High resolution proton MR spectroscopy of cerebrospinal fluid in MS patients. Comparison with biochemical changes in demyelinating plaques

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Abstract

Proton magnetic resonance spectroscopy (1H-MRS) investigation was performed on CSF samples of patients with neurological inflammatory diseases including 53 cases of multiple sclerosis (MS), 12 acute idiopathic polyneuropathies, 20 acute meningitides (10 viral and 10 bacterial). Spectra were compared with those acquired in 18 neurological controls. High CSF lactate levels were found in MS patients during clinical exacerbation of relapsing-remitting course (p = 0.036 vs. neurological controls). In MS patients with MRI evidence of Gd-enhanced plaques CSF lactate was higher than in patients with MRI inactive plaques (p = 0.017). CSF lactate positively correlated with number of CSF mononuclear cells in MS patients with clinical activity (p = 0.05) as well as in MS patients with MRI enhancement (p = 0.003). A comparative 1H-MRS investigation in vivo on localized demyelinating areas confirmed an elevated lactate signal in Gd-enhanced (61%) more frequently than in unenhanced (22%) plaques (p = 0.03). MS patients with high lactate signal in active plaques showed high lactate levels in CSF. Increased CSF lactate was found also in patients with acute meningitis and idiopathic polyneuropathy. These data suggest that changes in lactate levels may depend on anaerobic glycolytic metabolism in activated leukocytes during inflammatory diseases. A decrease of CSF formate levels was found in MS patients during active and inactive clinical phase (p = 0.037, p = 0.05 vs. neurological controls respectively). Formate changes might be related to a disorder of choline-glycine cycle in MS. 1H-MRS in vivo showed significant increase of choline in acute plaques, whereas a decrease of N-acetyl aspartate was found in chronic plaques; these metabolites are undetectable in CSF. CSF glucose levels were lower in bacterial than in viral meningitis (p = 0.014) and in neurological controls (p = 0.05). These observations suggest that 1H-MRS may be able to detect CSF metabolic impairment in neurological inflammatory diseases. In MS some CSF findings reflect metabolic changes occurring in brain demyelinating areas, and they could be useful for evaluation of disease activity in different stages of disease evolution.

Introduction

Multiple sclerosis (MS) is a central nervous system (CNS) inflammatory disease characterized by primary demyelination. Magnetic resonance imaging (MRI) is well established as the most sensitive tool for the diagnosis of MS (Ormerod et al., 1987, Paty et al., 1988) as well as for the assessment of activity of the disease (McFarland et al., 1992). Acute and chronic demyelinating plaques appear as areas of increased signal intensity on proton density and T2-weighted images (Young et al., 1981). In addition, the use of Gadolinium (Gd)-DTPA allows on T1-weighted imaging the identification of new or acute lesions characterized by blood-brain barrier (BBB) breakdown. Contrast enhancement has been shown to correlate with the histopathological findings of MS active lesions (Nesbit et al., 1991). Active plaques show an intense perivascular T and B lymphocyte reaction with macrophage infiltration, BBB damage, local edema, incomplete demyelination and reactive astrocytes (Adams, 1983). Inactive plaques are defined by a loss of myelin sheaths with secondary fibrillary gliosis, a variable degree of axonal sparing and an absence of inflammatory reaction (Prineas and Connell, 1978). Clinical studies using Gd enhancement showed that MRI activity is more frequent than clinical activity (Grossman et al., 1988).

Proton MR Spectroscopy (1H-MRS) has been proven to be a sensitive method for the analysis of tissue in vivo (Bottomley, 1989) and of biological fluids in vitro (Vion-Dury et al., 1992). Recent advances regarding the employment of 1H-MRS in vivo on localized demyelinating areas in MS disease showed that active and chronic plaques differ in their biochemical pattern (Matthews et al., 1991), providing more information on pathological MS processes than conventional MRI. Active plaques are characterized by an increase of lactate, depending on inflammatory reaction, and by an increase of choline/creatine ratio, marker of myelin breakdown. Chronic plaques are defined by a decrease of N-acetyl aspartate/creatine ratio, reflecting an irreversible axonal injury.

The application of 1H-MRS in cerebrospinal fluid (CSF) analysis indicates the feasibility of this technique in detecting and quantifying simultaneously many metabolites in normal and pathological conditions (Petroff et al., 1986; Koschorek et al., 1993). Alpha and beta glucose, lactate, acetate, citrate, formate, creatine-creatinine, alanine, beta-hydroxybutyrate, glutamine resonances are detected in CSF, whereas signals of N-acetyl aspartate and choline are not identified (Petroff et al., 1986). In a previous report, CSF 1H spectra of MS patients showed a significant increase of acetate levels; in addition, a decrease of formate and the presence of an unknown volatile N-methyl compound were found, suggesting a possible impairment of the choline-glycine pathway in this disease (Lynch et al., 1993).

The aims of present 1H-MRS study were to evaluate whether biochemical changes could be related to different clinical phases of MS and to establish whether the CSF composition in MS patients reflects some metabolic changes occurring in demyelinating plaques.

Section snippets

Patients

One hundred and three patients, admitted to the Neurology Department of the University of Bari, were included in the study. Eighteen patients without peripheral nervous system (PNS) or CNS inflammatory and degenerative diseases were considered to be suitable to represent a neurological logical control group.

Fifty-three patients affected by clinical or laboratory-supported definite diagnosis of MS (Poser et al., 1983) were selected. Forty-five patients had a relapsing-remitting (RR) course: 25

Results

The means of the CSF metabolite/creatine ratios in all patients are reported in Table 2. Significant group differences in lactate/creatine (F = 10.96, p = 0.0001), citrate/creatine (F = 7.16, p = 0.0002), formate/creatine (F = 4.04, p = 0.01) and a trend to significance for acetate/creatine (F = 2.46, p = 0.06) were evidenced by the Anova test.

Discussion

Previous studies have suggested that, complementary to the evaluation of intracellular metabolism by in vivo MRS on the brain tissue. 1H-MRS could be performed in CSF analysis to monitor some molecules of intermediary and oxidative metabolism of the brain (Nicoli et al., 1993). Changes of these metabolites appear to be of relevant significance in monitoring activity of disease in MS. Several investigations of 1H-MRS in vivo showed increased lactate and choline in MS active plaques, as markers

Acknowledgements

This work was supported by CNR grant No 95.04635.ST75 and by a 40% grant from the Italian Ministry of University and Scientific and Technological Research. We are grateful to G. Misciagna and Dr V. Guerra for statistic support. We thank Mr. Brian Molloy for his assistance in revising the manuscript.

References (39)

  • J.D Bell et al.

    High resolution proton nuclear magnetic resonance studies of human cerebrospinal fluid

    Clin. Sci.

    (1987)
  • I Brook

    Stability of lactic acid in cerebrospinal fluid specimens

    Am. J. Clin. Pathol.

    (1982)
  • P.A Bottomley

    Human in vivo NMR spectroscopy in diagnostic medicine: clinical tool or research probe?

    Radiology

    (1989)
  • C Confavreux et al.

    Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients

    Brain

    (1980)
  • C.A Davie et al.

    Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions

    Brain

    (1994)
  • J.A Detre et al.

    Regional variation in brain lactate in Leigh syndrome by localized 1H magnetic resonance spectroscopy

    Ann. Neurol.

    (1991)
  • J Frahm et al.

    Localized high-resolution proton NMR spectroscopy using stimulated echoes: initial application to human brain in vivo

    Magn. Reson. Med.

    (1989)
  • F.Y.K Ghauri et al.

    NMR spectroscopy of human post mortem cerebrospinal fluid: distinction of Alzheimer's disease from control using pattern recognition and statistics

    NMR Biomed.

    (1993)
  • F.B Goldstein

    Aminohydrolases of brain; enzymathic hydrolysis of N-Acetyl-L-Aspartate and other N-Acyl-L-amino acids

    J. Neurochem.

    (1976)
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