[Show abstract][Hide abstract] ABSTRACT: The biomarker potential of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) for the in vivo characterization of preclinical stages in Alzheimer's disease has not yet been explored. We measured GABA, glutamate + glutamine (Glx), and N-acetyl-aspartate (NAA) levels by single-voxel MEGA-PRESS magnetic resonance spectroscopy in the posterior cingulate cortex of 21 elderly subjects and 15 patients with amnestic mild cognitive impairment. Participants underwent Pittsburgh Compound B positron emission tomography, apolipoprotein E (APOE) genotyping, and neuropsychological examination. GABA, Glx, and NAA levels were significantly lower in patients. NAA was lower in Pittsburgh Compound B-positive subjects and APOE ε4 allele carriers. GABA, Glx, and NAA levels were positively correlated to CERAD word learning scores. Reductions in GABA, Glx, and NAA levels may serve as metabolic biomarkers for cognitive impairment in amnestic mild cognitive impairment. Because GABA and Glx do not seem to reflect amyloid β deposition or APOE genotype, they are less likely biomarker candidates for preclinical Alzheimer's disease.
[Show abstract][Hide abstract] ABSTRACT: Obsessive-compulsive disorder (OCD) is a disabling, mostly chronic, psychiatric condition with significant social and economic impairments and is a major public health issue. However, numerous patients are resistant to currently available pharmacological and psychological interventions. Given that recent animal studies and magnetic resonance spectroscopy research points to glutamate dysfunction in OCD, we investigated the metabotropic glutamate receptor 5 (mGluR5) in patients with OCD and healthy controls. We determined mGluR5 distribution volume ratio (DVR) in the brain of ten patients with OCD and ten healthy controls by using [11C]ABP688 positron-emission tomography. As a clinical measure of OCD severity, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed. We found no significant global difference in mGluR5 DVR between patients with OCD and healthy controls. We did, however, observe significant positive correlations between the Y-BOCS obsession sub-score and mGluR5 DVR in the cortico-striatal-thalamo-cortical brain circuit, including regions of the amygdala, anterior cingulate cortex, and medial orbitofrontal cortex (Spearman's ρ's⩾ = 0.68, p < 0.05). These results suggest that obsessions in particular might have an underlying glutamatergic pathology related to mGluR5. The research indicates that the development of metabotropic glutamate agents would be useful as a new treatment for OCD.
The International Journal of Neuropsychopharmacology 05/2014; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Quantitative measures of 11C-raclopride receptor binding can be used as a correlate of postsynaptic D2 receptor density in the striatum, allowing 11C-raclopride positron emission tomography (PET) to be used for the differentiation of Parkinson's disease from atypical parkinsonian syndromes. Comparison with reference values is recommended to establish a reliable diagnosis. A PET template specific to raclopride may facilitate direct computation of parametric maps without the need for an additional MR scan, aiding automated image analysis.
Sixteen healthy volunteers underwent a dynamic 11C-raclopride PET and a high-resolution T1-weighted MR scan of the brain. PET data from eight healthy subjects was processed to generate a raclopride-specific PET template normalized to standard space. Subsequently, the data processing based on the PET template was validated against the standard magnetic resonance imaging (MRI)-based method in 8 healthy subjects and 20 patients with suspected parkinsonian syndrome. Semi-quantitative image analysis was performed in Montreal Neurological Institute (MNI) and in original image space (OIS) using VOIs derived from a probabilistic brain atlas previously validated by Hammers et al. (Hum Brain Mapp, 15:165-174, 2002).
The striatal-to-cerebellar ratio (SCR) of 11C-raclopride uptake obtained using the PET template was in good agreement with the MRI-based image processing method, yielding a Lin's concordance coefficient of 0.87. Bland-Altman analysis showed that all measurements were within the +/-1.96 standard deviation range. In all 20 patients, the PET template-based processing was successful and manual volume of interest optimization had no further impact on the diagnosis of PD in this patient group. A maximal difference of <5 % was found between the measured SCR in MNI space and OIS.
The PET template-based method for automated quantification of postsynaptic D2 receptor density is simple to implement and facilitates rapid, robust and reliable image analysis. There was no significant difference between the SCR values obtained with either PET- or MRI-based image processing. The method presented alleviates the clinical workflow and facilitates automated image analysis.
[Show abstract][Hide abstract] ABSTRACT: Deposition of cortical amyloid beta (Aβ) is a correlate of aging and a risk factor for Alzheimer Disease (AD). While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using Pittsburgh Compound-B positron-emission-tomography (PiB-PET) late frame signals. Volumes of brain structures were assessed by applying an automated parcellation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent (BOLD) resting state functional magnetic resonance imaging (fMRI) at the high field strength of 7 Tesla for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling.Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus and thalamus. Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro-cerebellar system and risk for AD.
Frontiers in Aging Neuroscience 01/2014; 5:52. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: Arterial hypertension is an important risk factor for cerebrovascular diseases, such as transient ischemic attacks or stroke, and represents a major global health issue. The effects of hypertension on cerebral blood flow, particularly at the microvascular level, remain unknown. METHODS: Using the spontaneously hypertensive rat (SHR) model, we examined cortical hemodynamic responses on whisker stimulation applying a multimodal imaging approach (multiwavelength spectroscopy, laser speckle imaging, and 2-photon microscopy). We assessed the effects of hypertension in 10-, 20-, and 40-week-old male SHRs and age-matched male Wistar Kyoto rats (CTRL) on hemodynamic responses, histology, and biochemical parameters. In 40-week-old animals, losartan or verapamil was administered for 10 weeks to test the reversibility of hypertension-induced impairments. RESULTS: Increased arterial blood pressure was associated with a progressive impairment in functional hyperemia in 20- and 40-week-old SHRs; baseline capillary red blood cell velocity was increased in 40-week-old SHRs compared with age-matched CTRLs. Antihypertensive treatment reduced baseline capillary cerebral blood flow almost to CTRL values, whereas functional hyperemic signals did not improve after 10 weeks of drug therapy. Structural analyses of the microvascular network revealed no differences between normo- and hypertensive animals, whereas expression analyses of cerebral lysates showed signs of increased oxidative stress and signs of impaired endothelial homeostasis upon early hypertension. CONCLUSIONS: Impaired neurovascular coupling in the SHR evolves upon sustained hypertension. Antihypertensive monotherapy using verapamil or losartan is not sufficient to abolish this functional impairment. These deficits in neurovascular coupling in response to sustained hypertension might contribute to accelerate progression of neurodegenerative diseases in chronic hypertension.
[Show abstract][Hide abstract] ABSTRACT: Background and Purpose—Arterial hypertension is an important risk factor for cerebrovascular diseases, such as transient ischemic attacks or stroke, and represents a major global health issue. The effects of hypertension on cerebral blood flow, particularly at the microvascular level, remain unknown.
Methods—Using the spontaneously hypertensive rat (SHR) model, we examined cortical hemodynamic responses on whisker stimulation applying a multimodal imaging approach (multiwavelength spectroscopy, laser speckle imaging, and 2-photon microscopy). We assessed the effects of hypertension in 10-, 20-, and 40-week-old male SHRs and age-matched male Wistar Kyoto rats (CTRL) on hemodynamic responses, histology, and biochemical parameters. In 40-week-old animals, losartan or verapamil was administered for 10 weeks to test the reversibility of hypertension-induced impairments.
Results—Increased arterial blood pressure was associated with a progressive impairment in functional hyperemia in 20- and 40-week-old SHRs; baseline capillary red blood cell velocity was increased in 40-week-old SHRs compared with age-matched CTRLs. Antihypertensive treatment reduced baseline capillary cerebral blood flow almost to CTRL values, whereas functional hyperemic signals did not improve after 10 weeks of drug therapy. Structural analyses of the microvascular network revealed no differences between normo- and hypertensive animals, whereas expression analyses of cerebral lysates showed signs of increased oxidative stress and signs of impaired endothelial homeostasis upon early hypertension.
Conclusions—Impaired neurovascular coupling in the SHR evolves upon sustained hypertension. Antihypertensive monotherapy using verapamil or losartan is not sufficient to abolish this functional impairment. These deficits in neurovascular coupling in response to sustained hypertension might contribute to accelerate progression of neurodegenerative diseases in chronic hypertension.
[Show abstract][Hide abstract] ABSTRACT: Long-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug-naïve control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with (11)C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared with non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen (d=1.46, 18%). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest, indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls, while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation.Molecular Psychiatry advance online publication, 30 April 2013; doi:10.1038/mp.2013.51.
[Show abstract][Hide abstract] ABSTRACT: Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [(11)C]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system.
Proceedings of the National Academy of Sciences 12/2012; · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kinetic modeling of PET data derived from mouse models remains hampered by the technical inaccessibility of an accurate input function (IF). In this work, we tested the feasibility of IF measurement with an arteriovenous shunt and a coincidence counter in mice and compared the method with an image-derived IF (IDIF) obtained by ensemble-learning independent component analysis of the heart region. METHODS: (18)F-FDG brain kinetics were quantified in 2 mouse strains, CD1 and C57BL/6, using the standard 2-tissue-compartment model. Fits obtained with the 2 IFs were compared regarding their goodness of fit as assessed by the residuals, fit parameter SD, and Bland-Altman analysis. RESULTS: On average, cerebral glucose metabolic rate was 10% higher for IDIF-based quantification. The precision of model parameter fitting was significantly higher using the shunt-based IF, rendering the quantification of single process rate constants feasible. CONCLUSION: We demonstrated that the arterial IF can be measured in mice with a femoral arteriovenous shunt. This technique resulted in higher precision for kinetic modeling parameters than did use of the IDIF. However, for longitudinal or high-throughput studies, the use of a minimally invasive IDIF based on ensemble-learning independent component analysis represents a suitable alternative.
Journal of Nuclear Medicine 11/2012; · 5.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Sleep deprivation (wake therapy) provides rapid clinical relief in many patients with major depressive disorder (MDD). Changes in glutamatergic neurotransmission may contribute to the antidepressant response, yet the exact underlying mechanisms are unknown. Metabotropic glutamate receptors of subtype 5 (mGluR5) are importantly involved in modulating glutamatergic neurotransmission and neuronal plasticity. The density of these receptors is reduced in the brain of patients with MDD, particularly in brain structures involved in regulating wakefulness and sleep. We hypothesized that prolonged wakefulness would increase mGluR5 availability in human brain. METHODS: Metabotropic glutamate receptor subtype 5 binding was quantified with positron emission tomography in 22 young healthy men who completed two experimental blocks separated by 1 week. Two positron emission tomography examinations were conducted in randomized, crossover fashion with the highly selective radioligand, (11)C-ABP688, once after 9 hours (sleep control) and once after 33 hours (sleep deprivation) of controlled wakefulness. (11)C-ABP688 uptake was quantified in 13 volumes of interest with high mGluR5 expression and presumed involvement in sleep-wake regulation. RESULTS: Sleep deprivation induced a global increase in mGluR5 binding when compared with sleep control (p<.006). In anterior cingulate cortex, insula, medial temporal lobe, parahippocampal gyrus, striatum, and amygdala, this increase correlated significantly with the sleep deprivation-induced increase in subjective sleepiness. CONCLUSIONS: This molecular imaging study demonstrates that cerebral functional mGluR5 availability is increased after a single night without sleep. Given that mGluR5 density is reduced in MDD, further research is warranted to examine whether this mechanism is involved in the potent antidepressant effect of wake therapy.
[Show abstract][Hide abstract] ABSTRACT: Reliable 18F-fluorodeoxyglucose (FDG) uptake quantification is crucial for cancer treatment monitoring. While interobserver variability has been found to be lower for a maximum standard uptake value (SUV)max than for an averaged SUV (SUVmean), the repeatability has not been investigated yet. In this study, we determined the repeatability of SUV values in two sequential measurements 5 min apart.
Positron emission tomography data of malignant chest tumors were acquired dynamically during 45 min in 20 patients. SUV values were derived from the hottest (SUVmax), the mean of the 5 (SUV5) and 10 (SUV10) hottest voxels and the mean of a volume of interest (SUVmean). The repeatability of the SUV measurements was determined as the standard deviation of the difference between the values at 40 and 45 min and represented as Bland-Altman graphs.
The standard deviation of the difference between the two sequential scans for SUVmax, SUV5, SUV10 and SUVmean was 1.01, 0.53, 0.37 and 0.28.
The repeatability of SUV is markedly increased by deriving the value from multiple voxels. Compared to SUVmax, the variability in SUV measurements is reduced by a factor of 2.7 (2.7=1.01/0.37) if 10 voxels are pooled.
Nuclear Medicine and Biology 02/2012; 39(5):666-70. · 2.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although alterations of serotonin (5-HT) system functioning have been proposed for a variety of psychiatric disorders, a direct method quantitatively assessing 5-HT release capacity in the living human brain is still lacking. Therefore, we evaluated a novel method to assess 5-HT release capacity in vivo using dexfenfluramine challenge and [18F]altanserin positron emission tomography (PET).Thirteen healthy male subjects received placebo and single oral doses of 40 mg (n = 6) or 60 mg (n = 7) of the potent 5-HT releaser dexfenfluramine separated by an interval of 14 days. Three further subjects received placebo on both days. Two hours after placebo/drug administration, 250 MBq of the 5-HT2A receptor selective PET-radiotracer [18F]altanserin was administered intravenously as a 30 s bolus. Dynamic PET data were subsequently acquired over 90 min. Moreover, arterial blood samples were drawn for measurement of total activity and metabolite correction of the input function. Dexfenfluramine as well as cortisol and prolactin plasma concentration-time profiles was quantitatively determined. Tracer distribution volumes for five volumes-of-interest (prefrontal and occipital cortex, insula, thalamus, caudatum) were calculated by the Logan plot and a 2-tissue compartment model. Dexfenfluramine dose-dependently decreased the total distribution volume of [18F]altanserin in cortical regions independent of the PET modeling approach. Cortisol and prolactin plasma concentrations were dose-dependently increased by dexfenfluramine. The decrease in cortical [18F]altanserin receptor binding under dexfenfluramine was correlated with the increase of plasma prolactin. These data suggest that the combination of a dexfenfluramine-induced 5-HT release and subsequent assessment of 5-HT2A receptor availability with [18F]altanserin PET is suitable to measure cortical 5-HT release capacity in the human brain.Highlights► Dexfenfluramine-induced 5-HT release decreased cortical [18F]altanserin binding. ► Change in cortical 5-HT2AR binding was correlated with change of plasma prolactin. ► New method to measure cortical serotonin release capacity in the human brain.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to develop a two-compartment metabolic model of brain metabolism to assess oxidative metabolism from [1-(11)C] acetate radiotracer experiments, using an approach previously applied in (13)C magnetic resonance spectroscopy (MRS), and compared with an one-tissue compartment model previously used in brain [1-(11)C] acetate studies. Compared with (13)C MRS studies, (11)C radiotracer measurements provide a single uptake curve representing the sum of all labeled metabolites, without chemical differentiation, but with higher temporal resolution. The reliability of the adjusted metabolic fluxes was analyzed with Monte-Carlo simulations using synthetic (11)C uptake curves, based on a typical arterial input function and previously published values of the neuroglial fluxes V(tca)(g), V(x), V(nt), and V(tca)(n) measured in dynamic (13)C MRS experiments. Assuming V(x)(g)=10 × V(tca)(g) and V(x)(n)=V(tca)(n), it was possible to assess the composite glial tricarboxylic acid (TCA) cycle flux V(gt)(g) (V(gt)(g)=V(x)(g) × V(tca)(g)/(V(x)(g)+V(tca)(g))) and the neurotransmission flux V(nt) from (11)C tissue-activity curves obtained within 30 minutes in the rat cortex with a beta-probe after a bolus infusion of [1-(11)C] acetate (n=9), resulting in V(gt)(g)=0.136±0.042 and V(nt)=0.170±0.103 μmol/g per minute (mean±s.d. of the group), in good agreement with (13)C MRS measurements.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 11/2011; 32(3):548-59. · 5.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The standard uptake value (SUV) is the most often used semi-quantitative measure of (18)F-fluorodeoxyglucose (FDG) uptake. We tested the hypothesis that the autoradiographic method with a population-based input curve yields an approximation of FDG metabolism represented by the flux value Ki, which is less dependent on the acquisition time point than SUV.
We analyzed 20 patients with chest tumors (16 males, age 65±10 years). After injection of 350 MBq FDG using the INTEGO PET infusion system, a series of 35 scans of 10- to 300-s duration were acquired until 45 min. FDG flux was calculated using the Patlak method (Ki(patlak)) and also quantified with the autoradiographic method using the last acquisition only and the individual image-derived input function (Ki(autoreal)), as well as with a population-based input function (Ki(autonorm)). In a simulation study, the time courses of tumor SUV, tumor-to-blood ratio and tumor Ki values were calculated from 30 to 90 min.
The FDG flux values (Ki) of the different tumors, obtained with the autoradiographic methods and the Patlak method, showed a high correlation. The simulation study showed a 16.8±3.3% increase in the SUV values from 50 to 70 min, but only a 1.3±2.8% change in the Ki values calculated with the autoradiographic method.
Compared to the SUV, the autoradiographic Ki values are advantageous for various reasons. First, they are much less dependent on the time of acquisition than the SUV. Second, their calculation does not require the knowledge of the body weight or the injected activity. Furthermore, the values are comparable to the ones obtained with the widely accepted Patlak method. The method can be easily implemented in a clinical setting, as it uses only one static scan.
Nuclear Medicine and Biology 08/2011; 38(6):835-41. · 2.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Activation of astrocytic metabotropic glutamate receptor 5 (mGluR5) is postulated to elicit calcium transients, triggering a chain of events that ultimately regulates cerebral blood flow by changing the tone of smooth muscle cells of nearby arterioles. Using concurrent in vivo optical imaging and determination of receptor occupancy with (11)C-ABP688, we report here that blocking ∼80% of mGluR5 in vivo does not affect transient hemodynamic responses on brief whisker stimulations while transiently reducing neuronal activity as measured by voltage-sensitive dye imaging. Our results show that mechanisms other than activation of mGluR5 are required to trigger the initial hemodynamic response in normal physiological conditions.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 07/2011; 31(9):e1-10. · 5.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Astrocytes have various important roles in brain physiology. To further elucidate the details of astrocytic functions under normal and pathological states, astrocyte-specific measurements are mandatory. For studying brain energy metabolism, the use of the astrocyte-specific energy substrate acetate has proven to be of great value. Since the first applications of labeled acetate for brain studies about 50 years ago, numerous methodologies have been developed and employed in compartment-specific investigations of brain metabolism. Here, we provide an overview of these different methodological approaches and review studies employing acetate labeled with the most commonly used carbon isotopes.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 06/2011; 31(8):1668-74. · 5.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cerebral energy metabolism is a highly compartmentalized and complex process in which transcellular trafficking of metabolites plays a pivotal role. Over the past decade, a role for lactate in fueling the energetic requirements of neurons has emerged. Furthermore, a neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported. The majority of the current evidence concerning lactate metabolism at the cellular level is based on in vitro data; only a few recent in vivo results have demonstrated that the brain preferentially utilizes lactate over glucose. Using voltage-sensitive dye (VSD) imaging, beta-probe measurements of radiotracer kinetics, and brain activation by sensory stimulation in the anesthetized rat, we investigated several aspects of cerebral lactate metabolism. The present study is the first in vivo demonstration of the maintenance of neuronal activity in the presence of lactate as the primary energy source. The loss of the voltage-sensitive dye signal found during severe insulin-induced hypoglycemia is completely prevented by lactate infusion. Thus, lactate has a direct neuroprotective effect. Furthermore, we demonstrate that the brain readily oxidizes lactate in an activity-dependent manner. The washout of 1-[(11)C]L-lactate, reflecting cerebral lactate oxidation, was observed to increase during brain activation from 0.077 ± 0.009 to 0.105 ± 0.007 min(-1). Finally, our data confirm that the brain prefers lactate over glucose as an energy substrate when both substrates are available. Using [(18)F]fluorodeoxyglucose (FDG) to measure the local cerebral metabolic rate of glucose, we demonstrated a lactate concentration-dependent reduction of cerebral glucose utilization during experimentally increased plasma lactate levels.
Journal of Neuroscience 05/2011; 31(20):7477-85. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects.
Images of mGluR5 receptor binding were acquired using PET with [(11)C]ABP688, which binds to an allosteric site with high specificity, in 11 unmedicated individuals with major depression and 11 matched healthy comparison subjects. The amount of mGluR5 protein was investigated using Western blot in postmortem brain samples of 15 depressed individuals and 15 matched comparison subjects.
The PET study revealed lower levels of regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus, and the hippocampus in the depression group relative to the comparison group. Severity of depression was negatively correlated with mGluR5 binding in the hippocampus. The postmortem study showed lower levels of mGluR5 protein expression in the prefrontal cortex (Brodmann's area 10) in the depression group relative to the comparison group, while prefrontal mGluR1 protein expression did not differ between groups.
The lower levels of mGluR5 binding observed in the depression group are consonant with the lower levels of protein expression in brain tissue in the postmortem depression group. Thus, both studies suggest that basal or compensatory changes in excitatory neurotransmission play roles in the pathophysiology of major depression.
American Journal of Psychiatry 04/2011; 168(7):727-34. · 14.72 Impact Factor