Differential diagnosis between radiation necrosis and tumor recurrence is important in the clinical management of glioma. Multi-modality imaging including proton magnetic resonance spectroscopy ((1)H-MRS) and positron emission tomography (PET) with L-[methyl-(11)C]methionine (MET) was evaluated. Eighteen patients underwent sequential (1)H-MRS and MET-PET. The expressions of metabolites including choline-containing compounds (Cho), creatine phosphate (Cre), and lactate (Lac) were calculated as the ratios of Cho to Cre (Cho/Cre) and Lac to Cho (Lac/Cho). The uptake of MET was determined as the ratio of the lesion to the contralateral reference region (L/R). The final diagnoses were determined by histological examination and/or follow-up MR imaging and clinical course. The Lac/Cho ratio was 0.63 +/- 0.25 (mean +/- standard deviation) in recurrence (7 cases) and 2.35 +/- 1.81 in necrosis (11 cases). The Lac/Cho ratio was significantly different between the two groups (p < 0.01). Consecutive investigation of (1)H-MRS revealed temporary elevation of Cho in 4 of 9 cases of necrosis, which could be identified as false positive findings for recurrence. Including those cases, MET-PET demonstrated significant difference in the L/R ratio between the two groups (2.18 +/- 0.42 vs. 1.49 +/- 0.35, p < 0.01). According to a 2 x 2 factorial table analysis, the borderline values of Lac/Cho and L/R to differentiate recurrence from necrosis were 1.05 and 2.00, respectively.(1)H-MRS is reliable and accessible for the differentiation of recurrence and necrosis, although the temporary elevation of Cho in the course of necrosis should be recognized. Additional MET-PET imaging can establish the diagnosis.

Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

The classic pathway for agonist-induced generation of diacylglycerol is via activation of a phospholipase C-mediated hydrolysis of the "phosphoinositides." We now report findings from a variety of cell types, which indicate that tumor-promoting phorbol diesters, serum, and platelet-derived growth factor activate within seconds the hydrolysis of phosphatidylcholine, as detected by the formation of diacylglycerol and phosphocholine. It is known that phorbol diesters do not stimulate hydrolysis of the phosphoinositides. Yet, in cells prelabeled with either [14C]oleate or [32P]orthophosphate, addition of the tumor promoter phorbol dibutyrate (PBt2) resulted in the rapid generation of both diacylglycerol and phosphatidate in a time- and dose-dependent manner. The fatty acid composition of the phosphatidate most resembled the fatty acid profile of phosphatidylcholine from the same cell type. Taken together, these findings suggested a role for protein kinase C in the generation of diacylglycerol (and phosphatidate) from phosphatidylcholine. To define further the pathways involved, the metabolism of cellular phosphatidylcholine was studied. In cells prelabeled with [3H]choline, addition of PBt2, but not 4 alpha-phorbol, stimulated the formation of intracellular phosphocholine within 45 sec. Furthermore, addition of platelet-derived growth factor (PDGF) or serum to "serum-starved" cells prelabeled with [3H]choline resulted in increased levels of intracellular phosphocholine within 15-30 sec. Thus, the data suggest that agonists that stimulate protein kinase C either directly (e.g., PBt2) or indirectly via activation of phosphoinositide hydrolysis (e.g., PDGF and serum) may stimulate degradation of phosphatidylcholine by phospholipase C in intact cells. However, prior down-regulation of protein kinase C by prolonged pretreatment of cells with PBt2 almost totally abolished subsequent stimulation of phosphatidylcholine degradation by PBt2 but only partially attenuated subsequent stimulation by PDGF and serum. These observations suggest that PDGF and serum act, at least partially, through a protein kinase C-independent mechanism. Lastly, the size of the cellular choline and CDP-choline pools were shown to be small and relatively insensitive to agonist addition, as compared to the size and behavior of the phosphocholine pool. Thus, the rapidly increased levels of phosphocholine (and diacylglycerol) arising in response to agonist addition appear to be derived directly from phosphatidylcholine by a phospholipase C-mediated mechanism.

We report the chemical pathological changes on magnetic resonance spectroscopic images of 4 patients, each of whom had a single large demyelinating plaque. The patients were followed from soon after the onset of the symptoms for a minimum of 7 months to a maximum of 3 1/2 years. We observed increases in the relative resonance intensities of choline-containing compounds, lactate, and myo-inositol inside the lesion acutely. Decreases in relative resonance intensities of N-acetylaspartate and creatine were seen both in and around the magnetic resonance imaging-detected lesions. In all patients neurological deficits improved and creatine, lactate, and myo-inositol resonance intensities normalized during the follow-up. Choline compounds recovered more slowly and were still abnormally high in 1 patient after 7 months. Partial recovery of the N-acetylaspartate resonance was seen for all patients. Evaluation of the relationships between indices of cerebral chemical pathology, brain lesion volumes, and functional disability showed highly significant negative correlations between N-acetylaspartate resonance intensities and both brain lesion volumes (r =-0.80, p < 0.0001) and clinical disability (r =-0.73, p < 0.0001). As N-acetylaspartate is localized solely in neurons in the adult central nervous system, our results suggest that neuronal dysfunction may be a proximate mechanism of disability even in inflammatory disorders primarily affecting myelin and oligodendroglial cells.

The regional distribution of brain metabolites was studied in several cortical white and gray matter areas, cerebellum, and thalamus of young adults with use of quantitative single-voxel proton MRS at 2.0 T. Whereas the neuronal compound N-acetylaspartate is distributed homogeneously throughout the brain, N-acetylaspartylglutamate increases caudally and exhibits higher concentrations in white matter than in gray matter. Creatine, myo-inositol, glutamate, and glutamine are less concentrated in cortical white matter than in gray matter. The highest creatine levels are found in cerebellum, parallel to the distribution of creatine kinase and energy-requiring processes in the brain. Also myo-inositol has highest concentrations in the cerebellum. Choline-containing compounds exhibit a marked regional variability with again highest concentrations in cerebellum and lowest levels and a strong caudally decreasing gradient in gray matter. The present findings neither support a metabolic gender difference (except for a 1.3-fold higher myo-inositol level in parietal white matter of female subjects) nor a metabolic hemispheric asymmetry.

Image-guided localized proton magnetic resonance (MR) spectroscopy of intracranial tumors was performed to correlate spectral patterns and histologic findings. Thirty-six patients were examined prior to any specific treatment. Evaluation based on signal intensity ratios showed that all tumor spectra differed from spectra of healthy brain tissue. Ratios of creatine to choline-containing compounds (Cr/Cho) and nitrogen acetyl-aspartate to Cho (NAA/Cho) were reduced significantly in all tumor spectra compared with spectra of normal tissue in contralateral brain hemispheres (P less than .005). Noncerebral tumors typically showed a vanishing or missing NAA signal, strongly reduced Cr signal, and additional signals, assigned to alanine in meningiomas and lipids in metastases. In contrast, 11 gliomas of grades 2 and 3 exhibited NAA/Cho ratios and Cr/Cho ratios that were less than normal but that were significantly larger (P less than .01) than corresponding values in eight meningiomas. Ten glioblastomas displayed spectra with various signal ratios, so no significant differences between them and other tumor types could be established. In nine gliomas a clearly detectable lactate signal was present. However, no direct correlation between lactate level and histologic tumor grading was found.