Changes In Cerebral Glucose Utilization Research Articles

The effects of nicotine administration and drug cue on impulsivity

Several [18F]-FDG positron emission tomography (PET) studies in alcoholics have consistently reported decreases in overall brain glucose metabolism at rest and following acute alcohol administration. However, changes in cerebral glucose utilization associated with the transition to addiction are not well understood and require longitudinal translational imaging studies in animal models of alcoholism. Here, we studied brain glucose uptake in alcohol drinking rats in order to provide convergent evidence to what has previously been reported in human studies. Brain glucose metabolism was measured by [18F]-FDG microPET imaging in different male Wistar rat groups: short-term drinking (three months), long-term drinking (twelve months) and alcohol-naïve. Global and regional cerebral glucose uptake was measured at rest and following acute alcohol administration. We showed that alcohol significantly reduced the whole-brain glucose metabolism. This effect was most pronounced in the parietal cortex and cerebellum. Alcohol-induced decreases in brain [18F]-FDG uptake was most apparent in alcohol-naïve rats, less intense in short-term drinkers and absent in long-term drinkers. The latter finding indicates the occurrence of tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrast, some regions, like the ventral striatum and entorhinal cortex, showed enhanced metabolic activity, an effect that did not undergo tolerance during long-term alcohol consumption. Our findings are comparable to those described in human studies using the same methodology. We conclude that [18F]-FDG PET studies in rat models of alcoholism provide good translation and can be used for future longitudinal studies investigating alterations in brain function during different stages of the addiction cycle.

CEREBRAL GLUCOSE UTILIZATION MEASURED WITH HIGH RESOLUTION POSITRON EMISSION TOMOGRAPHY IN EPILEPTIC FINNISH SPITZ DOGS AND HEALTHY DOGS

In human epileptic patients, changes in cerebral glucose utilization can be detected 2-deoxy-2-[(18) F] fluoro-D-glucose positron emission tomography (FDG-PET). The purpose of this prospective study was to determine whether epileptic dogs might show similar findings. Eleven Finnish Spitz dogs with focal idiopathic epilepsy and six healthy dogs were included. Dogs were examined using electroencephalography (EEG) and FDG-PET, with epileptic dogs being evaluated during the interictal period. Visual and semi-quantitative assessment methods of FDG-PET were compared and contrasted with EEG findings. Three independent observers, unaware of dog clinical status, detected FDG-PET uptake abnormalities in 9/11 epileptic (82%), and 4/8 healthy dogs (50%). Occipital cortex findings were significantly associated with epileptic status (P = 0.013). Epileptic dogs had significantly lower standardized uptake values (SUVs) in numerous cortical regions, the cerebellum, and the hippocampus compared to the control dogs. The lowest SUVs were found in the occipital lobe. White matter normalized and left-right asymmetry index values for all pairs of homologous regions did not differ between groups. Visual evaluation of the EEGs was less sensitive (36%) than FDG-PET. Both diagnostic tests were consensual and specific (100%) for occipital findings, but EEG had a lower sensitivity for detecting lateralized foci than FDG-PET. Findings supported the use of FDG-PET as a diagnostic test for dogs with suspected idiopathic epilepsy. Visual and semiquantitative analyses of FDG-PET scans provided complementary information. Findings also supported the theory that epileptogenesis may occur in multiple brain regions in Finnish Spitz dogs with idiopathic epilepsy.

Latrepirdine increases cerebral glucose utilization in aged mice as measured by [18F]-fluorodeoxyglucose positron emission tomography

Latrepirdine is hypothesized to exert a unique mechanism of action involving stabilization of mitochondria that may have utility in treating Alzheimer's disease. However, the ability of latrepirdine to improve cognition in Alzheimer's disease (AD) is controversial due to a discrepancy between the positive signal reported in the multi-site phase II clinical trial where latrepirdine met all primary and secondary endpoints [Doody et al. (2008) Lancet 372:207-215], and the subsequent null effect observed in a multicenter, phase III trial. While dysfunction of mitochondria and abnormal energy metabolism has been linked to AD pathology, no studies have been reported that investigate latrepirdine's effect on cerebral glucose utilization (CGU). Glucose metabolism, following acute latrepirdine administration, can be used to help dose selection in Phase I dose-ranging studies. The aim of the current study was to assess changes in CGU in young and aged mice in vivo using [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) after acute treatment with latrepirdine. Two ages of B6SJLF2 mice (5 and 20 months old) were tested. Three test-retest FDG-PET baseline scans were assessed across all subjects. As CGU was heterogeneous in aged mice, compared to young mice, aged subjects were rank ordered and then counterbalanced into two CGU homogenous groups. In Studies 1 and 2, latrepirdine (1.0 mg/kg) significantly enhanced CGU in aged mice. In contrast, Study 3 revealed that latrepirdine did not modulate CGU in young mice. Monitoring changes in CGU in response to acute drug administration may represent an imaging biomarker for dose selection in AD. Further studies that would establish the translation from mice to non-human primates to humans need to be investigated to confirm the utility of FDG-PET in dose-selection for mitochondrial modulators.

Detection by voxel-wise statistical analysis of significant changes in regional cerebral glucose uptake in an APP/PS1 transgenic mouse model of Alzheimer's disease

Biomarkers and technologies similar to those used in humans are essential for the follow-up of Alzheimer's disease (AD) animal models, particularly for the clarification of mechanisms and the screening and validation of new candidate treatments. In humans, changes in brain metabolism can be detected by 1-deoxy-2-[18F] fluoro-d-glucose PET (FDG-PET) and assessed in a user-independent manner with dedicated software, such as Statistical Parametric Mapping (SPM). FDG-PET can be carried out in small animals, but its resolution is low as compared to the size of rodent brain structures. In mouse models of AD, changes in cerebral glucose utilization are usually detected by [14C]-2-deoxyglucose (2DG) autoradiography, but this requires prior manual outlining of regions of interest (ROI) on selected sections. Here, we evaluate the feasibility of applying the SPM method to 3D autoradiographic data sets mapping brain metabolic activity in a transgenic mouse model of AD. We report the preliminary results obtained with 4 APP/PS1 (64±1weeks) and 3 PS1 (65±2weeks) mice. We also describe new procedures for the acquisition and use of “blockface” photographs and provide the first demonstration of their value for the 3D reconstruction and spatial normalization of post mortem mouse brain volumes. Despite this limited sample size, our results appear to be meaningful, consistent, and more comprehensive than findings from previously published studies based on conventional ROI-based methods. The establishment of statistical significance at the voxel level, rather than with a user-defined ROI, makes it possible to detect more reliably subtle differences in geometrically complex regions, such as the hippocampus. Our approach is generic and could be easily applied to other biomarkers and extended to other species and applications.

Pathogenesis and Pharmacology of Epilepsy in the Lithium‐pilocarpine Model

To try to identify the critical structures during epileptogenesis, we used the lithium-pilocarpine model that reproduces most clinical and neuropathological features of temporal lobe epilepsy (TLE). We used imaging techniques as well as a disease modifying approach and pharmacological strategy. With [14C]-2-deoxyglucose autoradiography, we assessed changes in cerebral glucose utilization. T2-weighted magnetic resonance imaging (MRI, 4.7 T) allowed follow-up of structures involved in epileptogenesis. A potential disease-modifying effect was studied using preconditioning with brief seizures (amygdala kindling, maximal electroshocks) and pharmacological strategies including vigabatrin (250 mg/kg), caffeine (0.3 g/L in drinking water), topiramate (10-60 mg/kg), pregabalin (50 mg/kg followed by 10 mg/kg), or RWJ-333369 (10-120 mg/kg). In adult and PN21 rats that became epileptic, entorhinal, and piriform cortices were the initial structures exhibiting significant signal changes on MRI scans, from 6 h after status epilepticus (SE) onset, reflecting neuronal death. In PN21 rats that did not become epileptic, no signal occurred in parahippocampal cortices. In hippocampus, MRI signal change appeared 36-48 h after SE, and progressively worsened to sclerosis. During the latent and chronic phases, the metabolic level in the hilus of adult and PN21 epileptic rats was normal although neuronal loss reached 60-75%. Protection limited to CA1 and/or CA3 (caffeine, topiramate, vigabatrin, amygdala kindling) did not affect the latency to spontaneous seizures. Protection limited to the entorhinal and piriform cortices (pregabalin) delayed epileptogenesis. The combined protection of Ammon's horn and parahippocampal cortices (RWJ-333369) prolonged the latency before the onset of seizures in a dose-dependent manner or, in some cases, prevented the epilepsy. The entorhinal and piriform cortices are critically involved in the early phase of the epileptogenesis while the hilus may initiate and/or maintain epileptic seizures. Pharmacological protection of the basal cortices is necessary for a beneficial disease-modifying effect but this must be combined with protection of the hippocampus to prevent epileptogenesis in this model of TLE.

Changes in cerebral glucose utilization in patients with panic disorder treated with cognitive–behavioral therapy

Several neuroanatomical hypotheses of panic disorder have been proposed focusing on the significant role of the amygdala and PAG-related “panic neurocircuitry.” Although cognitive–behavioral therapy is effective in patients with panic disorder, its therapeutic mechanism of action in the brain remains unclear. The present study was performed to investigate regional brain glucose metabolic changes associated with successful completion of cognitive–behavioral therapy in panic disorder patients. The regional glucose utilization in patients with panic disorder was compared before and after cognitive–behavioral therapy using positron emission tomography with 18F-fluorodeoxyglucose. In 11 of 12 patients who showed improvement after cognitive–behavioral therapy, decreased glucose utilization was detected in the right hippocampus, left anterior cingulate, left cerebellum, and pons, whereas increased glucose utilization was seen in the bilateral medial prefrontal cortices. Significant correlations were found between the percent change relative to the pretreatment value of glucose utilization in the left medial prefrontal cortex and those of anxiety and agoraphobia-related subscale of the Panic Disorder Severity Scale, and between that of the midbrain and that of the number of panic attacks during the 4 weeks before each scan in all 12 patients. The completion of successful cognitive–behavioral therapy involved not only reduction of the baseline hyperactivity in several brain areas but also adaptive metabolic changes of the bilateral medial prefrontal cortices in panic disorder patients.

Neuropathology of cocaine abuse

The effects of cocaine abuse on brain structure and function are numerous. Some of these effects, such as catastrophic cerebrovascular incidents, are clearly neuropathological. Others, such as persistent perfusion deficits and changes in cerebral glucose utilization, await further functional definition. More recent findings of increases in dopamine transporter density and gene induction may be neuropathologic, but could represent neuroadaptive responses to cocaine's acute actions of cocaine, manifestations of the reinforcing properties of cocaine or epiphenomena of addiction. Recent technical advances directed at bridging the gap between preclinical and clinical studies hold significant promise for advancing our understanding regarding the neuropathology of cocaine abuse and addiction.

Mapping of change in cerebral glucose utilization during physiological stimulation using constrained graphical method of [ 18F]fluorodeoxyglucose (FDG) double injection

Mapping of change in cerebral glucose utilization during physiological stimulation using constrained graphical method of [ 18F]fluorodeoxyglucose (FDG) double injection

Brain energy metabolism in the acute stage of experimental subarachnoid haemorrhage: local changes in cerebral glucose utilization.

An experimental model was used to investigate acute alterations of cerebral metabolic activity in rats subjected to subarachnoid haemorrhage (SAH). Haemorrhages were produced in anaesthetized animals by injecting 0.3 ml of autologous, arterial nonheparinized blood into the cisterna magna. Control rats received subarachnoid injections of mock-cerebrospinal fluid to study the effect of sudden raised intracranial pressure, or underwent sham operation. Three hours after SAH rats were given an intravenous injection of [14C]-2-deoxyglucose. Experiments were terminated by decapitation, and the brains were removed and frozen. Regional brain metabolic activity was studied by quantitative autoradiography. In comparison with sham-operated controls, cerebral metabolic activity was diffusely decreased after SAH. Statistically significant decreases in metabolic rate were observed in 23 of 27 brain regions studied. Subarachnoid injections of mock-cerebrospinal fluid also produced depression of cerebral metabolic activity, but quantitatively these changes were not as pronounced and diffuse as in SAH rats. The present study shows that a widespread depression of brain metabolism occurs in the acute stage after experimental SAH and is probably secondary to the subarachnoid presence of blood itself and/or blood products.

Mapping of change in cerebral glucose utilization using fluorine-18 fluorodeoxyglucose double injection and the constrained weighted-integration method

The authors developed a method for mapping the change in cerebral glucose utilization at two different physiological states using [(18 )F]fluorodeoxyglucose (FDC) double infection and the constrained weighted-integration method. The authors studied young normal subjects without (baseline-baseline group, n=5) and with (baseline-stimulation group, n=5) vibrotactile stimulation of the fingertips of the right hand. Dynamic scans were performed using positron emission tomography (PET) following an initial dose (the first session, 0-30 min) and an additional dose (the second session, 30-60 min). The parametric images of the net clearance of FDG from blood to brain (K*), unidirectional blood-to-brain clearance (K(1)*), and cerebral metabolic rate of glucose (CMR(glc)) of the two sessions were generated. The averaged subtraction (second minus first session) and t-statistic images were generated, which were rendered into Talairach's stereotaxic coordinates and merged with the averaged magnetic resonance imaging (MRI) image. In the baseline-baseline group, regional K*, K(1)* and CMR(glc) in the first and second sessions were strongly correlated (r(2)=0.953, 0.935, and 0.951, respectively, n=330). In the baseline-stimulation group, significant increases in these estimates were obtained in the contralateral primary somatosensory cortex (SI) (from 3.43+/-0.78 to 4.02+/-1.01 ml/100 g/min for K*, 7.85+/-1.88 to 9.09+/-1.71 ml/100 g/min for K(1)*, and 280+/-5.9 to 32.3+/-5.5 mumol/100 g/min for CMR(glc)), while there were no significant changes in the ipsilateral SI (from 3.45+/-0.83 to 359+/-0.72 ml/100 g/min for K*, 8.17+/-2.33 to 837+/-1.75 ml/100 g/min for K(1 )* and 29.5+/-8.1 to 29.1+/-8.2 mumol/100 g/mln for CMR (glc)), Significant increases in K* and CMR(glc) in the contralateral SI were clearly demonstrated in the t-statistic image. In conclusion, the proposed method allows mapping of changes in cerebral glucose utilization during physiological stimulation of the brain, and will be useful for studying the relationship between neural activity and regional cerebral glucose metabolism.

The putative 5-HT 1A antagonist BMY 7378 blocks 8-OH-DPAT-induced changes in local cerebral glucose utilization in the conscious rat

It has previously been shown that the 5-HT 1A agonist, 8-OH-DPAT, caused discrete changes in cerebral glucose utilization in the rat, as assessed by quantitative 2-deoxyglucose autoradiography. Here, the effect of the putative 5-HT 1A antagonist, BMY 7378, on regional cerebral glucose utilization was examined, when injected alone and in rats treated with 8-OH-DPAT. In control rats, BMY 7378 (5 mg/kg, s.c.) markedly increased glucose utilization in the lateral habenular nucleus and moderately reduced glucose utilization in the hippocampal formation. Pretreatment with BMY 7378 (5 mg/kg) significantly attenuated the reductions in glucose utilization in the hippocampus, entorhinal, piriform and cingulate cortex, induced by 8-OH-DPAT (0.25 mg/kg). The 8-OH-DPAT-induced increase in glucose utilization in the copula pyramis, that is putatively associated with the appearance of the 5-HT behavioural syndrome, was also blocked by BMY 7378, as was the behavioural syndrome. In summary, BMY 7378 produced few of the discrete changes in cerebral glucose utilization that are seen with 8-OH-DPAT. However, many of the changes induced by 8-OH-DPAT were reversed by BMY 7378. These data are consistent with the hypothesis that the effects of 8-OH-DPAT on regional cerebral glucose utilization are mediated by 5-HT 1A receptors.

Changes of Hippocampal Glucose Utilization Subsequent to Amygdaloid‐Kindled Generalized Seizures

Local changes in cerebral glucose utilization during the postictal phase of amygdaloid-kindled generalized seizures were studied with the quantitative autoradiographic 2-[14C]deoxyglucose method in conscious rats. Measurement was initiated either just after termination of a behavioral seizure (GS-I) or 30 s after seizure termination (GS-II) to determine dynamic metabolic changes in the postictal phase. Although glucose utilization of the neocortex was remarkably depressed in both GS-I and GS-II, that of the hippocampus significantly increased in GS-I and then decreased in GS-II as compared with control. These changes of hippocampal glucose utilization were observed in all sectors of the pyramidal cell layer (CA 1-4) and in the molecular layer. Because metabolic changes associated with development of amygdaloid-kindled seizures begin in the limbic structures including the hippocampus, the transient increase in hippocampal glucose utilization observed in the early postictal phase indicates that the hippocampus is one of the key structures not only for initiating and maintaining but also for terminating kindled seizures.

Sphenopalatine ganglion stimulation increases regional cerebral blood flow independent of glucose utilization in the cat

Regional cerebral blood flow was determined using the tracer [ 14C]iodoantipyrine and regional brain dissection, and regional cerebral glucose utilization determined using the 2-deoxyglucose method, in the α-chloralose-anesthetized cat to evaluate the effect of electrical stimulation of the sphenopalatine (pterygopalatine) ganglion. Unilateral stimulation for either a short period (7–10 min) or a longer period (45 min) resulted in increases in blood flow in the ipsilateral cerebral cortex of up to 45% (parietal cortex) with, in addition, increased flow in the white matter of the corpus callosum (42%). The flow changes for both brief and prolonged stimulation were not significantly different. Flow was not altered in either the brainstem or basal ganglia (caudate nucleus). In contrast to these changes in cerebral blood flow no changes in cerebral glucose utilization were seen in any of the brain areas studied and in particular there were no changes in the areas in which blood flow increased. These data provide clear evidence that the innervation of the cerebral vasculature from the main parasympathetic ganglion can alter cerebral blood flow independent of cerebral metabolism.

Cerebrospinal fluid ionic regulation, cerebral blood flow, and glucose use during chronic metabolic alkalosis.

Chronic metabolic alkalosis was induced in rats by combining a low K+ diet with a 0.2 M NaHCO3 solution as drinking fluid for either 15 or 27 days. Local cerebral blood flow and local cerebral glucose utilization were measured in 31 different structures of the brain in conscious animals by means of the iodo-[14C]antipyrine and 2-[14C]deoxy-D-glucose method. The treatment induced moderate [15 days, base excess (BE) 16 mM] to severe (27 days, BE 25 mM) hypochloremic metabolic alkalosis and K+ depletion. During moderate metabolic alkalosis no change in cerebral glucose utilization and blood flow was detectable in most brain structures when compared with controls. Cerebrospinal fluid (CSF) K+ and H+ concentrations were significantly decreased. During severe hypochloremic alkalosis, cerebral blood flow was decreased by 19% and cerebral glucose utilization by 24% when compared with the control values. The decrease in cerebral blood flow during severe metabolic alkalosis is attributed mainly to the decreased cerebral metabolism and to a lesser extent to a further decrease of the CSF H+ concentration. CSF K+ concentration was not further decreased. The results show an unaltered cerebral blood flow and glucose utilization together with a decrease in CSF H+ and K+ concentrations at moderate metabolic alkalosis and a decrease in cerebral blood flow and glucose utilization together with a further decreased CSF H+ concentration at severe metabolic alkalosis.

Regional changes in cerebral glucose utilization in the postictal phase of amygdaloid kindled rats

Regional changes in cerebral glucose utilization in the postictal phase of amygdaloid kindled rats

Local Changes in Cerebral Glucose Utilization during Ketamine Anesthesia

Ketamine produces both excitatory and depressant actions in the brain, but there have been conflicting results regarding which structures are affected and the magnitude of the alteration in cerebral metabolism produced. The authors applied the 2-[14C]deoxyglucose method quantitatively to a study of

Local changes in cerebral glucose utilization during ketamine anesthesia.

Ketamine produces both excitatory and depressant actions in the brain, but there have been conflicting results regarding which structures are affected and the magnitude of the alteration in cerebral metabolism produced. The authors applied the 2-[14C]deoxyglucose method quantitatively to a study of ketamine anesthesia (10 or 30 mg/kg intravenously) in the rat. Ketamine caused both increases and decreases in local cerebral glucose utilization. The areas with altered glucose utilization could be grouped into functional systems. Some structures of the limbic system showed large increases in glucose utilization; indeed the 70 per cent increases in cingulate gyrus and hippocampus were the largest of all regions examined. The extrapyramidal motor system and corpus callosum showed significant but less dramatic (20-40 per cent) increases. On the other hand, decreased metabolism occurred in the somatosensory and auditory systems, with the greatest reduction (40 per cent) in the inferior colliculus. Within some structures, such as the caudate nucleus and visual cortex, a striking redistribution of metabolism which is characterized by a change in the autoradiographic pattern of activity was noted. Reduced glucose utilization in the somatosensory and auditory systems suggests that a selective sensory deprivation occurs during ketamine anesthesia while the increased metabolism in the limbic system is consistent with neurophysiologic studies which have demonstrated seizure activity in this region. Compared with other anesthetics, which tend to produce a generalized decrease in metabolism, the cerebral metabolic effects of ketamine are unique and emphasize that it produces a state of "anesthesia" which is quite different from that of other commonly used drugs.

Regional changes in cerebral glucose utilization associated with amygdaloid kindling and electroshock in the rat

A method using [ 3H]2-deoxyglucose was used to identify brain areas activated during partial and generalized amygdaloid kindled seizures and generalized seizures following electro-convulsive shock in rats. The amygdala, hippocampus, septal nuclei and hypothalamus were bilaterally activated in kindled convulsions. Electroshock caused a more widespread involvement including the thalamus, striatum, reticular formation and cerebellum. Changes in the amygdala and hippocampus but not hypothalamus, were found after partial kindling.

ACID-BASE CHANGES IN ARTERIAL BLOOD AND CEREBROSPINAL FLUID DURING CRANIOTOMY AND HYPERVENTILATION

SUMMARY Several studies in healthy man and animals have shown biochemical evidence of a change in cerebral glucose utilization to anaerobic metabolism during hyperventilation and hypocarbia. The increase in lactate in the cerebrospinal fluid was moderate at a Paco2 of 20 mm Hg but became more marked at lower values of Paco2. In this investigation patients were studied, during craniotomy, both at normal body temperature and under hypothermia. Arterial blood was sampled at hourly intervals and one sample of ventricular c.s.f. was obtained during the period of hyperventilation. With the exception of one patient in the hypothermia group no evidence of an excessive increase in c.s.f. lactate (indicative of deficient cerebral oxygenation) was seen at Paco2 values of approximately 20 mm Hg.