11C-methionine PET for differential diagnosis of low-grade gliomas.

Management of low-grade gliomas continues to be a challenging task, because CT and MRI do not always differentiate from nontumoral lesions. Furthermore, tumor extent and aggressiveness often remain unclear because of a lack of contrast enhancement. Previous studies indicated that large neutral amino acid tracers accumulate in most brain tumors, including low-grade gliomas, probably because of changes of endothelial and blood-brain barrier function. We describe 11C-methionine uptake measured with PET in a series of 196 consecutive patients, most of whom were studied because of suspected low-grade gliomas. Uptake in the most active lesion area, relative to contralateral side, was significantly different among high-grade gliomas, low-grade gliomas, and chronic or subacute nontumoral lesions, and this difference was independent from contrast enhancement in CT or MRI. Corticosteroids had no significant effect on methionine uptake in low-grade gliomas but reduced uptake moderately in high-grade gliomas. Differentiation between gliomas and nontumoral lesions by a simple threshold was correct in 79%. Recurrent or residual tumors had a higher uptake than primary gliomas. In conclusion, the high sensitivity of 11C-methionine uptake for functional endothelial or blood-brain barrier changes suggests that this tracer is particularly useful for evaluation and follow-up of low-grade gliomas.

Psychic trauma causing grossly reduced brain metabolism and cognitive deterioration.

While amnesia and other cognitive disturbances are usually caused by structural brain damage, there are a few instances in which environmental stress may induce neuronal death in memory-sensitive brain regions such as the hippocampus. Here we report on a patient who, after a single brief exposure to an event reminding him of a similar stressful event from his childhood, deteriorated immediately and persistently without manifesting structural, but manifesting functional, brain damage as measured by position emission tomography. This patient probably represents the first case in which a direct relation between a single psychic event and the occurrence of brain malfunctioning in cognition is documented by dynamic neuroimaging methods. Psychic shock may cause lasting reductions in brain metabolism with the consequence of severe intellectual malfunctioning.

Comparison of effects induced by toxic applications of kainate and glutamate by glucose deprivation on area CA1 of rat hippocampal slices.

Baseline and stimulus-induced changes in [Ca2+]o and [K+]o as well as field potentials (fp's) were studied during application of the excitatory amino acids kainate or glutamate, or during glucose deprivation in area CA1 and CA3 of rat hippocampal slices. Bath application of kainate in concentrations of 1, 2, 5, 8 and 10 mM induced a sudden rapid fall of [Ca2+]o in area CA1, associated with a negative shift of the slow fp. Kainate induced disappearance of stratum radiatum (SR) as well as alveus stimulation-evoked postsynaptic fp's, with partial recovery after application of up to 2 mM kainate, but no recovery after 5 mM kainate. Only afferent volleys and repetitive SR stimulation-induced decreases of [Ca2+]o recovered after 5 mM kainate. Similar observations were made with glutamate. Only when glutamate was applied with 20 mM, irreversible disappearance of postsynaptic fp's was noted. Glucose deprivation for 60-90 min led to an initial slow decline of [Ca2+]o in area CA1 and CA3, associated with increases in [K+]o, but no significant changes in the fp baseline. Before reaching the lowest level in [Ca2+]o, stimulation of afferent and efferent fibres in area CA1 and CA3 evoked epileptiform discharges. After reaching the lowest level in [Ca2+]o, all postsynaptic potential components were irreversibly abolished, sparing afferent volleys and SR stimulation-induced decreases in [Ca2+]o. The application of the glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 30 microM) and L-2-amino-5-phosphonovalerate (2AVP, 30 microM) during glucose deprivation did not prevent irreversible loss of alveus and SR stimulation-induced postsynaptic signals. These findings suggest that glutamate release during glucose deprivation is not the main factor of acute cell damage.

Effects of glucose deprivation in area CA1 of hippocampal slices from adult and juvenile rats.

The effects of glucose deprivation were studied in area CA1 of rat hippocampal slices obtained from adult and juvenile rats (postnatal days (PN) 6-8; 13-15; 20-22). Ion-sensitive microelectrodes were employed to monitor baseline and stimulus-induced changes in [Ca2+]0, [K+]0 and field potentials. In slices from juvenile animals, the decline of baseline [Ca2+]0 during glucose deprivation was delayed in comparison to adult slices. The minimum in [Ca2+]0 was reached in slices from adult rats after 50 +/- 8.5 min, in slices from PN 20-22 after 69 +/- 9 min, and in slices from PN 13-15 after 111 +/- 11 min. In slices from PN 6-8, [Ca2+]0 did not decrease significantly even during prolonged exposure of up to 4 h. Alvear stimulation failed to evoke any stimulus-induced responses in field potentials, rises in [K+]0 and decreases in [Ca2+]0 after the minimum in [Ca2+]0 was reached in slices from all age groups except for slices from PN 6-8. In the older age groups, afferent fibre stimulation still induced afferent volleys and small decreases in [Ca2+]0, which were about 20-30% of those under control conditions, suggesting that presynaptic fibres and endings maintained some of their functional properties even after prolonged glucose deprivation. In contrast, stimulation of the stratum radiatum failed to evoke synaptic responses in slices from PN 6-8, presumably due to a failure in synaptic transmission. These findings confirm that similar to hypoxia during the early postnatal stage, hippocampal neurons are much more resistant to glucose deprivation. The findings also show that during early postnatal development, glucose deprivation may result in a block of synaptic transmission independent of postsynaptic excitability.

Speech-induced cerebral metabolic activation reflects recovery from aphasia.

Six stroke patients with clinically significant aphasia were studied 4 weeks and again 12-18 months after their first left hemispheric ictus. The regional cerebral metabolic rate of glucose (rCMRglc) was measured repeatedly by PET at rest and during word repetition, and severity of speech impairment was assessed by a neuropsychologic test battery. The patterns of speech-associated activation of glucose metabolism were related to improvement in language performance as measured by the Token test. Three patients experienced significant recovery from aphasia (Token test: 47 to 3, 45 to 12, and 37 to 5 points, respectively), whereas 3 patients had poor outcome (Token test from 48 to 45, and from 47 to 39 and 24, respectively). Good recovery was related to activation of left hemispheric speech areas surrounding the infarct, especially left superior temporal gyrus. In contrast, the 3 patients with persistent aphasia showed rCMRglc recruitment in right hemispheric regions and were unable to activate left hemispheric speech areas on follow-up. These results indicate that favorable outcome is related to partial sparing of speech areas of the dominant hemisphere that can be (re-) activated. Predominant recruitment of contralateral areas is not efficacious for a considerable recovery from aphasia. It rather indicates unspecific involvement of widespread networks in the effort to perform a complex task.

Brain plasticity in poststroke aphasia: what is the contribution of the right hemisphere?

The brain may use two strategies to recover from poststroke aphasia: the structural repair of primarily speech-relevant regions or the activation of compensatory areas. We studied the cortical metabolic recovery in aphasic stroke patients with positron emission tomography (PET) at rest and during word repetition. The left supplementary motor area (SMA) showed the most prominent compensatory activation in the subacute state of stroke. The restitution of the left superior temporal cortex determined the long-term prognosis of aphasia. The brain recruited right-hemispheric regions for speech processing, when the left-hemispheric centers were permanently impaired. This strategy, however, was significantly less effective than the repair of the original speech-relevant network.

Cerebral networks and functional brain asymmetry: evidence from regional metabolic changes during word repetition.

Word repetition causes a significant bilateral metabolic increase in both superior temporal cortices. Frontal speech areas are less activated despite their presumable speech competence. We investigated in this study the relationship between frontal and temporal cortical areas during word repetition. We measured regional cerebral metabolic rates of glucose (CMRGI) in 15 normal subjects with positron emission tomography (PET) at rest and during word repetition. Significant correlations connected frontal and temporal areas of both hemispheres, notwithstanding their different levels of mean metabolic activation. The left planum temporale was a hub of significant interregional correlations, in contrast to its contralateral mate. This study indicates that an asymmetric network of significant connections orchestrates the speech-relevant cortical areas according to the actual needs of speech processing.

Widespread functional deficits in perception-related networks demonstrated by PET in a case with simple visual seizures.

PURPOSE: To study benzodiazepine receptor (BZR) density and functional deficits in occipital lobe epilepsy. METHODS: A 39-year-old man who had simple partial visual seizures after neurosurgical transtentorial extirpation of a pinealoma was studied by EEG, magnetic resonance imaging (MRI), and positron emission tomography (PET) of [18F]2-fluoro-2-deoxy-D-glucose (FDG) at rest and during visual activation task and[11C]flumazenil (FMZ). RESULTS: Electroencephalographic recordings were nonspecific, and MRI did not reveal any morphologic anomaly in the occipital lobe. Flumazenil-PET demonstrated a small epileptogenic region in the right visual association cortex and FDG-PET showed hypometabolism in a corresponding location and thalamic diaschisis. Stimulation of occipital metabolism by a continuous visual recognition task improved significantly the contrast between the dysfunctional zone and its surround. CONCLUSIONS: As BZR deficits are restricted to a small region, widespread hypometabolism in networks involved in visual information processing indicates an extensive functional deactivation by the epileptogenic focus.

Massive and persistent anterograde amnesia in the absence of detectable brain damage: anterograde psychogenic amnesia or gross reduction in sustained effort?

The case of a young patient with severe and persistent anterograde amnesia of no known cause is reported. Anterograde amnesia arose within a 1-month period and has persisted for more than 1 year. Although a wide variety of neurological and neuroradiological assessments were completed (EEG, evoked potential recordings, Doppler sonography, MRI, PET), no evidence of brain damage was detected. Neuropsychologically, the patient was of high intelligence, had average to above-average short-term memory, and normal retrograde memory abilities, but severe and persistent anterograde amnesia in both verbal and nonverbal domains. Furthermore, he demonstrated grossly reduced long-term concentration. It is likely that a complex chain of interacting variables can produce a syndrome that appears phenomenologically as anterograde amnesia without organically measurable correlates.

Early-onset cerebellar ataxia (EOCA) with retained reflexes: reduced cerebellar benzodiazepine-receptor binding, progressive metabolic and cognitive impairment.

A family with two members who had early-onset cerebellar ataxia (EOCA) with retained tendon reflexes had, in addition to their motor deficits, a progressive impairment of cognitive and visuospatial abilities. We used positron emission tomography (PET) with 11C-flumazenil to study gamma-aminobutyric type A/benzodiazepine receptor binding (BZR) and 18F-2-fluoro-2-deoxy-D-glucose to analyze longitudinally regional cerebral glucose metabolism. Flumazenil-PET demonstrated loss of BZR binding that has not been shown in Friedreich's ataxia and olivopontocerebellar atrophy. These findings may be useful for differentiation of EOCA from other types of cerebellar ataxia. In comparison to age-matched control subjects, these patients showed a global metabolic decline and predominant hypometabolism in the thalamus and cerebellum. The progressive metabolic derangement may be explainable by a disturbed integrity of cognition-related networks resulting from secondary degeneration of cerebello-thalamo-cortical projections.

Neuroimaging and behavioral correlates of recovery from mnestic block syndrome and other cognitive deteriorations.

OBJECTIVE: We conducted a follow-up study on a patient with enduring psychic shock-induced cognitive impairment to study by neuropsychological and functional imaging methods the degree of his recovery process on the brain and cognitive levels. BACKGROUND: Based on the assumption that trauma and stress conditions can alter the functions of the nervous systems, we report on a patient whom we studied 2 and 12 months after he suffered "mnestic block syndrome" and additional cognitive deterioration symptoms. METHODS: We report on a patient studied 2 and 12 months after he suffered "mnestic block syndrome" and additional cognitive deterioration symptoms. Magnetic resonance imaging and fluorodeoxyglucose positron emission tomography were used for neural and detailed neuropsychological testing for cognitive deficits. RESULTS: The patient initially manifested severe intellectual decline, including severe anterograde and retrograde amnesia. His symptoms were correlated with major, although selective, reductions in his brain metabolism (2-3 SD below those of controls). Presently, he shows a normal brain metabolism and has regained parts of his memory and many of his other intellectual capabilities. Nevertheless, he still has long-term memory impairments. CONCLUSIONS: This case demonstrates a close relation between brain metabolism and cognitive performance, with major deficits of both at 2 months and major recovery of both at 12 months after a shocking event. It can serve as an example for possible stress-related deteriorations in certain brain regions, which can be partly corrected by psychotherapeutic interventions, passing time, and favorable environmental conditions.

Interictal hippocampal benzodiazepine receptors in temporal lobe epilepsy: comparison with coregistered hippocampal metabolism and volumetry.

The significance of benzodiazepine receptor (BZR) concentration in comparison with hippocampal metabolism and volumetry was assessed in 14 patients diagnosed with temporal lobe epilepsy (TLE) without hippocampal signal change on T2-weighted magnetic resonance imaging (MRI) scans. Focus lateralization was achieved by clinical, electroencephalographic and neuropsychological examinations. Three-dimensional positron emission tomography (PET) and MRI scans were coregistered for determination of hippocampal 11C-flumazenil (FMZ) binding, normalized to average cortical values for glucose metabolism (rCMRglc) and volume. The hippocampi were individually outlined on T1-weighted MRI. Volumes of interest (VOI) were used for calculation of asymmetries between clinically affected and unaffected sides. Eleven out of 14 TLE patients presented a significant reduction in hippocampal volume. In nine of these 11 patients hippocampal FMZ binding and in seven cases hippocampal CMRglc was also reduced. In two patients without hippocampal volume asymmetry FMZ binding was markedly reduced in the mesial temporal lobe appropriately to the clinically diagnosed side. In our study volumetry is therefore the most sensitive tool for the detection of hippocampal abnormality in TLE. However, in cases without hippocampal atrophy the reduction of FMZ may indicate functional impairment of BZR before neuronal loss becomes evident. Our results emphasize the complementary nature of these tests in TLE patients.

MRI-guided flumazenil- and FDG-PET in temporal lobe epilepsy.

In temporal lobe epilepsy (TLE) patients without lesions, major hippocampal sclerosis, or atrophy on magnetic resonance imaging (MRI), the localizing power of [11C]flumazenil (FMZ) and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) was compared using high-resolution positron emission tomography (PET) studies and individually coregistered MRI scans. Following complete clinical, neuropsychological, and electrophysiological evaluation, benzodiazepine receptor density was assessed using the FMZ equilibrium method. Thirty minutes later, interictal FDG-PET was performed under resting conditions. PET images were matched to three-dimensionally coregistered, T1-weighted MRI. Each temporal lobe (TL) was divided into 12 volumes of interest. The regional FMZ data were normalized with respect to average cortical values. For each patient the right-left asymmetries of rCMRGlc and normalized FMZ data were calculated. In 7 to 10 patients, mesial TL structures showed reduced FMZ binding, with a decrease by at least 10% in the affected TL. Reductions of 10% or more of rCMRGlc usually were more widespread than FMZ reductions and often involved lateral temporal cortex. The regions of most pronounced disturbances are not necessarily identical in both methods. Three patients had a complex correspondence of lateralization with PET, neuropsychological, and EEG data. In 4 patients, lateralization was less clear from EEG or neuropsychological results but was still consistent with lateralization by PET. In 3 of 10 patients, however, major discrepancies were found. These data suggest that the combination of neuropsychological testing, EEG, and MRI-guided FMZ- and FDG-PET will help to select patients with clearly defined epileptogenic foci especially in mesial TLE. Even in cases without MRI lesions, TL epileptic foci can be lateralized with consistency across the methods; FMZ-PET shows the pathologic focus more circumscribed than FDG-PET.