Jean Vion-Dury

A multiparametric data analysis showing the potential of localized proton MR spectroscopy of the brain in the metabolic characterization of neurological diseases

We conducted an extended clinical evaluation of localized proton magnetic resonance spectroscopy (MRS) of the brain, performed on various brain diseases using short stimulated echo times. Pathologies studied were mainly multiple sclerosis, stroke, leukoaraiosis, AIDS-related leukoencephalopathies and glial tumors. Other miscellaneous pathologies were also studied. Magnetic resonance examination of the brain was conducted on a Siemens Magnetom SP63 (equipped with a 1.5 T magnet). Localized proton MRS was performed on a routine basis immediately after imaging, using the STEAM (stimulated echo acquisition mode) with a short echo time (20 ms) combined with a CHESS (chemical shift selective excitation) sequence. One or two VOI (8 ml) were examined. Data on 125 spectra were processed by principal component analysis (PCA) and conventional variance analysis. The following metabolite resonances were studied: inositol-glycine, taurine-scyllo-inositol, choline derivatives, phosphocreatine-creatine, aspartate, glutamine glutamate, N-acetylaspartate, acetate and lactate. PCA demonstrates that the different metabolic variables are independent. The analysis of groups of spectra clearly demonstrates that the metabolic profiles detected by localized MRS in various pathologies (i) differ significantly from controls, and (ii) allow a metabolic discrimination between groups of pathologies. Results of PCA are confirmed by variance analysis. Strokes are characterized by an increase in lactate concentration and leukoaraiosis by a decrease in inositol-glycine resonance. AIDS-related leukodystrophies are characterized by increases in lactate and choline concentrations. Reduction in N-acetylaspartate which is observed in most pathologies is not significant in the small lesions of white matter. Lactate has often been found in MS plaques, but no variation in the choline/phosphocreatine ratio was observed. GABA was tentatively assigned in the spectrum of a patient with epilepsy under sodium valproate treatment. This study illustrates the clinical feasibility of the technique, the value of a multiparametric data analysis in the definition of the pertinent variables characterizing the metabolic impairment, and the impact of localized proton MR spectroscopy of the brain in the assessment of cerebral suffering.

Metabolic changes in undifferentiated and differentiated human colon adenocarcinoma cells studied by multinuclear magnetic resonance spectroscopy.

Aspects of energetic and intermediary metabolism were studied in a colon adenocarcinoma cell line (HT29) by multinuclear magnetic resonance spectroscopy. Experiments were carried out on the HT29-D4 clone, which was isolated by limit dilution techniques. This clone, usually undifferentiated (D4-UD), can be maintained in a differentiated state (D4-D) in a glucose-free medium. Metabolic data were obtained by NMR analysis of perchloric acid extracts from D4-UD and D4-D cells. Phosphorus-31 and proton NMR spectra showed the presence of a large amount of choline and phosphorylcholine in the differentiated state (400% and 200%, respectively, of the levels found in D4-UD cells). Other differences appeared in the content of phosphocreatine (absent in D4-D cells) and myoinositol (absent in D4-UD cells). Carbon-13 spectra were recorded from perchloric acid extracts of cells incubated with [1-13C]-labeled glucose or [2-13C]-labeled acetate. The data indicated that both types of cells metabolize glucose through the glycolytic pathway to give lactate, but only D4-D cells were able to store glucose as glycogen at a very high level. A mathematical analysis of fluxes through the tricarboxylic acid (TCA) cycle was developed on the basis of models derived from previous 14C tracer studies. The model was based on the steady-state labeling of glutamate carbons by the 13C isotope and gave the fraction of labeled acetyl-Coa entering the TCA cycle, and the activity y of anaplerotic reactions relative to the flux through the citrate synthetase reaction. The data indicated that y greater than 0.3 in all cases. Only 15% and 30% of labeled acetyl CoA entered the TCA cycle in D4-UD and D4-D cells, respectively, under labeled glucose incubation: these values were significantly different upon labeled acetate feeding, reaching 55% for D4-UD cells and 85% for D4-D cells. The main result of this study is that the process of differentiation of HT29 cells is correlated with a large increase in the activity of oxidative metabolism.

Localised proton magnetic resonance spectroscopy in X-linked adrenoleukodystrophy

We have performed localised proton magnetic resonance spectroscopy (MRS) of the brain on four patients with X-linked adrenoleukodystrophy (X-ALD). The spectrum is characterised at the beginning of the disease by a decrease in N-acetylaspartate and phosphocreatine-creatine content. Choline is strongly increased, and lactate can be detected in some cases. A proton signal from the CH2 groups borne by free intracellular very long chain fatty acids can also be observed. Later in the disease, the levels of all metabolites, in particular NAA, decrease significantly. The progression of neurometabolism documented by MRS correlates well with MRI and clinical progression on follow-up study. In one case, the metabolic profile recorded by proton MRS was abnormal before any change occurred on MRI. Proton MRS of the brain might be the method of choice for monitoring patients with X-ALD, to screen presumed cases and to study the effects of treatment.

MRI and localized proton MRS in early infantile form of neuronal ceroid-lipofuscinosis

A patient with early infantile neuronal ceroid-lipofuscinosis was examined by magnetic resonance imaging (MRI) and image-guided localized proton MR spectroscopy of brain using short-stimulated echo times. T2-weighted MRI revealed generalized cerebral atrophy and a reduction in signal intensity in thalamus and striatum associated with the presence of hyperintense white matter. The proton MR spectrum is characterized by an unusual increase of the inositol and taurine signals and by a reduction in the level of N-acetyl-aspartate contrasting with the presence of signals from glutamate-glutamine. The presence of a resonance from N-acetyl-methyl protons of N-acetyl-glucosamine (2.04 ppm) borne by dolichol is discussed.

Cerebral metabolic alterations in human immunodeficiency virus-related encephalopathy detected by proton magnetic resonance spectroscopy. Comparison between sequences using short and long echo times.

RATIONALE AND OBJECTIVES The aim of this study is to evaluate comparatively the metabolic information afforded by proton magnetic resonance (MR) spectroscopy with stimulated-echo acquisition mode (STEAM) (echo time [TE], 20 mseconds) and point-resolved spectroscopy sequence (PRESS) (TE, 135 mseconds) spectra in HIV-related encephalopathy. METHODS Sixty-three human immunodeficiency virus (HIV) patients and 8 controls were examined by single-voxel proton MR spectroscopy at 1.5 tesla, using both PRESS (TE, 135 mseconds) and STEAM (TE, 20 mseconds) sequences performed during the same MR examination, in the same volume of interest. Cerebral atrophy was quantitated using bicaudate ratio (BCR) and bifrontal ratio (BFR). RESULTS With the STEAM (TE, 20 mseconds) spectra, mean N-acetylaspartate (NAA)/choline (Cho) and NAA/creatine and phosphocreatine (Cr-PCr) ratios are reduced in acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) patients but not in neuroasymptomatics. The proportion of inositol signal is increased, that of NAA decreased in ADC patients. NAA/Cho and NAA/ Cr-PCr mean values measured with PRESS (TE, 135 mseconds) spectra are significantly reduced in ADC and neuroasymptomatic patients. Bifrontal ratio only correlates with NAA/Cr-PCr and NAA/Cho measured on the PRESS spectrum. PRESS (TE, 135 mseconds) spectra allow a definition of different metabolic patterns in HIV-related encephalopathy. At last, no correlation has been found between the NAA raw signals measured on the PRESS (TE, 135 mseconds) and STEAM (TE, 20 mseconds) spectra obtained in the same MR examination. CONCLUSIONS STEAM (TE, 20 mseconds) spectra provide more metabolic information-namely an evaluation of glial-neuronal status-than PRESS (TE, 135 mseconds) spectra, which afford a metabolic classification of the HIV-related encephalopathy. Because both sequences afford a similar diagnostic gain, MR spectroscopy examination probably requires spectrum acquisition with both sequences.

Entrapment of gadolinium-DTPA in liposomes. Characterization of vesicles by P-31 NMR spectroscopy.

The use of paramagnetic ion chelates to enhance contrast between pathologic and surrounding parenchyma is extensively documented in the magnetic resonance imaging (MRI) literature. Liposomes can be used to increase chelate concentration in the pathologic area, thereby enhancing the efficiency of paramagnetic compounds as contrast agents. Liposomes (50 +/- 20 nm) were prepared by sonicating a solution of dipalmitoylphosphatidylcholine and cholesterol containing 16.5 mM Gadolinium-DTPA (Gd-DTPA) in pharmaceutical formulation (Schering Laboratories, France) and 25 mM inorganic phosphate (Pi). The solutions were dialyzed against 0.9% NaCl before analysis by phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy. Spectra of liposomes displayed a sharp resonance ascribed to Pi and a broad signal arising from the phosphate groups of the phospholipid bilayer. The content of Gd-DTPA in liposomes was directly estimated, based on specific modifications of the longitudinal relaxation rate of intraliposomal Pi. Entrapment ratio was estimated by P-31 NMR spectroscopy and atomic absorption spectroscopy to represent 2.5% to 5% of the initial Gd-DTPA content in the solution. This work illustrates the usefulness of NMR spectroscopy in the characterization of liposomes to be used for MRI applications.

Localized Proton Magnetic Resonance Spectroscopy of the Brain in Children Infected with Human Immunodeficiency Virus with and without Encephalopathy

Twenty children older than 2 y infected with human immunodeficiency virus (HIV) were examined by in vivo proton magnetic resonance spectroscopy (1H MRS) to study their cerebral metabolism and to identify metabolic profiles in relation with different stages of the disease. Patients were rated regarding their clinical and immunologic status according to the Centers for Disease Control classification and were divided into two groups: without encephalopathy (E-, n = 15) and with progressive encephalopathy (E+, n = 5). The acquisition was performed in the centrum semiovale using the short echo stimulated echo acquisition mode 20-ms sequence. The MRS profile was abnormal in all HIV-infected children compared with healthy age-matched controls (n = 7), even when magnetic resonance images were normal. A significant increase of the proportion of the lipid signals (ANOVA, p < 0.05) was found in all HIV-infected children. In addition, a significant decrease of the proportion of the N-acetylaspartate signal and a significant increase of the proportion of the myo-inositol signal (ANOVA, p < 0.05) characterized the E+ group. The principal component analysis performed on eight variables on 30 spectra confirms that the spectra of HIV-infected children differ from control spectra. The E+ group and the E- group are clearly separated on the map of subjects on the principal plane. The E- group lies in an intermediate position between the E+ group and the control group. The evolution of metabolic alterations in the brain of HIV-infected children can clearly be monitored by 1H MRS and associated with the occurrence of an encephalopathy.

Skin conductance biofeedback training in adults with drug-resistant temporal lobe epilepsy and stress-triggered seizures: A proof-of-concept study

The present proof-of-concept study investigated the feasibility of skin conductance biofeedback training in reducing seizures in adults with drug-resistant temporal lobe epilepsy (TLE), whose seizures are triggered by stress. Skin conductance biofeedback aims to increase levels of peripheral sympathetic arousal in order to reduce cortical excitability. This might seem somewhat counterintuitive, since such autonomic arousal may also be associated with increased stress and anxiety. Thus, this sought to verify that patients with TLE and stress-triggered seizures are not worsened in terms of stress, anxiety, and negative emotional response to this nonpharmacological treatment. Eleven patients with drug-resistant TLE with seizures triggered by stress were treated with 12 sessions of biofeedback. Patients did not worsen on cognitive evaluation of attentional biases towards negative emotional stimuli (P>.05) or on psychometric evaluation with state anxiety inventory (P = .059); in addition, a significant improvement was found in the Negative Affect Schedule (P = .014) and in the Beck Depression Inventory (P = .009). Biofeedback training significantly reduced seizure frequency with a mean reduction of -48.61% (SD = 27.79) (P = .005). There was a correlation between the mean change in skin conductance activity over the biofeedback treatment and the reduction of seizure frequency (r(11) = .62, P = .042). Thus, the skin conductance biofeedback used in the present study, which teaches patients to achieve an increased level of peripheral sympathetic arousal, was a well-tolerated nonpharmacological treatment. Further, well-controlled studies are needed to confirm the therapeutic value of this nonpharmacological treatment in reducing seizures in adults with drug-resistant TLE with seizures triggered by stress.

Brain metabolic impairment in non‐cerebral and cerebral forms of x‐linked adrenoleukodystrophy by proton MRS: Identification of metabolic patterns by discriminant analysis

Cerebral metabolism in six children with X‐linked adrenoleukodystrophy (X‐ALD) was studied using 1H magnetic resonance spectroscopy (MRS), and the status of the patients was monitored for evaluating disease progression. Spectra were abnormal even in patients with no cerebral impairment. Four different metabolic patterns were identified, and a metabolic classification of the disease was proposed, from grade 0 to grade III. The evolution of the disease toward grade II appears to be systematic, but many patients did not evolve from this grade to grade III, which is the metabolic mark of severe progressive forms. Metabolic data of X‐ALD were processed using discriminant analysis, which provides a classification accuracy of 95.2%. Proton cerebral MRS together with discriminant analysis may be useful during the follow‐up in X‐ALD for monitoring the evolution of the disease and the effects of therapy. Magn Reson Med 41:1119–1126, 1999.

Variations of plasma sialic acid and N-acetylglucosamine levels in cancer, inflammatory diseases and bone marrow transplantation: a proton NMR spectroscopy study

Proton NMR spectroscopy allows the detection in plasma of resonances arising from N-acetyl-glucosamine (NAG) and N-acetyl-neuraminic acid (NANA) which have been shown to be borne by acute phase glycoproteins. These resonances can be identified using 2 different protocols of spectrum acquisition detecting different physical states in the global pool of glycoproteins, ie mobile and less mobile moieties of glycosylated chains. In this study we demonstrate that NMR spectroscopy allows a precise monitoring of the variations of glycosylated residues in cancers, inflammatory processes and bone marrow transplantation. The most important findings are that: i), the distribution of glycosylated residues varies with the origin of the cancerous tissue; ii), the level of these residues is a function of tumor development; iii), the concentrations in NAG and NANA are well correlated with the standard biological parameters of acute phase and leucocyte activation. Proton NMR spectroscopy of glycosylated residues in plasma may offer a new means of monitoring sialic acid in cancer and other pathological conditions.