N-acetylaspartate: usefulness as an indicator of viable neuronal tissue.
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Aspartic Acid↗
Biomedical subjects
D L Arnold
Publications and source records attributed to D L Arnold.
Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects.
Aerobic training has been shown to increase work and oxidative capacity in patients with mitochondrial myopathies, but the mechanisms underlying improvement are not known. We evaluated physiological (cycle exercise, 31P-MRS), biochemical (enzyme levels), and genetic (proportion of mutant/wild-type genomes) responses to 14 weeks of bicycle exercise training in 10 patients with heteroplasmic mitochondrial DNA (mtDNA) mutations. Training increased peak work and oxidative capacities (20-30%), systemic arteriovenous O2 difference (20%), and 31P-MRS indices of metabolic recovery (35%), consistent with enhanced muscle oxidative phosphorylation. Mitochondrial volume in vastus lateralis biopsies increased significantly (50%) and increases in deficient respiratory chain enzymes were found in patients with Complex I (36%) and Complex IV (25%) defects, whereas decreases occurred in 2 patients with Complex III defects (approximately 20%). These results suggest that the cellular basis of improved oxygen utilization is related to training-induced mitochondrial proliferation likely resulting in increased levels of functional, wild-type mtDNA. However, genetic analysis indicated the proportion of wild-type mtDNA was unchanged (3/9) or fell (6/9), suggesting a trend toward preferential proliferation of mutant genomes. The long-term implications of training-induced increases in mutant relative to wild-type mtDNA, despite positive physiological and biochemical findings, need to be assessed before aerobic training can be proposed as a general treatment option.
Adult↗
Modeling in vivo recovery of intracellular pH in muscle to provide a novel index of proton handling: application to the diagnosis of mitochondrial myopathy.
Post-exercise recovery of intracellular pH (pH(i)) assessed using phosphorus magnetic resonance spectroscopy has not been previously evaluated in its entirety due to its complex time-course and missing data points resulting from a transient loss of inorganic phosphate signal. By considering the transition from exercise to recovery as a step function input, pH(i) recovery was modeled based on the creatine-kinase equilibrium, and the entire pH(i) recovery was characterized by calculating the time required for pH(i) recovery (t(pHrec)). Applying this methodology, normal subjects showed a strong linear correlation between phosphocreatine (PCr) half-time and t(pHrec) (r = 0.90, P < 0.001). In mitochondrial myopathy (MM) patients with weakness in the limb examined, 9/10 had faster pH(i) recovery relative to PCr recovery; wide normal ranges from a control group which included deconditioned subjects resulted in 7 of those 10 patients having otherwise normal recovery indices. Therefore, modeling pH(i) recovery allows characterization of the entire pH(i) recovery and detects altered proton handling in MM patients, including those with otherwise normal recovery indices.
Adult↗
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.
Adjuvants, Immunologic↗
Toxicological consequences of toxaphene ingestion by cynomolgus (Macaca fascicularis) monkeys. Part 1: pre-mating phase.
A total of 40 menstruating cynomolgus monkeys (Macaca fascicularis) with an average age of 7.25 +/- 1.06 years (standard deviation), five male cynomolgus monkeys with an average age of 12.6 +/- 0.66 years, and five male cynomolgus males with an average age of 6.2 +/- 0.23 years were obtained from the Health Canada breeding laboratory. The females were initially randomized to the four test groups in accordance with their previous reproductive success and body weight. They were then randomly allocated between two similar environmentally-controlled rooms (20 females/room). The males were randomly assigned to one of the test rooms (six or four males/room). The female test groups self-ingested capsules containing doses of 0, 0.1, 0.4 or 0.8 mg (Groups A, B, C, D) of technical grade toxaphene/kg body weight/day (i.e. five females/dose group/room). The older males (Group E) were proven breeders and were used exclusively for mating and their capsules contained no toxaphene. The younger males (Group F) ingested capsules containing 0.8 mg of technical grade toxaphene/kg body weight/day. After 20 weeks of daily dosing, it was assumed, based on the results of a pilot study [Andrews P., Headrick K., Pilon J.-C., Bryce F., Iverson F. (1996) Capillary GC-ECD and ECNI GCMS characterization of toxaphene residues in primate tissues during a feed study. Chemosphere 32, 1043-1053], that the treated monkeys had attained a qualitative pharmacokinetic steady state regarding the concentration of toxaphene in their adipose tissue and blood. On a daily basis, each monkey's feed and water consumption as well as its health were monitored. In addition, the females were swabbed daily to determine menstrual status. On a weekly basis, each monkey's body weight was determined and its dose of toxaphene adjusted. Detailed clinical examinations were conducted at intervals of 4 weeks or less. Periodically, starting prior to the initiation of dosing, blood samples were taken for serum biochemistry, haematology and toxaphene analysis. In addition, specimens from the nuchal fat pad were also obtained for toxaphene analysis. Statistical analysis did not reveal any effect of treatment on body weight gain, feed consumption, water consumption or haematological parameters during the 75-week pre-mating phase. The only serum biochemistry parameter which was consistently affected by treatment was cholesterol, the level of which decreased in a linear fashion as a consequence of dose, and this effect increased with time on test (P = 0.037). No other biological effects of toxaphene ingestion were found during the premating phase of this toxicological-reproduction study.
Administration, Oral↗
Effects of toxaphene on the immune system of cynomolgus (Macaca fascicularis) monkeys.
Toxaphene, dissolved in glycerol/corn oil, was administered at 0.1, 0.4 or 0.8 mg/kg body weight/day in gelatin capsules to groups of 10 young adult female cynomolgus monkeys (Macaca fascicularis), while a group of five male monkeys (Macaca fascicularis) received 0.8 mg/kg body weight/day. Control male (a group of five) and female (a group of 10) monkeys ingested the glycerol/corn oil vehicle only. Treatment continued for 75 weeks. Testing for immune effects was initiated at 33 weeks of treatment. Immunization was initiated at 44 weeks of treatment. Pairwise comparisons between each of the treated female groups to the control indicated that the mean primary (post-immunization weeks 1-4) and secondary (post-immunization weeks 5-8) anti-SRBC IgM responses were significantly reduced at the 0.4 and 0.8 mg/kg body weight/day doses compared to the control (P< or =0.05). The mean primary (post-immunization weeks 1-4) anti-SRBC IgG response was significantly reduced compared to the control (P< or =0.05), while the secondary (post-immunization weeks 5-8) anti-SRBC IgG was not significantly affected by treatment (P>0.05). The mean anti-tetanus toxoid IgG response in the 0.8 mg/kg body weight/day dose group The mean primary anti-SRBC (IgM) response in the treated males was significantly different from the control (P<0.05), while the primary anti-SRBC IgG response was not affected by treatment. The mean absolute B-lymphocyte numbers in the female group administered 0.8 mg/kg of toxaphene was significantly reduced compared to the control (P< or =0.05). All other parameters including the natural killer cell activity, the delayed-type hypersensitivity response, the lymphoproliferative response of peripheral blood leukocytes to the mitogens Con A and PWM and the serum cortisol levels were not affected significantly by treatment (P>0.05). The no-observed-adverse-effect level (NOAEL) for the female monkeys based on the toxaphene effects on humoral immunity was 0.1 mg/kg body weight/day.
Administration, Oral↗
Effects elicited by toxaphene in the cynomolgus monkey (Macaca fascicularis): a pilot study.
Toxaphene, which was added to glycerol/corn oil, was administered at a level of 1 mg/kg body weight/day in gelatin capsules to four healthy young adult cynomolgus (Macaca fascicularis) monkeys for 52 weeks. Four control monkeys ingested capsules containing only glycerol/corn oil. Each group had two males and two females. On a daily basis, each monkey's feed and water consumption was determined, its health was monitored and the females were swabbed to evaluate menstrual status. On a weekly basis, each monkey's body weight was determined and a detailed clinical evaluation was performed. At 4-week intervals, blood samples were taken for serum biochemistry, haematology and toxaphene analysis. Also, a local anaesthetic was administered to the nuchal fat pad area of each monkey, and adipose samples were obtained for toxaphene analysis. 1 day prior to the biopsies, a 24-h urine and faecal collection was obtained for toxaphene analysis. After 34 weeks of treatment, the immune system of the monkeys was evaluated. After 52 weeks of dosing, all treated and two control animals were necropsied. Liver samples were obtained and microsomal fractions were prepared immediately. A portion of liver and kidney was taken for toxaphene analysis. All of the major internal organs were weighed and bone marrow evaluations were conducted. Organ and tissue samples were fixed in 10% formalin and processed for light microscopy. There was no effect of treatment on body weight gain, feed consumption, water consumption or haematological parameters. Two major clinical findings were inflammation and/or enlargement of the tarsal gland and impacted diverticulae in the upper and lower eye lids. At necropsy, the relative spleen and thymus weights were greater for the treated monkeys than the controls. Toxaphene administration produced an increase in metabolism of aminopyrene, methoxyresorufin and ethoxyresorufin, three substrates that are altered specifically by cytochrome P450-based hepatic monooxygenase enzymes. Histopathological examination of tissues was unremarkable by light microscopy. Tissue analysis for toxaphene and immunology findings have been published elsewhere.
Administration, Oral↗
Time course of postoperative recovery of N-acetyl-aspartate in temporal lobe epilepsy.
PURPOSE: To assess the time course of increases in N-acetyl-aspartate/creatine (NAA/Cr), which can be measured using proton MR spectroscopic imaging (1H-MRSI), in patients with intractable nonlesional temporal lobe epilepsy (TLE) after successful epilepsy surgery. METHODS: We performed pre- and postoperative 1H-MRSI in 16 seizure-free (SF) patients and 16 not seizure-free (NSF) TLE patients. We calculated a mixed-design analysis of variance (ANOVA) between SF and NSF groups, ipsi- and contralateral to the side of operation, and pre- and postoperative NAA/Cr measurements. We applied nonlinear regression between pre- and postoperative NAA/Cr differences and the time interval between 1H-MRSI scans to fit a negative exponential model to NAA recovery. RESULTS: Mixed-design ANOVA revealed that (a) postoperative NAA/Cr was significantly higher in SF than in NSF patients (p = 0.02) and that (b) in the SF group, postoperative NAA/Cr values were significantly higher than preoperative values (p < 0.05) and returned to the normal range in most patients. According to our nonlinear regression model, in SF patients, there was a 50% increase relative to preoperative NAA/Cr values after 5.8 months, whereas an improvement of 95% was reached after 25 months. CONCLUSIONS: Our results extend preliminary observations of postoperative NAA recovery of SF patients by characterizing the time course of recovery as an exponential function with a half-time of approximately 6 months. The reversal of neuronal metabolic dysfunction remote from the epileptic focus may underlie the clinical observation of improvement of cognitive dysfunction after successful epilepsy surgery.
Adolescent↗
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.
Adult↗
Magnetic resonance imaging of multiple sclerosis: new insights linking pathology to clinical evolution.
Magnetic resonance imaging methods allow observation of pathological changes in vivo. Magnetic resonance-based studies have provided a number of important insights into the spatio-temporal evolution of the pathology of multiple sclerosis in vivo, particularly with respect to the relation between pathology and progression of disability. Magnetic resonance techniques have shown that this pathology is not restricted to the plaques that are evident at autopsy, but also involve the so-called normal-appearing white matter. Nonconventional magnetic resonance imaging strategies such as magnetization transfer imaging and spectroscopic imaging provide measures with higher pathological specificity for myelin and axonal injury. These and other advanced magnetic resonance techniques (such as the measurement of atrophy, lesion relaxation spectra, and lesion dynamics) are affording opportunities to use observations of patients to test biologically specific hypotheses. This should help us to better define new targets for drug therapy and to assess responses to new therapeutic agents.
Aspartic Acid↗
Texture analysis and morphological processing of magnetic resonance imaging assist detection of focal cortical dysplasia in extra-temporal partial epilepsy.
In many patients, focal cortical dysplasia (FCD) is characterized by minor structural changes that may go unrecognized by standard radiological analysis. To increase the sensitivity of magnetic resonance imaging (MRI) for the detection of subtle lesions of FCD, we developed voxel-based image postprocessing methods, including first-order texture analysis and morphological processing modeled on known MRI features of FCD. We selected 16 patients with histologically proven FCD. Image processing features were calculated over a neighborhood for each voxel in the three-dimensional T1-weighted MRI. Three feature maps were generated: (1) gray matter thickness map to model cortical thickening, (2) gradient map to model blurring of the gray matter-white matter junction, and (3) relative intensity map to model the hyperintense signal within the lesion. Two observers detected lesions on conventional MRI in 8/16 and on ratio maps in 14/16 patients. Sensitivity was 87.5% (14/16) for the ratio maps compared to 50% (8/16) for MRI (p < 0.003). Specificity was 95% (19/20) for ratio maps and 100% (20/20) for MRIs. Cohen's kappa was 0.53 for MRIs, indicating moderate agreement, and 0.83 for ratio maps, indicating strong agreement beyond chance between the 2 observers. The image-processing methods developed in this study improve visual detection of FCD, even in cases where no lesion is obvious on MRI. These techniques could increase the number of patients with partial epilepsy who could benefit from surgery.
Cell Movement↗
Medial temporal lobe neuronal damage in temporal and extratemporal lesional epilepsy.
OBJECTIVE: To assess the extent of medial temporal lobe (TL) abnormalities of the neuronal marker N-acetylaspartate (NAA) in TL and extra-TL lesional partial epilepsy, and to determine whether decreases in NAA are related to lesion location, to lesion pathology, or to the seizures themselves. METHODS: The authors studied 19 patients with intractable partial epilepsy and an isolated structural cerebral lesion (10 TL, 9 extra-TL; 10 cortical dysplasia [CD], 9 non-CD lesions). Proton MRS imaging was used to determine the average relative resonance intensity of NAA for the TL regions of the left and right hemispheres. Values less than two SDs below the mean of normal control subjects were considered abnormal. RESULTS: Fourteen patients (74%) had abnormally low NAA relative to creatine (NAA/Cr) in at least one TL. Three-way analysis of variance (ANOVA; lesion pathology, lesion location, side of NAA/Cr decrease) showed that ipsilateral NAA/Cr was lower than contralateral (p = 0. 04). Three-way ANOVA (lesion location, generalized tonic-clonic seizures, side of NAA/Cr decrease) showed that generalized tonic-clonic seizures were associated with lower TL NAA/Cr (p = 0. 02). Lesion location and pathology showed no main effect on the NAA-to-Cr ratio in either analysis (p > 0.05). Linear regression analyses between seizure duration and NAA/Cr decrease was not significant. CONCLUSION: The authors demonstrated abnormally low TL NAA/Cr in the majority of patients with structural cerebral lesions. This abnormality did not differ with lesion location or pathology. They propose that the altered function of neuronal networks by an isolated structural cerebral lesion results in remote "functional dual pathology."
Action Potentials↗
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.
Adult↗
Is ictal recording mandatory in temporal lobe epilepsy? Not when the interictal electroencephalogram and hippocampal atrophy coincide.
OBJECTIVE: To investigate the concordance between scalp electroencephalogram (EEG) lateralization and side of hippocampal atrophy in patients with temporal lobe epilepsy (TLE). METHODS: We studied 184 consecutive patients with TLE without lesions other than those compatible with mesial temporal sclerosis. In this study, we studied specifically hippocampal atrophy and the results of scalp EEG investigation. Patients were classified according to the localization of interictal epileptiform discharges as unilateral, bilateral asymmetric, and bilateral symmetric. The EEG seizure onsets were also classified separately as unilateral, bilateral asymmetric, and bilateral symmetric. The hippocampal atrophy was determined by volumetric measurements using high-resolution magnetic resonance imaging (MRIVol). RESULTS: Only 3% of patients had discordance between the ictal and interictal EEG lateralizations; however, none of these had unilateral interictal EEG abnormalities. Interictal EEGs were considered unilateral in 62.0% of patients, bilateral asymmetric in 31.5%, and bilateral symmetric in 6.5%. Ictal EEGs were considered unilateral in 63.5% of patients, bilateral asymmetric in 30.0%, and bilateral symmetric in 6.5%. The MRIVol showed unilateral hippocampal atrophy in 60.9% of patients, bilateral asymmetric hippocampal atrophy in 19.0%, symmetric hippocampal atrophy in 3.8%, and normal volumes in 16.3%. There was a significant concordance between MRIVol lateralization and both interictal and ictal EEG lateralization (P<.001). All patients with unilateral hippocampal atrophy had concordant interictal and ictal EEG lateralization. Six (18.2%) of the 33 patients with bilateral asymmetric hippocampal atrophy had MRI lateralization discordant with EEG lateralization. CONCLUSIONS: We found a strong concordance between EEG and MRIVol lateralization in patients with TLE. Unilateral hippocampal atrophy predicted ipsilateral interictal epileptiform abnormalities and ipsilateral seizure onsets with no false lateralization. Previous studies in addition to the present series support that a concordant outpatient EEG evaluation in patients with TLE and unilateral hippocampal atrophy would obviate the need for inpatient EEG monitoring.
Adult↗
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.
Adenosine Diphosphate↗
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.
Energy Metabolism↗
T2 relaxometry can lateralize mesial temporal lobe epilepsy in patients with normal MRI.
In unselected patients with intractable temporal lobe epilepsy (TLE), approximately 15% do not have detectable hippocampal atrophy on MRI. The purpose of this study was to evaluate whether T2 relaxometry can identify hippocampal pathology and lateralize the epileptic focus in patients with intractable TLE, who do not demonstrate hippocampal atrophy on volumetric MRI (MRIV). We selected 14 patients with unilateral TLE who had unilateral atrophy and 11 patients with unilateral TLE who had no evidence of atrophy on MRIV. Images were acquired on a 1.5 T MR scan using a dual echo sequence with 23 contiguous oblique coronal slices in all patients and in 14 healthy subjects. Fitting a single exponential decay equation to the imaging data generated T2 maps. Averages of six slices containing the head, body, and tail of the hippocampus were used to calculate hippocampal T2 relaxation times (HT2). The epileptic focus was defined by history, video-EEG, and surgical response. All TLE patients with hippocampal atrophy and 9/11 (82%) patients with normal MRI had abnormally high HT2 ipsilateral to the epileptic focus. Bilateral abnormal HT2 were found in 6/14 (43%) of patients with unilateral hippocampal atrophy and 2/11 (18%) of patients with normal MRI. However, this increase was always greater ipsilateral to the epileptic focus. Qualitative hippocampal pathology showed gliosis and neuronal loss in 10/14 operated patients with hippocampal atrophy on MRIV and in 5/7 operated patients with normal MRI. In conclusion, hippocampal T2 mapping provides evidence of hippocampal damage in the majority of patients with intractable TLE who have no evidence of atrophy on MRI and can correctly lateralize the epileptic focus in most patients.
Adult↗
Imaging axonal damage in multiple sclerosis by means of MR spectroscopy.
Axonal damage in multiple sclerosis has become an important issue. This has been emphasized by recent in vivo proton magnetic resonance (MR) spectroscopy and in vitro pathology studies that have found axonal damage in both lesions and the surrounding normal-appearing white matter. In particular, proton MR spectroscopy, by monitoring levels of N-acetylaspartate (a putative marker of axonal integrity), has been particularly illuminating, as the extent of axonal injury associated with white matter inflammation and demyelination had not been well appreciated from classical pathology studies. Recent MR data demonstrate that cerebral axonal damage begins and contributes to disability from the earliest stages of the disease. This implies that the apparently primary role of axonal damage and loss in the pathogenesis of the disease should be given due importance, and argues for the early treatment of multiple sclerosis with agents directed not only against inflammation, but also towards axonal protection.
Animals↗