Whole-brain Glucose Metabolism Research Articles

Decomposed FDG PET-based phenotypic heterogeneity predicting clinical prognosis and decision-making in temporal lobe epilepsy patients.

This study utilized a data-driven Bayesian model to automatically identify distinct latent disease factors represented by overlapping glucose metabolism patterns from 18F-Fluorodeoxyglucose PET (18F-FDG PET) to analyze heterogeneity among patients with TLE. We employed unsupervised machine learning to estimate latent disease factors from 18F-FDG PET scans, representing whole-brain glucose metabolism patterns in seventy patients with TLE. We estimated the extent to which multiple distinct factors were expressed within each participant and analyzed their relevance to epilepsy burden, including seizure onset, duration, and frequency. Additionally, we established a predictive model for clinical prognosis and decision-making. We identified three latent disease factors: hypometabolism in the unilateral temporal lobe and hippocampus (factor 1), hypometabolism in bilateral prefrontal lobes (factor 2), and hypometabolism in bilateral temporal lobes (factor 3), variably co-expressed within each patient. Factor 3 demonstrated the strongest negative correlation with the age of onset and duration (r = - 0.33, - 0.38 respectively, P < 0.05). The supervised classifier, trained on latent disease factors for predicting patient-specific antiepileptic drug (AED) responses, achieved an area under the curve (AUC) of 0.655. For post-surgical seizure outcomes, the AUC was 0.857, and for clinical decision-making, it was 0.965. Decomposing 18F-FDG PET-based phenotypic heterogeneity facilitates individual-level predictions relevant to disease monitoring and personalized therapeutic strategies.

Aging and Cerebral Glucose Metabolism: 18F-FDG-PET/CT Reveals Distinct Global and Regional Metabolic Changes in Healthy Patients.

Alterations in cerebral glucose metabolism can be indicative of both normal and pathological aging processes. In this retrospective study, we evaluated global and regional neurological glucose metabolism in 73 healthy individuals (mean age: 35.8 ± 13.1 years; 82.5% female) using 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). This population exhibited a low prevalence of comorbidities associated with cerebrovascular risk factors. We utilized 18F-FDG-PET/CT imaging and quantitative regional analysis to assess cerebral glucose metabolism. A statistically significant negative correlation was found between age and the global standardized uptake value mean (SUVmean) of FDG uptake (p = 0.000795), indicating a decrease in whole-brain glucose metabolism with aging. Furthermore, region-specific analysis identified significant correlations in four cerebral regions, with positive correlations in the basis pontis, cerebellar hemisphere, and cerebellum and a negative correlation in the lateral orbital gyrus. These results were further confirmed via linear regression analysis. Our findings reveal a nuanced understanding of how aging affects glucose metabolism in the brain, providing insight into normal neurology. The study underscores the utility of 18F-FDG-PET/CT as a sensitive tool in monitoring these metabolic changes, highlighting its potential for the early detection of neurological diseases and disorders related to aging.

Brain Metabolic Correlates of Dopaminergic Denervation in Prodromal and Early Parkinson's Disease.

It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD). To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD. This cohort study included 28 patients with polysomnography-confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder (denovo PD), and 28 healthy controls (HCs) who underwent two positron emission tomography scans with 18 F-fluorodeoxyglucose (all participants) and 18 F-N-3-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)-nortropane (except for one denovo PD patient and 15 HCs). We analyzed striatal and voxel-wise whole-brain glucose metabolism in relation to nigrostriatal dopaminergic integrity and comparatively investigated the whole-brain metabolic connectivity among the groups. We also assessed longitudinal metabolic changes against progressive dopaminergic denervation over 4 years in the iRBD group. From HCs to iRBD and finally to the denovo PD, dopaminergic integrity positively correlated with metabolic activity in the caudate, whereas a negative correlation was observed in the posterior putamen. In the iRBD group, there was a metabolic increase in the inferior orbitofrontal cortex against putaminal dopaminergic denervation at baseline, but negative correlations were newly observed in the superior orbitofrontal cortex and superior frontal gyrus at the 4-year follow-up. The denovo PD group showed negative correlations in the cerebellum and fusiform gyrus. Intra- and inter-regional metabolic connectivities in the parieto-occipital cortices were enhanced in the iRBD group compared with the denovo PD and HC groups. In the iRBD group, overall metabolic connectivity was strengthened along with enhanced basal ganglia-frontal connection by advancing dopaminergic denervation. Our findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society.

Impaired self-awareness of cognitive deficits in Parkinson's disease relates to cingulate cortex dysfunction.

Impaired self-awareness of cognitive deficits (ISAcog) has rarely been investigated in Parkinson's disease (PD). ISAcog is associated with poorer long-term outcome in other diseases. This study examines ISAcog in PD with and without mild cognitive impairment (PD-MCI), compared to healthy controls, and its clinical-behavioral and neuroimaging correlates. We examined 63 PD patients and 30 age- and education-matched healthy controls. Cognitive state was examined following the Movement Disorder Society Level II criteria. ISAcog was determined by subtracting z-scores (based on controls' scores) of objective tests and subjective questionnaires. Neural correlates were assessed by structural magnetic resonance imaging (MRI) and 2-[fluorine-18]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) in 47 patients (43 with MRI) and 11 controls. We analyzed whole-brain glucose metabolism and cortical thickness in regions where FDG-uptake correlated with ISAcog. PD-MCI patients (N = 23) showed significantly more ISAcog than controls and patients without MCI (N = 40). When all patients who underwent FDG-PET were examined, metabolism in the bilateral superior medial frontal gyrus, anterior and midcingulate cortex negatively correlated with ISAcog (FWE-corrected p < 0.001). In PD-MCI, ISAcog was related to decreased metabolism in the right superior temporal lobe and insula (N = 13; FWE-corrected p = 0.023) as well as the midcingulate cortex (FWE-corrected p = 0.002). Cortical thickness was not associated with ISAcog in these regions. No significant correlations were found between ISAcog and glucose metabolism in controls and patients without MCI. Similar to Alzheimer's disease, the cingulate cortex seems to be relevant in ISAcog in PD. In PD-MCI patients, ISAcog might result from a disrupted network that regulates awareness of cognition and error processes.

Impact of acute sleep restriction on cerebral glucose metabolism during recovery non-rapid eye movement sleep among individuals with primary insomnia and good sleeper controls

BackgroundRestricting time in bed improves insomnia symptoms, but the neural mechanisms for this effect are unknown. Total and partial acute sleep restriction may be useful paradigms for elucidating these effects. We examined the impact of acute sleep restriction on cerebral glucose metabolism during non-rapid eye movement (NREM) sleep in individuals with primary insomnia (n = 17) and good sleep (n = 19). MethodsParticipants underwent [18F]fluorodeoxyglucose positron emission tomography scans during baseline and recovery NREM sleep following one night of partial or total sleep restriction. We compared group differences in baseline-recovery changes, as well as main effects of group and condition (baseline vs. recovery NREM sleep), for relative regional cerebral metabolic rate for glucose (rCMRglc), whole-brain glucose metabolism, and sleep quality. ResultsRelative rCMRglc was significantly lower during recovery NREM sleep compared to baseline in the left frontoparietal cortex, medial frontal cortex, posterior cingulate cortex, and thalamus, with no significant group differences. Good sleepers, but not insomnia patients, had lower whole-brain glucose metabolism during recovery NREM sleep compared to baseline. Acute sleep restriction improved sleep quality in individual with insomnia. Subgroup analyses including only participants who underwent partial sleep restriction yielded the same pattern of findings. ConclusionIndividuals with insomnia and good sleepers showed similar relative rCMRglc responses to acute sleep restriction. Brain regions showing the greatest baseline-recovery changes in both groups included regions previously shown to have smaller sleep-wake differences in patients with primary insomnia. Acute sleep restriction, and by extension sleep restriction therapy, may impact regional metabolic alterations that characterize insomnia.

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.

Cannabis Abusers Show Hypofrontality and Blunted Brain Responses to a Stimulant Challenge in Females but not in Males.

The extent to which cannabis is deleterious to the human brain is not well understood. Here, we test whether cannabis abusers (CA) have impaired frontal function and reactivity to dopaminergic signaling, which are fundamental to relapse in addiction. We measured brain glucose metabolism using PET and [(18)F]FDG both at baseline (placebo) and after challenge with methylphenidate (MP), a dopamine-enhancing drug, in 24 active CA (50% female) and 24 controls (HC; 50% female). Results show that (i) CA had lower baseline glucose metabolism than HC in frontal cortex including anterior cingulate, which was associated with negative emotionality. (ii) MP increased whole-brain glucose metabolism in HC but not in CA; and group by challenge effects were most profound in putamen, caudate, midbrain, thalamus, and cerebellum. In CA, MP-induced metabolic increases in putamen correlated negatively with addiction severity. (iii) There were significant gender effects, such that both the group differences at baseline in frontal metabolism and the attenuated regional brain metabolic responses to MP were observed in female CA but not in male CA. As for other drug addictions, reduced baseline frontal metabolism is likely to contribute to relapse in CA. The attenuated responses to MP in midbrain and striatum are consistent with decreased brain reactivity to dopamine stimulation and might contribute to addictive behaviors in CA. The gender differences suggest that females are more sensitive than males to the adverse effects of cannabis in brain.

Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases.

During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-(18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal.

Functional implications of hippocampal degeneration in early Alzheimer’s disease: a combined DTI and PET study

Hypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer's disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippocampal formation. Here, we explored the association between microstructural alterations within the hippocampus and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment. Twenty patients with early AD (Mini-Mental State Examination 25.7 ± 1.7) were studied with [(18)F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippocampus, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test for unique contributions of diffusivity and metabolic indices in the prediction of memory function. Diffusivity in the left anterior hippocampus negatively correlated with FDG uptake primarily in the left anterior hippocampus, parahippocampal gyrus and the PCC (p < 0.005). The same correlation pattern was found for right hippocampal diffusivity (p < 0.05). In linear regression analysis, left anterior hippocampal diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippocampal diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD. These findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippocampal output pathways as a significant contributor to the genesis of episodic memory impairment.

Recurrent Antecedent Hypoglycemia Alters Neuronal Oxidative Metabolism In Vivo

OBJECTIVEThe objective of this study was to characterize the changes in brain metabolism caused by antecedent recurrent hypoglycemia under euglycemic and hypoglycemic conditions in a rat model and to test the hypothesis that recurrent hypoglycemia changes the brain's capacity to utilize different energy substrates.RESEARCH DESIGN AND METHODSRats exposed to recurrent insulin-induced hypoglycemia for 3 days (3dRH rats) and untreated controls were subject to the following protocols: [2-13C]acetate infusion under euglycemic conditions (n = 8), [1-13C]glucose and unlabeled acetate coinfusion under euglycemic conditions (n = 8), and [2-13C]acetate infusion during a hyperinsulinemic-hypoglycemic clamp (n = 8). In vivo nuclear magnetic resonance spectroscopy was used to monitor the rise of13C-labeling in brain metabolites for the calculation of brain metabolic fluxes using a neuron-astrocyte model.RESULTSAt euglycemia, antecedent recurrent hypoglycemia increased whole-brain glucose metabolism by 43 ± 4% (P < 0.01 vs. controls), largely due to higher glucose utilization in neurons. Although acetate metabolism remained the same, control and 3dRH animals showed a distinctly different response to acute hypoglycemia: controls decreased pyruvate dehydrogenase (PDH) flux in astrocytes by 64 ± 20% (P = 0.01), whereas it increased by 37 ± 3% in neurons (P = 0.01). The 3dRH animals decreased PDH flux in both compartments (−75 ± 20% in astrocytes, P < 0.001, and −36 ± 4% in neurons, P = 0.005). Thus, acute hypoglycemia reduced total brain tricarboxylic acid cycle activity in 3dRH animals (−37 ± 4%, P = 0.001), but not in controls.CONCLUSIONSOur findings suggest that after antecedent hypoglycemia, glucose utilization is increased at euglycemia and decreased after acute hypoglycemia, which was not the case in controls. These findings may help to identify better methods of preserving brain function and reducing injury during acute hypoglycemia.

Low doses of alcohol substantially decrease glucose metabolism in the human brain

Moderate doses of alcohol decrease glucose metabolism in the human brain, which has been interpreted to reflect alcohol-induced decreases in brain activity. Here, we measure the effects of two relatively low doses of alcohol (0.25 g/kg and 0.5 g/kg, or 5 to 10 mM in total body H 2O) on glucose metabolism in the human brain. Twenty healthy control subjects were tested using positron emission tomography (PET) and FDG after placebo and after acute oral administration of either 0.25 g/kg, or 0.5 g/kg of alcohol, administered over 40 min. Both doses of alcohol significantly decreased whole-brain glucose metabolism (10% and 23% respectively). The responses differed between doses; whereas the 0.25 g/kg dose predominantly reduced metabolism in cortical regions, the 0.5 g/kg dose reduced metabolism in cortical as well as subcortical regions (i.e. cerebellum, mesencephalon, basal ganglia and thalamus). These doses of alcohol did not significantly change the scores in cognitive performance, which contrasts with our previous results showing that a 13% reduction in brain metabolism by lorazepam was associated with significant impairment in performance on the same battery of cognitive tests. This seemingly paradoxical finding raises the possibility that the large brain metabolic decrements during alcohol intoxication could reflect a shift in the substrate for energy utilization, particularly in light of new evidence that blood-borne acetate, which is markedly increased during intoxication, is a substrate for energy production by the brain.

Multiple cognitive deficits during the transition to Alzheimer's disease.

The literature on cognitive markers in preclinical AD is reviewed. The findings demonstrate that impairment in multiple cognitive domains is typically observed several years before clinical diagnosis. Measures of executive functioning, episodic memory and perceptual speed appear to be most effective at identifying at-risk individuals. The fact that these cognitive domains are most implicated in normal cognitive aging suggests that the cognitive deficit observed preclinically is not qualitatively different from that observed in normal aging. The degree of cognitive impairment prior to the diagnosis of Alzheimer's disease (AD) appears to generalize relatively well across major study characteristics, including sample ascertainment procedures, age and cognitive status of participants, as well as time to diagnosis of dementia. In episodic memory, there is evidence that the size of the preclinical deficit increases with increasing cognitive demands. The global cognitive impairment observed is highly consistent with observations that multiple brain structures and functions are affected long before the diagnosis of AD. However, there is substantial overlap in the distribution of cognitive scores between those who will and those who will not be diagnosed with AD, hence limiting the clinical utility of cognitive markers for early identification of cases. Future research should consider combining cognitive indicators with other types of markers (i.e. social, somatic, genetic, brain-based) in order to increase prediction accuracy.

In vivo imaging of anaesthetic action in humans: approaches with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)

In vivo imaging of anaesthetic action in humans: approaches with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)

Human regional cerebral glucose metabolism during non-rapid eye movement sleep in relation to waking.

Sleep is an essential human function. Although the function of sleep has generally been regarded to be restorative, recent data indicate that it also plays an important role in cognition. The neurobiology of human sleep is most effectively analysed with functional imaging, and PET studies have contributed substantially to our understanding of both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. In this study, PET was used to determine patterns of regional glucose metabolism in NREM sleep compared with waking. We hypothesized that brain structures related to waking cognitive function would show a persistence of function into the NREM sleep state. Fourteen healthy subjects (age range 21-49 years; 10 women, 4 men) underwent concurrent EEG sleep studies and [(18)F]fluoro-2-deoxy-D-glucose PET scans during waking and NREM sleep. Whole-brain glucose metabolism declined significantly from waking to NREM sleep. Relative decreases in regional metabolism from waking to NREM sleep occurred in wide areas of frontal, parietal, temporal and occipital association cortex, primary visual cortex, and in anterior/dorsomedial thalamus. After controlling for the whole-brain declines in absolute metabolism, relative increases in regional metabolism from waking to NREM were found bilaterally in the dorsal pontine tegmentum, hypothalamus, basal forebrain, ventral striatum, anterior cingulate cortex and extensive regions of the mesial temporal lobe, including the amygdala and hippocampus, and in the right dorsal parietal association cortex and primary somatosensory and motor cortices. The reductions in relative metabolism in NREM sleep compared with waking are consistent with prior findings from blood flow studies. The relative increases in glucose utilization in the basal forebrain, hypothalamus, ventral striatum, amygdala, hippocampus and pontine reticular formation are new observations that are in accordance with the view that NREM sleep is important to brain plasticity in homeostatic regulation and mnemonic processing.

Positron emission tomography study of regional cerebral metabolism in humans during isoflurane anesthesia.

Although the anesthetic effects of the intravenous anesthetic agent propofol have been studied in the living human brain using brain imaging technology, the nature of the anesthetic state evident in the human brain during inhalational anesthesia remains unknown. To examine this issue, the authors studied the effects of isoflurane anesthesia on human cerebral glucose metabolism using positron emission tomography (PET). Five volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism and the other scan assessed metabolism during isoflurane anesthesia titrated to the point of unresponsiveness (means +/- SD; expired = 0.5 +/- 0.1%). Scans were obtained with a GE2048 scanner (4.5-mm resolution-FWHM) using the 18fluorodeoxyglucose technique. Awake whole-brain glucose metabolism averaged 6.9 +/- 1.5 mg.100 g-1.min-1 (means +/- SD). Isoflurane reduced whole-brain metabolism 46 +/- 11% to 3.6 +/- 0.3 mg.100 g-1.min-1 (P < or = 0.005). Regional metabolism decreased fairly uniformly throughout the brain, and no evidence of any regional metabolic increases were found in any brain region for any participant. A region-of-interest analysis showed that the pattern of regional metabolism evident during isoflurane anesthesia was not significantly different from that seen when participants were awake. These data clarify that the anesthetic state evident in the living human brain during unresponsiveness induced with isoflurane is associated with a global, fairly uniform, whole-brain glucose metabolic reduction of 46 +/- 11%.

Regional brain metabolic response to lorazepam in subjects at risk for alcoholism.

The mechanisms underlying the blunted response to alcohol administration observed in subjects at risk for alcoholism are poorly understood and may involve GABA-benzodiazepine receptors. The purpose of this study was to investigate if subjects at risk for alcoholism had abnormalities in brain GABA-benzodiazepine receptor function. This study measured the effects of 30 micrograms/kg (i.v.) of lorazepam, on regional brain glucose metabolism using positron emission tomography and 2-deoxy-2[18F]fluoro-D-glucose in subjects with a positive family history for alcoholism (FP) (n = 12) and compared their response with that of subjects with a negative family history for alcoholism (FN) (n = 21). At baseline, FP subjects showed lower cerebellar metabolism than FN. Lorazepam decreased whole-brain glucose metabolism, and FP subjects showed a similar response to FN in cortical and subcortical regions, but FP showed a blunted response in cerebellum. Lorazepam-induced changes in cerebellar metabolism correlated with its motor effects. The decreased cerebellar baseline metabolism in FP as well as the blunted cerebellar response to lorazepam challenge may reflect disrupted activity of benzodiazepine-GABA receptors in cerebellum. These changes could account for the decreased sensitivity to the motor effects of alcohol and benzodiazepines in FP subjects.