Regional Cerebral Glucose Consumption Research Articles

Synaptic Damage and Its Clinical Correlates in People With Early Huntington Disease: A PET Study.

Synaptic damage has been proposed to play a major role in the pathophysiology of Huntington disease (HD), but in vivo evidence in humans is lacking. We performed a PET imaging study to assess synaptic damage and its clinical correlates in early HD in vivo. METHODS: In this cross-sectional study, premanifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and sex-matched healthy controls underwent clinical assessment of motor and nonmotor manifestations and time-of-flight PET with 11C-UCB-J, a radioligand targeting the ubiquitous presynaptic terminal marker synaptic vesicle protein 2A (SV2A). We also performed 18F-fluorodeoxyglucose (18F-FDG)-PET in all participants because regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated on the basis of individual 3-dimensional T1 MRI. Standardized uptake value ratio-1 images were calculated for 11C-UCB-J with the centrum semiovale as reference region. 18F-FDG-PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest- and voxel-based analyses were performed. Correlations between clinical scores and 11C-UCB-J PET data were calculated. Eighteen HD mutation carriers (age 51.4 ± 11.6 years; 6 female; 7 premanifest, 11 early manifest) and 15 healthy controls (age 52.3 ± 3.5 years; 4 female) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, and temporal and frontal cortex, whereas reduced 18F-FDG uptake was restricted to caudate and putamen. In the premanifest subgroup, 11C-UCB-J and 18F-FDG-PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment. Our data reveal loss of presynaptic terminal integrity in early HD, which begins in the striatum in the premanifest phase, spreads extensively to extrastriatal regions in the early manifest phase, and correlates with motor impairment. 11C-UCB-J PET is more sensitive than 18F-FDG-PET for detection of extrastriatal changes in early HD. This study provides Class III evidence that 11C-UCB-J PET accurately discriminates individuals HD from normal controls.

Effects of levocetirizine and diphenhydramine on regional glucose metabolic changes and hemodynamic responses in the human prefrontal cortex during cognitive tasks.

ObjectiveAntihistamines often have sedative side effects. This was the first study to measure regional cerebral glucose (energy) consumption and hemodynamic responses in young adults during cognitive tests after antihistamine administration.MethodsIn this double‐blind, placebo‐controlled, three‐way crossover study, 18 healthy young Japanese men received single doses of levocetirizine 5 mg and diphenhydramine 50 mg at intervals of at least six days. Subjective feeling, task performances, and brain activity were evaluated during three cognitive tests (word fluency, two‐back, and Stroop). Regional cerebral glucose consumption changes were measured using positron emission tomography with [18F]fluorodeoxyglucose. Regional hemodynamic responses were measured using near‐infrared spectroscopy.ResultsEnergy consumption in prefrontal regions was significantly increased after antihistamine administration, especially diphenhydramine, whereas prefrontal hemodynamic responses, evaluated with oxygenated hemoglobin levels, were significantly lower with diphenhydramine treatment. Stroop test accuracy was significantly impaired by diphenhydramine, but not by levocetirizine. There was no significant difference in subjective sleepiness.ConclusionsPhysiological “coupling” between metabolism and perfusion in the healthy human brain may not be maintained under pharmacological influence due to antihistamines. This uncoupling may be caused by a combination of increased energy demands in the prefrontal regions and suppression of vascular permeability in brain capillaries after antihistamine treatment. Further research is needed to validate this hypothesis.

Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: a study in baboons

It is classically recognized that regional cerebral glucose consumption (CMRglc), as measured by positron emission tomography (PET) and [18F]-2-fluorodeoxyglucose (FDG), is a precise index of the integrated local neuronal activity. However, despite extensive use of the FDG-PET method, the significance of the measured CMRglc has been little addressed so far. In the present study, we aimed for the first time to test whether resting-state CMRglc is directly related to synaptic density. To this end, we investigated in the baboon the relationships between CMRglc and the levels of synaptophysin (SY), a presynaptic protein classically used to assess synaptic density. CMRglc, measured in vivo by FDG-PET at the resting-state, and SY levels, assessed postmortem by the Western blot technique, were quantified in seven brain areas of five baboons. By applying these two techniques to the same animals, we found significant positive correlations between CMRglc and SY levels, across all regions and all animals, as well as within individual baboons. These findings strongly support the hypothesis that resting-state CMRglc reflects integrated synaptic activity.

Resting regional cerebral glucose metabolism in advanced Parkinson's disease studied in the off and on conditions with [(18)F]FDG-PET.

Studies of resting regional cerebral glucose consumption (rCMRGlc) in nondemented patients with Parkinson's disease (PD) have produced conflicting results, reporting both reduced and normal metabolism in advanced disease and reduced or normal metabolism after dopaminergic therapy. To investigate these issues, [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed in 11 nondemented PD patients with advanced disease and 10 age-matched controls. PD patients were studied after withdrawal of all dopaminergic medication to produce a practically defined off condition, and a second time 1 hour after levodopa, resulting in a clinical on state. Dynamic PET scans and simultaneous arterialised venous blood samples of [(18)F] activity were obtained. A graphical approach was used to generate parametric images of rCMRGlc and statistical parametric mapping to localise significant metabolic changes in PD. Compared with controls, global rCMRGlc was reduced in the on but not in the off condition in PD. In both states, significant regional reductions of glucose uptake were found in the parietal, frontal, temporal cortex, and caudate nucleus. Reductions correlated with the severity of disability in frontal and temporal cortex. Direct comparison between on and off conditions revealed relatively greater reductions of uptake in the ventral/orbital frontal cortex and the thalamus during on. Results suggest that cortical and caudate hypometabolism are common in advanced PD and that caution is mandatory if [(18)F]FDG PET is being used to differentiate advanced PD from dementia and progressive supranuclear palsy where similar reductions are seen. Furthermore, in PD, administration of levodopa is associated with further hypometabolism in orbitofrontal cortex; an area known to be relevant for reversal learning where performance is typically impaired after dopaminergic treatment.

Measurement of Temporal Asymmetries of Glucose Consumption Using Linear Profiles: Reproducibility and Comparison with Visual Analysis

One approach to regionally analyze temporal glucose consumption consists in drawing linear profiles over the maximal values measured in the temporal cortical ribbon. The aim of our study was to test the reproducibility of this method and to compare its diagnostic performance to that of visual analysis in patients with complex partial seizures (CPS). Regional cerebral glucose consumption (rCMRGIc) was measured interictally in 25 CPS patients and 10 controls using F-18-deoxyglucose and the positron emission tomography (PET) camera ECAT EXACT 47. The PET scans were visually analyzed for the occurrence of unilateral temporal hypometabolism. Furthermore, rCMRGIc was quantified on six contiguous coronal planes by manually tracing maximal values of temporal glucose consumption, thus creating line profiles of temporal glucose consumption for each side. Indices of asymmetry (ASY) were then calculated from these line profiles in four temporal regions and compared to the corresponding 95% confidence intervals of the control data. All analyses were performed by two observers independently from each other and without knowledge of the clinical findings. The agreement between the two observers with regard to focus lateralization was 96% (kappa = 0.93) on visual analysis and 100% (kappa = 1) on quantitative analysis. There was an excellent agreement with regard to focus lateralization between visual and quantitative evaluation (kappa = 0.8). Quantitation of local temporal rCMRGIc by using linear profile analysis is highly reproducible; for the lateralization of epileptogenic foci, however, this method does not possess significant advantages over the visual evaluation of the scans.

PET and SPECT in Medically Non-Refractory Complex Partial Seizures

In contrast to medically refractory complex partial seizures (CPS), only limited knowledge exists on cerebral perfusion and metabolism in medically non-refractory CPS. The aim of this study was to investigate the frequency of temporal asymmetries in regional cerebral glucose consumption (rCMRGlc), regional cerebral blood flow (rCBF), and regional cerebral benzodiazepine receptor density (BRD) in this group of patients. The study included 49 patients with medically non-refractory cryptogenic CPS (age: 36.0 +/- 16.1 years). rCMRGlc was studied with F-18-FDG-PET (FDG), rCBF with Tc-99m-ECD-SPECT (ECD), and BRD with l-123-iomazenil-SPECT (IMZ). All studies were performed interictally and within four weeks in each patient. Duration of epilepsy ranged from 0.1 to 42 years (median 4.0 years). SPECT was performed with the triple-headed SPECT camera Multispect 3, PET with the PET camera ECAT EXACT 47. Using linear profiles, glucose consumption, as well as uptake of ECD and IMZ, were measured in four temporal regions of interest (ROIs), and asymmetry indices were calculated (ASY). The results were compared to 95% confidence intervals determined in control subjects. Thirty-five of the 49 (71%) patients had at least one significantly elevated ASY; temporal rCMRGlc was asymmetrical in 41% of the patients, temporal BRD in 29%, and temporal rCBF in 24%. One patient had an asymmetry of all three variables, two of temporal rCMRGlc and BRD, three of temporal rCMRGlc and rCBF, and another four of rCBF and BRD. Fourteen patients had an isolated temporal asymmetry in rCMRGlc, seven in BRD, and four in rCBF. A discrepancy in lateralization between the three modalities was not observed. The majority of patients with medically non-refractory CPS have focal abnormalities of blood flow and metabolism in their temporal lobe. In this group of patients, FDG-PET demonstrates abnormalities with the highest frequency of the three modalities studied, followed by IMZ-SPECT, and ECD-SPECT.

Neurological impairment and recovery in Wilson's disease: evidence from PET and MRI

We studied the relationship of regional cerebral glucose consumption (rCMRGlc) and striatal dopamine D2 receptor binding as assessed with positron emission tomography (PET) with the structural abnormalities of the brain in magnetic resonance images (MR), and the degree of neurological impairment in 18 patients with Wilson's disease (WD). The rCMRGlc was determined in the. basal ganglia, the thalamus, the cerebral cortex, and the cerebellar hemispheres. The severity of neurological signs, defined by semiquantitative motor impairment scores, correlated highly ( r = −0.80) with the reduction of striatal rCMRGlc. Clinical scores, striatal rCMRGlc, and the degree of MRI abnormalities showed no correlation with different indices of dopamine D2 receptor binding. Sequential PET measurements in three patients during treatment with chelating agents revealed a moderate increase of striatal rCMRGlc (in two patients) and a moderate to marked increase of striatal D2 receptor binding (in three patients) in association with clinical improvement. Our data suggest that the rCMRGlc represents a sensitive and objective measure for assessing and monitoring striatal and extrastriatal involvement in WD. The lack of correlation between the dopamine D2 receptor binding and striatal rCMRGlc and structural abnormalities may be explained by the wide spectrum of clinical manifestations and different responses to treatment in WD patients.

Optimizing the measurement of regional cerebral glucose consumption with [6- 14C]glucose

[6- 14C]Glucose is used to trace the cerebral metabolic rate of glucose (CMR Glc) in vivo in experiments lasting 5–10 min. Initially 14C is trapped in intermediary metabolite pools. Subsequently 14C is lost as a function of time and metabolic rate, primarily as 14CO 2. Experiments were designed to evaluate the rate of 14C lost as 14CO 2 or as [ 14C]lactate from brain labeled with [6- 14C]glucose during times up to 15 min. CMR Glc was measured during 5, 7.5, 10 and 15 min in 60 brain areas. At longer times the loss of 14C was reflected by lower apparent values of brain CMR Glc. Arteriovenous measurements across brain revealed no significant loss of [ 14C]lactate in normal rats or rats with bicuculline-induced seizures. It was concluded that the primary form in which 14C was lost was as 14CO 2. As expected, the rate of 14CO 2 loss was greater in structures with high metabolic rates. The data were analyzed to determine the parameters necessary to rectify the data so that uniform values of CMR Glc were obtained up to 15 min. Tables were made to predict the degree of 14C loss as well as the 14C-metabolites/[6- 14C]glucose ratio as a function of time and metabolic rate. These tables can be used to plan the maximum and minimum experimental times for optimal results.

Extension of the 2-deoxyglucose method to the fetus in utero: theory and normal values for the cerebral glucose consumption in fetal guinea pigs.

Fetal cerebral metabolism changes during development. The normal fetal metabolic rate must be known to evaluate pathophysiological changes. Therefore, we determined the regional cerebral glucose consumption in the fetal guinea pig. This required the application of the 2-deoxyglucose method to this species. We measured both the transfer coefficients of deoxyglucose and glucose between the maternal arterial plasma and the fetal brain and the lumped constant in chronically prepared undisturbed guinea pig dams using a three-compartment model. Furthermore, the ratio between the initial clearances of deoxyglucose and glucose between the maternal arterial plasma and the fetal brain and the ratio between the phosphorylation coefficients of these substrates in the fetal brain were determined. The total cerebral glucose consumption measured by the deoxyglucose method (10 +/- 1.2 mumol/100 g/min) was similar to that calculated from the glucose concentration and the phosphorylation coefficient of glucose in the cerebrum (10 +/- 0.4 mumol/100 g/min). We conclude that the 2-deoxyglucose method is applicable to the guinea pig, and we further conclude that in the fetal guinea pig cerebral glucose consumption is 10 times lower than that in the adult.

Arterial line filtration protects brain microcirculation during cardiopulmonary bypass in the pig

Microemboli in the brain may inhibit brain function during cardiopulmonary bypass, and in a previous study in pigs of normothermic nonpulsatile bypass we reported a significant decrease in cerebral glucose consumption secondary to interruption of the capillary flow, possibly caused by microemboli. In the present study we measured the regional cerebral glucose consumption and the regional capillary diffusion capacity (that is, the number of perfused capillaries) in 10 different brain regions in two separate groups of animals with and without an arterial filter during normothermic cardiopulmonary bypass. Inclusion of a 40 micron arterial filter in the bypass circuit increased the regional brain glucose consumption 27% (median; range -12% to 145%) and regional capillary diffusion capacity increased 123% (median; range 36% to 829%). No change in brain histologic features, the cerebrovascular permeability to serum proteins, or cerebral water content was observed. The arterial filter probably protects the cerebral microcirculation and prevents the decrease in cerebral glucose consumption otherwise seen during bypass.

Posthypoxic amnesia: regional cerebral glucose consumption measured by positron emission tomography

Using positron emission tomography (PET), the regional cerebral metabolic rate of glucose consumption (rCMRG1c) was measured in 7 subjects suffering from chronic posthypoxic amnesia and in 12 controls. In 6 of the 7 patients regional decreases in rCMRG1c below normal limits were found involving the thalamus in 3 cases, the medial temporal cortex in 2 cases, and the caudate nucleus and cerebellum in one case each. No significant decrease in rCMRG1c was observed in any of the neocortical regions in any of the patients studied. Significant differences between group means of rCMRG1c were found only for the thalamus and the medial temporal cortex. These data suggest that posthypoxic amnesia stems from damage to the medial temporal cortex and its thalamic projection areas and not from neocortical dysfunction, confirming recent theories on the genesis of amnesia in man.

Regional cerebral glucose consumption measured by positron emission tomography in patients with Wilson's disease.

Using positron emission tomography (PET), the regional cerebral metabolic rate of glucose consumption (rCMRGlc) was measured in 14 patients with Wilson's disease (WD) and 23 normal subjects. In WD patients, cerebellar, striatal and--to a lesser extent--cortical and thalamic rCMRGlc were significantly decreased compared with controls. Striatal rCMRGlc was significantly reduced in those 4 patients who had recently started decoppering therapy as compared with striatal rCMRGlc measured in those 10 patients with longer duration of medication. Caudate rCMRGlc correlated significantly with various signs of extrapyramidal dysfunction. Cerebellar, thalamic and cortical rCMRGlc correlated significantly with the severity of pyramidal signs. These data indicate that the PET measurement of rCMRGlc may be a useful tool to evaluate cerebral involvement in WD and to monitor the response to treatment.

Regional Cerebral Glucose Consumption Measured by Positron Emission Tomography in Patients with Unilateral Thalamic Infarction

Regional cerebral glucose consumption (rCMRGlc) was measured in 7 patients with unilateral and isolated thalamic infarctions and 19 normal subjects using 18F-fluorodeoxyglucose and positron emission tomography. Using X-ray computerized tomography and previously published templates, the TI were classified according to the vascular territories involved. Three of the thalamic infarctions were localized in the territory of the paramedian arteries, 2 in the territory of the inferolateral arteries, and 2 in that of the tuberothalamic artery. In 5 of the patients, a significant asymmetry of rCMRGlc remote to the thalamic lesion was detected involving the cerebellum and the caudate nucleus in 3 cases, the prefrontal cortex in 4 cases, and – in 3 cases each – the motor/premotor and the parietal cortex. No significant asymmetry of rCMRGlc was found in the occipital or temporal cortex in any of the patients studied. These data show that the remote metabolic depression consecutive to thalamic infarctions does not affect the whole cortical mantle uniformly, but in a more regionalized manner, which may be due to the selective interruption of distinct thalamocortical pathways.

Positron emission tomography in Alzheimer's disease.

Twenty-one patients with a clinical diagnosis of dementia of the Alzheimer's type (DAT) and 29 healthy, age-matched controls were studied using positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose to measure regional cerebral glucose consumption in the resting state. Reductions in ratio measures of relative metabolism in some parietal, temporal, and frontal regions were found in mild, moderate, and severe DAT groups. A significant increase in right/left metabolic asymmetry, particularly in parietal regions, also was seen in mild and moderate groups. Only in the severely demented patients was the absolute cerebral metabolic rate reduced significantly from control values. Fourteen patients had repeated PET studies, but only those patients with moderate to severe dementia showed a decline in IQ over 6 to 15 months. There were no significant changes in metabolic measures over time. PET is useful in quantifying regional cerebral dysfunction in DAT, even in the early stages of the disease.

In vivo disturbance of the oxidative metabolism of glucose in human cerebral gliomas.

Abnormalities in the oxidative metabolism of glucose in human cerebral gliomas have been studied in seven patients using positron emission tomography. Measurements of regional cerebral blood flow and oxygen consumption were obtained using the oxygen-15 steady-state inhalation technique. Values of regional cerebral glucose consumption were obtained using fluorine 18-labeled 2-fluoro-2-deoxy-D-glucose and a simplification of the method of Sokoloff. Functional values were obtained for regions of tumor and brain tissue in the middle cerebral artery territory of the contralateral cortex. Values of regional glucose consumption were calculated for both regions using a value of the lumped constant quoted for normal brain tissue (0.42). Tumor regional cerebral blood flow was comparable to that in the contralateral cortex, whereas regional cerebral oxygen consumption was depressed. This depression resulted in low tumor values of the fractional oxygen extraction ratio (0.21 +/- 0.07), indicating that oxygen supply exceeded the metabolic demand. In contrast, tumor regional cerebral glucose consumption was not depressed and regional glucose extraction ratios were similar for tumor and brain tissue. The metabolic uncoupling between regional oxygen consumption and regional glucose consumption (CMRO2/CMRGlu = 0.24 +/- 0.07 ml of oxygen per milligram of glucose) is indicative of increased aerobic glycolysis.

Rotation induced increases of glucose uptake in rat vestibular nuclei and vestibulocerebellum

A new technique for the autoradiographic measurement of regional cerebral glucose consumption using tracer amounts of radioactive 2-deoxyglucose (2-DG) was employed to study the effects of vestibular inputs on local cerebral glucose metabolism. Rats rotated in the vertical plane showed localized increases of glucose utilization in the vestibular nuclei and several areas of the cerebellum: flocculus, nodulus, ventral uvula, and accessory paraflocculus. The changes in the cerebellum occurred both in the neuronal perikarya-rich granular layer and the neuropil-rich molecular layer. Differential changes resulting from rotation occurred within the granular layer of the nodulus, where at least 7 separate longitudinal zones of differing glucose consumption were seen. This type of longitudinal organization has been described previously in other areas of the vermis with other techniques.

Regional Cerebral Blood Flow in Physiologic and Pathophysiologic States

Publisher Summary The blood flow of the brain is markedly heterogeneous and the changes, which occur in cerebral perfusion in various physiologic and pathophysiologic conditions, are often focal in nature. This chapter deals with a quantitative method for measuring such regional changes in cerebral blood flow (rCBF) and delineates those changes that occur in cerebral hemodynamics under various conditions. The normal values for rCBF in cats are presented. The effect of slow wave sleep and rapid eye movement sleep on these flow values is discussed in relation to the distribution of changes seen and the possible mechanism responsible for these changes. Studies in cats following cerebral trauma are reported which demonstrate a focal loss of the normal autoregulatory capacity of the cerebral vessels. Prolonged partial asphyxia in the term monkey fetus and its effect on rCBF was also studied. The mechanism of production of these flow changes and their relation to the pathologic changes seen in these animals is discussed. Finally, preliminary results from the development of an autoradiographic technique for measuring regional cerebral glucose consumption in vivo utilizing [2- 14 C] deoxyglucose are presented.