate and mobile lipids in lesions with active macrophages. The multi-exponential behaviour of T2 relaxation time in brain white matter provides a tool to monitor the myelin water component in MS lesions (short T2 component) as well as the expansion of the extracellular space (long T2 component). Chemical exchange with macromolecules (e.g. myelin) can be measured using magnetization transfer imaging, and correlates with demyelination, axonal loss and matrix destruction. Increased water di¡usion has been found in MS lesions (relating to oedema and an expanded extracellular space) and a loss of anisotropy may indicate a loss of ¢bre orientation (compatible with demyelination).Apart from the histopathological heterogeneity within focal MS lesions, the normal-appearing white matter shows de¢nite abnormalities with all quanti¢able NMR techniques. A decrease in the concentration of NAA, decreased magnetization transfer values and prolonged T1 relaxation time values are probably all related to microscopic abnormalities, including axonal damage. This`invisible' lesion load may constitute a signi¢cant proportion of the total lesion load but is not visible on conventional NMR. Similarly, mechanisms for clinical recovery exist, which are not distinguished using MR imaging. Therefore, it is highly unlikely that the clinico-radiological paradox will ever be solved completely. However, NMR provides an opportunity to sequentially measure tissue changes in vivo. Using MR parameters with (presumed) histopathological speci¢city, the development of (irreversible) tissue damage can be ...

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Section: Magnetic Resonance Spectroscopy: In Vivo Metabolic Tissue Chsupporting

confidence: 88%

Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance

Barkhof

Walderveen²

1999

Phil. Trans. R. Soc. Lond. B

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“…However, the disease often goes through phases of remission and relapse, and white matter plaques visible in magnetic resonance images can wane with remission of symptoms. MRS studies show that NAA levels can be associated with neuronal dysfunction, as well as neuronal death, because levels have been shown to recover when MRI visible plaques resolve (Arnold et al, 1990a). Partial recovery of NAA levels has also been reported after treatment of patients with interferon beta-1b glatiramer acetate (Khan et al, 2005) or fluoxetine (Mostert et al, 2006) suggesting that NAA levels reflect not only neuronal and axonal integrity, but also may reflect improvements in neuronal energetics and possibly remyelination.…”

Section: Magnetic Resonance Spectroscopy and Imaging Of Naamentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,214

1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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“…MRS has been recently used for the in situ studying of metabolic changes in a wide variety of pathologic processes in the brains of human patients (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). By using multiple voxels chemical-shift imaging (CSI) technique on patients with intractable mesial TLE, we observed a decrease in N-acetylaspartate (NAA)/choline and NAA/ creatine ratios in sclerotic mesial structures interictally (27), as well as an increase in lactate concentrations during the early postictal phase (Y. Comair et al, unpublished observations).…”

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confidence: 99%

Temporal Changes in Proton MRS Metabolites After Kainic Acid‐Induced Seizures in Rat Brain

et al. 1997

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Summary: Purpose: In situ 'H-magnetic resonance spectroscopy (MRS) was used to study temporal metabolic changes in a rat model of temporal lobe epilepsy (TLE) by using kainic acid (KA).Methods: Rat brains were scanned at the level of the hippocampal body for MRS measurements. Relative ratios of Nacetyl groups (NA: N-acetylaspartate and N-acetylaspartyl glutamate), choline, and lactate (Lac) over creatine (Cr) were calculated.Results: NA/Cr ratios increased significantly during the ictal phase. During the postictal and interictal phases, the NA/Cr ratio decreased. There was a significant and prolonged increase of the lactate/Cr ratio in the hippocampi of rats that started 1 h after the onset of KA-induced seizure activity and persisted up to 24 h after the injection. The prolonged lactate/Cr increase in an area susceptible to neuronal damage (e.g., hippocampus) correlated with the onset of seizure activity but remained elevated thereafter.Conclusions: The ictal and early postictal increase in lactate ratios may reflect increased cellular activity and metabolism resulting from KA excitotoxicity. Assuming that the changes in NA/Cr ratios are due to NAA increase, we speculate that an activation of the N-acetylaspartylglutamate (NAAG) dipeptidase pathway may explain the ictal increase in NA/Cr ratios. The late postictal decrease in NNCr ratios is a reflection of KA-induced neuronal cell loss. Key Words: MRS-BrainSeizure-Kainic acid-Rat.Water-suppressed proton magnetic-resonance spectroscopy (MRS) was used to study in situ temporal metabolic changes in a rat model of temporal lobe epilepsy (TLE) by using kainic acid (KA). The systemic administration of the potent excitotoxic agent KA (10 mg/kg) induces a characteristic long-lasting tonic-clonic seizure and leads to a cascade of electrical, behavioral, and histopathologic changes in the rat brain that reproduce several characteristics of human TLE (1-10). Shortly after parenteral KA administration, epileptic electrical discharges occur in many areas of the limbic system, followed by behavioral tonic-clonic seizures. These electrical and clinical alterations are followed by the development of neuronal changes in various areas of the brain (11-13), with the most pronounced effects observed in selected areas of the hippocampus, mainly CA1, CA3, and CA4 subfields, the entorhinal cortex, and the amygdala. These changes consist of acute neuronal swelling and vacuolization leading eventually to neuronal death (24-48 h later) (7)(8)(9)(10)14). Previous studies showed that

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Proton magnetic resonance spectroscopy of human brain in vivo in the evaluation of multiple sclerosis: Assessment of the load of disease

Cited by 256 publications

References 10 publications

Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance

Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Temporal Changes in Proton MRS Metabolites After Kainic Acid‐Induced Seizures in Rat Brain

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