Performance in recognition memory is correlated with entorhinal/perirhinal interictal metabolism in temporal lobe epilepsy.

In addition to the hippocampus, the entorhinal/perirhinal cortices are often involved in temporal lobe epilepsy (TLE). It has been proposed that these anterior parahippocampal structures play a key role in recognition memory. We studied the voxel-based PET correlation between number of correctly recognized targets in a new recognition memory paradigm and interictal cerebral metabolic rate for glucose, in 15 patients with TLE with hippocampal sclerosis. In comparison to healthy subjects, patients had decreased recognition of targets (P<0.001) and ipsilateral hypometabolism (relative to side of hippocampal sclerosis) of the hippocampus, entorhinal/perirhinal cortices, medial temporal pole, and middle temporal gyrus (P<0.05, corrected by false discovery rate method). Performance correlated with interictal metabolism of ipsilateral entorhinal/perirhinal cortices (P<0.005, Spearman's rank test), but this relationship was not significant in the hippocampus itself (P>0.18, Spearman's rank test). These findings highlight the preferential involvement of entorhinal/perirhinal cortices in recognition memory in patients with TLE, and suggest that recognition memory paradigms may be useful in assessing anterior parahippocampal functional status in TLE.

Profile of memory impairment and gray matter loss in amnestic mild cognitive impairment.

The present study assessed the patterns of cortical gray matter (GM) loss in patients with amnestic mild cognitive impairment (aMCI) with distinct profiles of memory impairment, i.e. aMCI patients failing on both recall and recognition memory vs. aMCI patients showing impaired recall but preserved recognition memory. This distinction is usually not taken into account in studies on aMCI and the aim of the present study was to assess whether this distinction is useful. Twenty-eight aMCI patients and 28 matched controls subjects were included. All aMCI patients failed a recall memory task (inclusion criteria). All underwent a visual recognition memory task (DMS48). However, 12 succeeded on this task while 16 failed. Relative gray matter (GM) loss was measured using voxel-based morphometry. When comparing aMCI patients to controls regardless of the profile of memory impairment, GM loss was found in temporal, parietal and frontal areas. However, in aMCI patients with preserved recognition (but impaired recall), GM loss was confined to frontal areas. This contrasted with GM loss in the right medial temporal lobe and bilateral temporo-parietal regions in aMCI patients with impaired recall and recognition memory, a pattern of GM loss usually described in early AD. We conclude that different profiles of memory impairment in aMCI patients are associated with distinct patterns of GM loss.

[Imaging of brain tumors in children]. / Imagerie des tumeurs cérébrales de l'enfant.

Few studies exist in the literature on pediatric brain tumors examined with advances MRI techniques. The aim of this review is to try to find out some specific tissular characteristics of the main cerebral tumors encountered in children, especially through diffusion imaging, perfusion imaging and proton magnetic resonance spectroscopy (MRS). However, hemispheric cerebral tumors are not as common as in the adult population.

[Indications for cerebral MR proton spectroscopy in 2007]. / Spectroscopie par résonance magnétique du proton. Quelles indications neurologiques en 2007?

Magnetic resonance spectroscopy (MRS) is being increasingly performed alongside the more conventional MRI sequences in the exploration of neurological disorders. It is however important to clearly differentiate its clinical applications aiming at improving the differential diagnosis or the prognostic evaluation of the patient, from the research protocols, when MRS can contribute to a better understanding of the pathophysiology of the disease or to the evaluation of new treatments. The most important applications in clinical practice are intracranial space occupying lesions (especially the positive diagnosis of intracranial abscesses and gliomatosis cerebri and the differential diagnosis between edema and tumor infiltration), alcoholic, hepatic, and HIV-related encephalopathies and the exploration of metabolic diseases. Among the research applications, MRS is widely used in multiple sclerosis, ischemia and brain injury, epilepsy and neuro degenerative diseases.

Neuroimaging of neonatal encephalopathies.

Neonatal brain disorders consist of a wide chapter including brain malformations, hypoxic-ischemic encephalopathy (HIE), intracranial infections, perinatal trauma and metabolic encephalopathy. We will focus here on HIE, intracranial infections (especially materno-fetal infection with or without prolonged and/or premature rupture of membranes) and metabolic encephalopathy, those three conditions being the most frequent so far in our experience. Neonatal stroke is also analyzed. Moreover minor perinatal events might be superimposed on an already damaged (infective, edematous, metabolically abnormal or maldeveloped) brain, highlighting the main role and potential benefits of neuroimaging during the neonatal period. The different methods of brain imaging are thus reported with their advantages and disadvantages.

MR imaging of brain maturation.

Magnetic resonance imaging (MRI) is the imaging tool of choice to evaluate brain maturation and especially brain myelination. Magnetic resonance imaging also provides functional insight through diffusion images and proton spectroscopy. In this review the MRI techniques are analyzed for both pre- and postnatal periods. The origin of MR signal changes is also detailed in order to understand normal myelination evolution and the consequences on brain maturation of the different pathologies encountered prior and after birth. Because MRI is "blind" in terms of signal on conventional sequences after 2 years of age, a particular attention is given to diffusion images and proton spectroscopy of the developing brain.

Infratentorial pediatric brain tumors: the value of new imaging modalities.

The correct assessment of the four most frequent infratentorial brain tumors in children (medulloblastoma, ependymoma, pilocytic astrocytoma and infiltrating glioma) has always been problematic. They are known to often resemble one another on conventional magnetic resonance (MR) imaging. We tested the hypothesis whether the combined strength of diffusion-weighted imaging (DWI) and proton MR spectroscopy (MRS) could help differentiate these tumors. Seventeen children with untreated posterior fossa tumors were investigated between January 2005 and January 2006 with conventional MR imaging and combined DWI and MR spectroscopy using a single-voxel technique at short and long echo time (TE) of 30 ms and 135 ms respectively. Apparent diffusion coefficient (ADC) values were retrieved after regions of interest were manually positioned within non necrotic tumor core. Water signal was quantified and metabolite signals were compared and analyzed using linear discriminant analysis. When a combination of ADC values and normalized metabolites was used, all tumors could be discriminated against one other. This could only be achieved when metabolites were normalized using water as an internal standard. They could not be discriminated when using metabolite ratios or ADC values alone, nor could they be differentiated using creatine (Cr) as an internal reference even in combination with ADC values. In conclusion, linear discriminant analysis and multiparametric combination of DWI and MRS, although not replacing histology, fully discriminates the four most frequent posterior fossa tumors in children, but metabolites have to be normalized using water and not Cr signal as an internal reference.

[Brain magnetic resonance spectroscopy]. / Spectroscopie par résonance magnétique cérébrale.

MR spectroscopy (MRS) sequences allow noninvasive exploration of brain metabolism during a MRI examination. Their day-to-day use in a clinical setting has recently been improved by simple programming of sequences and automated quantification of metabolites. However, a few simple rules should be observed in the choice of sequences and the location of the voxels so as to obtain an informative, high-quality examination. The research applications of MR spectroscopy, where use of this examination seeks to better understand the pathophysiology of the disease, must be distinguished from its clinical indications, where MRS provides information that can be used directly in patient management. The most significant of the clinical uses are imaging intracranial tumors (positive and differential diagnosis, extension, treatment follow-up), diffuse brain injury, encephalopathies (especially hepatic and HIV-related), and the diagnosis of metabolic disorders.

New brain lesions with no impact on physical disability can impact cognition in early multiple sclerosis: A ten-year longitudinal study.

OBJECTIVE: In early multiple sclerosis, although brain T2 lesions accrual are hallmark of the disease, only weak correlations were found between T2 lesions accrual and EDSS progression, the disability scale commonly used in multiple sclerosis studies. This may be related to the very poor sensitivity of EDSS to cognitive dysfunctions that may occur and progress from the first stage of the disease. In the present study, we aimed to demonstrate that cognitive deficits progress during the first ten years of MS and are significantly impacted by new T2 lesions. METHODS: EDSS and extensive neuropsychological battery (22 measures) exploring memory, attention/speed of information processing and executive functions were assessed at baseline, Year 1 and Year 10 in 26 patients enrolled after their first clinical attack. To limit the bias of test-retest effect, only measures obtained at Year 1 and Year 10 were reported in the analysis. Raw scores of patients were transformed into z-scores using published normative data when available or scores of matched controls. Lesion probability mapping was used to assess the potential relationships between T2 lesions accumulation, cognitive decline and EDSS progression (P<0.05, FWE-corrected). RESULTS: At Year 1, 27% of patients showed attention/speed of information processing deficits, 11.5% executive dysfunction and 11.5% memory impairment. During the follow-up, frequency and severity of executive dysfunction increased (from 11.5% of patients at Year 1 to 42% at Year 10, p<0.01) while no significant changes were evidenced for the other cognitive domains. Median EDSS increased from 0.5 [range: 0-3] at Year 1 to 2.5 [range: 0-6.5] at Year 10 (p<0.001). During the ten-year follow-up, lesions accumulation in the left cerebellum and semi-ovale centers was associated with EDSS progression. In contrast, most lesions accumulation in the frontal, parietal and temporal lobes were associated with cognitive decline but had no effect on EDSS progression. CONCLUSION: The present study provides strong evidence that clinically silent T2 lesions impact cognition in early MS. In daily practice, early prevention of T2 lesions accrual may be useful to limit cognitive decline.

[MR spectroscopy of brain tumors]. / Spectroscopie par résonance magnétique des tumeurs cérébrales.

MR spectroscopy (MRS) can complement MRI in the evaluation of intracranial tumors. Before treatment, MRS can contribute to the differential diagnosis between tumor and non tumoral lesion (especially intracranial abscesses), to assess the aggressiveness of a glial tumor or to determine its extension to better delineate the surgical removal or the target volume of radiotherapy. During treatment follow-up, MRS helps differentiate recurrent tumor from radionecrosis or physiological post-surgical contrast enhancement. The current studies are trying to determine if the indications of MRS, alone or in association with other MR sequences can further be extended in the study of brain tumors, in particular the follow-up of lesions undergoing chemo or radiotherapy.

Metabolic counterpart of decreased apparent diffusion coefficient during hyperacute ischemic stroke: a brain proton magnetic resonance spectroscopic imaging study.

BACKGROUND AND PURPOSE: Recent studies have shown that the brain ischemic area defined by the map of decreased apparent diffusion coefficient (ADC) obtained by diffusion-weighted imaging (DWI) during the first hours of ischemic stroke includes a significant part of ischemic penumbra. We hypothesize that the misjudgment of the final infarct size by ADC mapping may be related to a restricted ability of DWI to capture variations in the intensity of cellular suffering. In an attempt to characterize metabolically the hypoperfused brain parenchyma, we studied the relationship between ADC values and brain metabolic parameters measured by proton MR spectroscopic imaging (SI). METHODS: Six patients with hyperacute ischemic stroke were explored within the first 7 hours after onset with the use of a MR protocol including T2*-weighted MRI, DWI, SI, perfusion-weighted imaging, and MR angiography. RESULTS: This study demonstrates, for the first time, a wide gradient of ischemia-related metabolic anomalies within the abnormal area delineated by DWI during hyperacute ischemic stroke. In the narrow range of decreased mean ADC values (0.60 to 0.40 x 10(-9) m2 x s(-1)), a 33% decrease in mean ADC is associated with a 122% increase in lactate/N-acetyl aspartate ratio. Mean ADC values never fall below 0.40 x 10(-9) m2 x s(-1) within the severely affected ischemic tissue, while SI still detects a large metabolic heterogeneity inside areas showing similar decreased mean ADC values close to this threshold. CONCLUSIONS: Our results indicate that the region of very low mean ADC values observed during hyperacute ischemic stroke contains areas of various tissue damage intensity characterized by SI in relation to different stages of cellular metabolic injury. This observation may explain why ADC mapping does not reliably predict final infarct size.

Pi trapping in glycogenolytic pathway can explain transient Pi disappearance during recovery from muscular exercise. A 31P NMR study in the human.

31P NMR spectroscopy at 4.7 T has been used to follow changes in phosphorylated metabolites and pHi in the flexor digitorum superficialis muscle of 15 healthy volunteers subjected to a rest-exercise-recovery protocol. Phosphomonoesters (Pme) increased during exercise and exhibited a delayed recovery to resting level. During early recovery, Pi fell below resting concentration without correlated PCr oversynthesis while Pme level stayed above its resting value. The sum Pi + Pme remained constant. These observations suggest that Pi could be trapped into the glycogenolytic pathway during exercise leading to Pme production. This trapping and the slow Pme recovery could account for transient Pi disappearance observed during recovery.

Heterogeneity of metabolic response to muscular exercise in humans. New criteria of invariance defined by in vivo phosphorus-31 NMR spectroscopy.

31P NMR spectroscopy at 4.7 T has been used in vivo to follow metabolic changes associated with exercise and subsequent recovery in the forearm flexor digitorum superficialis muscle of 14 healthy volunteers. The muscle content in phosphomonoesters at rest provides an index of glycogenolytic activity. Quantitative linear correlations have been shown to link end-of-exercise acidosis to recovery kinetics of phosphocreatine and phosphocreatine/organic phosphate ratio. These linear relationships constitute new metabolic invariants to be used in the study of myopathies and muscle adaptation to exercise.

Time-dependent and indirect effect of inorganic phosphate on force production in rat gastrocnemius exercising muscle determined by 31P-MRS.

The relationship of inorganic phosphate (P(i)) and its diprotonated form (H(2)PO(4)(-)) to isometric force (F) was analyzed non-invasively using 31P-magnetic resonance spectroscopy. Rat gastrocnemius muscles were electrically stimulated at six different frequencies in order to produce different levels of fatigue. A curvilinear relationship was demonstrated between force production and [P(i)] and [H(2)PO(4)(-)] accumulation. [P(i)] and [H(2)PO(4)(-)] were correlated with F at the end of the stimulation period but not when F was maximal at the early stage of the stimulation period. Interestingly, the respective [P(i)] and [H(2)PO(4)(-)] did not differ significantly between these two stages demonstrating that [P(i)] and [H(2)PO(4)(-)] cannot be considered as direct effectors of fatigue. This time-dependent and indirect effect of [P(i)] and [H(2)PO(4)(-)] on force production might be mediated by calcium ions.

31P NMR spectroscopy and ergometer exercise test as evidence for muscle oxidative performance improvement with coenzyme Q in mitochondrial myopathies.

Two patients with mitochondrial encephalomyopathy due to complexes I and IV deficiencies received 150 mg/d of coenzyme Q10 (CoQ). We studied them with a bicycle ergometer exercise test and 31P NMR spectroscopy before and after 10 months of treatment. Before treatment, we observed a low phosphocreatine/inorganic phosphate (PCr/P(i)) resting value along with abnormally high resting lactate concentration. During exercise, there was a pronounced acidosis with delayed kinetics of postexercise recovery for blood lactate, pH, PCr, and PCr/P(i) ratio. Oxygen uptake during exercise was reduced while the lowering of the ventilatory threshold indicated an early activation of glycolysis. After treatment, the bicycle ergometer exercise test indicated a significant improvement with a decrease in resting blood lactate level, an increase in oxygen consumption during exercise, and an increase in the kinetics of lactate disappearance during the recovery period. A shift of the ventilatory threshold to higher workload was present. 31P NMR spectroscopy confirmed the improvement, showing a significant increase in the PCr/P(i) ratio at rest and in the kinetics of recovery for pH, PCr, and PCr/P(i) ratio following exercise in patient 1. For patient 2, we observed a less pronounced acidosis correlated with a lesser amount of Pi produced during exercise. These observations indicate an improvement of mitochondrial function and a shift from high to low glycolytic activity in both patients consequent to CoQ treatment.

Two-dimensional 1H NMR spectroscopy of normal and pathological human plasma: complete water suppression and further assignment of resonances.

Two-dimensional J-resolved and correlated 1H NMR spectra with complete water suppression have been obtained to further characterize a metabolic pattern for normal and pathological human plasma samples. 1H COSY spectra have been recorded on plasma from 12 patients with cancer in order to check for the possible presence of fucose. Our results show that there is no evidence for the presence of fucosylated lipids in the plasma of these patients.

Energetic metabolism of glucose, mannose and galactose in glucose-starved rat insulinoma cells anchored on microcarrier beads. A phosphorus-31 NMR study.

Insulin-secreting cells (RINm5F) have successfully been grown on a large scale on poly-L-lysine coated-polystyrene microcarriers, providing a high cell number in a restricted volume under conditions that respect the metabolic integrity of these anchorage-dependent cells. The energetic metabolism of the perfused cells has been followed non-invasively by phosphorus-31 nuclear magnetic resonance spectroscopy. Glucose starvation induced a rapid decrease in nucleoside triphosphates (mainly ATP) pools, correlated with an increase in Pi level. The initial ATP level was rapidly recovered when the cells were refed with glucose or with mannose, but not with galactose, even after 2 h of perfusion. These differential effects of hexoses on energetic metabolism might be related to their various insulin-release actions on tumor islet cells.

Multimodal magnetic resonance imaging of the central nervous system.

The physiological and biochemical properties of the diseased brain that can be explored with magnetic resonance imaging (MRI) are increasing. Progress in MR-based technology affords a large panel of MRI sequences that explore different phenomena and, thus, provide complementary informations. The diagnostic accuracy of MRI is improved by the combination of all MR modalities. However, this abundance of data requires an efficient multiparametric analysis to fully achieve the goal of the multimodal strategy. We will discuss the potential impact of this advanced MRI analysis in the clinical management and the therapeutical strategies of the most common brain pathologies (intracranial tumors, multiple sclerosis, stroke, epilepsy and dementia). This non-invasive approach is of utmost importance since it already improves the diagnosis and the therapeutic choice in the management of several central nervous system diseases.

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.

High resolution NMR spectroscopy of physiological fluids: from metabolism to physiology.

High resolution NMR spectroscopy of physiological fluids provides quantitative, qualitative and dynamic information on the metabolic status of the interstitial and plasma compartments under a variety of pathophysiological conditions. The simultaneous detection and quantitation by NMR spectroscopy of numerous compounds of the intermediary metabolism offers a new insight in the understanding of the milieu intérieur. NMR spectroscopy of physiological fluids offers a unique way to define and monitor the global metabolic homeostasis in humans. The development of this analytical approach is still limited by the scarcity of pluridisciplinary teams able to fully exploit the wealth of information present on the NMR spectrum of a fluid. While application in pharmacology and toxicology is already established, the main areas of current development are cancer, hereditary metabolic disorders, organ transplantation and neurological diseases.