Glucose Metabolic Rate Research Articles

Non-invasive quantification of cerebral glucose metabolism using Gjedde-Patlak plot and image-derived input function from the aorta

IntroductionWe aimed at evaluating a Gjedde-Patlak plot and non-invasive image-derived input functions (IDIF) from the aorta to quantify cerebral glucose metabolic rate (CMRglc) in comparison to the reference standard based on sampling the arterial input function (AIF). MethodSix healthy subjects received 200 MBq [18F]FDG simultaneously with the initiation of a three-part dynamic PET recording consisting of a 15 min-recording of the aorta, a 40 min-recording of the brain and finally 2 min-recording of the aorta. Simultaneously, the arterial 18F concentration was measured via arterial cannulation. Regions of interest were drawn in the aorta and the brain and time-activity curves extracted. The IDIF was obtained by fitting a triple exponential function to the aorta time-activity curve after the initial peak including the late aorta frame, thereby interpolating the arterial blood activity concentration during the brain scan. CMRglc was calculated from Gjedde-Patlak plots using AIF and IDIF, respectively and the predictive value was examined. Results from frontal cortex, insula, hippocampus and cerebellum were compared by paired t-test and agreement between the methods was analyzed by Bland-Altman plot statistics. ResultsThere was a strong linear relationship and an excellent agreement between the methods (mean±SD of CMRglcIDIF (μmol 100 g−1 min−1), mean difference, mean relative difference, 95% limits of agreement): frontal cortex: 30.8 ± 3.3, 0.5, 2.2%, [-1,6:2.5], insula: 25.4 ± 2.2, 0.4, 2.4%, [-1.4:2.2], hippocampus: 16.9 ± 1.2, 0.4, 3.8%, [-1.1:2.0] and cerebellum: 23.4 ± 1.9, 0.5, 3.1%, [-1.4:2.5]). ConclusionWe found excellent agreement between CMRglc obtained with an IDIF from the aorta and the reference standard with AIF. A non-invasive three-part dynamic [18F]FDG PET recording is feasible as a non-invasive alternative for reliable quantification of cerebral glucose metabolism in all scanner systems. This is useful in patients with presumed global cerebral changes owing to systemic disease or for the monitoring of treatment effects.

Integrated Positron Emission Tomography/Magnetic Resonance Imaging for Resting-State Functional and Metabolic Imaging in Human Brain: What Is Correlated and What Is Impacted.

Integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) could simultaneously obtain both functional MRI (fMRI) and 18F-fluorodeoxyglucose (FDG) PET and thus provide multiparametric information for the analysis of brain metabolism. In this study, we aimed to, for the first time, investigate the interplay of simultaneous fMRI and FDG PET scan using a randomized self-control protocol. In total, 24 healthy volunteers underwent PET/MRI scan for 30–40 min after the injection of FDG. A 22-min brain scan was separated into MRI-off mode (without fMRI pulsing) and MRI-on mode (with fMRI pulsing), with each one lasting for 11 min. We calculated the voxel-wise fMRI metrics (regional homogeneity, amplitude of low-frequency fluctuations, fractional amplitude of low-frequency fluctuations, and degree centrality), resting networks, relative standardized uptake value ratios (SUVr), SUVr slope, and regional cerebral metabolic rate of glucose (rCMRGlu) maps. Paired two-sample t-tests were applied to assess the statistical differences between SUVr, SUVr slope, correlation coefficients of fMRI metrics, and rCMRGlu between MRI-off and MRI-on modes, respectively. The voxel-wise whole-brain SUVr revealed no statistical difference (P > 0.05), while the SUVr slope was significantly elevated in sensorimotor, dorsal attention, ventral attention, control, default, and auditory networks (P < 0.05) during fMRI scan. The task-based group independent-component analysis revealed that the most active network components derived from the combined MRI-off and MRI-on static PET images were frontal pole, superior frontal gyrus, middle temporal gyrus, and occipital pole. High correlation coefficients were found among fMRI metrics with rCMRGlu in both MRI-off and MRI-on mode (P < 0.05). Our results systematically evaluated the impact of simultaneous fMRI scan on the quantification of human brain metabolism from an integrated PET/MRI system.

PET CMRglc mapping and 1H-MRS show altered glucose uptake and neurometabolic profiles in BDL rats

Type C hepatic encephalopathy (HE) is a complex neuropsychiatric disorder occurring as a consequence of chronic liver disease. Alterations in energy metabolism have been suggested in type C HE, but in vivo studies on this matter remain sparse and have reported conflicting results. Here, we propose a novel preclinical 18F-FDG PET methodology to compute quantitative 3D maps of the regional cerebral metabolic rate of glucose (CMRglc) from a labelling steady-state PET image of the brain and an image-derived input function. This quantitative approach shows its strength when comparing groups of animals with divergent physiology, such as HE animals. PET CMRglc maps were registered to an atlas and the mean CMRglc from the hippocampus and the cerebellum were associated to the corresponding localized 1H MR spectroscopy acquisitions. This study provides for the first time local and quantitative information on both brain glucose uptake and neurometabolic profile alterations in a rat model of type C HE. A 2-fold lower brain glucose uptake, concomitant with an increase in brain glutamine and a decrease in the main osmolytes, was observed in the hippocampus and in the cerebellum. These novel findings are an important step towards new insights into energy metabolism in the pathophysiology of HE.

Psychosocial stress increases risk for type 2 diabetes in female cynomolgus macaques consuming a western diet

Chronic psychosocial stress is associated with increased risk of many chronic diseases including type 2 diabetes mellitus. However, it is difficult to establish a causal relationship between stress and diabetes in human studies because stressors often are self-reported and may be distant in time from metabolic consequences. Macaques are useful models of the effects of chronic psychosocial stress on health and may develop obesity and diabetes similar to human beings. Thus, we studied the relationships between social subordination stress – a well-validated psychological stressor in macaques – and body composition and carbohydrate metabolism in socially housed, middle-aged female cynomolgus monkeys (Macaca fascicularis; n = 42). Following an 8-week baseline phase, the monkeys were fed a Western diet for 36 months (about equivalent to 10 human years). Social status was determined based on the outcomes of agonistic interactions (X¯= 33.3 observation hours/monkey). Phenotypes collected included plasma cortisol, body composition, circulating markers of glucose metabolism, activity levels, and heart rate variability measured as RMSSD (root of mean square of successive differences) and SDDN (standard deviation of beat to beat interval) after 1.5- and 3-years on diet. Mixed model analyses of variance revealed that aggression received, submissions sent, and cortisol were higher, and RMSSD and SDNN were lower in subordinates than dominants (social status: p < 0.05). After 3 years of Western diet consumption, fasting triglyceride, glucose and insulin concentrations, calculated insulin resistance (HOMA-IR), body weight and body fat mass increased in all animals (time: all p’s < 0.05); however, the increase in fasting glucose and HOMA-IR was significantly greater in subordinates than dominants (time x social status: p’s < 0.05). Impaired glucose metabolism, (glucose > 100 mg/dl) incidence was significantly higher in subordinates (23%) than dominants (0%) (Fisher’s exact test, p < 0.05). These findings suggest that chronic psychosocial stress, on a Western diet background, significantly increases type 2 diabetes risk in middle-aged female primates.

Short-Term Efficacy of Transcranial Focused Ultrasound to the Hippocampus in Alzheimer's Disease: A Preliminary Study.

Preclinical studies have suggested that low-intensity transcranial focused ultrasound (tFUS) may have therapeutic potential for Alzheimer’s disease (AD) by opening the blood–brain barrier (BBB), reducing amyloid pathology, and improving cognition. This study investigated the effects of tFUS on BBB opening, regional cerebral metabolic rate of glucose (rCMRglu), and cognitive function in AD patients. Eight patients with AD received image-guided tFUS to the right hippocampus immediately after intravenous injection of microbubble ultrasound contrast agents. Patients completed magnetic resonance imaging (MRI), 18F-fluoro-2-deoxyglucose positron emission tomography (PET), and cognitive assessments before and after the sonication. No evidence of transient BBB opening was found on T1 dynamic contrast-enhanced MRI. However, immediate recall (p = 0.03) and recognition memory (p = 0.02) were significantly improved on the verbal learning test. PET image analysis demonstrated increased rCMRglu in the right hippocampus (p = 0.001). In addition, increases of hippocampal rCMRglu were correlated with improvement in recognition memory (Spearman’s ρ = 0.77, p = 0.02). No adverse event was observed. Our results suggest that tFUS to the hippocampus of AD patients may improve rCMRglu of the target area and memory in the short term, even without BBB opening. Further larger sham-controlled trials with loger follow-up are warranted to evaluate the efficacy and safety of tFUS in patients with AD.

Measuring the dynamics of glucose-stimulated oxygen consumption in individual pancreatic islets using islet-on-a-chip

Pancreatic islets secrete insulin in response to glucose in two phases involving a Ca2+ burst followed by smaller second phase of Ca2+-oscillations. This biphasic response is determined by the rate of glucose metabolism with models indicating that first phase Ca2+ influx is triggered by glycolysis while the second phase Ca2+ oscillations are controlled by oxidative phosphorylation (OXPHOS). Yet, it is presently unclear how quickly islets transition control between glycolysis and OXPHOS, and whether second phase oscillations are a direct result of metabolic fluctuations.

Hemodynamic and metabolic correspondence of resting-state voxel-based physiological metrics in healthy adults

Voxel-based physiological (VBP) variables derived from blood oxygen level dependent (BOLD) fMRI time-course variations include: amplitude of low frequency fluctuations (ALFF), fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity (ReHo). Although these BOLD-derived variables can detect between-group (e.g. disease vs control) spatial pattern differences, physiological interpretations are not well established. The primary objective of this study was to quantify spatial correspondences between BOLD VBP variables and PET measurements of cerebral metabolic rate and hemodynamics, being well-validated physiological standards. To this end, quantitative, whole-brain PET images of metabolic rate of glucose (MRGlu; 18FDG) and oxygen (MRO2; 15OO), blood flow (BF; H215O) and blood volume (BV; C15O) were obtained in 16 healthy controls. In the same subjects, BOLD time-courses were obtained for computation of ALFF, fALFF and ReHo images. PET variables were compared pair-wise with BOLD variables. In group-averaged, across-region analyses, ALFF corresponded significantly only with BV (R = 0.64; p < 0.0001). fALFF corresponded most strongly with MRGlu (R = 0.79; p < 0.0001), but also significantly (p < 0.0001) with MRO2 (R = 0.68), BF (R = 0.68) and BV (R=0.68). ReHo performed similarly to fALFF, with significant strong correspondence (p < 0.0001) with MRGlu (R = 0.78), MRO2 (R = 0.54), and, but less strongly with BF (R = 0.50) and BV (R=0.50). Mutual information analyses further clarified these physiological interpretations. When conditioned by BV, ALFF retained no significant MRGlu, MRO2 or BF information. When conditioned by MRGlu, fALFF and ReHo retained no significant MRO2, BF or BV information. Of concern, however, the strength of PET-BOLD correspondences varied markedly by brain region, which calls for future investigation on physiological interpretations at a regional and per-subject basis.

Four-modality imaging of unmedicated subjects with schizophrenia: 18F-fluorodeoxyglucose and 18F-fallypride PET, diffusion tensor imaging, and MRI

Diminished prefrontal function, dopaminergic abnormalities in the striatum and thalamus, reductions in white matter integrity and frontotemporal gray matter deficits are the most replicated findings in schizophrenia. We used four imaging modalities (18F-fluorodeoxyglucose and 18F-fallypride PET, diffusion tensor imaging, structural MRI) in 19 healthy and 25 schizophrenia subjects to assess the relationship between functional (dopamine D2/D3 receptor binding potential, glucose metabolic rate) and structural (fractional anisotropy, MRI) correlates of schizophrenia and their additive diagnostic prediction potential. Multivariate ANOVA was used to compare structural and functional image sets for identification of schizophrenia. Integration of data from all four modalities yielded better predictive power than less inclusive combinations, specifically in the thalamus, left dorsolateral prefrontal and temporal regions. Among the modalities, fractional anisotropy showed highest discrimination in white matter whereas 18F-fallypride binding showed highest discrimination in gray matter. Structural and functional modalities displayed comparable discriminative power but different topography, with higher sensitivity of structural modalities in the left prefrontal region. Combination of functional and structural imaging modalities with inclusion of both gray and white matter appears most effective in diagnostic discrimination. The highest sensitivity of 18F-fallypride PET to gray matter changes in schizophrenia supports the primacy of dopaminergic abnormalities in its pathophysiology.

Improved functional connectivity after a 6‐month ketogenic supplementation in mild cognitive impairment

AbstractBackgroundKetones, the brain’s alternative fuel to glucose, bypass the brain glucose deficit in mild cognitive impairment (MCI). The BENEFIC trial conducted in MCI showed improved measures of cognition in multiple domains after a 6‐month ketogenic intervention [Fortier et al. 2019]. Functional connectivity in the dorsal‐attention network (DAN) deteriorates early in MCI, and prior to changes in the ventral‐attention network [Zhang et al. 2015]. We aimed to assess whether improved cognitive outcomes in the BENEFIC Trial were linked to improved brain functional connectivity.MethodParticipants in this 6‐month intervention were randomized to a placebo (n= 15) or ketogenic medium chain triglyceride (kMCT; n= 17) drink. A neurocognitive battery and brain imaging were performed pre‐ and post‐intervention. Functional connectivity was computed from resting‐state functional magnetic resonance images. Independent component analysis (FSL Melodic) was used to segment seven major resting‐state networks (DAN, ventral‐attention, frontoparietal, limbic, somatomotor, default‐mode and visual) [Yeo et al. 2011]. Regional cortical ketone (11C‐acetoacetate) and glucose (18F‐fluorodeoxyglucose) metabolic rates were also quantified using positron emission tomography (PET).ResultChanges (post ‐ pre) in DAN functional connectivity was significantly higher in the kMCT group vs placebo (P= 0.024). After correction for age, sex, education, ApoE status and intracranial volume, the significant difference between groups was still present, with a large effect size (partial h2= 0.16; P= 0.043; Figure 1). Connectivity in no other networks was significantly different between groups. Changes in attention and processing speed composite Z‐score (r= 0.42; P= 0.021) and specific tests targeting attention (Trail Making visual scanning and number sequencing conditions) were significantly associated with the increased DAN functional connectivity. Change in ketone uptake specifically in DAN cortical regions (Figure 2C) was significantly higher in the kMCT vs placebo group (P= 0.001) and was directly associated with the improved DAN functional connectivity, with a large effect size (r= 0.69; P= 0.002; Figure 3).ConclusionWe show that a 6‐month ketogenic intervention improves DAN functional connectivity in MCI, an improvement that is directly linked to increased energy (ketone) supply to the DAN. The beneficial effect of ketones on cognition in MCI may be linked to improved DAN connectivity.

Influence of amyloid deposition on the interaction between tau and glucose metabolism

AbstractBackgroundPathological hallmarks of Alzheimer’s disease include the formation of extracellular Aβ plaques and intracellular neurofibrillary tau tangles, which with recent PET imaging advances can be assessed in vivo. Accumulation of tau has been closely linked to metabolic abnormalities in PET imaging studies, with inverse associations between tau deposition and glucose metabolism. This study aimed to assess whether the association between [18F]FDG and [18F]AV1451 in cognitively impaired patients is dependent on the presence of significant amyloid pathology.Method240 patients with mild cognitive impairment or Alzheimer’s disease (Mean age = 74.5 years, SD = 8.03) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu). All participants completed a T1‐weighted MPRAGE MRI, amyloid ([18F]AV45 or [18F]florbetaben), [18F]AV1451 and [18F]FDG scans. Standard uptake ratio values were calculated in SPM12 to identify the glucose metabolic rate and tau deposition within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a whole brain cerebellar ratio with a cut‐off value of 1.11 ([18F]AV45) and 1.08 ([18F)florbetaben). Pearson’s correlation coefficients were calculated to assess the relationship between imaging modalities.ResultThere were significant negative associations between AV1451 and FDG tracer uptake in the medial temporal lobe (r = ‐0.389, p &lt;0 .001), occipital lobe (r = ‐0.276, p = 0.001), parietal lobe (r = ‐0.209, p = 0.014), and posterior cingulate (r = ‐0.245, p = 0.004) in Aβ‐positive patients. Similarly, a strong negative relationship was observed between the imaging modalities in Aβ‐negative patients in the medial temporal lobe (r = ‐0.345, p &lt; 0.001), however a significant positive association was also observed in the anterior cingulate cortex (r = 0.350, p &lt; 0.001).ConclusionThis study demonstrated that [18]FDG and [18F]AV1451 tracers have strong regional signal associations in patients with cognitive impairment. The results indicate that tau has a detrimental effect on glucose metabolism in the medial temporal lobe, independent of significant amyloid plaque formation. In patients determined as amyloid‐negative, we may be observing some compensatory regional increase in glucose metabolism in the early stages of tau accumulation.

Does [18F]FDG and [18F]AV1451 PET predict neurodegeneration?

AbstractBackground[18F]FDG PET is a well‐established and valuable biomarker in the assessment of neurodegenerative disorders, with high diagnostic utility, wide accessibility, and relatively low costs. Recent advances in PET imaging technology now allow for the in vivo exploration of tau deposition. However, it is still being debated which of [18F]FDG PET or [18F]AV1451 PET better predicts neurodegeneration. This study aimed to evaluate [18F]FDG PET and [18F]AV1451 PET imaging in predicting grey matter atrophy in patients with cognitive impairment.Method190 patients with mild cognitive impairment or Alzheimer’s disease (Mean age = 74.3 years, SD = 8.04) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu). All participants completed a T1‐weighted MPRAGE MRI, [18F]AV1451 and [18F]FDG PET scans. Standard uptake ratio values were calculated in SPM12 to identify the glucose metabolic rate and tau deposition within the medial temporal lobe. Whole brain grey matter volumes were obtained from processed data from ADNI. Pearson’s correlation coefficients were calculated to assess the relationship between imaging modalities.ResultThere was a significant negative association between [18F]AV1451 uptake in the medial temporal lobe and whole brain grey matter volume (r = ‐0.288, p = 0.001). A stronger positive relationship was identified between medial temporal lobe [18F]FDG uptake and whole brain grey matter volume (r = 0.444, p &lt; 0.001).ConclusionThis study demonstrated that regional FDG and tau tracer uptake in patients with cognitive impairment both display a significant relationship with total grey matter volume. Whilst both tracers show utility in predicting a patient’s level of neurodegeneration, glucose metabolism as indicated by [18F]FDG PET appears to have a closer relationship to grey matter atrophy than PET markers of tau deposition.

Evaluating the relationship between soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and pathological substrates of Alzheimer’s disease (AD)

AbstractBackgroundDeveloping novel biomarkers of Alzheimer’s disease (AD) is critical for early disease detection and intervention. sTREM2 has proposed to be an early marker of glial activation. However, there has been significant controversy about the function of sTREM2. This study investigated the relationship between cerebral spinal fluid (CSF) sTREM2, and pathological changes in AD.MethodWe included patients with mild cognitive impairment, AD and healthy controls (n= 493, mean age= 73.7, SD= 6.1) were recruited for the Alzheimer’s Disease Neuroimaging Initiative. All participants completed a T1‐weighted MPRAGE MRI, amyloid ([18F]AV45 or [18F]Florbetaben), [18F]AV1451 and [18F]FDG scans. Standard uptake ratio values were calculated in SPM12 to identify the glucose metabolic rate and tau deposition within cortical regions. Amyloid status (Aβ positive/Aβ negative) was determined from processed data using a whole brain cerebellar ratio with a cut‐off value of 1.11. Correlations between CSF measurements, ROI, and voxel‐wise analyses were conducted using data from ADNI.ResultROI analyses demonstrated that increased CSF sTREM2 was associated with increased amyloid load in the whole brain, temporal, parietal, and occipital lobes of MCI patients. Additionally, increased CSF sTREM2 was associated with decreased glucose metabolism in the Posterior cingulate and parietal lobe in MCI patients. On the other hand, CSF sTREM2 was not significantly correlated with pathological changes in AD patients. However, voxel‐wise analysis comparing Aβ+ MCI patients to Aβ‐ CN subjects showed that increased CSF sTREM2 levels were associated with greater Aβ deposition in temporal and motor regions, increased grey matter volume in frontal and parietal regions, and decreased grey matter volume in the MT gyrus.ConclusionsTREM2 levels are associated with amyloid deposition in MCI patients but not in the late stage of AD patients, this suggest that glial activation is associated early on the disease.

Evaluation of liraglutide in the treatment of Alzheimer's disease

AbstractBackgroundLiraglutide is a glucagon‐like peptide‐1 (GLP‐1) analogue licensed for the treatment of type 2 diabetes. Preclinical evidence in transgenic models of Alzheimer’s disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells.MethodsELAD is a 12‐month, multi‐centre, randomised, double‐blind, placebo‐controlled, phase IIb trial of liraglutide in participants with mild to moderate Alzheimer’s dementia, conducted at several centres in the UK – (NCT01843075). [18F]FDG‐PET and MRI brain scans of all patients will be performed at baseline and after 12 months treatment with liraglutide or matching placebo. Once enrolled, all subjects had a neuropsychological battery of tests All scans and tests will be repeated after 12 months. A total of 204 participants were randomised to receive either liraglutide or placebo as a daily subcutaneous injection for 12 months. The primary objective was to evaluate the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to 12‐month follow‐up in participants with Alzheimer’s disease receiving treatment with liraglutide compared to those receiving placebo. The key secondary outcomes were the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer’s Disease Assessment Scale – Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer’s Disease Cooperative Study – Activities of Daily Living) and the incidence and severity of treatment‐emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes were 12‐month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group.ResultsThe study demonstrated that liraglutide treated patients performed significantly better than placebo arm in temporal lobe and whole cortical MRI volume and cognitive function measured by ADAS‐EXEC (ADAS‐Cog with Executive domains of the Neuropsychological Test Battery).ConclusionThis demonstrates that GLP1 analogues can improve cognitive function and MRI volume in AD subjects and could be a potential treatment for treatment for Alzheimer's

Cognitive and Behavior Deficits in Parkinson’s Disease with Alteration of FDG-PET Irrespective of Age

Significant progress has been made in our understanding of the neurobiology of Parkinson’s disease (PD). Post-mortem studies are an important step and could help to comprehend not only the progression of motor symptoms, but also the involvement of other clinical domains, including cognition, behavior and impulse control disorders (ICDs). The correlation of neuropathological extension of the disease with the clinical stages remains challenging. Molecular imaging, including positron emission tomography (PET) and single photon computed tomography (SPECT), could allow for bridging the gap by providing in vivo evidence of disease extension. In the last decade, we have observed a plethora of reports describing improvements in the sensitivity of neuroimaging techniques. These data contribute to increasing the accuracy of PD diagnosis, differentiating PD from other causes of parkinsonism and also obtaining a surrogate marker of disease progression. FDG-PET has been used to measure cerebral metabolic rates of glucose, a proxy for neuronal activity, in PD. Many studies have shown that this technique could be used in early PD, where reduced metabolic activity correlates with disease progression and could predict histopathological diagnosis. The aim of this work is to report two particular cases of PD in which the assessment of brain metabolic activity (from FDG-PET) has been combined with clinical aspects of non-motor symptoms. Integration of information on neuropsychological and metabolic imaging allows us to improve the treatment of PD patients irrespective of age.

Voxel-Based Analysis of [18F]-FDG Brain PET in Rats Using Data-Driven Normalization.

Introduction: [18F]-FDG PET is a widely used imaging modality that visualizes cellular glucose uptake and provides functional information on the metabolic state of different tissues in vivo. Various quantification methods can be used to evaluate glucose metabolism in the brain, including the cerebral metabolic rate of glucose (CMRglc) and standard uptake values (SUVs). Especially in the brain, these (semi-)quantitative measures can be affected by several physiological factors, such as blood glucose level, age, gender, and stress. Next to this inter- and intra-subject variability, the use of different PET acquisition protocols across studies has created a need for the standardization and harmonization of brain PET evaluation. In this study we present a framework for statistical voxel-based analysis of glucose uptake in the rat brain using histogram-based intensity normalization.Methods: [18F]-FDG PET images of 28 normal rat brains were coregistered and voxel-wisely averaged. Ratio images were generated by voxel-wisely dividing each of these images with the group average. The most prevalent value in the ratio image was used as normalization factor. The normalized PET images were voxel-wisely averaged to generate a normal rat brain atlas. The variability of voxel intensities across the normalized PET images was compared to images that were either normalized by whole brain normalization, or not normalized.To illustrate the added value of this normal rat brain atlas, 9 animals with a striatal hemorrhagic lesion and 9 control animals were intravenously injected with [18F]-FDG and the PET images of these animals were voxel-wisely compared to the normal atlas by group- and individual analyses.Results: The average coefficient of variation of the voxel intensities in the brain across normal [18F]-FDG PET images was 6.7% for the histogram-based normalized images, 11.6% for whole brain normalized images, and 31.2% when no normalization was applied. Statistical voxel-based analysis, using the normal template, indicated regions of significantly decreased glucose uptake at the site of the ICH lesion in the ICH animals, but not in control animals.Conclusion: In summary, histogram-based intensity normalization of [18F]-FDG uptake in the brain is a suitable data-driven approach for standardized voxel-based comparison of brain PET images.

Salbutamol Increases Leg Glucose Uptake and Metabolic Rate but not Muscle Glycogen Resynthesis in Recovery From Exercise.

Exercise blunts the effect of beta2-agonists on peripheral glucose uptake and energy expenditure. Whether such attenuation extends into recovery is unknown. To examine the effect of a beta2-agonist on leg glucose uptake and metabolic rate in recovery from exercise. Using leg arteriovenous balance technique and analyses of thigh muscle biopsies, we investigated the effect of a beta2-agonist (24 mg of oral salbutamol) vs placebo on leg glucose, lactate, and oxygen exchange before and during quadriceps exercise, and 0.5 to 5 hours in recovery from quadriceps exercise, as well as on muscle glycogen resynthesis and activity in recovery. Twelve healthy, lean, young men participated. Before exercise, leg glucose uptake was 0.42 ± 0.12 and 0.20 ± 0.02 mmol × min-1 (mean ± SD) for salbutamol and placebo (P = .06), respectively, while leg oxygen consumption was around 2-fold higher (P < .01) for salbutamol than for placebo (25 ± 3 vs 14 ± 1 mL × min-1). No treatment differences were observed in leg glucose uptake, lactate release, and oxygen consumption during exercise. But in recovery, cumulated leg glucose uptake, lactate release, and oxygen consumption was 21 mmol (95% CI 18-24, P = .018), 19 mmol (95% CI 16-23, P < .01), and 1.8 L (95% CI 1.6-2.0, P < .01) higher for salbutamol than for placebo, respectively. Muscle glycogen content was around 30% lower (P < .01) for salbutamol than for placebo in recovery, whereas no treatment differences were observed in muscle glycogen resynthesis or glycogen synthase activity. Exercise blunts the effect of beta2-agonist salbutamol on leg glucose uptake, but this attenuation diminishes in recovery. Salbutamol increases leg lactate release in recovery, which may relate to glycolytic trafficking due to excessive myocellular glucose uptake.

In vivo Imaging of Cannabinoid Type 2 Receptors: Functional and Structural Alterations in Mouse Model of Cerebral Ischemia by PET and MRI

PurposeStroke is one of the most prevalent vascular diseases. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptor (CB2R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [18F]RoSMA-18-d6 and structural imaging by magnetic resonance imaging (MRI).ProceduresOur recently developed CB2R PET tracer [18F]RoSMA-18-d6 was used for imaging neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB2R and other inflammatory markers were analyzed by quantitative real-time polymerase chain reaction using brain tissues from tMCAO (1 h occlusion) and sham-operated mice. [18F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging and T2-weighted imaging were performed for anatomical reference and delineating the lesion in tMCAO mice.ResultsmRNA expressions of inflammatory markers TNF-α, Iba1, MMP9 and GFAP, CNR2 were increased to 1.3–2.5 fold at 24 h after reperfusion in the ipsilateral compared to contralateral hemisphere of tMCAO mice, while mRNA expression of the neuronal marker MAP-2 was markedly reduced to ca. 50 %. Reduced [18F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [18F]RoSMA-18-d6 in ex vivo biodistribution studies and higher standard uptake value ratio (SUVR) were detected in the ischemic ipsilateral compared to contralateral striatum in tMCAO mice, the in vivo specificity of [18F]RoSMA-18-d6 was confirmed only in the CB2R-rich spleen.ConclusionsThis study revealed an increased [18F]RoSMA-18-d6 measure of CB2R and a reduced [18F]FDG measure of CMRglc in the ischemic striatum of tMCAO mice at subacute stage. [18F]RoSMA-18-d6 might be a promising PET tracer for detecting CB2R alterations in animal models of neuroinflammation without neuronal loss.

Neural Correlates of Autobiographical Memory: Evidence From a Positron Emission Tomography Study in Patients With Mild Cognitive Impairment and Alzheimer's Disease.

Background: Autobiographical memory (AM) changes are the hallmark of Alzheimer's disease (AD) and mild cognitive impairment (MCI). In recent neuroimaging studies, AM changes have been associated with numerous cerebral sites, such as the frontal cortices, the mesial temporal lobe, or the posterior cingulum. Regional glucose uptake in these sites was investigated for underlying subdimensions using factor analysis. Subsequently, the factors were examined with respect to AM performance in a subgroup of patients.Methods: Data from 109 memory clinic referrals, who presented with MCI (n = 60), mild AD (n = 49), or were cognitively intact, were analyzed. The glucose metabolic rates determined by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in 34 cerebral sites important for AM were investigated for underlying subdimensions by calculating factor analysis with varimax rotation. Subsequently, the respective factor scores were correlated with the episodic and semantic AM performance of 22 patients, which was measured with a semi-structured interview assessing episodic memories (characterized by event-related emotional, sensory, contextual, and spatial–temporal details) and personal semantic knowledge from three periods of life (primary school, early adulthood, and recent years).Results: Factor analysis identified seven factors explaining 69% of the variance. While patients with MCI and AD showed lower values than controls on the factors frontal cortex, mesial temporal substructures, and occipital cortex, patients with MCI presented with increased values on the factors posterior cingulum and left temporo-prefrontal areas. The factors anterior cingulum and right temporal cortex showed only minor, non-significant group differences. Solely, the factor mesial temporal substructures was significantly correlated with both episodic memories (r = 0.424, p < 0.05) and personal semantic knowledge (r = 0.547, p < 0.01) in patients with MCI/AD.Conclusions: The factor structure identified corresponds by large to the morphological and functional interrelations of the respective sites. While reduced glucose uptake on the factors frontal cortex, mesial temporal substructures, and occipital cortex in the patient group may correspond to neurodegenerative changes, increased values on the factors posterior cingulum and left temporo-prefrontal areas in MCI may result from compensatory efforts. Interestingly, changes of the mesial temporal substructures were correlated with both semantic and episodic AM. Our findings suggest that AM deficits do not only reflect neurodegenerative changes but also refer to compensatory mechanisms as they involve both quantitative losses of specific memories and qualitative changes with a semantization of memories.

Lipid accumulation product (LAP) as a potential index to predict risk of insulin resistance in young, non-obese Asian Indian males from Southern India: observations from hyperinsulinemic-euglycemic clamp studies

IntroductionWe aimed to compare the predictive accuracy of surrogate indices namely the lipid accumulation product (LAP) index, homeostatic model of assessment of insulin resistance (HOMA-IR), fasting glucose-insulin ratio (FG-IR) and...

Significantly Decreased Islet β Cell Function is Closely Associated with Hyperglycemia in Chronic Hepatitis B Patients.

Aim This study is aimed at the characteristics of glucose metabolism and islet β cell function evaluated by the homeostasis model assessment of β cell function (HOMA-β) value and its risk factors in chronic hepatitis B (CHB) patients. Method This cross-sectional study recruited 110 CHB patients (CHB group) and 110 patients without hepatitis B virus (non-HBV group); the groups were matched according to sex, age, and body mass index under the same glucose metabolism status. The risk factors, characteristics, and differences in glucose metabolism and HOMA-β values between the two groups were analyzed. Results The abnormal glucose metabolism rate was higher in CHB patients with liver cirrhosis (LC) or hepatitis B envelope antigen (HBeAg) (−) status. In addition, under the same glucose metabolism status, the fasting plasma glucose (FPG) levels and 2-hour postprandial plasma glucose (2h-PG) levels in the CHB group were higher, while the HOMA-β values were significantly lower and the homeostasis model assessment of insulin resistance (HOMA-IR) value was not higher than that in the non-HBV group (all P < 0.0001). Further analyses revealed that the main risk factors for abnormal glucose metabolism were HBeAg (−) status and hepatitis B envelope antibody levels. But HBV serological and virological indicators had no effects on the HOMA-β values. Conclusion Islet β cell function in patients with CHB was compromised, which is closely associated with fasting and postprandial hyperglycemia in chronic hepatitis B patients. Further research should be done to verify the compromised islet β cell function and then to investigate the mechanisms behind the effect of hepatitis B virus infection on islet β cell function in CHB patients.