MRI correlates of cognitive impairment in childhood-onset multiple sclerosis.

OBJECTIVE: Brain MRI measures were correlated with neuropsychological function in 35 pediatric-onset multiple sclerosis (MS) patients and 33 age- and sex-matched healthy controls. METHOD: Mean age of MS patients was 16.3 ± 2.3 years with average disease duration of 4.3 ± 3.1 years. Cortical gray matter, thalamic, and global brain volumes were calculated for all participants using a scaling factor computed using normalization of atrophy method to normalize total and regional brain volumes for head size. T1- and T2-weighted lesion volumes were calculated for MS patients. RESULTS: Cognitive impairment (CI) was identified in 29% of the MS cohort. Cognitive deficits predominantly involved attention and processing speed, expressive language, and visuomotor integration. Relative to controls, the MS group showed significantly lower thalamic volume (p < .001), total brain volume (p < .008), and gray matter volume (p < .015). Corpus callosum area and thalamic volume differentiated patients identified as having CI from those without CI (p < .05). Regression models controlling for disease duration and age indicated that thalamic volume accounted for significant incremental variance in predicting global IQ, processing speed, and expressive vocabulary (ΔR2 ranging from .43 to .60) and was the most robust MRI predictor of cognition relative to other MRI metrics. CONCLUSIONS: The robust association between cognitive function and reduced size of thalamus and global brain volume in pediatric-onset MS patients implicate neurodegenerative processes early in the disease course, and suggest that plasticity of an immature central nervous system is not sufficient to protect patients from the deleterious consequences of MS on cognitive neural networks. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Cerebral degeneration predicts survival in amyotrophic lateral sclerosis.

OBJECTIVE: To determine the relationship of cerebral degeneration with survival in amyotrophic lateral sclerosis (ALS). METHODS: Patients with probable or definite ALS underwent magnetic resonance spectroscopic imaging (MRSI) of the brain between July 1996 and May 2002, and were followed prospectively until March 2004. Creatine (Cr), choline (Cho) and the neuronal marker N-acetylaspartate (NAA) were quantified as ratios in the motor cortex. RESULTS: In 63 patients compared with 18 healthy people, NAA/Cho was reduced by 13% (p<0.001), NAA/Cr was reduced by 5% (p = 0.01) and Cho/Cr was increased by 8% (p = 0.01). NAA/Cho was used for survival analysis, given its larger effect size and superior test accuracy (a sensitivity of 67% and a specificity of 83%). Median survival after MRSI was 24 months. Multivariate analysis showed reduced survival for lower NAA/Cho (hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.08 to 0.72, p = 0.01), older age (HR 1.03, 95% CI 1.00 to 1.06, p = 0.04) and shorter symptom duration (HR 0.96, 95% CI 0.93 to 0.99, p = 0.01). Patients with NAA/Cho <2.11 had a reduced survival of 19.4 v 31.9 months (HR 2.05, 95% CI 1.12 to 4.03, p = 0.02). CONCLUSIONS: Cerebral degeneration is predictive of reduced survival in ALS.

ALS surrogate markers. MRS.

Magnetic resonance spectroscopy (MRS) allows the quantitative assessment of neuronal integrity in vivo based on the resonance intensity of N-acetylaspartate (NAA). A simple approach to quantitation that is commonly used is to quantify the resonance intensity of NAA with respect to creatine (Cr). In patients with ALS, NAA/Cr density is decreased in areas of the brain that contribute significantly to the corticospinal tract. Since MRS is non-invasive, it can be easily used to monitor the evolution of regional changes in NAA/Cr over time. The changes in NAA/Cr over a period of months are small, however, and challenge the precision of the method.

Magnetic resonance spectroscopy and imaging of the thalamus in idiopathic generalized epilepsy.

Experimental work in animal models of generalized epilepsy and clinical data in humans with idiopathic generalized epilepsy (IGE) indicate that the thalamo-cortical circuitry is involved in the generation of epileptic activity. The purpose of this study was to evaluate in vivo the chemical and structural integrity of the thalamus in patients with IGE. Thalamic proton magnetic resonance spectroscopic imaging (1H-MRSI), measuring N-acetylaspartate (NAA), choline-containing compounds and creatine (Cr) was performed in 20 IGE patients and in a group of age-matched healthy subjects. Additionally, 1H-MRSI measurements were taken in the insular cortex, the posterior temporal lobe white matter and the splenium of the corpus callosum. MRI volumetric analysis of the thalamus was performed in all patients. At the time of the examination, seizures were well controlled in 10 IGE patients and poorly controlled in nine. One patient was newly diagnosed and had the MRI and MRSI examination prior to starting the antiepileptic medication. In IGE patients, 1H-MRSI showed a reduction of mean thalamic NAA/Cr compared with normal controls; no difference was found in NAA/Cr in the other examined areas. There was no difference in NAA/Cr between patients whose seizures were well controlled and those in whom seizures were not controlled. There was no correlation between thalamic NAA/Cr and mean number of spike and wave complexes. We found a significant negative correlation between thalamic NAA/Cr and duration of epilepsy. The mean thalamic volume in patients with IGE was not different from normal controls. These results show evidence of progressive thalamic neuronal dysfunction in patients with IGE supporting the notion of abnormal thalamo-cortical circuitry as a substrate of seizure generation in this form of epilepsy. The thalamic dysfunction may occur regardless of amount of spike and wave activity.

Unusual imaging findings in progressive myoclonus epilepsy.

We describe a patient with progressive myoclonus epilepsy (PME), white matter hyperintensities in the corpus callosum, cerebral hemispheres, and left cerebral peduncle on magnetic resonance imaging (MRI), and positive oligoclonal bands. A phosphorus magnetic resonance spectrum was compatible with mitochondrial dysfunction. Abnormal white matter signals are not a feature of the known PME syndromes, although they occur in Leber's hereditary optic neuropathy (LHON). These abnormalities oriented the diagnosis toward mitochondrial disease.

Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta-1b.

Patients with multiple sclerosis (MS) can benefit from treatment with interferon beta-1b. However, the mechanisms of action of this drug are incompletely understood and effects of interferon beta-lb on axonal injury are not known. A measure of axonal injury can be obtained in vivo using magnetic resonance spectroscopy to quantify the resonance intensity of the neuronal marker, N-acetylaspartate (NAA). In a small pilot study, we performed combined magnetic resonance imaging and magnetic resonance spectroscopic imaging on 10 patients with relapsing-remitting MS before and 1 year after starting treatment with subcutaneous interferon beta-lb. Resonance intensities of NAA relative to creatine (Cr) were measured in a large, central brain volume. These measurements were compared with those made in a group of 6 untreated patients selected to have a similar range of scores on the Expanded Disability Status Scale and mean NAA/Cr at baseline. NAA/Cr in the treated group [2.74 (0.16), mean (SD)] showed an increase of 5.5% 12 months after the start of therapy [2.89 (0.24),p = 0.05], while NAA/Cr in the untreated group decreased, but not significantly [2.76 (0.1) at baseline, 2.65 (0.14) at 12 months,p > 0.1]. NAA/Cr had become significantly higher in the treated group at 12 months than in the untreated group (p = 0.03). Our data suggest that, in addition to losing axons, patients with chronic multiple sclerosis suffer from chronic, sublethal axonal injury that is at least partially reversible with interferon beta-lb therapy.

Excision from tRNA genes of a large chromosomal region, carrying avrPphB, associated with race change in the bean pathogen, Pseudomonas syringae pv. phaseolicola.

Pseudomonas syringae pv. phaseolicola (Pph) race 4 strain 1302A carries avirulence gene avrPphB. Strain RJ3, a sectoral variant from a 1302A culture, exhibited an extended host range in cultivars of bean and soybean resulting from the absence of avrPphB from the RJ3 chromosome. Complementation of RJ3 with avrPphB restored the race 4 phenotype. Both strains showed similar in planta growth in susceptible bean cultivars. Analysis of RJ3 indicated loss of > 40 kb of DNA surrounding avrPphB. Collinearity of the two genomes was determined for the left and right junctions of the deleted avrPphB region; the left junction is approximately 19 kb and the right junction > 20 kb from avrPphB in 1302A. Sequencing revealed that the region containing avrPphB was inserted into a tRNALYS gene, which was re-formed at the right junction in strain 1302A. A putative lysine tRNA pseudogene (PsitRNALYS) was found at the left junction of the insertion. All tRNA genes were in identical orientation in the chromosome. Genes near the left junction exhibited predicted protein homologies with gene products associated with a virulence locus of the periodontal pathogen Actinobacillus actinomycetemcomitans. Specific oligonucleotide primers that differentiate 1302A from RJ3 were designed and used to demonstrate that avrPphB was located in different regions of the chromosome in other strains of Pph. Deletion of a large region of the chromosome containing an avirulence gene represents a new route to race change in Pph.

Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis.

Axonal injury occurs even in the earliest stages of multiple sclerosis. Magnetic resonance spectroscopic imaging (MRSI) measurements of brain N:-acetylaspartate (NAA), a marker of axonal integrity, show that this axonal injury can occur even in the absence of clinically evident functional impairments. To test whether cortical adaptive responses contribute to the maintenance of normal motor function in patients with multiple sclerosis, we performed MRSI and functional MRI (fMRI) examinations of nine multiple sclerosis patients who had unimpaired hand function. We found that activation of the ipsilateral sensorimotor cortex with simple hand movements was increased by a mean of fivefold relative to normal controls (n = 8) and that the extent of this increase was strongly correlated (sigma = -0.93, P = 0.001) with decreases in brain NAA. These results suggest that compensatory cortical adaptive responses may help to account for the limited relationship between conventional MRI measures of lesion burden and clinical measures of disability, and that therapies directed towards promoting cortical reorganization in response to brain injury could enhance recovery from relapses of multiple sclerosis.

Insights into muscle diseases gained by phosphorus magnetic resonance spectroscopy.

Phosphorus magnetic resonance spectroscopy (P-MRS) has now been used in the investigation of muscle energy metabolism in health and disease for over 15 years. The present review describes the basics of the metabolic observations made by P-MRS including the assumptions and problems associated with the use of this technique. Extramuscular factors, which may affect the P-MRS results, are detailed. The important P-MRS observations in patients with mitochondrial myopathies, including the monitoring of experimental therapies, are emphasized. The findings in other metabolic myopathies (those associated with glycolytic defects or endocrine disturbances) and in the destructive myopathies (the dystrophies and the inflammatory myopathies) are also described. Observations made in normal and abnormal fatigue, fibromyalgia, and malignant hyperthermia are considered. Finally, a summary of the possible diagnostic use of P-MRS in exercise intolerance is provided.

Using proton magnetic resonance spectroscopic imaging to predict in vivo the response of recurrent malignant gliomas to tamoxifen chemotherapy.

OBJECTIVE: Most patients with a malignant glioma spend considerable time on a treatment protocol before their response (or nonresponse) to the therapy can be determined. Because survival time in the absence of effective therapy is short, the ability to predict the potential chemosensitivity of individual brain tumors noninvasively would represent a significant advance in chemotherapy planning. METHODS: Using proton magnetic resonance spectroscopic imaging (1H MRSI), we studied 16 patients with a recurrent malignant glioma before and during treatment with high-dose orally administered tamoxifen. We evaluated whether 1H MRSI data could predict eventual therapeutic response to tamoxifen at the pretreatment and early treatment stages. RESULTS: Seven patients responded to tamoxifen therapy (three with glioblastomas multiforme; four with anaplastic astrocytomas), and nine did not (six with glioblastomas multiforme; three with anaplastic astrocytomas). Responders and nonresponders exhibited no differences in their age, sex, tumor type, mean tumor volume, mean Karnofsky scale score, mean number of weeks postradiotherapy, or mean amount of prior radiation exposure. Resonance profiles across the five metabolites measured on 1H MRSI spectra (choline-containing compounds, creatine and phosphocreatine, N-acetyl groups, lactate, and lipids) differed significantly between these two groups before and during treatment. Furthermore, linear discriminant analyses based on patients' in vivo biochemical information accurately predicted individual response to tamoxifen both before and at very early treatment stages (2 and 4 wk). Similar analyses based on patient sex, age, Karnofsky scale score, tumor type, and tumor volume could not reliably predict the response to tamoxifen treatment at the same time periods. CONCLUSION: It is possible to accurately predict the response of a tumor to tamoxifen on the basis of noninvasively acquired in vivo biochemical information. 1H MRSI has potential as a prognostic tool in the pharmacological treatment of recurrent malignant gliomas.

Muscle phosphorus magnetic resonance spectroscopy oxidative indices correlate with physical activity.

The purpose of this study was to assess the effect of physical deconditioning on skeletal muscle's oxidative metabolism as evaluated by phosphorus-31 magnetic resonance spectroscopy ((31)P MRS). Twenty-seven subjects without muscle disease, representing a wide range of fitness levels, were evaluated with (31)P MRS. Spectra were obtained at rest and during recovery from in-magnet exercise. The data show a significant correlation between maximum resting metabolic equivalent (MET) score and the following (31)P MRS recovery indices: adenosine diphosphate and phosphocreatine recovery half-time; initial phosphocreatine resynthesis rate; calculated estimation of mitochondrial capacity; pH at end of exercise; and phosphocreatine depletion. In addition, significant differences between the deconditioned and conditioned group were found for all of the aforementioned recovery indices. At rest, only the inorganic phosphate concentration was significantly different between the two groups. These data indicate that physical activity level should be taken into account when assessing patients' oxidative metabolism with (31)P MRS.

Relating axonal injury to functional recovery in MS.

A patient was followed after the new onset of hemiparesis from relapse of MS with serial MR spectroscopy and functional MRI. The association of clinical improvement with recovery of N-acetylaspartate, a marker of neuronal integrity, and progressive reduction of abnormally large functional MRI cortical activation with movement demonstrates that dynamic reorganization of the motor cortex accompanies remission of MS.

Relation of interictal spike frequency to 1H-MRSI-measured NAA/Cr.

PURPOSE: Whereas EEG spiking and decreases of the neuronal marker N-acetyl-aspartate (NAA) both localize well the epileptic focus, the significance of the intensity of these variables is unclear. Therefore we investigated whether the frequency of interictal surface spikes is related to the degree of N-acetyl-aspartate/creatine (NAA/Cr) ratio decrease as measured by proton magnetic resonance (MR) spectroscopic imaging (1H-MRSI) in patients with intractable partial epilepsy. METHODS: We retrospectively studied 14 patients, nine with temporal lobe epilepsy and five with frontal lobe epilepsy. Spikes that occurred during prolonged video-EEG monitoring from electrodes placed according to the International 10-20 system were counted blinded to the 1H-MRSI results. Eight electrode positions (F3/4, C3/4, T3/4, T5/6) were assigned to underlying brain subregions in the 1H-MRSI volume of interest. We converted NAA/Cr ratios into z-scores (NAA/Cr(z)) to compared NAA/Cr values directly across subregions. We calculated Spearman rank-order (p) and Pearson product-moment (r) correlations between spike frequency and NAA/Cr(z) values overall, as well as within each brain subregion. RESULTS: We found an overall negative relation between spike-frequency data and NAA/Cr(z) data (p = -0.341). When analyzing only spiking subregions, this negative relation became slightly stronger (p = -0.442; r = -0.338). When data from the eight sites were considered separately, this negative relation remained in most instances. CONCLUSIONS: Our results reveal a trend toward higher interictal spike frequencies on surface EEG in regions of pronounced neuronal metabolic damage or dysfunction. This suggests that both variables parallel an underlying pathologic substrate, although the pathophysiologic processes may be distinct.

Identification of a pathogenicity island, which contains genes for virulence and avirulence, on a large native plasmid in the bean pathogen Pseudomonas syringae pathovar phaseolicola.

The 154-kb plasmid was cured from race 7 strain 1449B of the phytopathogen Pseudomonas syringae pv. phaseolicola (Pph). Cured strains lost virulence toward bean, causing the hypersensitive reaction in previously susceptible cultivars. Restoration of virulence was achieved by complementation with cosmid clones spanning a 30-kb region of the plasmid that contained previously identified avirulence (avr) genes avrD, avrPphC, and avrPphF. Single transposon insertions at multiple sites (including one located in avrPphF) abolished restoration of virulence by genomic clones. Sequencing 11 kb of the complementing region identified three potential virulence (vir) genes that were predicted to encode hydrophilic proteins and shared the hrp-box promoter motif indicating regulation by HrpL. One gene achieved partial restoration of virulence when cloned on its own and therefore was designated virPphA as the first (A) gene from Pph to be identified for virulence function. In soybean, virPphA acted as an avr gene controlling expression of a rapid cultivar-specific hypersensitive reaction. Sequencing also revealed the presence of homologs of the insertion sequence IS100 from Yersinia and transposase Tn501 from P. aeruginosa. The proximity of several avr and vir genes together with mobile elements, as well as G+C content significantly lower than that expected for P. syringae, indicates that we have located a plasmid-borne pathogenicity island equivalent to those found in mammalian pathogens.

The ability of the rat to metabolize myristoyl-methionine: an acylamino acid with potentially useful antibacterial properties.

Two experiments with Sprague Dawley rats tested their ability to hydrolyse myristoyl-methionine (M-M) into myristic acid and L-methionine (M). In the first experiment, lasting for 3 days. male rats were orally administered [9,10-3H]myristoyl-L-[35S]methionine. The recovery of radioactivity was approximately 90% for both isotopes; 19% of the administered 3H was recovered in the urine and 16% in the faeces, while the recovered 35S activity was 13 and 12%, respectively. The balance of the radioactivity was found among the tissues, organs and blood. In the second experiment, male and female rats received soybean-based diets which were supplemented with either 0.305% M-M or 0.2% M (both diets contained equal amounts of M) for periods up to 4 weeks. The growth rate of the rats receiving the 0.305% M-M diets was slightly slower than that for the rats on the 0.2% M diet, but the difference was not statistically significant (P > 0.05). The M-M rats had a transitory decrease in feed consumption, suggesting that palatability may have contributed to the growth difference and that a somewhat greater amount of M-M was necessary for the rat to attain the same growth rate as that produced by 0.2% M. When the amount of dietary M-M was increased to 3.05% M-M, a greater reduction in feed consumption and body weight gain was observed. This latter diet was an initial attempt to study the potential toxicity of M-M. None of the haematological, clinical chemistry or organ weight data suggested that M-M was overtly toxic per se, but longer-term feeding studies are needed to evaluate the potential toxicity of M-M more fully.

Spectroscopic imaging of frontal neuronal dysfunction in hyperekplexia.

We used proton magnetic resonance spectroscopic imaging (MRSI) to assess in vivo cortical neuronal involvement in hyperekplexia. Cerebral neuronal function was measured using proton MRSI in four unrelated patients with hyperekplexia and 20 healthy controls. All patients had the major form of hyperekplexia, with additional atypical clinical features in two of them. Family history was positive in three patients and absent in one. The neuronal marker N-acetylaspartate (NAA), choline-containing compounds (Cho) and creatine (Cr) were measured in frontal, central and parietal areas. The MRSI showed a reduction of the relative resonance intensity of NAA/(Cr + Cho) in frontal and central regions in three patients, and in the right frontal region of the fourth. In one patient a second MRSI showed normal relative NAA resonance intensities over both temporal lobes as well as in the brainstem. In two subjects the topography of EEG abnormalities in the frontal lobes coincided with the MRSI findings. This proton MRSI study indicates the presence of frontal neuronal dysfunction in hyperekplexia. Whether this represents cortical dysfunction or an epiphenomenon of diencephalic or brainstem abnormalities remains open. However, the observation of normal proton MRSI in the temporal regions and brainstem in one of the patients seems to concur with the hypothesis of a facilitatory role of cortical dysfunction within areas of sensorimotor representation in the generation of the pathological startle reaction in hyperekplexia.

Recovery of N-acetylaspartate in corticomotor neurons of patients with ALS after riluzole therapy.

Riluzole, a glutamate antagonist, has been shown to be efficacious in the treatment of patients with amyotrophic lateral sclerosis (ALS), allowing prolonged survival and time to tracheostomy. The efficacy of riluzole in thought to result from reduced glutamate excitotoxicity on motor neurons of patients with ALS, but this has never been demonstrated directly in vivo. N-acetylaspartate (NAA), a compound that is readily measured in vivo using proton magnetic resonance spectroscopy, can be used as a surrogate marker for neuronal loss or sublethal injury. To determine whether riluzole reverses sublethal corticomotoneuron damage in patients with ALS we measured NAA/creatine (Cr) relative intensity ratios in the motor cortex before and after treatment with riluzole 50 mg bid. After 3 weeks of riluzole therapy in 11 patients NAA/Cr increased from 2.14 +/- 0.26 to 2.27 +/- 0.24 (p = 0.044), whereas, in 12 untreated patients NAA/Cr decreased from 2.17 +/- 0.20 to 2.08 +/- 0.20 (p = 0.099). Thus the change in NAA/Cr between the treated and untreated groups was 0.22 +/- 0.095 (p = 0.008). The magnitude of increase in NAA/Cr in those treated was not correlated with age, sex, duration of treatment or disease, the presence of probable or definite upper motor neuron (UMN) signs, bulbar features, or pre-treatment NAA/Cr. We conclude that magnetic resonance spectroscopy can provide a novel surrogate measure of neuronal integrity that demonstrates reversal of sublethal UMN injury in patients with ALS within weeks of initiating riluzole therapy.

Proton magnetic resonance spectroscopic imaging in patients with extratemporal epilepsy.

PURPOSE: Reduced levels of N-acetylaspartate (NAA) in temporal lobes responsible for temporal lobe epilepsy have been observed consistently in proton magnetic resonance spectroscopy (MRS) studies. METHODS: We investigated the potential of proton MRS to detect low NAA outside of the temporal lobes in patients with non-lesional partial extratemporal epilepsy. Proton MR spectroscopic imaging (MRSI) data of both frontal lobes and central/postcentral regions were obtained in 20 such patients and 16 normal control subjects. The epileptogenic region was determined by an extensive clinical-EEG investigation, including the recording of habitual seizures in each patient, and intracranial EEG recordings in 10 patients. RESULTS: The relative NAA resonance intensities (i.e., NAA/phosphocreatine plus creatine (CR(t)), NAA/choline-containing metabolites (Cho(t)) and NAA/Cr(t) + Cho(t)), were all significantly reduced throughout the spectroscopic image as compared with that of the controls. Furthermore, reduction of the NAA ratios was greater in the epileptogenic region as compared with the nonepileptogenic regions, on EEG investigation. CONCLUSIONS: In vivo proton MRSI of patients with nonlesional partial extratemporal epilepsy detected evidence of widespread neuronal damage or dysfunction that was greatest in the region of seizure focus.

Magnetic resonance spectroscopy in vivo: applications in neurological disorders.

Magnetic resonance (MR) spectroscopy (MRS) is performed using the same magnets and computers as conventional MR imaging (MRI). However, unlike conventional MRI, which provides structural information, MRS provides chemical information that represents pathologically specific measures useful for diagnosis and monitoring of patients affected by neurological disorders. This review will focus on selected clinical applications of MRS that have been demonstrated to have clinical use. These include phosphorus MRS of muscle to diagnose metabolic muscle disease, and proton MRS of brain to lateralize temporal lobe epilepsy, to classify brain tumors, and to evaluate the natural history and pathology of multiple sclerosis.

Muscle high-energy phosphates in central nervous system disorders. The phosphorus MRS experience.

Phosphorus magnetic resonance spectroscopy (MRS) was used to study muscle phosphates metabolism in several brain disorders. Those with primary mitochondrial encephalomyopathies showed the typical pattern of impaired oxidative metabolism at rest and during recovery after exercise. In migraine, Parkinson's disease and alternating hemiplegia muscle MRS observations lend support to a possible mitochondrial dysfunction. Similar observations in multiple sclerosis are probably the result of secondary deconditioning. In post polio syndrome and in some of the hereditary ataxias, elevated intracellular inorganic phosphates may be the result of another, yet unknown, metabolic impairment. Thus, muscle phosphate metabolism may be altered in various central nervous system (CNS) disorders by different metabolic impairments. All these possibilities should be taken into account when evaluating MRS results in brain diseases.