phosphocreatine and Multiple-Sclerosis

In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear. This review describes a number of pathways by which dysfunctional astrocytes in MS might lead to axonal degeneration. White-matter astrocytes in MS show a reduced metabolism of adenosine triphosphate-generating phosphocreatine, which may impair the astrocytic sodium potassium pump and lead to a reduced sodium-dependent glutamate uptake. Astrocytes in MS white matter appear to be deficient in β(2) adrenergic receptors, which are involved in stimulating glycogenolysis and suppressing inducible nitric oxide synthase (NOS2). Glutamate toxicity, reduced astrocytic glycogenolysis leading to reduced lactate and glutamine production, and enhanced nitric oxide (NO) levels may all impair axonal mitochondrial metabolism, leading to axonal degeneration. In addition, glutamate-mediated oligodendrocyte damage and impaired myelination caused by a decreased production of N-acetylaspartate by axonal mitochondria might also contribute to axonal loss. White-matter astrocytes may be considered as a potential target for neuroprotective MS therapies.

Topics: Astrocytes; Axons; Brain; Energy Metabolism; Glutamic Acid; Humans; Mitochondria; Multiple Sclerosis; Nerve Degeneration; Phosphocreatine

We determined if a high-intensity aerobic exercise program would be safe, improve expected fitness and clinical outcomes, and alter exploratory phosphorous magnetic resonance spectroscopy (P MRS) outcomes in persons with multiple sclerosis (PwMS).. This open-label prospective pilot study compared two cohorts of ambulatory PwMS matched for age, sex and V˙O2max. Cohorts underwent 8 wk of high-intensity aerobic exercise (MS-Ex, n = 10) or guided stretching (MS-Ctr, n = 7). Aerobic exercise consisted of four 30-min sessions per week while maintaining ≥70% maximal HR. Changes in cardiorespiratory fitness, clinical outcomes, and P MRS of tibialis anterior (TA) muscle and brain were compared. Cross-sectional P MRS comparisons were made between all MS participants and a separate matched healthy control population.. The MS-Ex cohort achieved target increases in V˙O2max (mean, +12.7%; P = <0.001, between-group improvement, P = 0.03). One participant was withdrawn for exercise-induced syncope. The MS-Ex cohort had within-group improvements in fat mass (-5.8%; P = 0.04), lean muscle mass (+2.6%; P = 0.02), Symbol Digit Modalities Test (+15.1%; P = 0.04), and cognitive subscore of the Modified Fatigue Impact Scale (-26%; P = 0.03), whereas only the physical subscore of the Modified Fatigue Impact Scale improved in MS-Ctr (-16.1%; P = 0.007). P MRS revealed significant within-group increases in MS-Ex participants in TA rate constant of phosphocreatine (PCr) recovery (+31.5%; P = 0.03) and adenosine triphosphate/PCr (+3.2%; P = 0.01), and near significant between-group increases in TA PCr recovery rate constant (P = 0.05) but no significant changes in brain P MRS after exercise. Cross-sectional differences existed between MS and healthy control brain PCr/inorganic phosphate (4.61 ± 0.44, 3.93 ± 0.19; P = 0.0019).. High-intensity aerobic exercise in PwMS improved expected cardiorespiratory and clinical outcomes but provoked one serious adverse event. The P MRS may serve to explore underlying mechanisms by which aerobic exercise exerts cerebral benefits.

Topics: Adenosine Triphosphate; Adult; Body Composition; Brain; Cardiorespiratory Fitness; Cognition; Exercise Therapy; Fatigue; Female; High-Intensity Interval Training; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Muscle Stretching Exercises; Muscle, Skeletal; Phosphates; Phosphocreatine; Pilot Projects; Prospective Studies; Syncope

To evaluate the effectiveness of ingesting creatine monohydrate in elevating intramuscular creatine stores and improving exercise capacity in individuals with multiple sclerosis (MS).. Randomized, double-blind, placebo-controlled, pre-posttrial.. A university-based exercise physiology laboratory.. Sixteen individuals with relapsing-remitting MS (median Expanded Disability Status Scale score, 4.75; range, 1.5-6.0).. Eight individuals with MS were randomized to the creatine group (20g/d of creatine monohydrate for 5d), and 8 others were randomized to the placebo group. Needle biopsies were performed on the vastus lateralis at rest before and after treatment. Subjects performed 3 bouts of 30 maximal knee extensions and flexions at 180 degrees /s with 1 minute of recovery between bouts before and after treatment.. Intramuscular total creatine, phosphocreatine, free creatine, and total work output.. Creatine ingestion did not significantly elevate intramuscular total creatine, phosphocreatine, or free creatine or improve total work production.. Creatine ingestion had no significant effect on muscle creatine stores or high-intensity exercise capacity in individuals with MS.

Topics: Adult; Biopsy, Needle; Creatine; Disability Evaluation; Double-Blind Method; Ergometry; Exercise; Exercise Tolerance; Female; Humans; Male; Multiple Sclerosis; Muscle Contraction; Muscle, Skeletal; Phosphocreatine; Placebo Effect; Treatment Outcome

We investigated the role of metabolism in muscle fatigue during voluntary exercise in persons with mild multiple sclerosis (MS). Six MS and 8 healthy control subjects performed intermittent, progressive, isometric contractions of the ankle dorsiflexors, during which we measured maximum voluntary force (MVC), inorganic phosphate (Pi), phosphocreatine (PCr), and pH. During exercise, MVC fell sooner in MS, but by the end of exercise the relative decrease in MVC was similar in both groups. In contrast, at the end of exercise Pi/PCr increased to 1.86 +/- 0.22 in controls but to only 0.66 +/- 0.04 in MS (P < 0.01); likewise, pH was 6.75 +/- 0.04 in controls and unchanged (7.06 +/- 0.04) in MS (P < 0.01). The smaller metabolic change at the same relative exercise intensity suggests a failure of muscle activation that is present even in mild MS. Neurophysiologic measures of activation indicated some central activation failure and no neuromuscular junction impairment in MS, and suggested that activation failure beyond the muscle membrane (excitation-contraction coupling) may be important in MS. We conclude that metabolic factors do not play a significant role in the development of muscle fatigue during voluntary exercise in mild MS.

Topics: Adult; Exercise; Fatigue; Female; Humans; Isometric Contraction; Magnetic Resonance Spectroscopy; Male; Multiple Sclerosis; Muscles; Phosphates; Phosphocreatine; Phosphorus; Reference Values

We employed diffusion-weighted magnetic resonance spectroscopy (DW-MRS), which allows to measure in vivo the diffusion properties of metabolites, to explore the functional neuro-axonal damage and the ongoing energetic dysregulation in multiple sclerosis (MS).. Twenty-five patients with MS and 18 healthy controls (HC) underwent conventional magnetic resonance imaging (MRI) and DW-MRS. The apparent diffusion coefficient (ADC) of total N-acetyl-aspartate (tNAA) and creatine-phosphocreatine (tCr) were measured in the parietal normal-appearing white matter (NAWM) and in the thalamic grey matter (TGM). Multiple regressions were used to compare metabolite ADCs between groups and to explore clinical correlations.. In patients compared with HCs, we found a reduction in ADC(tNAA) in the TGM, reflecting functional and structural neuro-axonal damage, and in ADC(tCr) in both NAWM and TGM, possibly reflecting a reduction in energy supply in neurons and glial cells. Metabolite ADCs did not correlate with tissue atrophy, lesional volume or metabolite concentrations, while in TGM metabolite ADCs correlated with clinical scores.. DW-MRS showed a reduction in tCr diffusivity in the normal-appearing brain of patients with MS, which might reflect a state of ongoing energy dysregulation affecting neurons and/or glial cells. Reversing this energy dysregulation before neuro-axonal degeneration arises may become a key objective in future neuroprotective strategies.

Topics: Adult; Aspartic Acid; Atrophy; Creatine; Diffusion Magnetic Resonance Imaging; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Phosphocreatine; Thalamus; White Matter

Two studies using (31)P-magnetic resonance spectroscopy (MRS) reported enhanced phosphocreatine (PCr) levels in normal appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but this finding could not be properly explained.. We performed (31)P-MRS and (1)H-MRS in the NAWM in 36 subjects, including 17 with progressive MS, 9 with benign MS, and 10 healthy controls. Compared to controls, PCr/beta-ATP and PCr/total (31)P ratios were significantly increased in subjects with progressive MS, but not with benign MS. There was no correlation between PCr ratios and the N-acetylaspartate/creatine ratio, suggesting that elevated PCr levels in NAWM were not secondary to axonal loss. In the central nervous system, PCr is degraded by creatine kinase B (CK-B), which in the white matter is confined to astrocytes. In homogenates of NAWM from 10 subjects with progressive MS and 10 controls without central nervous system disease, we measured CK-B levels with an ELISA, and measured its activity with an enzymatic assay kit. Compared to controls, both CK-B levels and activity were decreased in subjects with MS (22.41 versus 46.28 microg/ml; p = 0.0007, and 2.89 versus 7.76 U/l; p<0.0001).. Our results suggest that PCr metabolism in the NAWM in MS is impaired due to decreased CK-B levels. Our findings raise the possibility that a defective PCr metabolism in astrocytes might contribute to the degeneration of oligodendrocytes and axons in MS.

Topics: Adenosine Triphosphate; Aspartic Acid; Astrocytes; Brain; Case-Control Studies; Creatine Kinase, BB Form; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Models, Biological; Multiple Sclerosis; Phosphocreatine; Postmortem Changes

Multiple sclerosis (MS) plaques and age related white matter lesions (WML) are of similar morphological appearance on T2 weighted MRI. Therefore their differentiation is sometimes crucial. Proton magnetic resonance spectroscopy ((1)H-MRS) adds metabolic information to conventional imaging and may help to distinguish inflammatory MS plaques from vascular related WML. This study was performed to evaluate the metabolite pattern in MS plaques and WML. 15 MS patients, 14 elderly individuals with WML and 16 controls were investigated by conventional MRI and short echo quantitative (1)H-MRS (TE: 30ms, TR: 3000ms). The mean metabolite concentrations in normal control white matter (NCWM), MS plaques and WML were: t-NAA: 8.96 mmol/l (SD: 0.93) vs 6.79 mmol/l (SD: 1.99) vs 7.18 mmol/l (SD: 1.41); Cho:1.66 mmol/l (SD: 0.4) vs 1.49 mmol/l (SD: 0.45) vs 1.46 mmol/l (SD: 0.34); PCr:5.64 mmol/l (SD: 0.83) vs 4.9mmol/l (SD: 1.3) vs 4.95 mmol/l (SD: 0.86); myo-Ins: 4.57 mmol/l (SD:1.05) vs 6.34 mmol/l (SD: 2.03) vs 4.5 mmol/l (SD: 0.96). t-NAA reduction in MS plaques and WML was significant compared with controls (p

Topics: Adult; Aged; Analysis of Variance; Aspartic Acid; Brain; Case-Control Studies; Creatine; Female; Fourier Analysis; Humans; Inositol; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Multiple Sclerosis; Phosphocreatine

In vivo proton magnetic resonance spectroscopy (1H-MRS) has been used to assess biochemical changes that occur in demyelinating lesions and in normal appearing white matter (NAWM) in multiple sclerosis (MS) patients. N-acetylaspartate (NAA) levels in MS patients may indicate neural viability. In early stages of MS, patients may suffer from slight cognitive impairment. The objective of this study was to investigate memory function in relation to biochemical properties of frontal brain areas of MS patients. Twenty-one patients with relapsing-remitting MS and 21 healthy comparison subjects were examined psychometrically using the Wechsler Memory Scale (WMS) and the Multiple Sclerosis Functional Composite (MSFC) scale, and (1H-MRS) was used to examine frontal deep white matter (left hemisphere) and the frontal cingulate gyrus (Brodmann areas 24/32, bihemispheric). A significant reduction of the NAA/Creatine (Cr) ratio in the frontal cingulate gyrus among the MS patient group was detected when compared to healthy subjects. A significant decrease in the NAA/Cr ratio was also found in volumes of cerebral deep white matter, including plaques, in the MS patients. No NAA/Cr ratio changes were found in NAWM. Differences in MSFC results did not reach statistical significance, but the WMS general memory score showed a significant statistical difference between the patient group and healthy subjects. Regression analysis showed the gray matter NAA/Cr ratio of the frontal cingulate gyrus to be significantly related to distinct memory functions. The authors conclude that (1H-MRS) of gray matter in early stages of MS may be pertinent in the detections of early metabolic disturbances, particularly in subjects with or without minor neurological impairment. Findings suggest a general relationship between the metabolic status of the frontal cortices and memory function.

Topics: Adolescent; Adult; Aspartic Acid; Choline; Disability Evaluation; Female; Frontal Lobe; Humans; Magnetic Resonance Spectroscopy; Male; Memory; Multiple Sclerosis; Neuropsychological Tests; Phosphocreatine; Protons; Statistics, Nonparametric

Brain MRI in multiple sclerosis (MS) frequently shows areas of hypointensity in the white matter on T1 weighted sequences ("T1 black holes"). These areas are thought to be consistent with irreversible axonal loss. In this study T1 black holes were characterized in Theiler's Murine Encephalitis Virus infection, an established model of demyelinating diseases in mice. The spectrum of TMEV is broad in different strains. C57BL/6J mice develop a self-limited brain disease, which resolves within 4-6 weeks. We followed six mice with serial MRI and MRS on days 0, 3,7,21 and 45. The studies were performed in a 7 Tesla magnet. Periventricular and parahippocampal T1 black holes seen as early as 3 days, with decreasing NAA/Cre ratio on MRS. The extent of pathology was most severe on days 3 and 7. T1 black holes are thought to be consistent with areas of irreversible axonal loss. This is challenged by our observations of resolution of T1 black holes by day 45. This was concomitant with the normalization of MRS findings in the areas of interest. We conclude that T1 black holes may represent a transient phenomenon in this model of MS. The recovery of these areas studied suggests an active repair mechanism.

Topics: Animals; Aspartic Acid; Brain; Brain Chemistry; Cardiovirus Infections; Choline; Creatine; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Phosphocreatine

Normal-appearing white matter (NAWM) in established multiple sclerosis has been shown to be abnormal using a variety of magnetic resonance (MR) techniques, including proton MR spectroscopy ((1)H-MRS), although the stage at which these changes first appear is less clear. Using a 1.5 T scanner and single-voxel (1)H-MRS [TR 3000 ms, TE 30 ms, point-resolved spectroscopy (PRESS) localization], we determined NAWM metabolite concentrations in 96 patients a mean of 19 weeks (range 12-28 weeks) after onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis and in 44 healthy control subjects. Absolute concentrations of N-acetyl-aspartate, total creatine and phosphocreatine (Cr), choline-containing compounds, glutamate plus glutamine, and myo-inositol (Ins) were estimated automatically using the LCModel. Compared with control subjects, the concentration of Ins was elevated in CIS NAWM (mean 3.31 mM, SD 0.86 versus mean 3.82 mM, SD 1.06; P = 0.001). The increase in Ins was also seen in the patient subgroup with abnormal T2-weighted MRI (mean 3.88 mM, SD 1.10; P = 0.001) and in those who satisfied the McDonald criteria for multiple sclerosis (mean 4.04 mM, SD 1.31; P = 0.001). An increase in Cr was also observed in CIS NAWM (P = 0.023), but other metabolites did not significantly differ between the whole CIS group and control subjects. There was no significant correlation between NAWM Ins and T2 lesion load. The early increase in Ins may reflect a process of pathogenic importance in multiple sclerosis NAWM. Follow-up studies will investigate whether the increase in NAWM Ins is of prognostic importance for future relapses and disability.

Topics: Adolescent; Adult; Aspartic Acid; Biomarkers; Brain; Creatine; Female; Humans; Inositol; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Phosphocreatine; Prospective Studies; Syndrome

Involvement of the autonomic system in multiple sclerosis (MS) may concur with dysfunction of the cardiovascular system. The introduction of potentially cardiotoxic immunosuppressive drugs like Mitoxantrone into the treatment of MS warrants proper assessment of preexisting heart disease. However, systematic analyses of functional and metabolic derangements in MS are missing. Using quantitative 31P-MR-spectroscopy (MRS) and MR-imaging (MRI) metabolic and functional parameters were analyzed in patients with MS in comparison to healthy volunteers.. 14/15 patients with MS could be included in the study, as the MRS examination of one patient had to be excluded from analysis due to movement during the examination. Using chemical shift imaging (CSI) and AMARES, phosphocreatine (PCr) to adenosine triphosphate (ATP) ratios, characterizing myocardial high-energy phosphate metabolism, were determined. Additionally, absolute concentrations of PCr and ATP were calculated by SLOOP (Spatial Localization with Optimal Pointspread Function). Analysis of functional changes was performed by Cine-MRI. 14 healthy volunteers matched for age and gender served as control.. A significant decrease of absolute PCr concentration was observed in patients with MS compared to matched volunteers (p < 0.05), whereas ATP concentrations showed no significant changes (p = 0.27). Metabolite ratios calculated by SLOOP or AMARES showed a tendency to be reduced in patients, however, did not reach significance (p = 0.08, SLOOP; p = 0.47, AMARES). Using volunteers' mean values +/- 2 x SD as cut off value revealed PCr changes in 5 of 14 patients, whereas only 2 also had pathologic PCr/ATP ratios. Functional analysis by MRI depicted depressed left ventricular ejection fraction in 4 patients.. The reduction in cardiac high-energy phosphates in some patients with MS points to a subclinical involvement of the heart. This may be important for treatment with potentially cardiotoxic drugs. Longitudinal studies are need to understand the clinical relevance of our findings.

Topics: Adenosine Triphosphate; Adult; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Myocardium; Phosphocreatine; Stroke Volume

To test the hypothesis that a lower mean arterial pressure (MAP) response during voluntary isometric exercise in multiple sclerosis (MS) is related to a dampened muscle metabolic signal, 9 MS and 11 control subjects performed an isometric dorsiflexor contraction at 30% maximal voluntary contraction until target failure (endurance time). We made continuous and noninvasive measurements of heart rate and MAP (Finapres) and of intramuscular pH and P(i) (phosphorus magnetic resonance spectroscopy) in a subset of 6 MS and 10 control subjects. Endurance times and change in heart rate were similar in MS and control subjects. The decrease in pH and increase in P(i) were less throughout exercise in MS compared with control subjects, as was the change in MAP response. Differences in muscle strength accounted for some of the difference in MAP response between groups. Cardiovascular responses during Valsalva and cold pressor tests were similar in MS and control subjects, suggesting that the blunted MAP response during exercise in MS was not due to a generalized dysautonomia. The dampened metabolic response in MS subjects was not explained by inadequate central muscle activation. These data suggest that the blunted pressor response to exercise in MS subjects may be largely appropriate to a blunted muscle metabolic response and differences in contracting muscle mass.

Topics: Adult; Autonomic Nervous System; Blood Pressure; Case-Control Studies; Cold Temperature; Electromyography; Female; Heart Rate; Humans; Hydrogen-Ion Concentration; Isometric Contraction; Male; Middle Aged; Multiple Sclerosis; Muscle Fatigue; Muscle, Skeletal; Phosphates; Phosphocreatine; Valsalva Maneuver

1H magnetic resonance spectroscopy (MRS) provides a unique tool to detect and quantify brain metabolites. In multiple sclerosis it can be used to investigate axonal loss or dysfunction through measurement of N-acetyl aspartate (NAA), a neuronal marker. Previous studies in adults have reported variable effects of aging on metabolite concentrations but have predominantly focused on changes in the elderly. This study has examined a younger adult age group to provide a reference database more applicable to the multiple sclerosis population. Single voxel (1)H MRS was carried out in 44 subjects between 22 and 62 years of age. Sixteen subjects underwent repeat examination after one year. Absolute concentrations of NA (the sum of NAA and N-acetyl aspartate glutamate), NAA, creatine/phosphocreatine (Cr), choline containing compounds (Cho) and myo-inositol (mI) were measured. NA, NAA and mI concentrations did not correlate with age but there were significant correlations between age and Cr (r = 0.43, p = 0.004) and Cho (r = 0.38, p = 0. 011) concentrations. No significant differences in metabolite concentrations were seen over one year. This study provides evidence that age-related changes of metabolite concentrations occur even in a young to middle aged adult population. This emphasizes the need to perform absolute quantification of metabolite concentrations rather than ratios and the importance of age-matching in (1)H MRS studies of multiple sclerosis.

Topics: Adolescent; Adult; Aged; Aging; Aspartic Acid; Brain Chemistry; Choline; Creatine; Female; Humans; Inositol; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Phosphocreatine

The objective of this study was to characterize and compare the proton magnetic resonance spectrum of a voxel, containing lesions or normal-appearing white matter (NAWM), in primary-progressive (PP) and secondary-progressive (SP) multiple sclerosis (MS) patients. Single-voxel proton magnetic resonance spectroscopy and magnetic resonance imaging were performed in 35 MS patients (17 PP and 18 SP) and 17 controls. Spectra from an 8 ml voxel located in the parieto-occipital region were obtained with a spin-echo pulse sequence (1600 ms/135 ms/256, TR/TE/acquisitions). Resonance areas due to N-acetylaspartate (NAA), creatine/phosphocreatine (Cr) and choline compounds (Cho) were determined, and results expressed in terms of area in arbitrary units or as metabolite ratios. With respect to the control group, there were significant reductions in NAA and NAA/Cho ratio in the PP-lesion, SP-lesion, PP-NAWM and SP-NAWM groups. There were no significant differences between the PP-NAWM and SP-NAWM groups. These results support the existence of metabolic changes in the white matter of PP and SP patients and suggest that there is neuronal damage and/or loss in both clinical courses. Finally, characterization of the parieto-occipital region showed no significant differences in the spectral pattern of NAWM between PP and SP clinical courses of MS.

Topics: Adult; Aged; Aspartic Acid; Brain; Choline; Creatine; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Phosphocreatine

The aim of this research was to obtain an absolute quantification of the N-acetyl-aspartate, choline, creatine and phosphocreatine levels in normal-appearing white matter by means of 1H magnetic resonance spectroscopy in a group of multiple sclerosis patients (27 with the relapsing-remitting form and 13 with the secondary progressive form). These values were compared with those of a group of 12 age-matched healthy control subjects. A significant decrease in the N-acetyl-aspartate concentration was found in normal-appearing white matter of frontal and parietal brain areas in multiple sclerosis patients compared with the same areas in control subjects. This reduction was more evident in progressive patients. The decrease in the N-acetyl-aspartate concentration in normal-appearing white matter significantly correlated with the Expanded Disability Status and the lesional load. No significant change was found in the concentration of creatine or choline. This finding concurs with previous evidence of heterogeneity in the multiple sclerosis pathological process which is not confined to the lesions and involves not only myelin, but also axons, even in white matter which appears normal on MRI.

Topics: Adult; Algorithms; Aspartic Acid; Brain; Choline; Creatine; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Multiple Sclerosis; Phosphocreatine

Conventional MR imaging of multiple sclerosis (MS) provides relatively poor pathologic specificity, which has led to the investigation of more sophisticated MR techniques. The purpose of this study was to combine magnetization transfer (MT) imaging and proton MR spectroscopic imaging (MRSI) to evaluate the specific pathologic features of myelination and neuronal integrity in patients with MS and to determine the relationship between these measures within plaques.. We acquired conventional MR, MT, and proton MRSI data and evaluated clinical disability in 30 patients with MS, whose conditions were categorized as relapsing-remitting, primary progressive, or secondary progressive. The lesions were classified, using a semiautomated edge-following technique, on T2-weighted MR images, and an analysis of MT and proton MRSI data was conducted for lesion regions as well as for tissue that was categorized as normal.. The MT ratio (MTR) of normal-appearing white matter in the patients with MS was significantly lower than in the healthy participants, whereas gray matter values were unchanged. MS lesions showed a large reduction in MTR, with old lesions exhibiting a lower MTR than new lesions. The average lesion MTR and the MR spectroscopic imaging-measured relative concentration of N-acetylaspartate, a marker of neuronal integrity, was positively correlated in patients with relapsing-remitting MS. This relationship was strengthened in regions containing new lesions.. The integrated use of MT and MR spectroscopic imaging provides a more complete description of the pathologic features of MS than does conventional MR imaging alone, and our data suggest that axonal damage occurs in step with new demyelination and is not a late feature of the disease.

Topics: Adult; Aspartic Acid; Brain; Brain Chemistry; Creatine; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Phosphocreatine

The current study was designed to determine the relative distribution of decreases of N-acetylasparate (NAA), a marker of axonal damage, between lesions and normal-appearing white matter of patients with established multiple sclerosis and to test for associations between changes in the ratio of NAA to creatine/phosphocreatine (NAA:Cr) in those compartments and changes in disability. Data were collected from a 30-month longitudinal study of 28 patients with either a relapsing course with partial remissons and no progression between attacks (relapsing/remitting) (11 patients) or a course of progressively increasing disability, following a period of relapsing/remitting disease (secondary progressive) (17 patients). Proton magnetic resonance spectroscopic imaging (MRSI) and conventional MRI examinations were performed at 6-8-month intervals with concurrent clinical assessments of disability. General linear models were used to test associations between MRSI, MRI, lesion volume and clinical data. Analysis confirmed that the NAA:Cr ratio is lower in lesions than in the normal-appearing white matter (-15.3% in relapsing/remitting multiple sclerosis and -8.8% in secondary progressive multiple sclerosis). The lower NAA:Cr ratio per unit lesion volume previously observed for secondary progressive relative to relapsing/remitting patients was found to result from a lower ratio (8.2%, P < 0.01) in the normal-appearing white matter rather than from any differences within lesions. The importance of changes in the normal-appearing white matter was emphasized further with the observation that the NAA:Cr ratio in the normal-appearing white matter accounted for most of the observed 15.6% (P < 0.001) decrease in the NAA:Cr ratio in the brains of relapsing/remitting patients over the period of study. The decrease in the NAA:Cr ratio in normal-appearing white matter correlated strongly (P < 0.001) with changes in disability in the relapsing/remitting subgroup. These results add to data suggesting that axonal damage or loss may be responsible for functional impairments in multiple sclerosis. The accumulation of secondary axonal damage in the normal-appearing white matter may be of particular significance for understanding chronic disability in this disease.

Topics: Aspartic Acid; Axons; Brain; Creatine; Disability Evaluation; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Models, Neurological; Multiple Sclerosis; Phosphocreatine; Reference Values; Time Factors; Tissue Distribution

We wanted to compare the metabolite status of brain lesions in different clinical subtypes of multiple sclerosis (MS). Two acute MS lesions with ringlike appearances were also investigated.. Twenty-three clinically stable MS patients, 2 patients with acute relapses, and 15 healthy individuals were examined by MR imaging and localized proton MRS.. No metabolite differences were seen in plaques of different subtypes. Decreased NAA/Cr and NAA/choline ratios as well as increased inositol/Cr ratios were observed in the plaques of the clinically stable or chronic active MS patients as compared with controls. The ring plaques had hyperintense cores with surrounding halos, separated from the cores by rings with low signal intensity in T2-weighted images. The core exhibited a prolonged T2 relaxation time. Proton spectra initially contained lactate.. No differences between the metabolite status of nonacute plaques in different clinical subtypes could be detected. The ring plaques contained lactate signals indicating oedema, inflammation, and macrophage invasion, and may be transition forms between acute oedematous lesions and chronic demyelinated plaques.

Topics: Adult; Aged; Aspartic Acid; Brain; Case-Control Studies; Choline; Creatine; Female; Humans; Inositol; Lactates; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Phosphocreatine

Localized short echo time (TE = 20 ms), stimulated echo acquisition mode, and double spin echo (TE = 135 ms) proton spectroscopy were performed in clearly defined, acute Gadolinium (Gd)-enhancing multiple sclerosis (MS) plaques of 22 patients with clinically definite MS. The resonances of N-acetylated metabolites (NA), creatine/phosphocreatine (Cr), choline-containing compounds (Cho), glycine/myo-inositol (Ino), and lactate were evaluated. The ratios of NA/Cr and NA/Cho were significantly decreased, Cho/Cr increased, and Ino/Cr remained unchanged. No marker peaks or elevated lactate levels were found. The measured metabolic changes were practically independent of the relative plaque size within the volume of interest (8 ml). Thus, the spectral changes measured with 1H MRS in acute Gd-enhancing MS plaques originate not only from the lesion as depicted by MRI, but also from the surrounding normal-appearing white matter.

Topics: Adult; Brain Chemistry; Choline; Contrast Media; Creatine; Gadolinium; Heterocyclic Compounds; Humans; Magnetic Resonance Spectroscopy; Middle Aged; Multiple Sclerosis; Organometallic Compounds; Phosphocreatine

Magnetization transfer imaging (MT) and localized proton spectroscopy (1H-MRS) were utilized in the evaluation of lesions (high signal abnormalities on T2-weighted images) and normal-appearing white matter (NAWM) in multiple sclerosis (MS). Eleven patients with a clinical diagnosis of MS were independently evaluated with both 1H-MRS and MT. The magnetization transfer ratio (MTR) of lesions was compared with the relative concentration of N-acetyl-aspartate (NAA) and a composite peak at 2.1 to 2.6 ppm termed "marker peaks." The MTR of white matter lesions in the MS patients was markedly decreased (6-34%; normal approximately 42%), and correlated well with increase in the marker peaks region (0.94-3.89). There was no correlation between the relative concentration of NAA and MTR. Increased resonance peaks in the 2.1 to 2.6 ppm range and marked decreases in MTR may be a relatively specific indicators of demyelination.

Topics: Adolescent; Adult; Aged; Aspartic Acid; Brain; Choline; Cohort Studies; Creatine; Demyelinating Diseases; Humans; Hydrogen; Image Enhancement; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Middle Aged; Multiple Sclerosis; Phosphocreatine; Signal Processing, Computer-Assisted

To determine whether skeletal muscle oxidative metabolism is impaired in multiple sclerosis (MS), phosphorus magnetic resonance spectroscopy was used to measure the rate of intramuscular phosphocreatine (PCr) resynthesis following exercise in MS and controls. Thirteen MS patients underwent intermittent isometric tetanic contractions of the dorsiflexor muscles elicited by stimulation of the peroneal nerve. Eight healthy control subjects performed voluntary isometric exercise of the same muscles. During exercise, there were no differences between groups in the fall of either PCr or pH. However, the half-time (T1/2) of PCr recovery following exercise was significantly longer in MS (2.3 +/- 0.3 min) compared to controls (1.2 +/- 0.1 min, P < 0.02). These data provide evidence of slowed PCr resynthesis following exercise in MS, which indicates impaired oxidative capacity in the skeletal muscle of this group. This finding suggests that intramuscular changes consistent with deconditioning may be important in the altered muscle function of persons with MS.

Topics: Adult; Exercise; Fatigue; Female; Humans; Male; Multiple Sclerosis; Muscles; Phosphocreatine

The goals of the current study were threefold: first, to confirm previous single volume proton (1H) magnetic resonance spectroscopy results of reduced N-acetyl aspartate (NAA, a putative marker of neurons) in multiple sclerosis (MS) white matter lesions using multiple volume 1H magnetic resonance spectroscopic imaging (MRSI); second, to measure the phospholipid metabolites phosphomonoesters and phosphodiesters in such lesions using phosphorus (31P) MRSI; and third, to test the hypothesis that biochemical changes occur in the normal-appearing (on spin echo T2-weighted magnetic resonance images) white matter in patients with MS. Thirteen subjects with clinically definite MS were studied with both 1H and 31P MRSI, and 19 controls were studied with either 1H MRSI, 31P MRSI, or both. MS lesion, MS normal-appearing white matter, and region-matched control spectra from the centrum semiovale were analyzed. The major findings of this study were that in both white matter lesions and normal-appearing white matter in patients with MS, the metabolite ratio NAA/creatine and the total 31P peak integrals were significantly reduced compared with controls. In addition, in MS lesions NAA/choline and phosphodiesters/total 31P were significantly reduced compared with controls, and in MS normal-appearing white matter there was a trend for NAA/choline to be reduced compared with controls. In normal-appearing white matter in patients with MS, total creatine and phosphocreatine were significantly increased compared to controls, as detected with both 1H (total creatine peak integrals) and 31P (phosphocreatine/total 31P) MRSI techniques. These results suggest reduced neuronal density and altered phospholipid metabolites in white matter lesions in patients with MS.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aspartic Acid; Brain; Choline; Creatine; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Phosphocreatine; Phosphorus

Automated formation of MR spectroscopic images (MRSI) is necessary before routine application of these methods is possible for in vivo studies; however, this task is complicated by the presence of spatially dependent instrumental distortions and the complex nature of the MR spectrum. A data processing method is presented for completely automated formation of in vivo proton spectroscopic images, and applied for analysis of human brain metabolites. This procedure uses the water reference deconvolution method (G. A. Morris, J. Magn. Reson. 80, 547(1988)) to correct for line shape distortions caused by instrumental and sample characteristics, followed by parametric spectral analysis. Results for automated image formation were found to compare favorably with operator dependent spectral integration methods. While the water reference deconvolution processing was found to provide good correction of spatially dependent resonance frequency shifts, it was found to be susceptible to errors for correction of line shape distortions. These occur due to differences between the water reference and the metabolite distributions.

Topics: Artifacts; Aspartic Acid; Body Water; Brain; Choline; Creatine; Electronic Data Processing; Fourier Analysis; Humans; Hydrogen; Image Enhancement; Lactates; Lipid Metabolism; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Multiple Sclerosis; Phosphocreatine; Protons; Water

Localized phosphorus magnetic resonance spectroscopy at 1.5 T was performed in 39 patients with multiple sclerosis and in 15 healthy controls. The multiple sclerosis spectra showed increased creatine phosphate levels. This increase was correlated with the severity of the handicap and was greater in patients with a progressive course of the disease than in patients with relapsing-remitting disease. No clear abnormalities were observed in the spectra of patients with multiple sclerosis regarding the phosphomonoesters, phosphodiesters, inorganic phosphate, and beta-adenosine triphosphate or with respect to pH values. There was an increased creatine phosphate level in the spectra in relation to a low metabolic state of the brain.

Topics: Adenosine Triphosphate; Adult; Aged; Brain; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Organophosphates; Phosphocreatine

Magnetic resonance spectroscopy (MRS) was performed on a superficial part of the brain containing a large multiple sclerosis (MS) lesion. Reduced levels of phosphocreatine (PCr) relative to adenosine triphosphate (ATP) were found suggesting an abnormality in energy metabolism, with an increase in the phosphodiester (PDE) peak. A follow up study 16 months later revealed reduction in size of the lesion on MRI and normal intracellular biochemistry by MRS. Four MS patients without visible superficial cerebral lesions showed no significant changes in phosphorus metabolism.

Topics: Adenosine Triphosphate; Adult; Brain; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Multiple Sclerosis; Phosphocreatine; Phosphoric Diester Hydrolases

Localized proton spectroscopy of the brain was performed on MS patients (n = 18) and the results are compared with those of a control group (n = 17). The experiments were performed in a 1.5-T Siemens Magnetom using the stimulated echo method and selective water suppression. Acquisition parameters were TR/TE/TM = 3000/270/30 ms, NA = 256, and Acq = 13 min. Localized volumes ranged from 8 to about 80 cc. The patients (ages 25 to 66) were at various stages of the disease. Three of the eighteen patients did not show any plaques on the MR images. VOIs were chosen to contain as much plaque volume as possible in the cerebrum white matter. In the controls and in the patients with no plaques, the VOI were localized in similar white matter regions. All spectra were characterized by the presence of Cho (3.2 ppm), PCr + Cr (3.0 ppm), and NAA (2.0 ppm). The ratios NAA/Cho and NAA/(PCr + Cr) were calculated for both the MS and the control group. The results for the three MS patients with no detectable plaques did not differ significantly from the results of the control group. The former group is, however, too limited to draw any conclusion for the moment. For the MRI positive patients, the following values were found (means +/- 1 SD); NAA/Cho = 1.98 +/- 0.33 and NAA/(PCr + Cr) = 2.16 +/- 0.14. In the normals, these values were NAA/Cho = 2.54 +/- 0.39 and NAA/(PCr + Cr) = 2.76 +/- 0.25. The results quoted are TR and TE dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aspartic Acid; Brain; Brain Chemistry; Choline; Creatine; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Multiple Sclerosis; Phosphocreatine