Search

The iodinated benzamide epidepride, which shows a picomolar affinity binding to dopamine D(2) receptors, has been designed for in vivo studies using SPECT. The aim of the present study was to apply a steady-state condition by the bolus/infusion approach with [(123)I]epidepride for the quantification of striatal and extrastriatal dopamine D(2) receptors in humans. In this way the distribution volume of the tracer can be determined from a single SPECT image and one blood sample. Based on bolus experiments, an algorithm using conventional convolution arguments for prediction of the outcome of a bolus/infusion (B/I) experiment was applied. It was predicted that a B/I protocol with infusion of one-third of the initial bolus per hour would be appropriate. Steady-state conditions were attained in extrastriatal regions within 3-4 h but the infusion continued up to 7 h in order to minimize the significance of individual differences in plasma clearance and binding parameters. A steady-state condition, however, could not be attained in striatal brain regions using a B/I protocol of 20 h, even after 11 h. Under near steady-state conditions a striatal:cerebellar ratio of 23 was demonstrated. Epidepride has a unique signal-to-noise ratio compared to [(123)I]IBZM but present difficulties for steady-state measurements of striatal regions. The bolus/infusion approach is particularly feasible for quantification of the binding potential in extrastriatal regions.

OBJECTIVE: To study the association between the cortical cerebral metabolic rate of glucose (CMRglc), MRI T2-weighted total lesion area (TLA), cognitive dysfunction, and neurologic disability in MS.BACKGROUND: MRI lesion load is widely used in the clinical evaluation of the MS patient but little is known about the associated changes in cortical activation.METHODS: Twenty-three patients with clinically definite MS underwent measurements of CMRglc, TLA, motor evoked potentials (MEPs), and cognitive and neurologic disability. CMRglc was calculated using PET and 18-F-deoxyglucose and compared with nine normal control subjects.RESULTS: Reductions in CMRglc (p < 0.01) were found in the cortical global and regional lobar measurements. Furthermore, regional CMRglc (rCMRglc) was reduced in the dorsolateral prefrontal cortex, orbitofrontal cortex, caudate, putamen, thalamus, and hippocampus. Global cortical CMRglc correlated with TLA (Spearman rank correlation coefficient [SRCC] = -0.66, p = 0.001), and rCMRglc correlated with regional lesion load in all cerebral lobes (p < or = 0.05). Global cortical CMRglc and cognitive disability also correlated (SRCC = 0.58, p = 0.015), and stepwise regression analysis showed a significant association between rCMRglc of the right thalamus and cognitive performance as well as TLA. There was no correlation between CMRglc and neurologic disability (Expanded Disability Status Scale) or MEP.CONCLUSION: Global and regional cortical CMRglc is reduced significantly in MS patients compared with normal control subjects. Furthermore, the CMRglc reductions correlate with TLA as well as with cognitive dysfunction, which indicates that MRI white matter lesion burden has a deteriorating effect on cortical cerebral neural function.

Limited spatial resolution of positron emission tomography (PET) can cause significant underestimation in the observed regional radioactivity concentration (so-called partial volume effect or PVE) resulting in systematic errors in estimating quantitative physiologic parameters. The authors have formulated four mathematical models that describe the dynamic behavior of a freely diffusible tracer (H215O) in a region of interest (ROI) incorporating estimates of regional tissue flow that are independent of PVE. The current study was intended to evaluate the feasibility of these models and to establish a methodology to accurately quantify regional cerebral blood flow (CBF) corrected for PVE in cortical gray matter regions. Five monkeys were studied with PET after IV H2(15)O two times (n = 3) or three times (n = 2) in a row. Two ROIs were drawn on structural magnetic resonance imaging (MRI) scans and projected onto the PET images in which regional CBF values and the water perfusable tissue fraction for the cortical gray matter tissue (hence the volume of gray matter) were estimated. After the PET study, the animals were killed and stereologic analysis was performed to assess the gray matter mass in the corresponding ROIs. Reproducibility of the estimated parameters and sensitivity to various error sources were also evaluated. All models tested in the current study yielded PVE-corrected regional CBF values (approximately 0.8 mL x min(-1) x g(-1) for models with a term for gray matter tissue and 0.5 mL x min(-1) x g(-1) for models with a term for a mixture of gray matter and white matter tissues). These values were greater than those obtained from ROIs tracing the gray matter cortex using conventional H2(15)O autoradiography (approximately 0.40 mL x min(-1) x g(-1)). Among the four models, configurations that included two parallel tissue compartments demonstrated better results with regards to the agreement of tissue time-activity curve and the Akaike's Information Criter

Previous fMRI studies of the cerebrovascular response to hypercapnia have shown signal change in cerebral gray matter, but not in white matter. Therefore, the objective of the present study was to compare (15)O PET and T *(2)-weighted MRI during a hypercapnic challenge. The measurements were performed under similar conditions of hypercapnia, which were induced by inhalation of 5 or 7% CO(2). The baseline rCBF values were 65.1 ml hg(-1) min(-1) for temporal gray matter and 28.7 ml hg(-1) min(-1) for white matter. By linear regression, the increases in rCBF during hypercapnia were 23.0 and 7. 2 ml hg(-1) min(-1) kPa(-1) for gray and white matter. The signal changes were 6.9 and 1.9% for the FLASH sequence and were 3.8 and 1. 7% for the EPI sequence at comparable echo times. The regional differences in percentage signal change were significantly reduced when normalized by regional flow values. A deconvolution analysis is introduced to model the relation between fMRI signal and end-expiratory CO(2) level. Temporal parameters, such as mean transit time, were derived from this analysis and suggested a slower response in white matter than in gray matter regions. It was concluded that the differences in the magnitude of the fMRI response can largely be attributed to differences in flow and that there is a considerable difference in the time course of the response between gray and white matter.

The purpose of this study was to investigate the relation between APOE genotype and Multiple Sclerosis (MS) in a genetically homogeneous population. We examined 240 patients consulting the MS-clinic during a period of 3 years (1996 - 1999). The mean age of the patients was 41.7 years (range 19 - 80 Y, SD 10.0 Y). As a measure of the progression rate (PR) the last registered Expanded Disability Status Scale (EDSS) score was divided by the time span (years) from disease onset until the latest assessment. The APOE genotype was determined from saliva and/or blood samples using PCR-techniques. The prevalence of different APOE genotypes was compared with the allele-distribution in a population of 361 persons from a Danish cross-sectional population study. The frequency of APOE-epsilon 4/epsilon 4 homozygotes was significantly higher in the MS-group as compared to controls (P<0.05, odds ratio: 2.3), whereas the frequency distribution of other genotypes did not differ significantly. The rate of progression was significantly faster in the APOE-epsilon 4/epsilon 4 homozygotes compared to other genotypes in the MS group (P<0.05). This study suggests that the APOE-epsilon 4/epsilon 4 homozygotes have an increased risk of developing MS. MS patients with the APOE-epsilon 4/epsilon 4 allele may also have an increased rate of disease progression. Multiple Sclerosis (2000) 6 226 - 230

Specific cerebral lesions have shown the crucial role of the brain in the control of micturition. The precise identification of the anatomical cerebral structures involved in micturition can contribute to a better understanding of the control of micturition and the development of therapeutic models. Various neuropathological and animal studies have referred to the medulla oblongata, pons, limbic system, superior frontal lobe and premotor cortical regions as areas implicated in micturition control. The aim of this study was to investigate whether the activity of these areas during micturition can be confirmed by PET in normal men. The distribution of the regional cerebral blood flow after bolus injection of (15)O water was used as an indirect measure of cerebral activation. PET scans were performed during the following three conditions: (i) at rest with the bladder empty; (ii) during simulated micturition after instillation of isotonic saline into the urinary bladder; and (iii) the withholding of urine (saline). Normal micturition using this model was achieved in eight out of 12 right-handed normal subjects. The changes in bladder contraction, bladder pressure and intra-abdominal pressure were monitored on-line during the whole scanning session by a cystometry device. The images were analysed using statistical parametric mapping at a significance threshold of P < 0.05 with correction for multiple independent comparisons. Micturition versus rest was associated with bilateral activation of areas close to the postcentral gyrus, inferior frontal gyrus, globus pallidus, cortex cerebelli, vermis and midbrain. On the left side, activation of the middle frontal gyrus, superior frontal gyrus, superior precentral gyrus, thalamus and the caudal part of the anterior cingulate gyrus was seen, while on the right side we found activation in the supramarginal gyrus, mesencephalon and insula. When the threshold value was lowered to P < 0.001 (Z > 3.09) without correction

Emission tomography investigations of the pathophysiological involvement of the cerebral dopaminergic transmitter system in the living human brain relies heavily on a careful selection of the most suitable radioligand. In recent years, many clinical studies have employed [(123)I]IBZM in SPECT studies. The aim of the present study was to characterize the binding of IBZM to dopaminergic receptor subtypes as a means of elucidating which receptor subtypes are visualized and examined by [(123)I]IBZM. The affinity of IBZM for each of the major human dopamine receptors (D1, D2(short), D3, D4(4. 2), and D5 receptor) was determined by competitive radioligand binding assay using membranes prepared from clonal cell lines expressing the different subtypes. Radioligands with high affinity for the D1(A) and D5 receptors ([(3)H]SCH-23390), dopamine D2(short) and D4(4.2) receptors ([(3)H]Spiroperidol), and dopamine D3 receptor ([(3)H]7-OH-DPAT) were used to measure specific binding. Corresponding unlabeled displacing ligands for determination of nonspecific binding were employed. Assays were performed at 25 degrees C. These experiments show that for IBZM K(i) values were 1.6 nM for dopamine D2(s) receptors and 2.2 nM for dopamine D3 receptors. There was no binding of IBZM to D1(A), D5, or D4(4.2) receptors. In conclusion, when [(123)I]IBZM is used as SPECT tracer, the studies reflect dopaminergic D2 as well as D3 receptor binding.

Previous fMRI studies of the cerebrovascular response to hypercapnia have shown signal change in cerebral gray matter, but not in white matter. Therefore, the objective of the present study was to compare (15)O PET and T *(2)-weighted MRI during a hypercapnic challenge. The measurements were performed under similar conditions of hypercapnia, which were induced by inhalation of 5 or 7% CO(2). The baseline rCBF values were 65.1 ml hg(-1) min(-1) for temporal gray matter and 28.7 ml hg(-1) min(-1) for white matter. By linear regression, the increases in rCBF during hypercapnia were 23.0 and 7. 2 ml hg(-1) min(-1) kPa(-1) for gray and white matter. The signal changes were 6.9 and 1.9% for the FLASH sequence and were 3.8 and 1. 7% for the EPI sequence at comparable echo times. The regional differences in percentage signal change were significantly reduced when normalized by regional flow values. A deconvolution analysis is introduced to model the relation between fMRI signal and end-expiratory CO(2) level. Temporal parameters, such as mean transit time, were derived from this analysis and suggested a slower response in white matter than in gray matter regions. It was concluded that the differences in the magnitude of the fMRI response can largely be attributed to differences in flow and that there is a considerable difference in the time course of the response between gray and white matter.

The present study investigated the effect of attention on brain activation in a dichotic listening situation. Dichotic listening is a technique to study laterality effects in the auditory sensory modality. Two different stimuli were presented simultaneously, one in each ear. Twelve subjects listened to lists of consonant-vowel syllables, or short musical instrument passages, with the task of detecting a "target" syllable or musical instrument by pressing a button. The target stimulus appeared an equal number of times in the left and right ear. The subjects were instructed to either concentrate on the stimuli presented in both ears, or only on the left or right ear stimulus. Brain activation was measured with 15O-PET, and significant changes in regional normalized counts (rNC) were evaluated using statistical parametric mapping (SPM96) software. Concentrating on either the right or left ear stimulus significantly decreased activity bilaterally in the temporal lobes compared to concentrating on both ear stimuli, at the expense of an increased activation in the right posterior and inferior superior parietal lobe. The CV-syllables activated areas corresponding to the classic language areas of Broca and Wernicke. The musical instrument stimuli mainly activated areas in visual association cortex, cerebellum, and the hippocampus. An interpretation of the findings is that attention has a facilitating effect for auditory processing, causing reduced activation in the primary auditory cortex when attention is explicitly recruited. The observed activations in the parietal lobe during the focused attention conditions could be part of a modality non-specific "attentional network".

Cerebral activation will increase cerebral blood flow (CBF) and cerebral glucose uptake (CMRglc) more than it increases cerebral uptake of oxygen (CMR(O2)). To study this phenomenon, we present an application of the Kety-Schmidt technique that enables repetitive simultaneous determination of CBF, CMR(O2), CMRglc and CMRlac on awake, non-stressed animals. After constant intravenous infusion with 133Xenon, tracer infusion is terminated, and systemic arterial blood and cerebral venous blood are continuously withdrawn for 9 min. In this paper, we evaluate if the assumptions applied with the Kety-Schmidt technique are fulfilled with our application of the method. When measured twice in the same animal, the intra-individual variation for CBF, CMR(O2), and CMRglc were 10% (SD: 25%), 8% (SD: 25%), and 9% (SD: 28%), respectively. In the awake rat the values obtained for CBF, CMR(O2) and CMRglc were 106 mL [100 g](-1) min(-1), 374 micromole [100 g](-1) min(-1) and 66 micromole [100 g](-1) min(-1), respectively. The glucose taken up by the brain during wakefulness was fully accounted for by oxidation and cerebral lactate efflux. Anaesthesia with pentobarbital induced a uniform reduction of cerebral blood flow and metabolism by approximately 40%. During halothane anaesthesia CBF and CMRglc increased by approximately 50%, while CMR(O2) was unchanged.

Generalization can be defined quantitatively and can be used to assess the performance of principal component analysis (PCA). The generalizability of PCA depends on the number of principal components retained in the analysis. We provide analytic and test set estimates of generalization. We show how the generalization error can be used to select the number of principal components in two analyses of functional magnetic resonance imaging activation sets.

The effect of hyperinsulinemia on glucose blood-brain barrier (BBB) transport and cerebral metabolism (CMRglc) was studied using the intravenous double-indicator method and positron emission tomography using [18F]fluorodeoxyglucose as tracer (PET-FDG). Sixteen normal healthy control subjects (25 +/- 4 years old) were studied twice during a euglycemic and a euglycemic-hyperinsulinemic condition. Our hypothesis was that high physiologic levels of insulin did not affect the BBB transport or net metabolism of glucose. During insulin infusion, arterial plasma insulin levels increased from 48.5 to 499.4 pmol/l. The permeability-surface area products for glucose and FDG BBB transport obtained with the double-indicator method remained constant during hyperinsulinemia. Similarly using PET-FDG, no changes were observed in the unidirectional clearance of FDG from blood to brain. k2* (FDG transport from brain to blood) increased significantly by 15 and 18% (gray and white matter, respectively), and k4* (dephosphorylation of FDG) increased by 18%. The increase in k2* may be caused by insulin inducing a decrease in the available FDG brain pool. The increase in k4* may be related to an increased loss of labeled products during insulin fusion. Irrespective of these changes, CMRglc remained unchanged in all brain regions. We conclude that hyperinsulinemia within the normal physiologic range does not affect BBB glucose transport or net cerebral glucose metabolism.

This report describes the operation of a multidisciplinary university hospital memory clinic in a neurological setting, and the diagnostic evaluations in 400 consecutive patients referred for cognitive symptoms and possible dementia during a period of 27 months (1 September 1995-31 December 1997). The mean age of the patients was 63.6 years (range 19-97). On clinical and neuropsychological examination, 46% of the patients fulfilled DSM IV criteria for dementia, 5% had selective amnesia, and 14% had other selective cognitive deficits. The remaining patients had either no significant cognitive deficits (31%) or were not evaluable (4%). A wide range of disorders from the fields of neurology, psychiatry, neurosurgery and internal medicine were identified as the underlying etiologies for the cognitive symptoms. Potentially reversible conditions were observed in 26% of the patients, not including the 11% in whom no specific underlying disease was identified. Concomitant conditions or risk factors with a potential influence on cognitive functions were identified in 61% of the patients. Diagnostic evaluation of patients with mild to moderate cognitive symptoms and possible dementia is an integrated multidisciplinary task, which should focus on the identification of non-progressive and potentially reversible etiologies, co-morbidity, selective cognitive deficits, and rare or atypical neurological conditions, as well as on the early identification of common progressive dementia disorders.

To localize a central nervous feed-forward mechanism involved in cardiovascular regulation during exercise, brain activation patterns were measured in eight subjects by employing positron emission tomography and oxygen-15-labeled water. Scans were performed at rest and during rhythmic handgrip before and after axillary blockade with bupivacaine. After the blockade, handgrip strength was reduced to 25% (range 0-50%) of control values, whereas handgrip-induced heart rate and blood pressure increases were unaffected (13 +/- 3 beats/min and 12 +/- 5 mmHg, respectively; means +/- SE). Before regional anesthesia, handgrip caused increased activation in the contralateral sensory motor area, the supplementary motor area, and the ipsilateral cerebellum. We found no evidence for changes in the activation pattern due to an interaction between handgrip and regional anesthesia. This was true for both the blocked and unblocked arm. It remains unclear whether the activated areas are responsible for the increase in cardiovascular variables, but neural feedback from the contracting muscles was not necessary for the activation in the mentioned areas during rhythmic handgrip.

Udgivelsesdato: 1999-Sep, The calculated fraction of receptor ligands available for blood-brain barrier passage in vivo (f(avail)) may differ from in vitro (f(eq)) measurements. This study evaluates the protein-ligand interaction for iomazenil and flumazenil in rats by comparing f(eq) and f(avail). Repeated measurements of blood-brain barrier permeability for two benzodiazepine antagonists were performed in 44 rats by the double-indicator technique. Cerebral blood flow was measured by intracarotid Xe-injection. The apparent permeability-surface product (PSapp) was measured while CBF or bolus composition was changed. Comparison of PSapp obtained in the absence and presence of 5% albumin in the injectate yielded f(avail), whereas f(eq) was measured by equilibrium dialysis. Iomazenil and flumazenil f(avail) was 62% and 82%, respectively, whereas f(eq) was significantly lower, 42% and 61%. The PSapp for iomazenil and flumazenil increased significantly by 89% and 161% after relative CBF increases of 259% and 201%, respectively. The results demonstrate that application of f(eq) in neuroreceptor studies underestimates the plasma input function to the brain. Model simulations render possible that the differences between f(avail) and f(eq) as well as the effect of CBF on PSapp can be caused by capillary heterogeneity.

BACKGROUND: This study re-evaluates previously published data on blood-brain barrier transfer coefficients in humans exposed to high insulin levels.DESIGN: In this study of seven volunteers, global blood-brain barrier permeability to glucose and phenylalanine was measured by means of the intracarotid double-indicator method before, during, and after an insulin-glucose clamp. Data were reanalyzed by means of a mathematical model that takes capillary heterogeneity and labelled glucose backflux from the brain into account.RESULTS: The permeability-surface area product (PS) for glucose transport from the blood into the brain, PS1, was 0.145 (0.102-0.211) (median and quartiles), 0.146 (0.113-0.259), and 0.157 (0.133-0.181) ml g-1 min-1 before, during, and after insulin challenge, respectively. In six of the subjects, PS for transport from brain to blood over the brain glucose distribution volume, PS2/Ve decreased under hyperinsulinemia, from a baseline value of 6.56 (3.0-14.9) to 3.86 (1.41-5.32), and restored to a value of 3.8 (2.8-12.1) min-1 after insulin challenge. This decrease in PS2/Ve is probably due to an increase in the brain glucose distribution volume induced by an insulin induced increased intracellular glucose uptake during the experiment. For phenylalanine (n = 5), PS1 was unchanged before, during, and after insulin challenge. In hyperinsulinemia, PS3/Ve for phenylalanine decreased in all subjects.CONCLUSION: We conclude that acutely elevated high plasma insulin levels in humans does not alter the brain uptake of glucose or phenylalanine from the blood. It seems, however, that high plasma insulin levels induce an increase in the movement of D-glucose and L-phenylalanine from the brain interstitial fluid into the intracellular compartment.

The purpose of the present PET study was (i) to investigate the neural correlates of object recognition, i.e. the matching of visual forms to memory, and (ii) to test the hypothesis that this process is more difficult for natural objects than for artefacts. This was done by using object decision tasks where subjects decided whether pictures represented real objects or non-objects. The object decision tasks differed in their difficulty (the degree of perceptual differentiation needed to perform them) and in the category of the real objects used (natural objects versus artefacts). A clear effect of task difficulty was found in both the behavioural and in the PET data. In the PET data, the increase in task difficulty was associated with increased regional cerebral blood flow in the posterior part of the right inferior temporal gyrus and in the anterior part of the right fusiform gyrus. This may be the neural correlate of matching visual forms to memory, and the amount of activation in these regions may correspond to the degree of perceptual differentiation required for recognition to occur. With respect to behaviour, it took significantly longer to make object decisions on natural objects than on artefacts in the difficult object decision tasks. Natural objects also recruited larger parts of the right inferior temporal and anterior fusiform gyri compared with artefacts as task difficulty increased. Differences in the amount of activation in these regions may reflect the greater perceptual differentiation required for recognizing natural objects. These findings are discussed in relation to category-specific impairments after neural damage.

A number of extrastriate visual areas in the parieto-occipital cortex are known from single-cell recordings of the macaque monkey to be involved in the coding of eye-position signals in the brain. These are important for the accurate location of visual objects in extrapersonal space. It can be predicted that these areas will show increased activation during the performance of eye movements at high frequency. In the present study PET and measurements of the regional distribution of cerebral blood flow (rCBF) were used as indirect measures of neural activity. Two independent groups of normal volunteers performed large-amplitude self-generated eye movements in complete darkness, thus removing the confounding effects of visual stimulation on parieto-occipital activation. The first group (group A; n = 5) served as a hypothesis-generating group and the second group (group B; n = 4) served as a hypothesis-testing group. The data were analysed using statistical parametric mapping at a significance level corrected for multiple comparisons (group A, Z > 4.08; group B, Z > 4.04). Significant rCBF increases were found for both groups in the frontal eye fields, supplementary eye fields, cerebellar vermis and putamina/thalami. Additionally, activation was found in the cunei in the posterior bank of the parieto-occipital sulcus. Also, the extraocular muscles were activated and, as a consequence of the partial volume effect, projected to the orbitofrontal cortices. At a less conservative threshold, activation was found close to the intraparietal sulci on the left side (Z = 3.91, P = 0.09) and right side (Z = 3.33, P = 0.42). The locations of these areas were confirmed in group B with reference to high-resolution structural MRI scans. The activation of the parieto-occipital cortex without overt visual stimuli is interpreted as the result of neural activity related to the reception of efferent copies of motor commands and/or the activation of neurons coding for eye position

Brain metastases from small cell lung cancer respond to chemotherapy, but response duration is short and the intracerebral concentration of chemotherapy may be too low because of the characteristics of the blood-brain barrier. Positron emission tomography has been applied in a variety of tumors for studies of metabolic and hemodynamic features. This study was performed to determine regional cerebral metabolic rate of glucose (rCMRglu), regional cerebral blood flow (rCBF), and regional cerebral blood volume (rCBV) in brain metastases from small cell lung cancer and the surrounding brain. Tumor rCMRglu, rCBF, and rCBV exerted a broad variability, but were higher than the corresponding values in white matter and higher than or similar to those of gray matter. Tumor rCMRglu and rCBF were highly correlated (P < 0.01, r = 0.79). No correlation between survival and metabolic or hemodynamic parameters could be demonstrated. After radiotherapy, mean tumor rCMRglu decreased from 0.40 to 0.31 micromol/g/min (not significant), and rCBF and rCBV remained unchanged. However, cortical rCBF demonstrated a trend of increased values after radiotherapy from 0.37 to 0.49 ml/g/min (P = 0.13). No change in rCMRglu was observed in gray or white matter after radiotherapy. Global CBF seems to be reversibly depressed by the metastases, but local hemodynamic changes in the tumor could not be detected with positron emission tomography in this study. An association between high tumor rCMRglu and rCBF as an indicator of hypoxia was not observed. Other methods for noninvasive in vivo analysis of tumor hemodynamics are needed, especially for discrimination between tumor necrosis and hypoxia.

In the clinical setting it has been shown that activation will increase cerebral glucose uptake in excess of cerebral oxygen uptake. To study this phenomenon further, this study presents an experimental setup that enables precise determination of the ratio between cerebral uptake of glucose and oxygen in the awake rat. Global CBF was measured by the Kety-Schmidt technique, and the ratio between cerebral uptake rates for oxygen, glucose, and lactate was calculated from cerebral arterial-venous differences. During baseline conditions, rats were kept in a closed box designed to minimize interference. During baseline conditions CBF was 1.08 +/- 0.25 mL x g(-1) x minute(-1), and the cerebral oxygen to glucose uptake ratio was 5.5. Activation was induced by opening the sheltering box for 6 minutes. Activation increased CBF to 1.81 mL x g(-1) x minute(-1). During activation cerebral glucose uptake increased disproportionately to cerebral oxygen uptake, and the cerebral oxygen to glucose uptake ratio was 4.2. The accumulated excess glucose uptake during 6 minutes of activation amounted to 2.4 micromol/g. Activation was terminated by closure of the sheltering box. In the postactivation period, the cerebral oxygen to glucose uptake ratio rose to a maximum of 6.4. This response is exactly opposite to the excess cerebral glucose uptake observed during activation.

Previous memory research has suggested that the effects of prior study observed in priming tasks are functionally, and neurobiologically, distinct phenomena from the kind of memory expressed in conventional (explicit) memory tests. Evidence for this position comes from observed dissociations between memory scores obtained with the two kinds of tasks. However, there is continuing controversy about the meaning of these dissociations. In recent studies, Ostergaard (1998a, Memory Cognit, 26:40-60; 1998b, J. Int. Neuropsychol. Soc., in press) showed that simply degrading visual word stimuli can dramatically alter the degree to which word priming shows a dissociation from word recognition; i.e., effects of a number of factors on priming paralleled their effects on recognition memory tests when the words were degraded at test. In the present study, cerebral blood flow changes were measured while subjects performed the word identification (reading) and recognition memory tasks used previously by Ostergaard. The results are the direct comparisons of the two tasks and the effects of stimulus degradation on blood flow patterns during the tasks. Clear differences between word identification and word recognition were observed: the latter task evoked considerably more prefrontal activity and stronger cerebellar activation. Stimulus degradation was associated with focal increases in bilateral fusiform regions within the occipital lobe. No task, degradation, or item repetition effects were demonstrated in mesial temporal regions, no repetition effects were observed in any region, and there was no evidence for different effects of stimulus degradation in the priming and recognition memory conditions. Power limitations may have contributed to the null effects.

The lumped constant defined as the conversion factor between the net uptake of fluoro-2-deoxy-D-glucose (FDG) and glucose was calculated from global CMRglc and from positron emission tomography (PET) using FDG as tracer (CMRFDG). Fifteen healthy, normal volunteers (mean age 24 +/- 4 years) were studied. Global CBF and CMRglc were measured with the Kety-Schmidt technique using 133Xe as tracer, and values were corrected for errors from incomplete diffusion equilibrium for inert gas tracer between brain tissue and cerebral venous blood. Measurements of CMRFDG were obtained with PET using the dynamic and single-scan methods and the K1-k3 model. Measurements with the Kety-Schmidt technique and PET-FDG were performed simultaneously. Global CBF was 47.1 +/- 8.0 mL.100 g-1.min-1, and CMRglc was 22.8 +/- 4.1 mumol.100 g-1.min-1. No difference in CMRFDG was found with the two methods (17.8 +/- 1.6 and 18.2 +/- 1.3 mumol .100 g-1.min-1, dynamic and single scan methods, respectively). Accordingly, the lumped constant ranged from 0.80 +/- 0.16 to 0.82 +/- 0.15, with a mean value of 0.81 +/- 0.15. The mean ratio between phosphorylation of FDG and glucose (k3*/k3) was 0.39 +/- 0.25. The discrepancy between the lumped constant determined in this study and previously obtained values can be explained partly by methodologic problems, and we conclude that most of the discrepancy results from previous overestimation of global CBF.

The effect of the migraine drugs ergotamine and sumatriptan on the cerebral blood flow (CBF) autoregulation was studied in halothane/nitrous oxide-anesthetized normotensive Wistar Kyoto rats. Ergotamine, an ergot alkaloid affecting 5HT, norepinephrine, and dopamine receptors, was administered intravenously as a single dose of 25 microg/kg. Sumatriptan, a selective 5HT1-like receptor agonist, was administered by intravenous infusion of 300 microg/kg/h. CBF was measured with the intracarotid 133Xe-injection method. The blood pressure limits of CBF autoregulation were determined by computerized least sum of square analysis. CBF autoregulation was preserved after both ergotamine and sumatriptan. Ergotamine shifted the lower blood pressure limit of CBF autoregulation towards higher blood pressures from 60 +/- 3 mmHg to 82 +/- 4 mmHg (p<0.01), but did not significantly affect the upper blood pressure limit of CBF autoregulation. Sumatriptan had no significant effects on the blood pressure limits of CBF autoregulation.

The deoxyglucose method for calculation of regional cerebral glucose metabolism by PET using 18F-2-fluoro-2-deoxy-d-glucose (FDG) requires knowledge of the lumped constant, which corrects for differences in the blood-brain barrier (BBB) transport and phosphorylation of FDG and glucose. The BBB transport rates of FDG and glucose have not previously been determined in humans. In the present study these transport rates were measured with the intravenous double-indicator method in 24 healthy subjects during normoglycemia (5.2 +/- 0.7 mM). Nine subjects were restudied during moderate hypoglycemia (3.4 +/- 0.4 mM) and five subjects were studied once during hyperglycemia (15.0 +/- 0.7 mM). The global ratio between the unidirectional clearances of FDG and glucose (K1*/K1) was similar in normoglycemia (1.48 +/- 0.22), moderate hypoglycemia (1.41 +/- 0.23), and hyperglycemia (1.44 +/- 0.20). This ratio is comparable to what has been obtained in rats. We argue that the global ratio is constant throughout the brain and may be applied for the regional determination of LC. We also determined the transport parameters of the two hexoses from brain back to blood and, assuming symmetrical transport across the BBB, we found evidence of a larger initial distribution volume of FDG in brain (0.329 +/- 0.236) as compared with that of glucose (0.162 +/- 0.098, p < 0.005). The difference can be explained by the very short experimental time, in which FDG may distribute both intra- and extracellularly, whereas glucose remains in a volume comparable to the interstitial fluid of the brain.

BACKGROUND/AIMS: Normally, cerebral blood flow responds to changes in the arterial carbon dioxide tension (PaCO2) but not to changes in mean arterial pressure, commonly referred to as the cerebral CO2-reactivity and autoregulation. In patients with fulminant hepatic failure and in the rat with thioacetamide-induced liver failure, autoregulation is absent, presumably due to cerebral vasoparalysis. Since also CO2-reactivity may then be compromised, it was studied in patients with fulminant hepatic failure and rats with thioacetamide-induced liver failure.METHODS: In ten patients (median age 32 (range 20-48) years)) and in ten age-matched volunteers, cerebral perfusion was elevated by transcranial Doppler assessed mean flow velocity (V(mean)) in the middle cerebral artery during hypo- and hyper-capnia. In six rats with liver failure and in six control rats, cerebral blood flow was measured repeatedly by the intracarotid 133 Xenon injection technique.RESULTS: In the patients and volunteers, PaCO2 was lowered from 33 (23-44) to 28 (23-39) mmHg by hypocapnia and raised to 40 (34-48) mmHg by hypercapnia or 5% CO2 inhalation. During hypocapnia, the CO2-reactivity did not differ significantly between patients and volunteers, 4.0 (1.1-7.4) vs. 3.0 (1.7-5.0)% mmHg(-1), while it was reduced during hypercapnia in the patients, 2.2 (1.8-5.2) vs. 4.6 (3.0-8.0)% mmHg(-1) (p < 0.05). In the rats, PaCO2 was reduced from 39 (37-40) to 30 (29-31) mmHg and then raised to 51 (41-55) mmHg. During hypocapnia, CO2-reactivity was similar in rats with liver failure and in control rats, 2.3 vs 2.7% mmhg(21), respectively. In all rats with liver failure CO2-reactivity was abolished during hypercapnia, while it was 1.5% mmHg(-1) in the control rats (p < 0.01).CONCLUSIONS: The finding that cerebral CO2 reactivity is reduced in hypercapnia, while it is preserved in hypocapnia, suggests that gradual dilation of the cerebral resistance vessels develops in fulminant hepa

Acute mental disorder in early Multiple Sclerosis (MS) is rare and little is known about the structural and metabolic changes in this relation. We present an MS patient with discrete motor and sensory deficits, who developed severe behavioral changes over a period of nine months during the initial course of the disease. The cerebral metabolic rate of glucose (CMRglc) was measured using positron emission tomography (PET), and the patient underwent MRI as well as a comprehensive battery of neuropsychological tests. Significantly reduced values of CMRglc were found bilaterally in the frontal and temporal cortex, the putamen, the thalamus and the hippocampus. The MRI revealed progression of MS lesions in the frontal lobes during the development of mental symptoms. Neuropsychological examination showed wide spread cognitive dysfunction, and a pronounced frontal lobe syndrome. The study demonstrates the remote metabolic effects of lesions affecting subcortical neural connections in an MS patient with severe cognitive dysfunction.

Using repeated positron emission tomography (PET) measures of regional cerebral counts, we investigated the regional cortical activations induced in eight normal subjects performing eight different frequencies of fingertapping (0.5-4 Hz) with the right index finger. The task was auditorially cued and the performance recorded during the scanning procedure. Performance evaluation showed increased error rates, during fingertapping, of high and low frequencies, and the best tapping performance was measured in the midrange of frequencies. Significantly activated areas (p < 0.05) of normalized cerebral counts were located in the left sensorimotor cortex (MISI), right motor cortex, left thalamus, right insula, supplementary motor area (SMA), and bilaterally in the primary auditory cortex and the cerebellum. Statistical evaluation showed a significant (p < 0.01) and positive dependence of cerebral activation upon movement rate in the contralateral MISI. There was no significant rate dependence of cerebral activation in other activated motor areas. The SMA and the right cerebellar hemisphere showed a more uniform activation throughout the tapping frequency range. Furthermore, we found a stimulus rate dependence of cerebral activation in the primary auditory cortex. We believe that the present data provide useful information for the preparation and interpretation of future motor activation studies of normal human subjects and may serve as reference points for studies of pathological conditions.

During starvation, brain energy metabolism in humans changes toward oxidation of ketone bodies. To investigate if this shift is directly coupled to circulating blood concentrations of ketone bodies, we measured global cerebral blood flow (CBF) and global cerebral carbohydrate metabolism with the Kety-Schmidt technique before and during intravenous infusion with ketone bodies. During acute hyperketonemia (mean beta-hydroxybutyrate blood concentration 2.16 mM), cerebral uptake of ketones increased from 1.11 to 5.60 mumol.100 g-1.min-1, counterbalanced by an equivalent reduction of the cerebral glucose metabolism from 25.8 to 17.2 mumol.100 g-1.min-1, with the net result being an unchanged cerebral uptake of carbohydrates. In accordance with this, global cerebral oxygen metabolism was not significantly altered (144 vs. 135 mumol.100 g-1.min-1). The unchanged global cerebral metabolic activity was accompanied by a 39% increase in CBF from 51.0 to 70.9 ml.100 g-1.min-1. Regional analysis of the glucose metabolism by positron emission tomography-[18F]fluoro-2-deoxy-D-glucose indicated that mesencephalon does not oxidize ketone bodies to the same extent as the rest of the brain. It was concluded that the immediate oxidation of ketone bodies induced a decrease in cerebral glucose uptake in spite of an adequate glucose supply to the brain. Furthermore, acute hyperketonemia caused a resetting of the coupling between CBF and metabolism that could not be explained by alterations in arterial CO2 tension or pH.

Cerebral magnetic resonance imaging (MRI) has revealed white matter changes in patients with phenylketonuria (PKU), an inborn error of metabolism with increased plasma phenylalanine level. Because the significance of these lesions is unknown, this study was undertaken to determine whether glucose metabolism was depressed in cerebral white matter MRI changes in patients with PKU. Four patients with PKU and nine healthy volunteers with an average age of 23 y (range 19-26 y) and 23 y (range 20-27 y), respectively, were studied. The IQ of patients with PKU was between 58 and 97. Cerebral MRI and positron emission tomography images with 18F-deoxyglucose were obtained, and arteriovenous differences for oxygen and glucose as well as cerebral blood flow was measured simultaneously to determine global cerebral oxygen and glucose metabolism. Cerebral MRI revealed that all patients with PKU had white matter changes with characteristic localization. In patients with PKU, regional glucose metabolism was 36% lower in the anterior periventricular areas, 0.14 +/- 0.06 compared with 0.22 +/- 0.04 mumol.g-1.min-1 in controls (mean +/- SD, p < 0.05, Mann-Whitney). Further, the ratio between glucose metabolism in the affected white matter and the cortex was 14% lower in the patients, decreasing from 0.57 +/- 0.05 to 0.48 +/- 0.06 (p < 0.05). Global cerebral blood flow, oxygen and glucose consumption were similar in the two groups. In conclusion, regional glucose metabolism is lower in MRI-demonstrated white matter changes. In mildly intellectually impaired patients with PKU, global cerebral glucose and oxygen metabolism remain intact.

Cerebral blood flow (CBF) is the same in hypertensive and normotensive man without neurological deficit. Chronic hypertension shifts the lower and upper blood pressure limits of CBF autoregulation towards higher pressure. Acute blood pressure reduction will lower CBF only if the pressure is taken below the lower limit of autoregulation. Added to this, some drugs are cerebral vasodilatators and have the potential for paralysing autoregulation and raising intracranial pressure, an effect also seen with at least some calcium antagonists. Converting enzyme inhibitors improve autoregulation during hypotension, probably by releasing angiotensin II dependent tone in the larger cerebral resistance vessels. With chronic antihypertensive treatment, CBF autoregulation may re-adapt towards normal. Converting enzyme inhibitors when given chronically probably retain their beneficial effect on the lower limit of autoregulation. Apart from this, it is uncertain whether there are chronic pharmacological effects of antihypertensive drugs directly on the cerebral circulation.

Global cerebral blood flow (CBF), global cerebral metabolic rates for oxygen (CMRO2), and for glucose (CMRglc), and lactate efflux were measured during rest and during cerebral activation induced by the Wisconsin card sorting test. Measurements were performed in healthy volunteers using the Kety-Schmidt technique. Global CMRO2 was unchanged during cerebral activation, whereas global CBF and global CMRglc both increased by 12%, reducing the molar ratio of oxygen to glucose consumption from 6.0 during baseline conditions to 5.4 during activation. Data obtained in the period following cerebral activation showed that the activation-induced resetting of the relation between CMRglc and CMRO2 persisted virtually unaltered for > or = 40 min after the mental activation task was terminated. The activation-induced increase in cerebral lactate efflux measured over the same time period accounted for only a small fraction of the activation-induced excess glucose uptake. These data confirm earlier reports that brain activation can induce resetting of the cerebral oxygen/glucose consumption ratio, and indicate that the resetting persists for a long period after cerebral activation has been terminated and physiologic stress indicators returned to baseline values. Activation-induced resetting of the cerebral oxygen/glucose uptake ratio is not necessarily accounted for by increased lactate production from nonoxidative glucose metabolism.

Impairment of cerebral blood flow (CBF) autoregulation may have serious implications for patients with cirrhosis if arterial hypotension occurs during coma, anesthesia, bleeding, or sepsis. In this study, CBF autoregulation was investigated in patients with cirrhosis with no or mild encephalopathy. Ten patients (median age, 45 years; range, 30 to 61 years) and six healthy volunteers (median age, 30 years; range 21 to 61 years) were included. Catheters were placed in a radial artery and in the internal jugular veins. Baseline CBF was measured using single-photon emission computed tomography (SPECT) with concomitant measurements of cerebral arteriovenous oxygen content differences (AVDO2). CBF autoregulation was evaluated using the AVDO2 method and changes in mean flow velocity in the middle cerebral artery (Vmean) as determined by transcranial Doppler (TCD). Mean arterial pressure (MAP) was increased by 30 mm Hg by intravenous norepinephrine, and subsequently decreased by a combination of lower body negative pressure and ganglion blockade, whereas AVDO2 and Vmean were measured at each 5 mm Hg change in MAP. CBF was 61 (range, 45 to 78) mL 100 g-1 min-1 in patients with cirrhosis and 65 (range < 53 to 88) mL 100 g-1 min-1 in volunteers (not significant [NS]). There were no regional differences in CBF between the two groups. Arterial carbon dioxide tension was 31 (23 to 35) mm Hg in patients with cirrhosis and lower, compared with 36 (range, 34 to 47) mm Hg in the volunteers (P < .01). For evaluation of autoregulation, MAP was raised to 116 (range, 100 to 145) and then decreased to 39 (range, 34 to 50) mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

We have studied the effects of labetalol on cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2) in eight healthy volunteers. CBF was measured by single photon emission computerized tomography before and during infusion of labetalol. CMRO2 was calculated as CBF x cerebral arteriovenous oxygen content difference (CaO2-CvO2). CBF autoregulation was tested during infusion of labetalol by changing arterial pressure and estimating relative changes in global CBF from changes in (CaO2-CvO2). CBF before and during infusion of labetalol was 67 and 65 ml/100 g min-1, respectively (P > 0.05). CMRO2 was 2.9 and 2.8 ml/100 g min-1, respectively (P > 0.05). CBF autoregulation was preserved in all subjects. The lower limit of CBF autoregulation was 88 mm Hg (94% of baseline mean arterial pressure). We conclude that labetalol did not influence global or regional CBF, or CMRO2, and CBF autoregulation was preserved.

OBJECTIVE: To investigate whether the angiotensin II (Ang II) subtype 1 receptor (AT1) antagonist CV-11974 had a similar effect to angiotensin converting enzyme inhibitors on cerebral blood flow autoregulation in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).METHODS: Sixteen WKY rats and 16 SHR were given CV-11974 0.1 mg/kg intravenously and compared with two control groups (n = 16). Their cerebral blood flow was measured with the intracarotid xenon-133 injection method and blood pressure was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis.RESULTS: The dose of CV-11974 given lowered blood pressure but did not influence baseline cerebral blood flow. In WKY rats the lower limit of autoregulation in control rats was 60 +/- 3 mmHg, whereas after CV-11974 administration it was 48 +/- 2 mmHg (P < 0.01). In SHR the corresponding values were 85 +/- 2 and 78 +/- 2 mmHg, respectively (P < 0.05). In WKY rats the upper limit of autoregulation in control rats was 144 +/- 5 mmHg, whereas after CV-11974 administration it was 126 +/- 7 mmHg (P < 0.05). In SHR the corresponding figures were 174 +/- 8 and 144 +/- 6 mmHg, respectively (P < 0.01).CONCLUSION: Thus, the AT1 receptor antagonist, although it did not influence baseline cerebral blood flow, shifted the autoregulation curve towards lower blood pressure. This effect is similar to that of angiotensin converting enzyme inhibitors, and might be due to release of Ang II-dependent tone in the larger cerebral resistance vessels.

Hypertension causes marked adaptive changes in the cerebral circulation. The excess risk of stroke associated with hypertension is eliminated in controlled trials of antihypertensive treatment. Such treatment may even prevent transient ischaemic attacks in the elderly. In rare cases, overzealous antihypertensive treatment may cause cerebral ischaemia, especially in the initial treatment of very severe hypertension. Headache may occasionally be caused by severe hypertension, which may also lead to the rare syndrome of acute hypertensive encephalopathy. Finally, the importance of white-matter lesions, or leukoaraiosis, in hypertension is not yet fully established.

The blood-brain barrier (BBB) permeability for glucose and beta-hydroxybutyrate (beta-OHB) was studied by the intravenous double-indicator method in nine healthy subjects before and after 3.5 days of starvation. In fasting, mean arterial plasma glucose decreased and arterial concentration of beta-OHB increased, whereas cerebral blood flow remained unchanged. The permeability-surface area product for BBB glucose transport from blood to brain (PS1) increased by 55 +/- 31%, whereas no significant change in the permeability from brain back to blood (PS2) was found. PS1 for beta-OHB remained constant during starvation. The expected increase in PS1 due to the lower plasma glucose concentration was calculated to be 22% using previous estimates of maximal transport velocity and Michaelis-Menten affinity constant for glucose transport. The determined increase was thus 33% higher than the expected increase and can only be partially explained by the decrease in plasma glucose. It is concluded that a modest upregulation of glucose transport across the BBB takes place after starvation. Brain transport of beta-OHB did not decrease as expected from the largely increased beta-OHB arterial level. This might be interpreted as an increase in brain transport of beta-OHB, which could be caused by induction mechanisms, but the large nonsaturable component of beta-OHB transport makes such a conclusion difficult. However, beta-OHB blood concentration and beta-OHB influx into the brain increased by > 10 times. This implies that the influx of ketone bodies into the brain is largely determined by the amount of ketones present in the blood, and any condition in which ketonemia occurs will lead to an increased ketone influx.

A steady state method for neuroreceptor quantification in vivo in small laboratory animals is described, using [123I]iomazenil as tracer for the benzodiazepine receptor. The method was used for determination of the receptor equilibrium constant for a non-radioactive ligand, flumazenil, in rats and involved measurement of the nonspecific binding of [123I]iomazenil. Thirty-five animals were intravenously infused for 2 h with [123I]iomazenil and flumazenil in different proportions to obtain occupancies of the benzodiazepine receptor from close to 0 to about 99%. The nonspecific binding of iomazenil in brain tissue was calculated by an iterative procedure from the data for the highly blocked animals, and it was found to be 1.04 ml per ml plasma (n = 6). The mean cortical Kd of flumazenil was 21 +/- 11 nM (n = 19). The method is discussed with special reference to the problems of ascertaining steady state and nonspecific binding.

Blood-brain barrier permeability to phenylalanine and leucine in four patients with phenylketonuria and in four volunteers was measured five times by the double-indicator method at increasing plasma concentrations of phenylalanine. Based on the permeability-surface area product (PS) from blood to brain (PS1) and on plasma phenylalanine levels, Vmax and the apparent Km for phenylalanine were determined. Statistically significant relationships between plasma phenylalanine and PS1 were established in three out of four volunteers, the average Vmax value being 46.7 nmol/g per min and the apparent Km 0.328 mmol/L. Owing to saturation of the carrier, such a relationship could not be established in the patients. In phenylketonuria, PS1 for phenylalanine and leucine decreased significantly by 55% and 46%, respectively. Transport from brain back to blood, PS2, decreased significantly and cerebral large neutral amino acid net uptake was generally decreased in patients with phenylketonuria. In conclusion, the transport of L-phenylalanine across the human blood-brain barrier follows Michaelis-Menten kinetics. In phenylketonuria, brain permeability to large neutral amino acids is reduced by about 50% and net uptake appears decreased.

Regional Cerebral Blood Flow (rCBF) measurements and neuropsychological evaluation were performed in 6 patients from a Danish family affected with X-linked Bulbo-Spinal Neuronopathy (XBSN). This inherited form of motor neuron disease (MND) has been shown to affect various functions within the nervous and the endocrine systems. We investigated the possibility that focal or diffuse cortical deficits, already demonstrated in MND, were present in XBSN. The global CBF values of the patients, when compared to age- and sex-matched healthy controls, were found reduced, but no focal rCBF alterations, nor increased regional side-to-side asymmetry were observed. The neuropsychological evaluation showed no cognitive impairments. We conclude that cortical perfusion and cognitive functions are not significantly altered in XBSN.