[Accuracy and clinical utility of quantitative proton magnetic resonance spectroscopy (MRS) on phantom and chronic cerebral ischemia].

We quantified the concentration of metabolites observed by proton MRS using the tissue water signal as an internal standard. A phantom containing known concentrations of NAA (10 mM) and Cr (5 mM) was used for the study of methodological accuracy. Clinical utility was evaluated by the measurement of patients with severe stenosis or obstruction of the unilateral internal carotid artery. The concentration of tissue water was compensated using a proton-density weighted image measured with a water bag attached to the head. The calculated concentrations of NAA and Cr in the phantom were 9.2 mM (SD: 1.2) and 5.6 mM (SD: 0.7), respectively. On the ischemic side of the brain, the concentrations of NAA and Cr were lower than on the opposite side, but the concentration of choline (Cho) was almost the same on the two sides. The NAA/Cr ratio showed no statistically significant differences between the two sides, because the concentration of Cr was shown to be decreased in the ischemic area. We consider that quantitative evaluation of proton MRS might reveal changes in single metabolites clearly, thereby facilitating understanding of the results of proton MRS.

Differences in brain metabolites between patients with autism and mental retardation as detected by in vivo localized proton magnetic resonance spectroscopy.

We performed volume-selective proton magnetic resonance spectroscopy (1H-MRS) of the brain with a 1.5 T magnet in 28 patients with autism, and compared the results with those from 28 age-matched patients with unclassified mental retardation and 25 age-matched healthy children. Peaks for N-acetylaspartate, choline and creatine, but not lactate, were observed in each group on 1H-MRS. The N-acetylaspartate/choline ratio was lower in patients with mental retardation than in patients with autism and controls (P = .05, respectively). However, there were no differences in the N-acetylaspartate/ choline ratios between patients with autism and controls, and the N-acetylaspartate/creatine and choline/creatine ratios did not differ among the three groups. These results suggest that N-acetylaspartate is decreased in patients with mental retardation and that a disorder or dysfunction of neurons in the brain exists. There also appear to be differences in the brain lesions or dysfunctions found in patients with autism and mental retardation.

[Age-dependent changes in metabolites of the normal brain in childhood : observation by proton MR spectroscopy].

We investigated aging-dependent changes in proton magnetic resonance spectroscopy (1H-MRS) of the normal brain in childhood, and observed differences in the four portions of the brain. Measurement by 1H-MRS was carried out on the frontal lobe, parietotemporal lobe, temporal lobe and cerebellum. The NAA/Cho ratio increased rapidly in the period from 0 to 2 years of age in all portions except for the cerebellum, and gradually increased after three years of age. The number of measurements of the cerebellum was not sufficient to reach a conclusion, but no clear aging-related change was found. The Cho/Cr ratio decreased according to the neural development in all portions except the cerebellum. Because the T2 relaxation time of water after four years of age was almost the same as that of young adults, we used the relaxation times specified in the literature to quantify the metabolites observed by 1H-MRS. The subjects used for quantification were aged from 4 to 12 years. The concentration of NAA in the temporal lobe was the lowest of the four portions, and that of Cho and Cr in the cerebellum was the highest in four portions. These results could not be obtained by signal ratios alone, and we considered that the quantification of metabolites is necessary for a better understanding of 1H-MRS. This study showed that the results of 1H-MRS vary depending on age and the portion in the brain. Our results may serve as a normal basis for the detection of pathological changes by 1H-MRS.

Therapeutic efficacy of a case of pyruvate dehydrogenase complex deficiency monitored by localized proton magnetic resonance spectroscopy.

We experienced a case of pyruvate dehydrogenase deficiency observed by proton magnetic resonance spectroscopy (1H MRS). This case was diagnosed as West syndrome by characteristic convulsion and the periodic hypsarrhythmia pattern of EEG. At the age of 11 months, the first examination of 1H MRS revealed a high peak of lactate, and the high concentration of lactate and pyruvate was confirmed in sampled cerebrospinal fluid (CSF). Deficiency of pyruvate dehydrogenase complex was finally diagnosed by genetic examination. Dichloroacetate was administered to the patient as therapy. Decrease of lactate in the brain was found by 1H MRS. Lactate and pyruvate in the CSF was also decreased. In accordance with the suspension of dichloroacetate, increase of lactate in the brain was detected and the convulsions reappeared. After readministration of dichloroacetate, the patient was almost symptom free and lactate in the brain and CSF had decreased to the normal extent. We considered that 1H MRS provides useful information for screening metabolic disorders of infants and assessing the efficacy of therapy.

Reduced N-acetylaspartate in the brain observed on in vivo proton magnetic resonance spectroscopy in patients with mental retardation.

Volume-selective proton magnetic resonance spectroscopy (1H-MRS) of the brain was performed with a 1.5T magnet in 28 patients with unclassified mental retardation (MR) and in 25 age-matched healthy children. Peaks of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr), but not of lactate, were observed in both groups on 1H-MRS. In all our subjects of this age range, 1H-MRS revealed an increase with advancing age in the ratio of NAA/Cho (P = .0031), but no developmental change in the NAA/Cr and Cho/Cr ratios. The NAA/Cho ratio was lower in patients with MR than in controls (P = .0016). The NAA/Cr ratio tended to be lower in the MR group, and the Cho/Cr ratio did not differ between patients with MR and controls. These results suggest that in patients with MR, NAA decreases and a disorder and/or dysfunction of neurons in the brain exists.

[A trial for quantification of proton MR spectroscopy: relaxation times of each metabolite and concentration using water signal as an internal standard].

We conducted quantification of proton MR spectroscopy (1H-MRS) using water signal as an internal standard. The 1H-MR spectrum was measured with and without water suppression pulses. For calculation of relaxation times, measurement conditions of the PRESS sequence were as follows: TR = 1500, 3000, 5000 ms, TE = 135,270 ms. The T1 relaxation and T2 relaxation of each metabolite were calculated by fitting to the curve of the equation of the spin echo sequence. The signal intensities of each metabolite were corrected using relaxation times and such corrected intensities were used for the quantitative calculation. The concentration of each metabolite was obtained from ratios of the corrected intensities of water and metabolites. The value of each concentration was coincident with that reported in the previous literature. We considered that this quantification using water signal as an internal standard would be very useful when the proton-weighted image does not show remarkable change.

Proton magnetic resonance spectroscopy of brain in congenital myotonic dystrophy.

Volume selective proton magnetic resonance spectroscopy of brain was performed on a 1.5 T magnet in 5 patients with congenital muscular dystrophy and compared to the results in 46 healthy children and 1 healthy adult. Peaks of N-acetyl aspartate, choline, and creatine but not lactate, were observed in both groups on proton magnetic resonance spectroscopy. Spectroscopy of controls revealed an increase with advancing age in the ratio of N-acetyl aspartate/choline and N-acetyl aspartate/creatine and a decrease in the choline/creatine ratio. In patients with congenital myotonic dystrophy, the N-acetyl aspartate/choline ratio did not increase with advancing age, but the N-acetyl aspartate/creatine ratio did. The choline/creatine ratio decreased with advancing age, which matched the results of controls. At any age older than 4 years, the N-acetyl aspartate/choline and N-acetyl aspartate/creatine ratios were lower in patients with congenital myotonic dystrophy than in controls. The choline/creatine ratio did not differ between congenital myotonic dystrophy and controls. These results suggest that in patients with congenital myotonic dystrophy N-acetyl aspartate decreases and there exists a developmental disorder of neurons in brain.

[Proton MR spectroscopy of the brain in patients with congenital myotonic dystrophy].

Volume selective proton MR spectroscopy (1H-MRS) of the brain was performed on a 1.5T magnet in five patients with congenital muscular dystrophy (CMyD), 46 healthy children, and one healthy adult. Peaks of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were observed in both patients and control groups on 1H-MRS, but lactate was not observed. 1H-MRS revealed an increase in the ratio of NAA/Cho and NAA/Cr, and a decrease in Cho/Cr ratio with age in control subjects. In patients with CMyD, the values of NAA/Cho ratio did not increase with age. The values of NAA/Cr ratio decreased with age. The values of Cho/Cr ratio decreased with age in both patient and control groups. At age more than 4 years, the values of NAA/Cho and NAA/Cr ratios were lower in patients with CMyD than in controls. The values of Cho/Cr ratio did not differ between CMyD and controls. These results suggest that in patients with CMyD, there is an NAA decrease and a developmental disorder of neurons in the brain.

Developmental brain changes investigated with proton magnetic resonance spectroscopy.

Volume-selective proton magnetic resonance spectroscopy (1H-MRS) of the brain was performed with a 1.5 Tesla magnet in 47 healthy children and in six healthy adults. Peaks of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were observed in all cases, but a lactate peak was not observed. In the right parietal region. 1H-MRS revealed increases in the rations of NAAJCho and NAA/Cr and a decrease in Cho/Cr with advancing age. The most rapid changes were noted between one and three years of age. 1H-MRS of the right frontal region also was performed in 21 cases (20 children and one adult). In the right frontal region, there was an increase in the ratio of NAA/Cho and a decrease in Cho/Cr with advancing age, while a developmental change was not observed in the ratio of NAA/Cr. The ratios of both NAA/Cho and NAA/Cr were lower in the right frontal region than in the right parietal region. These results show that developmental changes and regional variation of metabolites are observed in 1H-MRS of the brain, and need to be considered in its application.

Non-invasive characterization of brain tumor by in-vivo proton magnetic resonance spectroscopy.

We studied the feasibility of characterizing brain tumor tissue by localized proton magnetic resonance spectroscopy (1H-MRS). Twenty-six newly diagnosed tumors were examined by in-vivo 1H-MRS. The NAA (N-acetylaspartate)/Cho (choline) ratio of Grade 2 astrocytoma was higher than that of Grade 4. The Cho/Cr (creatine and phosphocreatine) ratio of meningioma was considerably higher than that of glioma of all grades. We have experienced only two cases of ependymoma and the Cho/Cr ratios of both were lower than that of glioma. It seems likely that 1H-MRS can be used to differentiate Grade 2 from Grade 4 in most cases of astrocytoma based on the NAA/Cho ratio, though a few cases will overlap. Meningioma can be distinguished easily from glioma, and the results of our study suggest that ependymoma shows a characteristic pattern on 1H-MRS, different from those of other brain tumors.

Brain abscess observed by localized proton magnetic resonance spectroscopy.

We encountered a case of brain abscess that was difficult to differentiate from glioblastoma. Localized 1H-MRS was found to be useful for obtaining information on the biochemical status of brain abscess. The peak of lipid and high residual peak of NAA (N-acetyl-aspartate) were observed in the cystic lesion of the brain abscess by 1H-MRS. The NAA/Cho (Choline-containing compounds) ratio in brain parenchyma showing an edematous lesion before therapy gradually increased with the relief of inflammation.

[Developmental changes in proton MR spectroscopy of the brain].

Volume-selective proton MR spectroscopy (1H-MRS) of the brain was performed on a 1.5 T magnet in 31 healthy children aged from 1 month to 15 years and one healthy adult. Peaks of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were observed in all cases on 1H-MRS, but not lactate. On 1H-MRS of the right parietal region, with advancing age, 1H-MRS revealed an increase in the ratios of NAA to Cho and NAA to Cr and a decrease in Cho to Cr. The most rapid change was noted during the first one to three years of life. 1H-MRS of the right frontal region was also performed in eleven cases. The ratio of NAA/Cho was smaller in the right frontal region than in the right parietal region. From this result, it may be suggested that the neuronal maturation in the frontal region delays as compared with the parietal region.

[Eight cases of intracranial arteriovenous malformations treated by conventional radiation therapy].

We conducted radiotherapy in 8 cases of intracranial arteriovenous malformation that had difficult embolectomy and other surgery from 1983 to October, 1988. The results in 6 cases of dural arteriovenous malformation at the cavernous sinus were "marked effect" in 4 cases, "relapse" in 1 case, and "no effect" in 1 case. One case of dural arteriovenous malformation at the sigmoid venous sinus demonstrated only slight irradiation effect. No irradiation effect was observed in 1 case of cerebral arteriovenous malformation.

Simultaneous deletion of the intervening sequences from the human interferon-gamma gene by oligodeoxynucleotide-directed mutagenesis.

Oligodeoxynucleotide (oligo)-directed mutagenesis was used to simultaneously delete the three intervening sequences (IVS) from the human interferon-gamma (IFN-gamma) gene. Prior to the deletion experiment, the two largest IVS of the native gene were shortened by restriction enzyme digestion and subsequent ligation (IVS-1 was reduced from 1239 bp to 399 bp and IVS-3 from 2425 bp to 183 bp). This modified gene was cloned into vector M13mp9. Three oligos [21-25 nucleotides (nt) long] were synthesized, one to bridge each of the three introns. A different set of three oligos was made for use as hybridization probes to identify colonies containing the correct deletion. A study was made of enzymatic reaction and primer annealing conditions needed to optimize intron deletions. The efficiency of the simultaneous deletions was higher than the product of the efficiencies of the deletions of the individual IVS, suggesting that the deletion events are not independent. The gene created by the simultaneous deletion was cloned into an Escherichia coli plasmid expression vector and IFN-gamma activity was produced.

Proposal of standardized methods and reference for assaying recombinant human tumor necrosis factor.

Two assay methods for recombinant human tumor necrosis factor (rH-TNF) were developed, one a biological L-cell assay and the other an enzyme-linked immunosorbent assay. The accuracy and reproducibility of each and the correlation between the two were studied. As a result of this investigation, the two assay methods were found appropriate for standardization of rH-TNF. A freeze-dried reference was prepared, and examination of its potency and stability showed it to be suitable for use as a reference standard for rH-TNF assays.