Kim Vang - Academia.edu (original) (raw)
Papers by Kim Vang
Journal of Cerebral Blood Flow & Metabolism, 2015
Acute nicotine administration stimulates [ 14 C]deoxyglucose trapping in thalamus and other regio... more Acute nicotine administration stimulates [ 14 C]deoxyglucose trapping in thalamus and other regions of rat brain, but acute effects of nicotine and smoking on energy metabolism have rarely been investigated in human brain by positron emission tomography (PET). We obtained quantitative PET measurements of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO 2 ) in 12 smokers who had refrained from smoking overnight, and in a historical group of nonsmokers, testing the prediction that overnight abstinence results in widespread, coupled reductions of CBF and CMRO 2 . At the end of the abstention period, global grey-matter CBF and CMRO 2 were both reduced by 17% relative to nonsmokers. At 15 minutes after renewed smoking, global CBF had increased insignificantly, while global CMRO 2 had increased by 11%. Regional analysis showed that CMRO 2 had increased in the left putamen and thalamus, and in right posterior cortical regions at this time. At 60 and 105 minutes after smoking resumption, CBF had increased by 8% and CMRO 2 had increased by 11-12%. Thus, we find substantial and global impairment of CBF/CMRO 2 in abstaining smokers, and acute restoration by resumption of smoking. The reduced CBF and CMRO 2 during acute abstention may mediate the cognitive changes described in chronic smokers.
Lecture Notes in Computer Science, 1998
Abstract. Brain surgery simulation requires a mathematical model of the geometric and elastic pro... more Abstract. Brain surgery simulation requires a mathematical model of the geometric and elastic properties of the entire brain. To allow for realtime manipulation of the model it is necessary to differentiate the level of accuracy between different subparts of the brain model. A Finite ...
Journal of Nuclear Medicine, 2015
We quantified the binding potentials (BP ND ) of [ 11 C]yohimbine binding in rat brain to alpha-2... more We quantified the binding potentials (BP ND ) of [ 11 C]yohimbine binding in rat brain to alpha-2 adrenoceptors to evaluate [ 11 C]yohimbine as an in vivo marker of noradrenergic neurotransmission and to examine its sensitivity to the level of noradrenaline. Dual [ 11 C]yohimbine dynamic positron emission tomography (PET) recordings were applied to five Sprague Dawley rats at baseline, followed by acute amphetamine administration (2 mg/kg) to induce elevation of the endogenous level of noradrenaline. The volume of distribution (V T ) of [ 11 C]yohimbine was obtained using Logan plot with arterial plasma input. Because alpha-2 adrenoceptors are distributed throughout the brain, the estimation of the BP ND is complicated by the absence of an anatomic region of no displaceable binding. We used the Inhibition plot to acquire the reference volume, V ND , from which we calculated the BP ND . Acute pharmacological challenge with amphetamine induced a significant decline of [ 11 C]yohimbine BP ND of~38% in all volumes of interest. The BP ND was greatest in the thalamus and striatum, followed in descending order by, frontal cortex, pons, and cerebellum. The experimental data demonstrate that [ 11 C]yohimbine binding is sensitive to a challenge known to increase the extracellular level of noradrenaline, which can benefit future PET investigations of pathologic conditions related to disrupted noradrenergic neurotransmission.
Frontiers in Behavioral Neuroscience, 2013
Dopaminergic medication for motor symptoms in Parkinson's disease (PD) recently has been linked w... more Dopaminergic medication for motor symptoms in Parkinson's disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [ 11 C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [ 11 C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG.
Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the br... more Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with 18 fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P ¼ 0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P ¼ 0.039) but not to the same extent in all regions (P ¼ 0.022). The unidirectional glucose transfer across the blood--brain barrier remained unchanged (P ¼ 0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P ¼ 0.013 and 0.017), leading to increased net clearance of the glucose tracer (P ¼ 0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia.
Radiotherapy and Oncology, 2009
Background: PET allows non-invasive mapping of tumor hypoxia, but the combination of low resoluti... more Background: PET allows non-invasive mapping of tumor hypoxia, but the combination of low resolution, slow tracer adduct-formation and slow clearance of unbound tracer remains problematic. Using a murine tumor with a hypoxic fraction within the clinical range and a tracer post-injection sampling time that results in clinically obtainable tumor-to-reference tissue activity ratios, we have analyzed to what extent inherent limitations actually compromise the validity of PET-generated hypoxia maps. Materials and methods: Mice bearing SCCVII tumors were injected with the PET hypoxia-marker fluoroazomycin arabinoside (FAZA), and the immunologically detectable hypoxia marker, pimonidazole. Tumors and reference tissue (muscle, blood) were harvested 0.5, 2 and 4 h after FAZA administration. Tumors were analyzed for global (well counter) and regional (autoradiography) tracer distribution and compared to pimonidazole as visualized using immunofluorescence microscopy. Results: Hypoxic fraction as measured by pimonidazole staining ranged from 0.09 to 0.32. FAZA tumor to reference tissue ratios were close to unity 0.5 h post-injection but reached values of 2 and 6 when tracer distribution time was prolonged to 2 and 4 h, respectively. A fine-scale pixel-by-pixel comparison of autoradiograms and immunofluorescence images revealed a clear spatial link between FAZA and pimonidazole-adduct signal intensities at 2 h and later. Furthermore, when using a pixel size that mimics the resolution in PET, an excellent correlation between pixel FAZA mean intensity and density of hypoxic cells was observed already at 2 h post-injection. Conclusions: Despite inherent weaknesses, PET-hypoxia imaging is able to generate quantitative tumor maps that accurately reflect the underlying microscopic reality (i.e., hypoxic cell density) in an animal model with a clinical realistic image contrast.
NeuroImage, 2008
Introduction: In-vivo binding of specific D 2 receptor tracers, like [ 11 C]raclopride, can be me... more Introduction: In-vivo binding of specific D 2 receptor tracers, like [ 11 C]raclopride, can be measured by a number of kinetic reference tissue models. The variation in the results of different models reflects differences and susceptibilities of the natural process of receptor binding. To what extent these methods can be trusted to numerically explain biological makeup is critical. The variability among the methods is in itself interesting. To investigate this phenomenon, we applied five kinetic models commonly used to determine binding potentials in [ 11 C]raclopride PET scans including the full reference tissue method (RTM) [1], the simplified reference tissue method (STRM) [2], ERLiBiRD [3], Logan-Ichise [4] and Logan Reference Tissue [5] plots. Our goal was to determine, if possible, a gold standard method to apply to clinical data.
![Research paper thumbnail of Age-related decline of dopamine D2/3 receptor availability measured with [11C]raclopride in non-striatal human brain regions: Comparison of four methods](https://attachments.academia-assets.com/45816798/thumbnails/1.jpg)
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NeuroImage, 2008
Introduction: In positron emission tomography (PET) studies of 14 cerebral blood flow (CBF) and m... more Introduction: In positron emission tomography (PET) studies of 14 cerebral blood flow (CBF) and metabolism, the large interindividual 15 variation commonly is minimized by normalization to the global mean 16
Journal of Neurochemistry, 2012
Recent studies suggest that L-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a sev... more Recent studies suggest that L-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a severe complication of conventional L-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT 1A agonist [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the L-DOPA-induced increase in extracellular DA and decrease in [ 11 C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to L-DOPA or a combination of L-DOPA and the 5-HT 1A agonist, 8-OHDPAT, with microdialysis, and determined [ 11 C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [ 11 C]raclopride at baseline and after two pharmacological challenges with L-DOPA + benserazide with or without 8-OHDPAT co-treatment. Identical challenge regimens were used with the subsequent microdialysis concomi-tant with ratings of LID severity. The baseline increase of [ 11 C]raclopride-binding potential (BP ND ) in lesioned striatum was eliminated by the L-DOPA challenge, while the concurrent administration of 8-OHDPAT prevented this L-DOPA-induced displacement of [ 11 C]raclopride significantly in lesioned ventral striatum and near significantly in the dorsal striatum. With microdialysis, the L-DOPA challenge raised the extracellular DA in parallel with the emergence of strong LID. Co-treatment with 8-OHDPAT significantly attenuated the release of extracellular DA and LID. The 8-OHDPAT co-treatment reversed the L-DOPA-induced decrease of [ 11 C]raclopride binding and increase of extracellular DA and reduced the severity of LID. The reversal of the effect of L-DOPA on [ 11 C]raclopride binding, extracellular DA and LID by 5-HT agonist administration is consistent with the notion that part of the DA increase associated with LID originates in serotonergic neurons. Keywords: 5-HT 1A receptor agonist, 6-hydroxydopamine, L-DOPA induced dyskinesia, micro-positron emission tomography and microdialysis, Parkinson's disease.
Journal of Cerebral Blood Flow & Metabolism, 2012
Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the br... more Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with 18 fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P ¼ 0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P ¼ 0.039) but not to the same extent in all regions (P ¼ 0.022). The unidirectional glucose transfer across the blood--brain barrier remained unchanged (P ¼ 0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P ¼ 0.013 and 0.017), leading to increased net clearance of the glucose tracer (P ¼ 0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia.
European Neuropsychopharmacology, 2010
Absent Skin Conductance Response (SCR) in pathological gambling (PG) may relate to dopaminergic m... more Absent Skin Conductance Response (SCR) in pathological gambling (PG) may relate to dopaminergic mechanisms. We recruited equal numbers of PG subjects and healthy control (HC) subjects, and then tested the claim that SCR is less conditioned by dopaminergic activity in PG subjects. During active gambling, SCR differed in PG and HC subjects (P b 0.05), but positron emission tomography revealed the same dopamine receptor availability. However, highly sensation-seeking (HS) PG subjects had lower dopamine receptor availability (P b 0.0001) in the baseline, compared to normal sensation-seeking (NS) PG subjects. We find that HS versus NS controls had the same observation of significant increase of binding potential (BP ND ) in high compared to normal sensation seekers. In both groups, PG and HC, highly sensation-seeking subjects had significant increase of receptor availability in striatum, compared to normally sensation-seeking subjects, separately (P b 0.05 and P = 0.02, respectively) and together (P b 0.0005). We conclude that SCR is less conditioned by dopaminergic activity in highly sensation-seeking subjects, regardless of PG status.
European Journal of Nuclear Medicine and Molecular Imaging, 2013
Tumour hypoxia is linked to treatment resistance. Positron emission tomography (PET) using hypoxi... more Tumour hypoxia is linked to treatment resistance. Positron emission tomography (PET) using hypoxia tracers such as fluoroazomycin arabinoside (FAZA) may allow identification of patients with hypoxic tumours and the monitoring of the efficacy of hypoxia-targeting treatment. Since hypoxia PET is characterized by poor image contrast, and tumour hypoxia undergoes spontaneous changes and is affected by therapy, it remains unclear to what extent PET scans are reproducible. Tumour-bearing mice are valuable in the validation of hypoxia PET, but identification of a reliable reference tissue value (blood sample or image-derived muscle value) for repeated scans may be difficult due to the small size of the animal or absence of anatomical information (pure PET). Here tumour hypoxia was monitored over time using repeated PET scans in individual tumour-bearing mice before and during fractionated radiotherapy. Mice bearing human SiHa cervix tumour xenografts underwent a PET scan 3 h following injection of FAZA on two consecutive days before initiation of treatment (baseline) and again following irradiation with four and ten fractions of 2.5 Gy. On the last scan day, mice were given an intraperitoneal injection of pimonidazole (hypoxia marker), tumours were collected and the intratumoral distribution of FAZA (autoradiography) and hypoxia (pimonidazole immunohistology) were determined in cryosections. Tissue section analysis revealed that the intratumoral distribution of FAZA was strongly correlated with the regional density of hypoxic (pimonidazole-positive) cells, even when necrosis was present, suggesting that FAZA PET provides a reliable measure of tumour hypoxia at the time of the scan. PET-based quantification of tumour tracer uptake relative to injected dose showed excellent reproducibility at baseline, whereas normalization using an image-derived nonhypoxic reference tissue (muscle) proved highly unreliable since a valid and reliable reference value could not be determined. The intratumoral distribution of tracer was stable at baseline as shown by a voxel-by-voxel comparison of the two scans (R = 0.82, range 0.72-0.90). During treatment, overall tracer retention changed in individual mice, but there was no evidence of general reoxygenation. Hypoxia PET scans are quantitatively correct and highly reproducible in tumour-bearing mice. Preclinical hypoxia PET is therefore a valuable and reliable tool for the development of strategies that target or modify hypoxia.
Diseases of the Colon & Rectum, 2011
This study aimed to test the hypothesis that sacral nerve stimulation affects afferent vagal proj... more This study aimed to test the hypothesis that sacral nerve stimulation affects afferent vagal projections to the central nervous system associated with frontal cortex activation in patients with fecal incontinence. Nine women and one man received temporary sacral nerve stimulation with permanent electrodes as a treatment for fecal incontinence. We used positron emission tomography to record indices of regional cerebral blood flow before and after 30 minutes of continuous stimulation. We repeated this procedure after 2 weeks of continued stimulation, before and 30 minutes after arrest of the stimulation. The initial stimulation activated a region of the contralateral frontal cortex that normally is active during focused attention. After 2 weeks of stimulation, this activation had been replaced by activity in parts of the ipsilateral caudate nucleus, a region of the brain thought to be specifically involved in learning and reward processing. Sacral nerve stimulation induces changes in cerebral activity consistent with an effect on afferent projections of the vagus. The initial activation of the frontal cortex may reflect focused attention, whereas the subsequent activation of the caudate nucleus may reflect recruitment of mechanisms involved in learning and reward processing. These changes may contribute to the improved continence, which is an acquired result of the stimulation.
Brain Research, 2009
Hyperoxic therapy for cerebral ischemia reduces cerebral blood flow (CBF) principally from the va... more Hyperoxic therapy for cerebral ischemia reduces cerebral blood flow (CBF) principally from the vasoconstrictive effect of oxygen on cerebral arterioles. Based on a recent study in normal volunteers, we now claim that the vasodilatory effect of carbon dioxide predominates when 5% CO 2 is added to inhaled oxygen (the mixture known as carbogen).
Acta Neurologica Scandinavica, 2012
Acta Anaesthesiologica Scandinavica, 2012
Background: General anaesthetics can alter the relationship between regional cerebral glucose met... more Background: General anaesthetics can alter the relationship between regional cerebral glucose metabolism rate (rGMR) and regional cerebral blood flow (rCBF). With the present study, we wanted to assess quantitatively the effects of propofol on rCBF and rGMR in the same healthy volunteers measured with positron emission tomography (PET). Methods: 15 O-labelled water and 18 F fluorodeoxyglucose were used as PET tracers to determine rCBF and rGMR, respectively, in eight healthy volunteers during the waking state (baseline) and during propofol anaesthesia. Propofol was titrated to keep a constant hypnotic depth (Bispectral Indes 35-40) throughout the anaesthesia. Changes in rGMR and rCBF were quantified using region-of-interest and voxel-based analyses. Results: The measured mean propofol concentration was 4.1 Ϯ 0.8 mg/ml during anaesthesia. Compared with the conscious state, total CBF and GMR decreased during the anaesthetic state with 47% and 54%, respectively. In the white and grey matter, rCBF and rGMR were reduced by 37% and 49%, and by 45% and 57%, respectively. Propofol decreased rCBF in all brain structures by 46-55% (P Յ 0.01) with highest significant decreases in the thalamus and parietal lobe. Regional GMR was reduced in all brain areas to 48-66% (P Յ 0.01) with highest significant reductions in the occipital lobe, the lingual gyrus, parietal lobe, temporal lobe and thalamus. No increases in rCBF or rGMR happened anywhere. Conclusions: General anaesthesia with propofol is associated with a global metabolic and vascular depression in the human brain, with significant shifts in regional blood flow and metabolism indicating marked metabolic and vascular responsiveness in some cortical areas and thalamus.
Acta Anaesthesiologica Scandinavica, 2010
The precise mechanism by which sevoflurane exerts its effects in the human brain remains unknown.... more The precise mechanism by which sevoflurane exerts its effects in the human brain remains unknown. In the present study, we quantified the effects of sevoflurane on regional cerebral glucose metabolism (rGMR) in the human brain measured with positron emission tomography. Eight volunteers underwent two dynamic 18F-fluorodeoxyglucose positron emission tomography (PET) scans. One scan assessed conscious-baseline metabolism and the other scan assessed metabolism during 1 minimum alveolar concentration (MAC) sevoflurane anaesthesia. Cardiovascular and respiratory parameters were monitored and bispectral index responses were registered. Statistical parametric maps and conventional regions of interest analysis were used to determine rGMR differences. All subjects were unconsciousness at 1.0 MAC sevoflurane. Cardiovascular and respiratory parameters were constant over time. In the awake state, rGMR ranged from 0.24 to 0.35 mumol/g/min in the selected regions. Compared with the conscious state, total GMR decreased 56% in sevoflurane anaesthesia. In white and grey matter, GMR was averaged 42% and 58% of normal, respectively. Sevoflurane reduced the absolute rGMR in all selected areas by 48-71% of the baseline (P< or = 0.01), with the most significant reductions in the lingual gyrus (71%), occipital lobe in general (68%) and thalamus (63%). No increases in rGMR were observed. Sevoflurane caused a global whole-brain metabolic reduction of GMR in all regions of the human brain, with the most marked metabolic suppression in the lingual gyrus, thalamus and occipital lobe.
Journal of Cerebral Blood Flow & Metabolism, 2015
Acute nicotine administration stimulates [ 14 C]deoxyglucose trapping in thalamus and other regio... more Acute nicotine administration stimulates [ 14 C]deoxyglucose trapping in thalamus and other regions of rat brain, but acute effects of nicotine and smoking on energy metabolism have rarely been investigated in human brain by positron emission tomography (PET). We obtained quantitative PET measurements of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO 2 ) in 12 smokers who had refrained from smoking overnight, and in a historical group of nonsmokers, testing the prediction that overnight abstinence results in widespread, coupled reductions of CBF and CMRO 2 . At the end of the abstention period, global grey-matter CBF and CMRO 2 were both reduced by 17% relative to nonsmokers. At 15 minutes after renewed smoking, global CBF had increased insignificantly, while global CMRO 2 had increased by 11%. Regional analysis showed that CMRO 2 had increased in the left putamen and thalamus, and in right posterior cortical regions at this time. At 60 and 105 minutes after smoking resumption, CBF had increased by 8% and CMRO 2 had increased by 11-12%. Thus, we find substantial and global impairment of CBF/CMRO 2 in abstaining smokers, and acute restoration by resumption of smoking. The reduced CBF and CMRO 2 during acute abstention may mediate the cognitive changes described in chronic smokers.
Lecture Notes in Computer Science, 1998
Abstract. Brain surgery simulation requires a mathematical model of the geometric and elastic pro... more Abstract. Brain surgery simulation requires a mathematical model of the geometric and elastic properties of the entire brain. To allow for realtime manipulation of the model it is necessary to differentiate the level of accuracy between different subparts of the brain model. A Finite ...
Journal of Nuclear Medicine, 2015
We quantified the binding potentials (BP ND ) of [ 11 C]yohimbine binding in rat brain to alpha-2... more We quantified the binding potentials (BP ND ) of [ 11 C]yohimbine binding in rat brain to alpha-2 adrenoceptors to evaluate [ 11 C]yohimbine as an in vivo marker of noradrenergic neurotransmission and to examine its sensitivity to the level of noradrenaline. Dual [ 11 C]yohimbine dynamic positron emission tomography (PET) recordings were applied to five Sprague Dawley rats at baseline, followed by acute amphetamine administration (2 mg/kg) to induce elevation of the endogenous level of noradrenaline. The volume of distribution (V T ) of [ 11 C]yohimbine was obtained using Logan plot with arterial plasma input. Because alpha-2 adrenoceptors are distributed throughout the brain, the estimation of the BP ND is complicated by the absence of an anatomic region of no displaceable binding. We used the Inhibition plot to acquire the reference volume, V ND , from which we calculated the BP ND . Acute pharmacological challenge with amphetamine induced a significant decline of [ 11 C]yohimbine BP ND of~38% in all volumes of interest. The BP ND was greatest in the thalamus and striatum, followed in descending order by, frontal cortex, pons, and cerebellum. The experimental data demonstrate that [ 11 C]yohimbine binding is sensitive to a challenge known to increase the extracellular level of noradrenaline, which can benefit future PET investigations of pathologic conditions related to disrupted noradrenergic neurotransmission.
Frontiers in Behavioral Neuroscience, 2013
Dopaminergic medication for motor symptoms in Parkinson's disease (PD) recently has been linked w... more Dopaminergic medication for motor symptoms in Parkinson's disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [ 11 C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [ 11 C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG.
Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the br... more Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with 18 fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P ¼ 0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P ¼ 0.039) but not to the same extent in all regions (P ¼ 0.022). The unidirectional glucose transfer across the blood--brain barrier remained unchanged (P ¼ 0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P ¼ 0.013 and 0.017), leading to increased net clearance of the glucose tracer (P ¼ 0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia.
Radiotherapy and Oncology, 2009
Background: PET allows non-invasive mapping of tumor hypoxia, but the combination of low resoluti... more Background: PET allows non-invasive mapping of tumor hypoxia, but the combination of low resolution, slow tracer adduct-formation and slow clearance of unbound tracer remains problematic. Using a murine tumor with a hypoxic fraction within the clinical range and a tracer post-injection sampling time that results in clinically obtainable tumor-to-reference tissue activity ratios, we have analyzed to what extent inherent limitations actually compromise the validity of PET-generated hypoxia maps. Materials and methods: Mice bearing SCCVII tumors were injected with the PET hypoxia-marker fluoroazomycin arabinoside (FAZA), and the immunologically detectable hypoxia marker, pimonidazole. Tumors and reference tissue (muscle, blood) were harvested 0.5, 2 and 4 h after FAZA administration. Tumors were analyzed for global (well counter) and regional (autoradiography) tracer distribution and compared to pimonidazole as visualized using immunofluorescence microscopy. Results: Hypoxic fraction as measured by pimonidazole staining ranged from 0.09 to 0.32. FAZA tumor to reference tissue ratios were close to unity 0.5 h post-injection but reached values of 2 and 6 when tracer distribution time was prolonged to 2 and 4 h, respectively. A fine-scale pixel-by-pixel comparison of autoradiograms and immunofluorescence images revealed a clear spatial link between FAZA and pimonidazole-adduct signal intensities at 2 h and later. Furthermore, when using a pixel size that mimics the resolution in PET, an excellent correlation between pixel FAZA mean intensity and density of hypoxic cells was observed already at 2 h post-injection. Conclusions: Despite inherent weaknesses, PET-hypoxia imaging is able to generate quantitative tumor maps that accurately reflect the underlying microscopic reality (i.e., hypoxic cell density) in an animal model with a clinical realistic image contrast.
NeuroImage, 2008
Introduction: In-vivo binding of specific D 2 receptor tracers, like [ 11 C]raclopride, can be me... more Introduction: In-vivo binding of specific D 2 receptor tracers, like [ 11 C]raclopride, can be measured by a number of kinetic reference tissue models. The variation in the results of different models reflects differences and susceptibilities of the natural process of receptor binding. To what extent these methods can be trusted to numerically explain biological makeup is critical. The variability among the methods is in itself interesting. To investigate this phenomenon, we applied five kinetic models commonly used to determine binding potentials in [ 11 C]raclopride PET scans including the full reference tissue method (RTM) [1], the simplified reference tissue method (STRM) [2], ERLiBiRD [3], Logan-Ichise [4] and Logan Reference Tissue [5] plots. Our goal was to determine, if possible, a gold standard method to apply to clinical data.
NeuroImage, 2008
Introduction: In positron emission tomography (PET) studies of 14 cerebral blood flow (CBF) and m... more Introduction: In positron emission tomography (PET) studies of 14 cerebral blood flow (CBF) and metabolism, the large interindividual 15 variation commonly is minimized by normalization to the global mean 16
Journal of Neurochemistry, 2012
Recent studies suggest that L-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a sev... more Recent studies suggest that L-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a severe complication of conventional L-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT 1A agonist [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the L-DOPA-induced increase in extracellular DA and decrease in [ 11 C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to L-DOPA or a combination of L-DOPA and the 5-HT 1A agonist, 8-OHDPAT, with microdialysis, and determined [ 11 C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [ 11 C]raclopride at baseline and after two pharmacological challenges with L-DOPA + benserazide with or without 8-OHDPAT co-treatment. Identical challenge regimens were used with the subsequent microdialysis concomi-tant with ratings of LID severity. The baseline increase of [ 11 C]raclopride-binding potential (BP ND ) in lesioned striatum was eliminated by the L-DOPA challenge, while the concurrent administration of 8-OHDPAT prevented this L-DOPA-induced displacement of [ 11 C]raclopride significantly in lesioned ventral striatum and near significantly in the dorsal striatum. With microdialysis, the L-DOPA challenge raised the extracellular DA in parallel with the emergence of strong LID. Co-treatment with 8-OHDPAT significantly attenuated the release of extracellular DA and LID. The 8-OHDPAT co-treatment reversed the L-DOPA-induced decrease of [ 11 C]raclopride binding and increase of extracellular DA and reduced the severity of LID. The reversal of the effect of L-DOPA on [ 11 C]raclopride binding, extracellular DA and LID by 5-HT agonist administration is consistent with the notion that part of the DA increase associated with LID originates in serotonergic neurons. Keywords: 5-HT 1A receptor agonist, 6-hydroxydopamine, L-DOPA induced dyskinesia, micro-positron emission tomography and microdialysis, Parkinson's disease.
Journal of Cerebral Blood Flow & Metabolism, 2012
Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the br... more Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with 18 fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P ¼ 0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P ¼ 0.039) but not to the same extent in all regions (P ¼ 0.022). The unidirectional glucose transfer across the blood--brain barrier remained unchanged (P ¼ 0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P ¼ 0.013 and 0.017), leading to increased net clearance of the glucose tracer (P ¼ 0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia.
European Neuropsychopharmacology, 2010
Absent Skin Conductance Response (SCR) in pathological gambling (PG) may relate to dopaminergic m... more Absent Skin Conductance Response (SCR) in pathological gambling (PG) may relate to dopaminergic mechanisms. We recruited equal numbers of PG subjects and healthy control (HC) subjects, and then tested the claim that SCR is less conditioned by dopaminergic activity in PG subjects. During active gambling, SCR differed in PG and HC subjects (P b 0.05), but positron emission tomography revealed the same dopamine receptor availability. However, highly sensation-seeking (HS) PG subjects had lower dopamine receptor availability (P b 0.0001) in the baseline, compared to normal sensation-seeking (NS) PG subjects. We find that HS versus NS controls had the same observation of significant increase of binding potential (BP ND ) in high compared to normal sensation seekers. In both groups, PG and HC, highly sensation-seeking subjects had significant increase of receptor availability in striatum, compared to normally sensation-seeking subjects, separately (P b 0.05 and P = 0.02, respectively) and together (P b 0.0005). We conclude that SCR is less conditioned by dopaminergic activity in highly sensation-seeking subjects, regardless of PG status.
European Journal of Nuclear Medicine and Molecular Imaging, 2013
Tumour hypoxia is linked to treatment resistance. Positron emission tomography (PET) using hypoxi... more Tumour hypoxia is linked to treatment resistance. Positron emission tomography (PET) using hypoxia tracers such as fluoroazomycin arabinoside (FAZA) may allow identification of patients with hypoxic tumours and the monitoring of the efficacy of hypoxia-targeting treatment. Since hypoxia PET is characterized by poor image contrast, and tumour hypoxia undergoes spontaneous changes and is affected by therapy, it remains unclear to what extent PET scans are reproducible. Tumour-bearing mice are valuable in the validation of hypoxia PET, but identification of a reliable reference tissue value (blood sample or image-derived muscle value) for repeated scans may be difficult due to the small size of the animal or absence of anatomical information (pure PET). Here tumour hypoxia was monitored over time using repeated PET scans in individual tumour-bearing mice before and during fractionated radiotherapy. Mice bearing human SiHa cervix tumour xenografts underwent a PET scan 3 h following injection of FAZA on two consecutive days before initiation of treatment (baseline) and again following irradiation with four and ten fractions of 2.5 Gy. On the last scan day, mice were given an intraperitoneal injection of pimonidazole (hypoxia marker), tumours were collected and the intratumoral distribution of FAZA (autoradiography) and hypoxia (pimonidazole immunohistology) were determined in cryosections. Tissue section analysis revealed that the intratumoral distribution of FAZA was strongly correlated with the regional density of hypoxic (pimonidazole-positive) cells, even when necrosis was present, suggesting that FAZA PET provides a reliable measure of tumour hypoxia at the time of the scan. PET-based quantification of tumour tracer uptake relative to injected dose showed excellent reproducibility at baseline, whereas normalization using an image-derived nonhypoxic reference tissue (muscle) proved highly unreliable since a valid and reliable reference value could not be determined. The intratumoral distribution of tracer was stable at baseline as shown by a voxel-by-voxel comparison of the two scans (R = 0.82, range 0.72-0.90). During treatment, overall tracer retention changed in individual mice, but there was no evidence of general reoxygenation. Hypoxia PET scans are quantitatively correct and highly reproducible in tumour-bearing mice. Preclinical hypoxia PET is therefore a valuable and reliable tool for the development of strategies that target or modify hypoxia.
Diseases of the Colon & Rectum, 2011
This study aimed to test the hypothesis that sacral nerve stimulation affects afferent vagal proj... more This study aimed to test the hypothesis that sacral nerve stimulation affects afferent vagal projections to the central nervous system associated with frontal cortex activation in patients with fecal incontinence. Nine women and one man received temporary sacral nerve stimulation with permanent electrodes as a treatment for fecal incontinence. We used positron emission tomography to record indices of regional cerebral blood flow before and after 30 minutes of continuous stimulation. We repeated this procedure after 2 weeks of continued stimulation, before and 30 minutes after arrest of the stimulation. The initial stimulation activated a region of the contralateral frontal cortex that normally is active during focused attention. After 2 weeks of stimulation, this activation had been replaced by activity in parts of the ipsilateral caudate nucleus, a region of the brain thought to be specifically involved in learning and reward processing. Sacral nerve stimulation induces changes in cerebral activity consistent with an effect on afferent projections of the vagus. The initial activation of the frontal cortex may reflect focused attention, whereas the subsequent activation of the caudate nucleus may reflect recruitment of mechanisms involved in learning and reward processing. These changes may contribute to the improved continence, which is an acquired result of the stimulation.
Brain Research, 2009
Hyperoxic therapy for cerebral ischemia reduces cerebral blood flow (CBF) principally from the va... more Hyperoxic therapy for cerebral ischemia reduces cerebral blood flow (CBF) principally from the vasoconstrictive effect of oxygen on cerebral arterioles. Based on a recent study in normal volunteers, we now claim that the vasodilatory effect of carbon dioxide predominates when 5% CO 2 is added to inhaled oxygen (the mixture known as carbogen).
Acta Neurologica Scandinavica, 2012
Acta Anaesthesiologica Scandinavica, 2012
Background: General anaesthetics can alter the relationship between regional cerebral glucose met... more Background: General anaesthetics can alter the relationship between regional cerebral glucose metabolism rate (rGMR) and regional cerebral blood flow (rCBF). With the present study, we wanted to assess quantitatively the effects of propofol on rCBF and rGMR in the same healthy volunteers measured with positron emission tomography (PET). Methods: 15 O-labelled water and 18 F fluorodeoxyglucose were used as PET tracers to determine rCBF and rGMR, respectively, in eight healthy volunteers during the waking state (baseline) and during propofol anaesthesia. Propofol was titrated to keep a constant hypnotic depth (Bispectral Indes 35-40) throughout the anaesthesia. Changes in rGMR and rCBF were quantified using region-of-interest and voxel-based analyses. Results: The measured mean propofol concentration was 4.1 Ϯ 0.8 mg/ml during anaesthesia. Compared with the conscious state, total CBF and GMR decreased during the anaesthetic state with 47% and 54%, respectively. In the white and grey matter, rCBF and rGMR were reduced by 37% and 49%, and by 45% and 57%, respectively. Propofol decreased rCBF in all brain structures by 46-55% (P Յ 0.01) with highest significant decreases in the thalamus and parietal lobe. Regional GMR was reduced in all brain areas to 48-66% (P Յ 0.01) with highest significant reductions in the occipital lobe, the lingual gyrus, parietal lobe, temporal lobe and thalamus. No increases in rCBF or rGMR happened anywhere. Conclusions: General anaesthesia with propofol is associated with a global metabolic and vascular depression in the human brain, with significant shifts in regional blood flow and metabolism indicating marked metabolic and vascular responsiveness in some cortical areas and thalamus.
Acta Anaesthesiologica Scandinavica, 2010
The precise mechanism by which sevoflurane exerts its effects in the human brain remains unknown.... more The precise mechanism by which sevoflurane exerts its effects in the human brain remains unknown. In the present study, we quantified the effects of sevoflurane on regional cerebral glucose metabolism (rGMR) in the human brain measured with positron emission tomography. Eight volunteers underwent two dynamic 18F-fluorodeoxyglucose positron emission tomography (PET) scans. One scan assessed conscious-baseline metabolism and the other scan assessed metabolism during 1 minimum alveolar concentration (MAC) sevoflurane anaesthesia. Cardiovascular and respiratory parameters were monitored and bispectral index responses were registered. Statistical parametric maps and conventional regions of interest analysis were used to determine rGMR differences. All subjects were unconsciousness at 1.0 MAC sevoflurane. Cardiovascular and respiratory parameters were constant over time. In the awake state, rGMR ranged from 0.24 to 0.35 mumol/g/min in the selected regions. Compared with the conscious state, total GMR decreased 56% in sevoflurane anaesthesia. In white and grey matter, GMR was averaged 42% and 58% of normal, respectively. Sevoflurane reduced the absolute rGMR in all selected areas by 48-71% of the baseline (P< or = 0.01), with the most significant reductions in the lingual gyrus (71%), occipital lobe in general (68%) and thalamus (63%). No increases in rGMR were observed. Sevoflurane caused a global whole-brain metabolic reduction of GMR in all regions of the human brain, with the most marked metabolic suppression in the lingual gyrus, thalamus and occipital lobe.