Brain Glucose Uptake Research Articles

The influence of propofol on [3H]-glucose uptake in brain and chosen organs in rats. Studies in an animal model of Parkinson’s disease

The influence of propofol on [H]-glucose uptake in brain and chosen organs in rats. Studies in an animal model of Parkinson’s disease Magdalena Beœka1, Monika Rykaczewska-Czerwinska1, Przemys3aw Nowak1,2 1Department of Pharmacology, Medical University of Silesia, H. Jordana 38, PL 41-808 Zabrze, Poland; 2Occupational Health Protection Unit, Public Health Faculty, Medical University of Silesia, Medykow 18, PL 40-752 Katowice Ligota, Poland

Dorsal Striatum and Its Limbic Connectivity Mediate Abnormal Anticipatory Reward Processing in Obesity

Obesity is characterized by an imbalance in the brain circuits promoting reward seeking and those governing cognitive control. Here we show that the dorsal caudate nucleus and its connections with amygdala, insula and prefrontal cortex contribute to abnormal reward processing in obesity. We measured regional brain glucose uptake in morbidly obese (n = 19) and normal weighted (n = 16) subjects with 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) positron emission tomography (PET) during euglycemic hyperinsulinemia and with functional magnetic resonance imaging (fMRI) while anticipatory food reward was induced by repeated presentations of appetizing and bland food pictures. First, we found that glucose uptake rate in the dorsal caudate nucleus was higher in obese than in normal-weight subjects. Second, obese subjects showed increased hemodynamic responses in the caudate nucleus while viewing appetizing versus bland foods in fMRI. The caudate also showed elevated task-related functional connectivity with amygdala and insula in the obese versus normal-weight subjects. Finally, obese subjects had smaller responses to appetizing versus bland foods in the dorsolateral and orbitofrontal cortices than did normal-weight subjects, and failure to activate the dorsolateral prefrontal cortex was correlated with high glucose metabolism in the dorsal caudate nucleus. These findings suggest that enhanced sensitivity to external food cues in obesity may involve abnormal stimulus-response learning and incentive motivation subserved by the dorsal caudate nucleus, which in turn may be due to abnormally high input from the amygdala and insula and dysfunctional inhibitory control by the frontal cortical regions. These functional changes in the responsiveness and interconnectivity of the reward circuit could be a critical mechanism to explain overeating in obesity.

Arterial lactate above 2 mM is associated with increased brain lactate and decreased brain glucose in patients with severe traumatic brain injury.

Lactate fuels cerebral energy-consuming processes and it is neuroprotective. The impact of arterial lactate on brain metabolism determined by microdialysis was investigated retrospectively in patients with severe traumatic brain injury (TBI). Cerebral microdialysis (glucose, lactate), neuromonitoring (ICP, CPP, ptiO2, SjvO2) and blood gas data collected in 20 patients during pharmacologic coma were grouped within predefined arterial lactate clusters (<1, 1-2, >2 mM). Microdialysis samples were only taken from time points characterized by normoventilation (paCO2 34.5-42 mmHg), sufficient oxygenation (paO2 >75 mmHg) and hematocrit (≥24%) to exclude confounding influences. Elevated arterial lactate ≥2 mM was associated with significantly increased brain lactate which coincided with markedly decreased brain glucose despite significantly increased arterial glucose levels and sufficient cerebral perfusion indirectly determined by normal SjvO2 and ptiO2 values. At elevated arterial lactate levels signs of significantly increased cerebral lactate uptake coincided with markedly decreased cerebral glucose uptake. Infused lactate above 50 mM per 24 hours was associated with significantly decreased cerebral glucose. Increased arterial lactate levels were associated with increased cerebral lactate uptake and elevated brain lactate. At the same time brain glucose uptake and brain glucose were significantly reduced. It remains unclear whether arterial lactate is the driving force for the increased cerebral lactate levels or if the reduced glucose uptake also contributed to the increased cerebral lactate levels. Further studies are required to assess the impact of lactate infusion under clinical conditions.

PS1 - 3. The relationship between plasma and brain glucose levels under hypoglycemic conditions in humans

Since glucose is the main source of energy for the brain, understanding the kinetics of brain glucose uptake under hypoglycemic conditions is highly important. Under normo- and hyperglycemic conditions the relationship between plasma and brain glucose levels is linear and behaves according to reversible Michaelis-Menten (MM) kinetics. In the present study brain glucose levels during hypoglycemia were measured by 13C magnetic resonance spectroscopy (MRS).

Donepezil causes acute increases in regional cerebral blood flow in normal rat

associated to aging and AD. (Kalpouzos 2009, Mosconi, 2007). We focused on the small primate (Microcebus murinus (M.m.), during aging some animals develop cognitive impairments (Picq, 2007), amyloid plaque depositions, and altered Tau protein accumulation associated with cerebral atrophy (Kraska, 2009). Brain atrophy is predictive of cognitive alterations (Picq, 2010). The aim of the current study was to evaluate age-associated evolution of glucose uptake in M.m. by using non-invasive FDG PET. Methods: SeventeenM.m. (1.5 to 9 years) were evaluated by PET with MicroPET Focus220 system (FDG: 900mCurie/100g, i.v.) and 3D-MR images were recorded (PharmaScan Bruker 7T). M.m were anesthetized by isoflurane duringimages acquisition. MR and PET images were co-registered by rigid transformations to define volumes of interest (VOI) in brain and appraise Standard UptakeValues (SUV) as well as relative values as compared to whole brain. Results: MR images didn’t reveal any severe atrophy this study is focused on normal aging. PET study revealed a relationship between age and SUVs in the frontal cortex, the cerebellum, and in the whole brain. However, relative values were not correlated with age. The cohort was split by theM.m.midlife (4.5 years) in two groups, young (1.960.2 years) and old animals (6.460.5 years).This second analyse showed a difference between young and old animals in thewhole brain, frontal cortex and cerebellum (t-test).Conclusions:Anage-associated evolution of glucose uptake as measured by SUVs could bedetected in non-severely atrophied M.m. and resembles evolution of the regionalcerebral metabolic rates for glucose (rCMRGlc) observed in healthy aged humans.This study is a first step toward the characterization of age-associated changesof brain glucose uptake inM.m. and will be useful to understand brain aging inM.m.

Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F-fluorodeoxyglucose: a dual-tracer PET imaging study in rats

Brain glucose and ketone uptake was investigated in Fisher rats subjected to mild experimental ketonemia induced by a ketogenic diet (KD) or by 48 hours fasting (F). Two tracers were used, 11C-acetoacetate (11C-AcAc) for ketones and 18F-fluorodeoxyglucose for glucose, in a dual-tracer format for each animal. Thus, each animal was its own control, starting first on the normal diet, then undergoing 48 hours F, followed by 2 weeks on the KD. In separate rats on the same diet conditions, expression of the transporters of glucose and ketones (glucose transporter 1 (GLUT1) and monocarboxylic acid transporter (MCT1)) was measured in brain microvessel preparations. Compared to controls, uptake of 11C-AcAc increased more than 2-fold while on the KD or after 48 hours F (P < 0.05). Similar trends were observed for 18FDG uptake with a 1.9–2.6 times increase on the KD and F, respectively (P < 0.05). Compared to controls, MCT1 expression increased 2-fold on the KD (P < 0.05) but did not change during F. No significant difference was observed across groups for GLUT1 expression. Significant differences across the three groups were observed for plasma beta-hydroxybutyrate (beta-HB), AcAc, glucose, triglycerides, glycerol, and cholesterol (P < 0.05), but no significant differences were observed for free fatty acids, insulin, or lactate. Although the mechanism by which mild ketonemia increases brain glucose uptake remains unclear, the KD clearly increased both the blood–brain barrier expression of MCT1 and stimulated brain 11C-AcAc uptake. The present dual-tracer positron emission tomography approach may be particularly interesting in neurodegenerative pathologies such as Alzheimer's disease where brain energy supply appears to decline critically.

Brain glucose transporter (Glut3) haploinsufficiency does not impair mouse brain glucose uptake

Mouse brain expresses three principal glucose transporters. Glut1 is an endothelial marker and is the principal glucose transporter of the blood-brain barrier. Glut3 and Glut6 are expressed in glial cells and neural cells. A mouse line with a null allele for Glut3 has been developed. The Glut3−/− genotype is intrauterine lethal by 7days post-coitis, but the heterozygous (Glut3+/−) littermate survives, exhibiting rapid post-natal weight gain, but no seizures or other behavioral aberrations. At 12weeks of age, brain uptake of tail vein-injected 3H-2-deoxy glucose in Glut3+/− mice was not different from Glut3+/+ littermates, despite 50% less Glut3 protein expression in the brain. The brain uptake of injected 18F-2-fluoro-2-deoxy glucose was similarly not different from Glut3+/− littermates in the total amount, time course, or brain imaging in the Glut3+/− mice. Glut1 and Glut6 protein expressions evaluated by immunoblots were not affected by the diminished Glut3 expression in the Glut3+/− mice. We conclude that a 50% decrease in Glut3 is not limiting for the uptake of glucose into the mouse brain, since Glut3 haploinsufficiency does not impair brain glucose uptake or utilization.

Impact of EEG-vigilance on brain glucose uptake measured with [ 18F]FDG and PET in patients with depressive episode or mild cognitive impairment

Introduction [ 18F]fluorodeoxyglucose positron emission tomography ([ 18F]FDG-PET) is a well-established method for the examination of the cerebral glucose metabolism of patients with affective disorder or memory impairment. An understudied question is how far results are influenced by interindividual differences in central nervous arousal as assessed with electroencephalogram (EEG-vigilance) during the PET recording. Building upon previous neuroimaging studies, we supposed an association between EEG-vigilance and normalized brain [ 18F]FDG-uptake (nFDGu) as measured by [ 18F]FDG-PET. For the first time, the present study exploratively investigated this association in a routine diagnostic work-up. Materials and methods Simultaneous 31-channel EEG and [ 18F]FDG-PET under resting conditions were acquired from 14 patients with depressive episode or mild cognitive impairment (MCI). EEG-vigilance was automatically classified by using the VIGALL algorithm (Vigilance Algorithm Leipzig). A nonparametric voxelwise simple linear regression with vigilance measure as predictor and nFDGu as criterion was performed using the Statistical nonParametric Mapping toolbox. Results The main finding was a significant negative correlation between vigilance measure and nFDGu in bilateral frontal and temporal regions, bilateral cingulate gyrus and right thalamus with vigilance-related changes of nFDGu between 17.1 and 44.4%. Discussion Simultaneous EEG and [ 18F]FDG-PET under resting conditions revealed that brain regions associated with EEG-vigilance partly overlapped with regions of impaired nFDGu in depression and MCI, as reported by previous studies. Vigilance-related changes of nFDGu were about the same magnitude as disease-related metabolic changes in patients with affective disorder or memory impairment as reported in previous studies. Therefore, our data suggest that differences in EEG-vigilance might influence alterations of nFDGu in disorders such as depression or MCI. Whether this possible impact of vigilance on nFDGu should be taken into account during the routine diagnostic application of [ 18F]FDG-PET has to be explored in future studies with larger patient groups.

Clinical pleomorphism of major depression as a challenge to the study of its pathophysiology

There are many studies showing that, as a group, major depressive disorder is associated with abnormalities in neurotransmitter systems such as serotonin, norepinephrine, dopamine, GABA and glutamate, as well as in neurotrophic factors which are in turn affected by hyper-responsive stress response systems such as the hypothalamic-pituitary-adrenal axis and altered cytokine function. Finally, there are alterations in circadian rhythms and sleep architecture which may be the consequence of these abnormalities or contribute to the risk or alter the course of major depression. It has long been puzzling how to reconcile research approaches looking at a single biologic explanatory model with the heterogeneity of the clinical picture of major depression. It would seem that this pleomorphic picture must be reflected by an equal variety in the pathophysiology. An examination of the DSM-IV criteria for a major depressive episode indicates there are over 1000 combinations of features that allow one to make that diagnosis. Furthermore, researchers point to the interindividual variability in score profile across the items of scales like the Hamilton Depression Rating Scale (HDRS). But this view only tells part of the story. We reported that there was no quantitative relationship within patients between episodes of major depression 1. This was true whether one examined the overall severity of successive episodes (as in the HDRS total score), or factors derived from a factor analysis looking at relatively independent domains of psychopathology, or even when one examined individual item scores. The key point here is that clinical presentation seems to vary about as much within patients in successive episodes, as between patients. The implications of this phenomenon were recognized by Eugen Bleuler in his landmark book on schizophrenia 2. He linked catatonia, paranoid schizophrenia, hebephrenia and what he called a defect state because he observed all of these in different combinations appearing in the same patient over time. In other words, even though these clinical pictures looked very different, they seemed to be part of a single illness since they were manifested by the same patient. If we consider that illnesses such as major depressive disorder or schizophrenia result from genetic causes and reported childhood adversity, including famine and physical or sexual abuse, and these environmental effects occur early in life, then the biological predisposition to illness should be largely set in an individual by early adolescence. If we presume that this biological substrate is fairly stable, then it is difficult to explain why there is such a variation in clinical picture within individuals. One possibility is that each episode alters the brain biology due to some sort of scaring or sensitization. Epigenetic effects may be a mechanism for enduring changes. But then one would predict a similar set of steps in terms of the evolution of the illness over time (as seen in schizophrenia with the evolution towards more negative symptoms and fewer positive symptoms). In major depression, the changes in clinical picture do not seem to follow a simple pattern, except perhaps for a longer duration of episodes. Brain imaging studies offer some clue in this respect and raise further questions. We have reported that the severity of different clinical domains of major depression, as defined by factors derived from either the HDRS or the Beck Depression Inventory (BDI), correlate with relative resting regional brain glucose uptake as measured by [18F]-FDG positron emission tomography (PET) 3. The degree to which these factor scores are correlated with each other is highly related to the degree to which the brain regions overlap for different factors. Each factor is related to a partly independent brain region 3. Clinical heterogeneity is reflected in a corresponding variety in relative resting regional brain activity in major depression. Not surprisingly, successful treatment with antidepressants or psychotherapy can alter this pattern towards that seen in healthy volunteers, and induced sadness in healthy volunteers can reproduce some of the changes seen in major depression 4. This provides a biological basis for variation in clinical picture, but not a causal explanation or mechanism. There are more stable biologic abnormalities that are present during episodes of major depression and between episodes. The best example is the abnormality in the serotonin system, which has been shown in terms of return of depression during remission after acute tryptophan depletion from the brain, the blunted prolactin response to the indirect serotonin releasing drug fenfluramine during an episode and between episodes, and the higher 5-HT1A receptor binding on PET imaging in depressed and remitted drug-free patients. To further study the clinical and biological heterogeneity between patients, one would recommend a focus on regional brain variation as revealed by the PET FDG studies and then seeking a cause for that variation in terms of serotonin, neorepinephrine and dopamine inputs and GABA and glutamatergic target neuron function.

Thioperamide, an H3 Receptor Antagonist Prevents [3H]Glucose Uptake in Brain of Adult Rats Lesioned as Neonates with 5,7-Dihydroxytryptamine

As a first attempt at exploring an association between histaminergic and serotoninergic neuronal phenotypes in glucose regulation, the influence of the histamine H₃ receptor antagonist thioperamide on glucose uptake by brain was determined in rats in which the serotoninergic innervations of brain was largely destroyed perinatally. Male Wistar rats were initially treated on the 3rd day after birth with the serotoninergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) (75 μg icv) or saline vehicle (10 μl icv). At 8 weeks lesioned and control rats were terminated in order to validate the effectiveness of 5,7-DHT: reduction in 5-HT and 5-HIAA by 83-91% and 69-83% in striatum, frontal cortex, and hippocampus (HPLC/ED method). Other groups of rats were pretreated with thioperamide (5.0 mg/kg ip) or saline vehicle 60 min prior to 6-[³H]-D-glucose (500 μCi/kg ip). Fifteen-min later rats were decapitated and brains were excised and dissected to remove frontal cortex, striatum, hippocampus, thalamus/hypothalamus, pons, and cerebellum. Liquid scintillation spectroscopy was used to determine that [³H]glucose uptake, which was enhanced in 5,7-DHT lesioned rats in cortex (by 88%), hippocampus, thalamus/hypothalamus, pons and cerebellum (each by 47-56%), and in striatum (by 35%). In contrast, thioperamide prevented the enhancement in [³H]glucose uptake in all brain regions of 5,7-DHT neonatally lesioned rats; and [³H]glucose levels were significantly different in all brain regions (except thalamus/hypothalamus) in thioperamide-versus saline-treated rats. These findings indicate a functional association between histaminergic and serotoninergic systems in brain in relation to glucose regulation.

I09 Brain glucose hypometabolism in a subject carrying an unstable allele of intermediate CAG33 repeat length in the Huntington's disease gene

BackgroundIt is a general belief that below 36 CAG triplet number, Huntington's disease (HD) does not manifest although unstable transmission of paternal alleles with intermediate length (27–35 CAG repeats) may...

Relationship of blood flow and metabolism to acoustic processing centers of the dolphin brain

Odontocete brain tissues associated with auditory processing are hypertrophied and modified relative to their terrestrial counterparts. The relationship between the functional demand on these tissues and metabolic substrate requirements is unknown. Using positron emission tomography (PET), relative cerebral blood flow was measured in a bottlenose dolphin. Approximately 60 mCi (13)NH(3) was administered to the dolphin via a catheter inserted into the hepatic vein and threaded proximate to the vena cava. Radiolabel initially appeared as distributed focal points in the cerebellum. Increasing scan time resulted in an increase in the number of focal regions and in the diffusivity of label activity throughout the brain. The time course and spatial distribution of radiolabel was consistent with a cerebral blood supply dominated by the spinal meningeal arteries. Blood flow was predominantly observed in the cerebellum and neocortex, particularly the auditory and visual cortex. Differential brain glucose uptake, previously measured in a separate dolphin, showed good agreement with the differential supply of blood to brain tissues. Rates of blood supply and glucose uptake in the auditory cortex, inferior colliculus, and cerebellum are consistent with a high metabolic demand of tissues which are important to the integration of auditory and other sensory inputs.

Dysregulation of brain insulin signaling: A mechanistic link between diabetes and Alzheimer's disease

Brain glucose uptake and utilization are impaired in Alzheimer's disease (AD). Type 2 diabetes mellitus (T2DM), which is characterized by deficient glucose uptake and utilization in the periphery due to insulin resistance, increases the risk for AD, but the underlying mechanism linking T2DM and AD is not understood. This study was aimed to understand whether brain insulin resistance is the link between T2DM and AD, which could contribute to AD via down-regulation of insulin-PI3K-AKT signaling. Autopsied frontal cortices from 9 AD, 10 T2DM, 8 T2DM-AD and 7 control cases were included in this study. All the groups had similar postmortem intervals (2.7 ± 0.6 hours) and ages (82.3 ± 4.9 years), The levels of the various components of the insulin-PI3K-AKT signaling pathway [including insulin receptor, insulin receptor substrate-1, phosphoinositide 3-kinase (PI3K), 3-phosphoinositide-dependent kinase-1, protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β)], total tau, phosphorylated tau, and calpain I were determined by quantitative Western blots. The activities of the insulin-PI3K-AKT signaling components were estimated by measuring the levels of the active/phosphorylated forms of the proteins. We found down-regulation of both the levels and activities of several components of the insulin-PI3K-AKT signaling pathway in the postmortem brains from individuals with T2DM or with AD. The deficiency of insulin-PI3K-AKT signaling was more severe in those individuals suffering from both T2DM and AD. The down-regulation of insulin-PI3K-AKT signaling was accompanied by activation of GSK-3β, the major tau kinase in the brain. The levels and the activation of the insulin-PI3K-AKT signaling components were correlated negatively with the level of tau phosphorylation at several abnormal phosphorylation sites and with the activation of calpain I in the brain. Our results suggest that the down-regulation of insulin-PI3K-AKT signaling, which appeared to be caused by calpain over-activation, might be the mechanistic link between T2DM and AD. Brain insulin resistance in T2DM may increase the risk for AD by decreased insulin-PI3K-AKT signaling and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration.

Molecular basis of cognitive improvement of pioglitazone and rosiglitazone

Brain glucose uptake and metabolism are impaired in Alzheimer's disease (AD), and this impairment appears to contribute to the pathogenesis of the disease. Insulin sensitizers, which are widely used for increasing insulin sensitivity and glucose utilization in diabetes, have shown some improvement in memory in AD mouse models and in AD clinical trials in AD patients. The present study was aimed to understand the possible molecular mechanisms by which two of these insulin sensitizers, pioglitazone and rosiglitazone, might cause the improvement. Ten-month-old female 3xTg-AD mice and the wild type controls were orally administered with pioglitazone (20 mg/kg body weight/day) and rosiglitazone (5 mg /kg body weight/day) for four months. Spatial memory was tested by using Morris water maze before and after the treatments. At the end of treatments and behavioral tests, the mice were sacrificed and the brain tissue was analyzed both by Western blots and immunohistochemistry for the insulin-PI3K-AKT signaling pathway, phosphorylation and deposition of tau, Aβ accumulation, and glial activation. We observed that four-month treatments of 3xTg-AD mice with pioglitazone or rosiglitazone attenuated the deficits in spatial reference memory of the 3xTg-AD mice. These drug treatments also resulted in activation of protein kinase B (AKT) and inhibition of GSK-3β in the brain, suggesting activation of the insulin-PI3K-AKT signaling pathway. At the same time, hyperphosphorylation of tau at several sites, including Ser202, Thr217, Thr231, Ser404 and Ser422, Aβ accumulation, and astrocyte over-activation were found to be attenuated in the drug-treated mice. Our results suggest that pioglitazone and rosiglitazone probably improve the memory deficits through several pathways, including elevation of insulin-PI3K-AKT signaling and attenuation of tau hyperphosphorylation, Aβ accumulation, and inhibition of astrocyte over-activation. These findings suggest the potential usefulness of glitazones in the treatment for AD.

Brain Insulin Action Regulates Hypothalamic Glucose Sensing and the Counterregulatory Response to Hypoglycemia

OBJECTIVEAn impaired ability to sense and appropriately respond to insulin-induced hypoglycemia is a common and serious complication faced by insulin-treated diabetic patients. This study tests the hypothesis that insulin acts directly in the brain to regulate critical glucose-sensing neurons in the hypothalamus to mediate the counterregulatory response to hypoglycemia.RESEARCH DESIGN AND METHODSTo delineate insulin actions in the brain, neuron-specific insulin receptor knockout (NIRKO) mice and littermate controls were subjected to graded hypoglycemic (100, 70, 50, and 30 mg/dl) hyperinsulinemic (20 mU/kg/min) clamps and nonhypoglycemic stressors (e.g., restraint, heat). Subsequently, counterregulatory responses, hypothalamic neuronal activation (with transcriptional marker c-fos), and regional brain glucose uptake (via 14C-2deoxyglucose autoradiography) were measured. Additionally, electrophysiological activity of individual glucose-inhibited neurons and hypothalamic glucose sensing protein expression (GLUTs, glucokinase) were measured.RESULTSNIRKO mice revealed a glycemia-dependent impairment in the sympathoadrenal response to hypoglycemia and demonstrated markedly reduced (3-fold) hypothalamic c-fos activation in response to hypoglycemia but not other stressors. Glucose-inhibited neurons in the ventromedial hypothalamus of NIRKO mice displayed significantly blunted glucose responsiveness (membrane potential and input resistance responses were blunted 66 and 80%, respectively). Further, hypothalamic expression of the insulin-responsive GLUT 4, but not glucokinase, was reduced by 30% in NIRKO mice while regional brain glucose uptake remained unaltered.CONCLUSIONSChronically, insulin acts in the brain to regulate the counterregulatory response to hypoglycemia by directly altering glucose sensing in hypothalamic neurons and shifting the glycemic levels necessary to elicit a normal sympathoadrenal response.

Regional cerebral glucose uptake in the 3xTG model of Alzheimer's disease highlights common regional vulnerability across AD mouse models

We have previously used fluorodeoxyglucose (FDG) autoradiography to detect the pattern of metabolic declines in two different transgenic mouse models of fibrillar beta-amyloid pathology in Alzheimer's disease (AD), including the PDAPP mouse, which overexpresses a mutant form of human APP, and the PSAPP mouse, which overexpresses mutant forms of the human APP and PS1 genes. In this study, we used the same approach to study a triple-transgenic (3xTG) model of AD, which overexpresses human APP, PS1 and tau mutations, and progressively develops amyloid plaques, neurofibrillary tangles, and synaptic dysfunction. Densitometric measurements from 55 brain regions were characterized and compared in 2, 12, and 18 month-old 3xTG and wildtype control mice (n = 12/group). By 18 months of age, the 3xTG mice had significant reductions in FDG uptake in every measured brain region, including cortical and subcortical gray matter, cerebellar and brainstem regions. However, regional differences in normalized FDG uptake were apparent in the 2- and 12-month-old 3xTG mice, in a brain network pattern reminiscent of our previous analyses in the other mouse models. This prominently included the posterior cingulate/retrosplenial cortex, as in each previously-analyzed model. Overall, our analyses highlight consistencies in brain glucose uptake abnormalities across multiple mouse models of amyloid-associated pathophysiology. These mouse brain regional changes are homologous to alterations seen in PET scans from human AD patients and could thus be useful biomarkers for early testing of novel interventions.

Targeting Tau Protein in Alzheimerʼs Disease

Alzheimer's disease (AD) is characterized histopathologically by numerous neurons with neurofibrillary tangles and neuritic (senile) amyloid-beta (Abeta) plaques, and clinically by progressive dementia. Although Abeta is the primary trigger of AD according to the amyloid cascade hypothesis, neurofibrillary degeneration of abnormally hyperphosphorylated tau is apparently required for the clinical expression of this disease. Furthermore, while approximately 30% of normal aged individuals have as much compact plaque burden in the neocortex as is seen in typical cases of AD, in several tauopathies, such as cortical basal degeneration and Pick's disease, neurofibrillary degeneration of abnormally hyperphosphorylated tau in the absence of Abeta plaques is associated with dementia. To date, all AD clinical trials based on Abeta as a therapeutic target have failed. In addition to the clinical pathological correlation of neurofibrillary degeneration with dementia in AD and related tauopathies, increasing evidence from in vitro and in vivo studies in experimental animal models provides a compelling case for this lesion as a promising therapeutic target. A number of rational approaches to inhibiting neurofibrillary degeneration include inhibition of one or more tau protein kinases, such as glycogen synthase kinase-3beta and cyclin-dependent protein kinase 5, activation of the major tau phosphatase protein phosphatase-2A, elevation of beta-N-acetylglucosamine modification of tau through inhibition of beta-N-acetylglucosaminidase or increase in brain glucose uptake, and promotion of the clearance of the abnormally hyperphosphorylated tau by autophagy or the ubiquitin proteasome system.

Brain Glucose Overexposure and Lack of Acute Metabolic Flexibility in Obesity and Type 2 Diabetes: A PET-[18F]FDG Study in Zucker and ZDF Rats

Brain glucose exposure may complicate diabetes and obesity. We used positron emission tomography with (18)F-fluorodeoxyglucose in Zucker obese, diabetic, and control rats to determine the contributions of blood glucose mass action versus local mechanisms in regulating central glucose disposal in fasted and acutely glucose-stimulated states, and their adaptations in obesity and diabetes. Our study data indicate that brain glucose uptake is dependent on both local and mass action components, and is stimulated by acute glucose intake in healthy rats. In diseased animals, the organ was chronically overexposed to glucose, due to high fasting glucose uptake, almost abolishing the physiologic response to glucose loading.

EFFECTS OF ANESTHETIC PROTOCOL ON NORMAL CANINE BRAIN UPTAKE OF18F-FDG ASSESSED BY PET/CT

The purpose of this study was to assess the effects of four anesthetic protocols on normal canine brain uptake of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) using positron emission tomography/computed tomography (PET/CT). Five clinically normal beagle dogs were anesthetized with (1) propofol/isoflurane, (2) medetomidine/pentobarbital, (3) xylazine/ketamine, and (4) medetomidine/tiletamine-zolazepam in a randomized cross-over design. The standard uptake value (SUV) of FDG was obtained in the frontal, parietal, temporal and occipital lobes, cerebellum, brainstem and whole brain, and compared within and between anesthetic protocols using the Friedman test with significance set at P < 0.05. Significant differences in SUVs were observed in various part of the brain associated with each anesthetic protocol. The SUV for the frontal and occipital lobes was significantly higher than in the brainstem in all dogs. Dogs receiving medetomidine/tiletamine-zolazepam also had significantly higher whole brain SUVs than the propofol/isoflurane group. We concluded that each anesthetic protocol exerted a different regional brain glucose uptake pattern. As a result, when comparing brain glucose uptake using PET/CT, one should consider the effects of anesthetic protocols on different regions of the glucose uptake in the dog's brain.

The new FDG brain revolution: the neurovascular unit and the default network

F-fluorodeox-yglucose (FDG), it was possible to see and study the livingbrain in humans! Pioneers were top experts who provideddifferent specialized expertise, but strictly cooperatingbetween themselves [1]. Physicists, engineers and mathe-maticians were actively involved in producing the besthardware and software. The research on crystals, inidentifying the most effective electronics, in definingaccurate methods for attenuation and scatter correctionand so on, was nevertheless limited by the relatively poortechnology, with the main consideration being limitedcomputer power. These developments stimulated a majorinterest in the brain. Satisfactory sensitivity and resolution,together with reliable solutions to the technical problems,were only achieved with dedicated cerebral PET scannerswhich had a field of view that permitted exclusive analysisof the brain.Basic scientists had the possibility of realizing ascientific dream: the transfer of data on cerebral glucosemetabolism acquired in animals by quantitative autoradi-ography to humans. Another issue in the original FDG PETresearch was to consider mandatory absolute quantification.Thus arterial (or arterialized) sampling, to obtain data to beincluded in mathematical models, was routinely performed.However, because the equations included nonmeasurableparameters, the presence of a lumped constant affectedabsolute measurement in an individual [2–4]. PET teamsincluded (and were directed by) clinical experts includingnot only nuclear physicians, but also other professionalssuch as neuroradiologists, neurologists and psychiatrists,who frequently cooperated with psychologists, anatomistsand physiologists.Because of the unsatisfactory spatial resolution and thenegative influence of the partial volume effect, inpresence of glucose uptake in the normal brain, only alow lesion/background ratio was achievable, except forhot spots, i.e. the presence of focal areas of increaseduptake determined by physiological and/or pathologicalcauses. Therefore, the use of FDG as a positive indicatorwasrestrictedinthefirststudiesandinthesearchforhotspots, many studies involved physiological stimulationtests (closed/open eyes, auditory system, etc.) in normalsubjects [5, 6]. Similarly, major interest in pathologicalanalysis was directed to the evaluation of brain tumours,starting from Warburg’s hypothesis of higher FDG uptakein malignant lesions with respect to benign ones [7]. Withfurther clinical experience, in the analysis of patients withepilepsy, a higher sensitivity was clearly demonstratedduring the ictal phase, the focus being seen as a hot spot,with respect to the interictal period when the lesion wasnot easily detectable, being an area with a slightly reducedoverall FDG uptake [8, 9]. Discrepant results in epilepsyclearly demonstrate how, in the absence of a structurallesion evident on CT, it is more difficult to search for afunctional alteration when it corresponds to an area ofdecreased uptake (cold spot).