ORCID Profile
0000-0002-0257-9621
Current Organisations
University of Bern
,
Queensland University of Technology
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Publisher: Springer Science and Business Media LLC
Date: 11-07-2016
Publisher: Oxford University Press (OUP)
Date: 28-05-2019
DOI: 10.1093/BRAIN/AWZ133
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S0969-8051(00)00175-X
Abstract: Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new selective serotonin reuptake inhibitor, NS2456, to determine whether it is suited for use in PET. Racemic NS2456 [(1RS,5SR)-8-methyl-3-[4-trifluoromethoxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analog, racemic NS2463, selectively inhibited serotonin uptake in rat brain synaptosomes their IC(50) values were 3000-fold lower for [(3)H]serotonin than for either [(3)H]dopamine or [(3)H]noradrenaline. The enantiomers of NS2463 were also potent inhibitors of serotonin uptake in vitro, but they failed to show stereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabelled by N-methylation with C-11, yielding [(11)C]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood-brain barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potentials were relatively low and no stereoselectivity was found. Thus, neither racemic [(11)C]NS2456 nor its [(11)C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.BMC.2013.12.011
Abstract: Both enantiomers of the epibatidine analogue flubatine display high affinity towards the α4β2 nicotinic acetylcholine receptor (nAChR) in vitro, accompanied by negligible interactions with erse off-target proteins. Extended single dose toxicity studies in rodent indicated a NOEL (No Observed Effect Level) of 6.2μg/kg for (-)-flubatine and 1.55μg/kg for (+)-flubatine. We developed syntheses for both flubatine enantiomers and their corresponding precursors for radiolabeling. The newly synthesized trimethylammonium precursors allowed for highly efficient (18)F-radiolabelling in radiochemical yields >60% and specific activities >750GBq/μmol, thus making the radioligands practical for clinical investigation.
Publisher: Elsevier BV
Date: 03-2014
Publisher: Elsevier BV
Date: 09-1990
DOI: 10.1016/0006-2952(90)90402-7
Abstract: 9-Amino-1,2,3,4-tetrahydroacridine (THA), an inhibitor of acetylcholinesterase, has been proposed as a treatment for Alzheimer's disease on the basis of its ability to increase cerebral levels of acetylcholine. THA shares structural features with aminoquinoline compounds known to be inhibitors of histamine-N-methyltransferase (HNMT). THA was found to be a potent competitive inhibitor of rat brain HNMT in vitro, with a Ki of 35 nM with respect to both histamine and S-adenosyl-L-methionine, the co-substrate. Two hours after systemic administration of THA (5 and 10 mg/kg, i.p.), HNMT from rat brain was largely inhibited. The levels of histamine in striatum and cerebral cortex were elevated by this treatment. Thus, THA at moderate doses is able to alter histamine metabolism in the central nervous system.
Publisher: Wiley
Date: 17-04-2012
DOI: 10.1002/SYN.21558
Abstract: The condition of steady-state receptor binding in positron emission tomography (PET) studies is best obtained through the use of a bolus plus steady-infusion paradigm. This is a particularly important consideration in the context of in vivo competition studies, where a pharmacological challenge can be administered during the interval of steady-state ligand binding, as in the case of [¹¹C]-raclopride studies with hetamine challenge. However, the short half-life of ¹¹C imposes limits on the practical duration of constant infusions. Therefore, we chose to test [¹⁸F]-DMFP as a tracer for dopamine D₂/₃ receptors in rat striatum in the paradigm. Using a conventional bolus injection, the [¹⁸F]-DMFP BP(ND) was 3.8 in striatum of anesthetized rats. When followed by a constant infusion, we obtained quasi-stable BP(ND) estimates of 4.5 within an interval of 45 min. During infusions lasting up to 4 h, BP(ND) declined progressively. This seemed due to the progressive spill-in of radioactivity from the cranium to the cerebellum reference region, despite optimized iterative reconstruction of the images. Therefore, we propose a new concept of compensation for this spill-in effect using pharmacokinetic considerations, without requiring high-resolution anatomical images. Challenge with hetamine (1 and 4 mg/kg) evoked an ∼25% reduction in BP(ND) . There was no clear evidence of dose-dependence in the striatal-binding changes, despite the considerably greater physiological effect, as documented by ECG. Thus, the general applicability of the bolus plus infusion method with [¹⁸F]-DMFP for small animal studies is impeded by the substantial labeling of the cranium. The cranial uptake was linear, indicating first-order kinetics for the enzymatic defluorination of the tracer. Based on this phenomenon, we developed an analytic method compensating for the effects of progressive cranial labeling on the estimation of specific binding in striatum.
Publisher: Wiley
Date: 06-2002
DOI: 10.1111/J.1749-6632.2002.TB04184.X
Abstract: Perinatal anoxia/ischemia or premature birth increases the risk of developing attention deficit/hyperactivity disorder (ADHD). Brain imaging studies of idopathic ADHD reveal elevated dopamine transporter density in striatum of patients, predicting abnormal response to a challenge with methylphenidate in this population. We hypothesized that the severity of attention deficit in adolescents should correlate with the sensitivity to psychostimulant-evoked dopamine release. To test this hypothesis, we investigated six adolescent subjects (mean age 14.2 +/- 2.4 yr) with documented birth trauma and/or low birth weight and a diagnosis of ADHD. Using positron emission tomography (PET), we measured the relative binding of [(11)C]raclopride to dopamine receptors in striatum, first in the baseline condition and again after methylphenidate challenge at a therapeutic dose for ADHD (0.3 mg/kg, p.o.) in order to map the altered dopamine release evoked by the psychostimulant challenge. Neuropsychological measurements of impulsivity and inattention were also performed. We found a positive correlation between commission errors and the methylphenidate-evoked decrease in [(11)C]raclopride binding, thought to reflect the balance of dopamine release and reuptake. The greater the decline in the [(11)C]raclopride binding, the greater the ability of methylphenidate to block the reuptake of dopamine. As the ability to block the reuptake depends on the relative dopamine concentration, the result suggests that the impulsivity in these adolescents is associated with abnormally low extracellular dopamine concentration.
Publisher: Elsevier BV
Date: 09-1992
DOI: 10.1016/0006-2952(92)90133-4
Abstract: Histamine-N-methyltransferase (HNMT), the major enzyme for the metabolism of histamine in rat brain, is potently inhibited by 9-amino-1,2,3,4-tetrahydroacridine (tacrine). Structural fragments of tacrine were less potent inhibitors of rat brain HNMT than was tacrine itself. Harmaline and a number of other beta-carbolines inhibited HNMT with IC50 values in the range of 1-10 microM. HNMT inhibition by harmaline was competitive with respect to both substrates, S-adenosylmethionine and histamine (Ki = 1.4 microM). These findings are discussed in the context of mechanisms for HNMT inhibition.
Publisher: Oxford University Press (OUP)
Date: 05-2012
DOI: 10.1017/S1461145712000764
Abstract: Previous positron emission tomography (PET) studies employing competition paradigms have shown either no change or substantial declines in striatal [11C]-raclopride binding after challenge with psychotogenic doses of the N-methyl-d-aspartate antagonist ketamine. We sought to probe the relationship between the severity of ketamine-induced psychotic symptoms and altered dopamine D2/3 receptor availability throughout brain using the high affinity ligand [18F]-fallypride (FP). PET recordings were obtained in a group of 10 healthy, young male volunteers, in a placebo condition, and in the course of an infusion with ketamine at a psychotomimetic dose. Administration of the Positive and Negative Syndrome Scale and the Thought and Language Index in both conditions revealed a substantial emergence of mainly negative symptoms of schizophrenia, persisting until the end of the 3 h PET recordings. The baseline FP binding in cortex, caudate nucleus and other brain regions was highly predictive of the in idual severity of psychotic symptoms in the ketamine condition. However, there was no evidence of ketamine-evoked reductions in FP binding. In the context of earlier findings, we speculate that high baseline D2/3-receptor availability may impart benefits with regard to cognitive flexibility, but increases the risk of maladaptive information processing in the face of environmental stresses and challenges.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2012
DOI: 10.1007/S12350-012-9663-1
Abstract: To measure left ventricular (LV) function parameters in heart of healthy rats by three different positron emission tomography (PET) imaging techniques and by magnetic resonance imaging (MRI). ECG-gated microPET examinations were obtained in seven healthy rats with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) for calculation of LV-function from the blood-pool phase of the dynamic recording (FDGBP), and also from the later myocardial uptake (FDGMyo). On subsequent days, we re-measured LV-function using the novel blood-pool tracer (68)Ga-albumin (AlbBP) and again by FDG (FDGMyo2) in one setting. Cine-MRI examination provided the reference standard measurement. The mean LV ejection fractions (LVEF) were 56 ± 3 (FDGBP), 55 ± 3 (FDGMyo), 56 ± 3 (FDGMyo2), 57 ± 3 (AlbBP), and 57 ± 2 (MRI). There were good to excellent correlations found between the LVEF-values as compared to MRI reference standard for FDGBP (r = 0.71), FDGMyo (r = 0.86) and AlbBP (r = 0.88). Both of the blood-pool methods significantly overestimated the magnitudes of end-diastolic-volume and end-systolic-volume, whereas FDGMyo matched closely to the MRI reference standard. There was no significant bias for both blood-pool methods and a minor negative bias for FDGMyo regarding the LV ejection fraction (LVEF) when compared to cine-MRI results. There was no significant difference between the means of FDGMyo and FDGMyo2 (P = .50). Relative to reference standard MRI measurements of LVEF, there was excellent agreement between PET-based measurements, notably for the novel blood-pool tracer (68)Ga-albumin.
Publisher: Elsevier BV
Date: 07-2004
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.JNS.2011.09.010
Abstract: Decreased activity of the mitochondrial electron transport chain (ETC) has been implicated in the pathogenesis of Parkinson's disease (PD). This model would most likely predict a decrease in the rate of cerebral oxygen consumption (CMRO(2)). To test this hypothesis, we compared CMRO(2) and cerebral blood flow (CBF) PET scans from PD patients and healthy controls. Nine early-stage PD patients and 15 healthy age-matched controls underwent PET scans for quantitative mapping of CMRO(2) and CBF. Between-group differences were evaluated for absolute data and intensity-normalized values. No group differences were detected in regional magnitudes of CMRO(2) or CBF. Upon normalization using the reference cluster method, significant relative CMRO(2) decreases were evident in widespread prefrontal, parieto-occipital, and lateral temporal regions. Sensory-motor and subcortical regions, brainstem, and the cerebellum were spared. A similar pattern was evident in normalized CBF data, as described previously. While the data did not reveal substantially altered absolute CMRO(2) in brain of PD patients, employing data-driven intensity normalization revealed widespread relative CMRO(2) decreases in cerebral cortex. The detected pattern was very similar to that reported in earlier CBF and CMRglc studies of PD, and in the CBF images from the same subjects. Thus, the present results are consistent with the occurrence of parallel declines in CMRO(2), CBF, and CMRglc in spatially contiguous cortical regions in early PD, and support the hypothesis that ETC dysfunction could be a primary pathogenic mechanism in early PD.
Publisher: Society of Nuclear Medicine
Date: 16-09-2010
DOI: 10.2967/JNUMED.110.078451
Abstract: Data collection in preclinical small-animal PET studies has been hindered by the small number of recordings typically obtained for a single radiosynthesis. Therefore, we tested procedures for obtaining 8 simultaneous small-animal PET recordings from the brains of 8 mice using an acrylic anesthesia distributor (the Octamouse), with the dopamine D(2/3) ligand (18)F-fallypride serving as a test substance for brain receptor imaging. The effect of scatter correction on the small-animal PET recordings was first evaluated in phantom studies in which sources of different radioactivity concentration were placed within the chambers of the Octamouse. Next, potential effects of mass on the (18)F-fallypride binding potential (BP(ND)) in the striatum were tested in groups of mice receiving (18)F-fallypride at 2 different specific activities (140 and 50 GBq/μmol), with and without scatter correction. Finally, the relationship between BP(ND) and injected dose of (18)F-fallypride (3.5-17 MBq/mouse) was tested. Scatter correction improved the contrast between sources and air space within the Octamouse phantom. The magnitude of (18)F-fallypride BP(ND) in mouse striatum was invariant across the tested range of specific activities, and scatter correction increased BP(ND) by a mean of 6% covariances of the inter- and intraoperator variability of BP(ND) were 10%. There was a positive correlation between radiochemical dose and BP(ND) with (R(2) = 0.53) and without (R(2) = 0.63) scatter correction, which was driven by increasing area under the percentage injected dose curve in the striatum. The quantitation of emission sources placed within the Octamouse is linear over a wide range of source activities. In the striatum of living mice, the magnitude of (18)F-fallypride BP(ND) was highly reproducible between operators and was constant over a 3-fold range of specific activities, indicating a lack of significant occupancy. Scatter correction improved quantitation but did not entirely correct for the dependence of BP(ND) on injected dose, which was deemed to arise because of effects propagating from detector dead time when the total radiochemical dose in the field of view exceeded 50 MBq. Given this consideration, we were still able to quantify (18)F-fallypride BP(ND) in 16 mice from a single radiosynthesis, an economy that should be generalizable to brain studies of erse radioligands.
Publisher: MDPI AG
Date: 30-04-2022
DOI: 10.3390/MOLECULES27092863
Abstract: 6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels–Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors.
Publisher: SAGE Publications
Date: 11-07-2011
Abstract: We report about a clinical observation in a well-characterized group of patients with obsessive–compulsive disorder (OCD) during an experimental medicine study in which a single dose of amisulpride (a selective D 2/3 antagonist) was administered. Almost half of the OCD patients, in particular those with less severe obsessive–compulsive symptoms, experienced acute akathisia in response to the amisulpride challenge. This unexpectedly high incidence of akathisia in the selective serotonin reuptake inhibitor (SSRI)-treated patients with OCD suggests that in idual differences in dopamine–serotonin interactions underlie the clinical heterogeneity of OCD, and may thus explain the insufficiency of SSRI monotherapy in those patients not experiencing a satisfactory outcome in symptom reduction. We further speculate about the neuropathology possibly underlying this clinical observation and outline a testable hypothesis for future molecular imaging studies.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2011
DOI: 10.1007/S00259-011-1882-1
Abstract: Hypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer's disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippoc al formation. Here, we explored the association between microstructural alterations within the hippoc us and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment. Twenty patients with early AD (Mini-Mental State Examination 25.7 ± 1.7) were studied with [(18)F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippoc us, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test for unique contributions of diffusivity and metabolic indices in the prediction of memory function. Diffusivity in the left anterior hippoc us negatively correlated with FDG uptake primarily in the left anterior hippoc us, parahippoc al gyrus and the PCC (p < 0.005). The same correlation pattern was found for right hippoc al diffusivity (p < 0.05). In linear regression analysis, left anterior hippoc al diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippoc al diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD. These findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippoc al output pathways as a significant contributor to the genesis of episodic memory impairment.
Publisher: Wiley
Date: 2000
Publisher: Wiley
Date: 10-1993
DOI: 10.1111/J.1471-4159.1993.TB13651.X
Abstract: L-DOPA is a large neutral amino acid subject to transport out of, as well as into, brain tissue. Competition between dopamine synthesis and L-DOPA egress from striatum must favor L-DOPA egress if decarboxylation declines relatively more than transport in Parkinson's disease. To test this hypothesis, we injected patients with Parkinson's disease with a radiolabeled analogue of L-DOPA and recorded regional brain radioactivity as a function of time by means of positron emission tomography. We simultaneously estimated the activity of the decarboxylating enzyme and the amino acid transport. In the striatum of patients, we found the L-DOPA decarboxylase activity to be reduced in the head of the caudate nucleus and the putamen. However, the rate of egress of the DOPA analogue was unaffected by the disease and thus inhibited dopamine synthesis more than predicted in the absence of L-DOPA egress.
Publisher: Wiley
Date: 24-09-2014
DOI: 10.1002/SYN.21785
Abstract: The efficient radiosynthesis for the MAO-A ligand [(18) F]fluoroethyl-harmol is reported. Initial PET examinations reveal the ligand to be retained throughout rat brain during 90 min, whereas pretreatment with pargyline results in substantially increased washout, from which binding potentials in the range of 1.4-2.1 can be calculated.
Publisher: American Chemical Society (ACS)
Date: 29-02-2008
DOI: 10.1021/JM701378E
Abstract: ( R)-(-)- and ( S)-(+)-1-(1-[ (11)C]methyl-1 H-pyrrol-2-yl)-2-phenyl-2-(1-pyrrolidinyl)ethanone 4 and 5 were synthesized, and their properties as tracers for positron emission tomography (PET) studies of monoamine oxidase type A (MAO-A) in the brain of living pigs were tested. Parametric maps of the distribution volume ( V d) 4 in pig brain were qualitatively similar to those obtained with [ (11)C]harmine, with prominent binding in the ventral forebrain and mesencephalon. Its binding was highly vulnerable to MAO blockade, suggesting a binding potential as high as 2 for MAO-A sites. The slow plasma metabolism of 4 and 5 may present advantages over [ (11)C]harmine for routine PET studies of MAO-A.
Publisher: Wiley
Date: 09-1995
DOI: 10.1046/J.1471-4159.1995.65031381.X
Abstract: To test the hypothesis that L-DOPA decarboxylase (DDC) is a regulated enzyme in the synthesis of dopamine (DA), we developed a model of the cerebral uptake and metabolism of [3H]DOPA. The unidirectional blood-brain clearance of [3H]DOPA (K1D) was 0.049 ml g-1 min-1. The relative DDC activity (k3D) was 0.26 min-1 in striatum, 0.04 min-1 in hypothalamus, and 0.02 min-1 in hippoc us. In striatum, 3,4-[3H]dihydroxyphenylacetic acid ([3H]DOPAC) was formed from [3H]DA with a rate constant of 0.013 min-1, [3H]homovanillic acid ([3H]HVA) was formed from [3H]DOPAC at a rate constant of 0.020 min-1, and [3H]HVA was eliminated from brain at a rate constant of 0.037 min-1. Together, these rate constants predicted the ratios of endogenous DOPAC and HVA to DA in rat striatum. Pargyline, an inhibitor of DA catabolism, substantially reduced the contrast between striatum and cortex, in comparison with the contrast seen in autoradiograms of control rats. At 30 min and at 4 h after pargyline, k3D was reduced by 50% in striatum and olfactory tubercle but was unaffected in hypothalamus, indicating that DDC activity is reduced in specific brain regions after monoamine oxidase inhibition. Thus, DDC activity may be a regulated step in the synthesis of DA.
Publisher: SAGE Publications
Date: 29-09-2009
Abstract: [ 18 F]Fluoro-3,4-dihydroxyphenyl-L-alanine (FDOPA) was one of the first successful tracers for molecular imaging by positron emission tomography (PET), and has proven immensely valuable for studies of Parkinson’s disease. Following intravenous FDOPA injection, the decarboxylated metabolite [ 18 F] fluorodopamine is formed and trapped within terminals of the nigrostriatal dopamine neurons reduction in the simple ratio between striatum and cerebellum is indicative of nigrostriatal degeneration. However, the kinetic analysis of dynamic FDOPA-PET recordings is formidably complex due to the entry into brain of the plasma metabolite O-methyl-FDOPA and due to the eventual washout of decarboxylated metabolites. Linear graphical analysis relative to a reference tissue input function is popular and convenient for routine clinical studies in which serial arterial blood s les are unavailable. This simplified approach has facilitated longitudinal studies in large patient cohorts. Linear graphical analysis relative to the metabolite-corrected arterial FDOPA input yields a more physiological index of FDOPA utilization, the net blood-brain clearance. Using a constrained compartmental model, FDOPA-PET recordings can be used to calculate the relative activity of the enzyme DOPA decarboxylase in living brain. We have extended this approach so as to obtain an index of steady-state trapping of [ 18 F]fluorodopamine in synaptic vesicles. Although simple methods of image analysis are sufficient for the purposes of routine clinical studies, the more complex approaches have revealed hidden aspects of brain dopamine in personality, healthy aging, and in the pathophysiologies of Parkinson’s disease and schizophrenia.
Publisher: Wiley
Date: 26-12-2014
DOI: 10.1111/EJN.12802
Publisher: Society of Nuclear Medicine
Date: 17-03-2010
DOI: 10.2967/JNUMED.109.071811
Abstract: We evaluated the utility of the selective dopamine D(2/3) receptor ligand (18)F-desmethoxyfallypride ((18)F-DMFP) for the differential diagnosis of patients with idiopathic parkinsonian syndrome (IPS) and nonidiopathic parkinsonian syndrome (non-IPS). On the basis of the superior sensitivity of PET, we hypothesized that (18)F-DMFP should have properties for the differential diagnosis of these syndromes superior to what has been reported for the more conventional SPECT procedures. A series of 81 patients with parkinsonism (26 women, 55 men mean age +/- SD, 68 +/- 11 y) were included in this retrospective analysis. A 30-min (18)F-DMFP PET recording was acquired starting 1 h after injection of the tracer (180-200 MBq, intravenously). The specific binding (SB) in isions of the striatum was calculated relative to the occipital cortex using an observer-independent semiautomatic volume-of-interest-based technique. The optimal SB threshold was defined by means of receiver-operating-characteristic analysis, which was also used for the evaluation of the diagnostic performance of SB, ratios between striatal subregions, and absolute asymmetries in SB. Significant differences (P < 0.001) were found in striatal SB between IPS and non-IPS, most notably in the posterior putamen, for which the diagnostic power for discrimination of IPS and non-IPS was the highest (sensitivity, 87% specificity, 96% and accuracy, 91%). A further gain of diagnostic power (sensitivity, 92% specificity, 96% and accuracy, 94%) was obtained through discriminant analysis combining 3 parameters: SB of the posterior putamen, the posterior-to-anterior putamen ratio, and the posterior putamen-to-caudate ratio. (18)F-DMFP PET is useful for the differential diagnosis of IPS and non-IPS in patients with parkinsonism. The findings are consistent with relative sparing of D(2/3) receptors in the dopamine-denervated putamen of IPS patients, in contrast to a more substantial loss of striatal dopamine receptors in non-IPS patients. The PET procedure for this differential diagnosis was superior to the reported experience with (123)I-iodobenzamide SPECT.
Publisher: Springer Science and Business Media LLC
Date: 23-10-2013
DOI: 10.1007/S00213-013-3308-1
Abstract: Molecular imaging studies with positron emission tomography have revealed that the availability of serotonin transporter (5-HTT) in the human brain fluctuates over the course of the year. This effect is most pronounced in carriers of the short allele of the 5-HTT promoter region (5-HTTLPR), which has in several previous studies been linked to an increased risk to develop mood disorders. We argue that long-lasting fluctuations in the cerebral serotonin transmission, which is regulated via the 5-HTT, are responsible for mediating responses to environmental changes based on an assessment of the expected "safety" of the environment this response is obtained in part through serotonergic modulation of the hypothalamic-pituitary-adrenal (HPA) axis. We posit that the intermediate phenotype of the s-allele may properly be understood as mediating a trade-off, wherein increased responsiveness of cerebral serotonin transmission to seasonal and other forms of environmental change imparts greater behavioral flexibility, at the expense of increased vulnerability to stress. This model may explain the somewhat higher prevalence of the s-allele in some human populations dwelling at geographic latitudes with pronounced seasonal climatic changes, while this hypothesis does not rule out that genetic drift plays an additional or even exclusive role. We argue that s-allele manifests as an intermediate phenotype in terms of an increased responsiveness of the 5-HTT expression to number of daylight hours, which may serve as a stable surrogate marker of other environmental factors, such as availability of food and safety of the environment in populations that live closer to the geographic poles.
Publisher: MDPI AG
Date: 07-2022
Abstract: Traumatic brain injury (TBI) has come to be recognized as a risk factor for Alzheimer’s disease (AD), with poorly understood underlying mechanisms. We hypothesized that a history of TBI would be associated with greater tau deposition in elders with high-risk for dementia. A Groups of 20 participants with self-reported history of TBI and 100 without any such history were scanned using [18F]-AV1451 positron emission tomography as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Scans were stratified into four groups according to TBI history, and by clinical dementia rating scores into cognitively normal (CDR = 0) and those showing cognitive decline (CDR ≥ 0.5). We pursued voxel-based group comparison of [18F]-AV1451 uptake to identify the effect of TBI history on brain tau deposition, and for voxel-wise correlation analyses between [18F]-AV1451 uptake and different neuropsychological measures and cerebrospinal fluid (CSF) biomarkers. Compared to the TBI-/CDR ≥ 0.5 group, the TBI+/CDR ≥ 0.5 group showed increased tau deposition in the temporal pole, hippoc us, fusiform gyrus, and inferior and middle temporal gyri. Furthermore, the extent of tau deposition in the brain of those with TBI history positively correlated with the extent of cognitive decline, CSF-tau, and CSF-amyloid. This might suggest TBI to increase the risk for tauopathies and Alzheimer’s disease later in life.
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.NEUROIMAGE.2009.05.040
Abstract: In a recent issue of NeuroImage, we presented evidence that biased global mean (GM) normalization of brain PET data can generate the appearance of subcortical foci with relative hypermetabolism in patients with Parkinson's disease (PD), and other degenerative disorders. In a commentary to our article, Ma and colleagues presented a study seeking to establish that a pattern of widespread hypermetabolism, known as the Parkinson's disease related pattern (PDRP) is a genuine metabolic feature of PD. In the present paper, we respond to the arguments presented by Ma et al., and we provide a critical reappraisal of the evidence for the existence of the PDRP. To this end, we present new analyses of PET data sets, which demonstrate that very similar patterns of relative subcortical increases are seen in PD, Alzheimer's disease, hepatic encephalopathy, healthy aging, and simulation data. Furthermore, longitudinal studies of PD previously reported relative hypermetabolism in very small anatomical structures such as the subthalamic nucleus. We now demonstrate how focal hypermetabolism attributed to small nuclei can similarly arise as a consequence of GM normalization. Finally, we give a comprehensive summary of the entire deoxyglucose autoradiography literature on acquired parkinsonism in experimental animals. Based on this evidence, we conclude that (1) there is no quantitative evidence for widespread subcortical hypermetabolism in PD, (2) very similar patterns of subcortical hyperactivity are evident in various other brain disorders whenever GM normalization is utilized, and (3) the PDRP is not evident in animal models of PD. In the absence of quantitative evidence for the PDRP, our alternative interpretation of normalization bias seems the more parsimonious explanation for the reports of relative hypermetabolism in PD.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 17-11-2010
DOI: 10.1007/S11307-010-0439-1
Abstract: This study investigates the effects of (111)In-oxine incorporation on human mesenchymal stem cells' (hMSC) biology and viability, and the applicability of (111)In-oxine for single-photon emission computed tomography/X-ray computed tomography (SPECT/CT) monitoring of hMSC in vivo. HMSC were labelled with 10 Bq/cell. Cellular retention of radioactivity, cell survival, and migration were evaluated over 48 h. Metabolic activity was assessed over 14 days and the hMSC's stem cell character was evaluated. Serial SPECT/CT was performed after intra-osseous injection to athymic rats over 48 h. Labelling efficiency was 25%, with 61% of incorporated (111)In remaining in the hMSC at 48 h. The radiolabelling was without effect on cell viability, stem cell character, and plasticity, whereas metabolic activity and migration were significantly reduced. Grafted cells could be imaged in situ with SPECT/CT. (111)In-oxine labelling moderately impaired hMSC's functional integrity while preserving their stem cell character. Combined SPECT/CT imaging of (111)In-oxine-labelled hMSC opens the possibility for non-invasive sequential monitoring of therapeutic stem cells.
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.NUCMEDBIO.2006.04.006
Abstract: Very few tracers are available for imaging studies of second messenger systems. We developed a radiosynthesis for the phosphodiesterase (PDE) 5 inhibitor [(11)C]RAL-01. Whole body distribution studies using positron emission tomography (PET) revealed a time-dependant passage through the liver and accumulation of radioactivity in the bile of the Landrace pig. Displaceable binding was readily discerned in the myocardium, and traces of binding were seen in pulmonary tissue, consistent with the use of this class of drug in the treatment of pulmonary hypertension and heart failure. [(11)C]RAL-01 readily entered the brain and obtained an equilibrium distribution volume of 4-5 ml g(-1). Mean parametric images suggested the presence of a small displaceable binding component, but this binding was not significant in the present group of three pigs. Thus, [(11)C]RAL-01 shows considerable promise for PET studies of biliary elimination and of PDE5 binding in the cardiovascular system. However, analogues of higher affinity may be required for investigations of central nervous system binding sites.
Publisher: Wiley
Date: 06-2002
DOI: 10.1111/J.1749-6632.2002.TB04185.X
Abstract: The ternary complex model of G-protein-linkage to receptors holds that agonists increase the affinity of the receptors for the G protein. Consequently, an agonist can exert the greatest inhibition of the binding of radioligands which are also agonists. We hypothesized that competition from endogenous dopamine in striatum of living mice should thus have a greater effect on the binding of the D(2,3) agonist N-[(3)H]propylnorapomorphine ([(3)H]NPA), than on the binding of the D(2,3) antagonist [(11)C]raclopride in living brain. The binding potential (p(B(0))), defined as the ratio of bound-to-unbound ligand after reserpine treatment, was measured in mouse striatum for [(11)C]raclopride (p(B(0))(RAC)(C)) = 8.5, and for [(3)H]NPA(p(B(0))(NPA)) = 5.3. Relative to these baseline values after dopamine depletion, saline-treatment decreased the p(B) of [(3)H]NPA by one-half, while the p(B) of [(11)C]raclopride declined by only one-third. Amphetamine decreased the p(B) of [(3)H]NPA to a greater extent than that of [(11)C]raclopride. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and declined to a value 1.66 times greater for [(3)H]NPA than for [(11)C]raclopride at its highest occupancies. Thus, the agonist binding was more sensitive than antagonist binding to competition from endogenous dopamine. Dopamine agonist ligands may be especially useful for PET studies of dopamine receptor occupancy by endogenous synaptic dopamine. Analysis of the effect of dopamine occupancy on the inhibition of agonist indicated a limited supply of G protein, with a maximum ternary complex fraction of 40% of maximum antagonist binding capacity.
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S0969-8051(02)00448-1
Abstract: The binding of radioligand agonists to dopamine receptors in living brain can be informative about the abundance of receptors which are coupled to intracellular second messenger systems. Therefore, we developed a radiosynthesis for the dopamine D(2,3) partial agonist (R)-N- [1-(11)C]n-propylnorapomorphine ([(11)C]NPA). The uptake of this tracer in brain of anesthetized Göttingen miniature pigs was recorded by positron emission tomography (PET) and analyzed by compartmental analysis using the metabolite-corrected arterial input, and using reference tissue methods. [(11)C]NPA had a blood-brain unidirectional clearance of approximately 0.35 ml g(-1) min(-1) and an apparent distribution volume of 6 ml g(-1) in cerebellum. The ligand had a binding potential of 1.5 in striatum, comparable to that reported previously for the receptor antagonist [(11)C]raclopride in the same strain of animals. Significant binding was detected in the hypophysis, thalamus, and medial forebrain bundle. The binding in striatum was of comparable magnitude in normal pigs and in pigs with a documented 50% dopamine depletion produced by MPTP-intoxication. Deep brain stimulation of the subthalamus was without conspicuous effect on the binding of [(11)C]NPA in vivo. Results of this preliminary study indicate that this tracer meets many requirements for assaying dopamine agonist binding sites by PET.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2013
DOI: 10.1007/S10554-013-0254-2
Abstract: To evaluate the prognostic significance of combined myocardial perfusion SPECT and [18F]FDG PET viability scanning for the prediction of survival in patients with ischemic cardiomyopathy (iCMP) and left ventricular dysfunction. 244 patients (64.0 ± 10.6 years, 86 % men) with iCMP and LVEF ≤ 45 % underwent SPECT/PET. Percent scar tissue and SPECT/PET-mismatch (%-mismatch) were calculated and correlated with event-free survival according to the type of therapy (medical therapy with/out revascularization) provided after imaging. Death from any cause was defined as the primary endpoint. Early revascularization (ER) was performed in 113/244 (46 %) patients within 32 ± 52 days (26 bypass surgeries and 87 percutaneous coronary interventions). 65 patients died during follow-up for a median of 33 months. Kaplan-Meier analysis showed that those patients with ≥ 5 % mismatch not undergoing ER had significantly higher mortality than did the group with similar mismatch who did receive ER. Cox analysis identified both SPECT/PET-mismatch and the interaction of SPECT/PET-mismatch with ER as independent predictors for death due to all causes. A threshold of ≥ 5 % SPECT/PET-mismatch predicted best which patients with iCMP and LV dysfunction would benefit from ER in terms of long-term survival.
Publisher: Society of Nuclear Medicine
Date: 18-06-2013
Publisher: Wiley
Date: 16-10-2017
DOI: 10.1111/JNC.13370
Abstract: We investigated [(18)F]fluoroethyl-harmol ([(18)F]FEH) as a reversible and selective ligand for positron emission tomography (PET) studies of monoamine oxidase A (MAO-A). Binding of [(18)F]FEH in rat brain cryostat sections indicated high affinity (KD = 3 nM), and density (Bmax 600 pmol/g). The plasma free fraction was 45%, and untransformed parent constituted only 13% of plasma radioactivity at 10 min after injection. Compartmental analysis of PET recordings in pargyline-treated rats showed high permeability to brain (K1 0.32 mL/g/min) and slow washout (k2 0.024/min), resulting in a uniformly high equilibrium distribution volume (VD 20 mL/g). Using this VD to estimate unbound ligand in brain of untreated rats, the binding potential ranged from 4.2 in cerebellum to 7.2 in thalamus. We also calculated maps of rats receiving [(18)F]FEH at a range of specific activities, and then estimated saturation binding parameters in the living brain. In thalamus, striatum and frontal cortex KD was globally close to 300 nM and Bmax was close to 1600 pmol/g the 100-fold discrepancy in affinity suggests a very low free fraction for [(18)F]FEH in the living brain. Based on a synthesis of findings, we calculate the endogenous dopamine concentration to be 0.4 μM in the striatal compartment containing MAO-A, thus unlikely to exert competition against [(18)F]FEH binding in vivo. In summary, [(18)F]FEH has good properties for the detection of MAO-A in the rat brain by PET, and may present logistic advantages for clinical research at centers lacking a medical cyclotron. We made a compartmental analysis of [(18)F]fluoroethylharmol ([(18)F]FEH) binding to monoamine oxidase A (MAO-A) in living rat brain and estimated the saturation binding parameters from the binding potential (BPND). The Bmax was of comparable magnitude to that in vitro, but with apparent affinity (300 nM), it was 100-fold lower in vivo. PET imaging with [(18) F]FEH is well suited for quantitation of MAO-A in living brain.
Publisher: SAGE Publications
Date: 19-12-2017
Abstract: The first phase of molecular brain imaging of microglial activation in neuroinflammatory conditions began some 20 years ago with the introduction of [ 11 C]-( R)-PK11195, the prototype isoquinoline ligand for translocator protein (18 kDa) (TSPO). Investigations by positron emission tomography (PET) revealed microgliosis in numerous brain diseases, despite the rather low specific binding signal imparted by [ 11 C]-( R)-PK11195. There has since been enormous expansion of the repertoire of TSPO tracers, many with higher specific binding, albeit complicated by allelic dependence of the affinity. However, the specificity of TSPO PET for revealing microglial activation not been fully established, and it has been difficult to judge the relative merits of the competing tracers and analysis methods with respect to their sensitivity for detecting microglial activation. We therefore present a systematic comparison of 13 TSPO PET and single photon computed tomography (SPECT) tracers belonging to five structural classes, each of which has been investigated by compartmental analysis in healthy human brain relative to a metabolite-corrected arterial input. We emphasize the need to establish the non-displaceable binding component for each ligand and conclude with five recommendations for a standard approach to define the cellular distribution of TSPO signals, and to characterize the properties of candidate TSPO tracers.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.EURONEURO.2005.10.008
Abstract: Previously, we used positron emission tomography (PET) for studying the pharmacokinetics of rac-[11C]mirtazapine in living brain. Our findings showed that rac-[11C]mirtazapine has suitable properties for PET neuroimaging. However, separate studies of enantiomers are typically required for characterizing the pharmacokinetics of a racemic drug. Therefore, we have determined the whole-body distribution and brain pharmacokinetics of S- and R-[11C]mirtazapine in pigs. The enantiomers of [11C]mirtazapine produced similar effective doses of radioactivity in most body organs, except for the brain, in which the dose was approximately 40% higher after injection of S-[11C]mirtazapine than the antipode. Kinetic analyses of dynamic brain PET recordings showed that values for regional accumulation of compound (k3) were significantly higher for S-[11C]mirtazapine than for the antipode, while the values for clearance of compounds from tissue to circulation (k2) were consistently lower for S-[11C]mirtazapine than for the R-form. No reliable difference occurred in the rate of metabolism of S- and R-[11C]mirtazapine in the bloodstream of the pigs. The present findings indicate that enantioselective processes affect the cerebral pharmacokinetics of rac-mirtazapine.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2008
Publisher: Wiley
Date: 02-2013
DOI: 10.1111/EJN.12146
Publisher: Wiley
Date: 07-04-2011
DOI: 10.1002/SYN.20916
Abstract: The abundances of dopamine (DA) D(1) and D(2) receptors have been assayed with radioligands in membrane preparations and by autoradiography in vitro, and also in living brain using positron emission tomography (PET). This review compares the saturation binding parameters (B(max) and K(D) ) obtained in striatum by these several methods, and in different species. Some uncertainty in quantitation is derived from the incomplete specificities of commonly used ligands, especially Sch 23,390 for D(1) sites and spiperone for D(2) -like sites. In striatal membrane preparations, the D(1) B(max) ranges from 10 to 139 pmol g(-1) tissue, whereas the D(2) B(max) ranges from 8 to 42 pmol g(-1) tissue. Receptor concentrations in human material, despite the more extended post mortem interval, are roughly similar to those reported in rodent and nonhuman primate. Estimates of B(max) by quantitative autoradiography are generally five times higher than corresponding results for similar ligands in membrane preparations. The saturation binding parameters in living striatum have been estimated by serial PET studies with ligands over a range of specific activities. The few PET estimates of D(1) B(max) , (40-80 pmol g(-1) ) and numerous PET estimates of D(2) B(max) (20-40 pmol g(-1) ) are in general agreement with membrane estimates, but fall far short of the mean of autoradiographic results in vitro. Apparent affinities for D(1) and D(2) ligands in vivo are typically 10 times lower than for corresponding in vitro studies, presumably because the unbound ligand concentration is not corrected for the free fraction in living brain tissue. The disparate B(max) results by method suggest the presence of a large reservoir or reserve of D(1) and D(2) receptors in intact brain sections, which are unavailable to PET ligands in vivo, and which may be lost during the preparation of washed membranes. A subset of receptors existing in a high affinity state for agonists is detected in washed membrane preparations, in which the coupling to intracellular G-proteins may have become artificially limiting. However, in most PET and autoradiographic studies in vitro, agonist and antagonist ligands have similar B(max) . Discrepancies in the literature highlight the need for a better understanding of affinity states in vivo and trafficking of G-protein coupled receptors between plasma membrane and intracellular compartments.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.JPSYCHIRES.2009.09.012
Abstract: The anatomical basis of visuo-constructive impairment in AD is widely unexplored. FDG-PET can be used to determine functional neuronal networks underlying specific cognitive performance in the human brain. In the present study, we determined the pattern of cortical metabolism that was associated with visuo-constructive performance in AD. We employed two widely used visuo-constructive tests that differ in their demand on visual perception and processing capacity. Resting state FDG-PET scans were obtained in 29 probable AD patients, and cognitive tests were administered. We made a voxel-based regression analysis of FDG uptake to scores in visual test performance, using the SPM5 software. Performance in the CERAD Drawing test correlated with FDG uptake in the bilateral inferior temporal gyri, bilateral precuneus, right cuneus, right supramarginal gyrus and right middle temporal gyrus covering areas of dorsal and ventral visual streams. In contrast, performance in the more complex RBANS Figure Copy test correlated with FDG uptake in the bilateral fusiform gyri, right inferior temporal gyrus, left anterior cingulate gyrus, left parahippoc al gyrus, right middle temporal gyrus and right insula, encompassing the ventral visual stream and areas of higher-level visual processing. The study revealed neuronal networks underlying impaired visual test performance in AD. The extent of involvement of visual and higher order association cortex increased with greater test complexity. From a clinical point of view, both of these widely used visual tests evaluate the integrity of complementary cortical networks and may contribute complementary information on the integrity of visual processing in AD.
Publisher: Springer Science and Business Media LLC
Date: 24-12-2013
DOI: 10.1038/BJC.2013.778
Publisher: MDPI AG
Date: 28-06-2019
DOI: 10.3390/JCM8070935
Abstract: Hyperglycemia is a common occurrence in hospitalized patients receiving parenteral and/or enteral nutrition. Although there are several approaches to manage hyperglycemia, there is no consensus on the best practice. We systematically searched PubMed, Embase, Cochrane Central, and ClinicalTrials.gov to identify records (published or registered between April 1999 and April 2019) investigating strategies to manage glucose control in adults receiving parenteral and/or enteral nutrition whilst hospitalized in noncritical care units. A total of 15 completed studies comprising 1170 patients were identified, of which 11 were clinical trials and four observational studies. Diabetes management strategies entailed adaptations of nutritional regimens in four studies, while the remainder assessed different insulin regimens and administration routes. Diabetes-specific nutritional regimens that reduced glycemic excursions, as well as algorithm-driven insulin delivery approaches that allowed for flexible glucose-responsive insulin dosing, were both effective in improving glycemic control. However, the assessed studies were, in general, of limited quality, and we see a clear need for future rigorous studies to establish standards of care for patients with hyperglycemia receiving nutrition support.
Publisher: Elsevier BV
Date: 1986
DOI: 10.1016/0304-3940(86)90048-0
Abstract: The distributions of catecholamine (CA) neurons in the medulla oblongata of the guinea pig and rat were compared using immunohistochemistry with rabbit antisera against the CA synthesizing enzymes, tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (D beta H) and phenylethanolamine-N-methyltransferase (PNMT). TH and D beta H distributions were similar in the two species. In contrast, the central nervous systems of both normal and colchicine-treated guinea pigs failed to demonstrate immunoreactivity for PNMT, the synthetic enzyme for adrenaline. The concentrations of biogenic amines in the hypothalamus and medulla were determined in guinea pig and rat tissues by high-performance liquid chromatography with electrochemical detection. No adrenaline was detected in the guinea pig brain. Thus it appears that guinea pigs lack central neurons capable of synthesizing adrenaline.
Publisher: Wiley
Date: 2005
DOI: 10.1002/SYN.20234
Abstract: The pig has been used as animal model for positron emission tomography (PET) studies of dopamine (DA) receptors and pharmacological perturbations of DA neurotransmission. However, the binding properties of DA receptors and transporters in pig brain have not been characterized in vitro. Therefore, the saturation binding parameters of [3H]SCH 23390 for DA D1 receptors and [3H]raclopride for DA D2/3 receptors were measured by quantitative autoradiography in cryostat sections from brain of groups of 8 week old and adult female Göttingen minipigs. The magnitudes of Bmax and Kd for these ligands were similar in young and old pigs, and were close to those reported for rat and human brain. Furthermore, gradients in the concentrations of D1 and D2/3 sites in striatum measured in vitro agreed with earlier findings in PET studies. However, the dopamine transporter (DAT) ligand [3H]GBR12935 did not bind in pig brain cryostat sections. Whereas the tropane derivative [125I]RTI-55 labeled serotonin transporters (serotonin transporter (SERT)) in pig brain, use of the same ligand under conditions specific for DAT, revealed a pattern of binding similar to that observed for SERT conditions. Parallel studies revealed the presence of DAT in rat and ferret brain. The distribution volume (Vd) of the selective DAT ligand [11C]NS2214 ([11C]Brasofensine) was mapped in groups of normal and MPTP-lesioned Göttingen miniature pigs. The in vivo pattern of Vd matched the distribution of SERT in vitro, and did not differ between the normal pigs and the lesioned animals with documented 60% DA depletions. However, the pattern of specific binding of the selective noradrenaline transporter ligand (S,S)-[11C]MeNER in a single Landrace pig showed that, of the three monoamine transporters, only DAT could not be detected in pig brain. We conclude that the pig is a suitable model for PET studies of DA D1 and D2/3 binding sites, which are fully developed on the eighth postnatal week. However, well-characterized piperazine and tropane radioligands failed to recognize DAT in pig brain the two tropane radioligands lacked pharmacological specificity for DAT and SERT in pig brain in vitro and in vivo.
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.RESUSCITATION.2007.03.020
Abstract: Cerebral blood flow (CBF) during cardiopulmonary resuscitation and after restoration of spontaneous circulation (ROSC) from cardiac arrest has previously been measured with the microspheres and laser Doppler techniques. We used positron emission tomography (PET) with [15O]--water to map the haemodynamic changes after ROSC in nine young pigs. After the baseline PET recording, ventricular fibrillation of 5 min duration was induced, followed by closed-chest cardiopulmonary resuscitation (CPR) in conjunction with IV administration of three bolus doses of adrenaline (epinephrine). After CPR, external defibrillatory shocks were applied to achieve ROSC. CBF was measured at intervals during 4h after ROSC. Relative to the mean global CBF at baseline (32+/-5 ml hg(-1)min(-1)), there was a substantial global increase in CBF at 10 min, especially in the diencephalon. This was followed by an interval of cortical hypoperfusion and a subsequent gradual return to baseline values.
Publisher: MDPI AG
Date: 22-04-2022
DOI: 10.3390/PH15050516
Abstract: The cerebral expression of the A2A adenosine receptor (A2AAR) is altered in neurodegenerative diseases such as Parkinson’s (PD) and Huntington’s (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A2AAR–specific antagonist radiotracer [18F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone–treated mice, and conducted dynamic PET studies with healthy pigs. We performed analysis of mouse brain time–activity curves to calculate the mean residence time (MRT) by non–compartmental analysis, and the binding potential (BPND) of [18F]FLUDA using the simplified reference tissue model (SRTM). For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume (VT) at baseline and under blocking conditions with tozadenant. The MRT of [18F]FLUDA in the striatum of mice was decreased by 30% after treatment with the A2AAR antagonist istradefylline. Mouse results showed the highest BPND (3.9 to 5.9) in the striatum. SRTM analysis showed a 20% lower A2AAR availability in the rotenone–treated mice compared to the control–aged group. Tozadenant treatment significantly decreased the VT (14.6 vs. 8.5 mL · g−1) and BPND values (1.3 vs. 0.3) in pig striatum. This study confirms the target specificity and a high BPND of [18F]FLUDA in the striatum. We conclude that [18F]FLUDA is a suitable tool for the non–invasive quantitation of altered A2AAR expression in neurodegenerative diseases such as PD and HD, by PET.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2019
Publisher: Wiley
Date: 26-08-2014
DOI: 10.1111/JNC.12848
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.NEUINT.2007.03.004
Abstract: The pathway for selective serotonergic toxicity of 3,4-methylenedioxymeth hetamine (MDMA, "Ecstasy") is poorly understood, but has been linked to hyperthermia and disturbed energy metabolism. We investigated the dose-dependency and time-course of MDMA-induced perturbations of cerebral glucose metabolism in freely moving rats using rapid s ling microdialysis (every minute) coupled to flow-injection analysis (FIA) with biosensors for glucose and lactate. Blood s les for analysis of glucose and lactate were taken at 30-45 min intervals before and after drug dosing and body temperature was monitored by telemetry. A single dose of MDMA (2-10-20 mg/kg i.v.) evoked a transient increase of interstitial glucose concentrations in striatum (139-223%) with rapid onset and of less than 2h duration, a concomitant but more prolonged lactate increase (>187%) at the highest MDMA dose and no significant depletions of striatal serotonin. Blood glucose and lactate levels were also transiently elevated (163 and 135%) at the highest MDMA doses. The blood glucose rises were significantly related to brain glucose and brain lactate changes. The metabolic perturbations in striatum and the hyperthermic response (+1.1 degrees C) following systemic MDMA treatment were entirely blocked in p-chlorophenylalanine pre-treated rats, indicating that these effects are mediated by endogenous serotonin.
Publisher: SAGE Publications
Date: 06-0012
Abstract: [68Ga]Annexin A5 positron emission tomography (PET) reveals the externalization of phosphatidylserine as a surrogate marker for apoptosis. We tested this technique for therapy monitoring in a murine model of myocardial infarction (MI) including parathyroid hormone (PTH) treatment. MI was induced in mice, and they were assigned to the saline or the PTH group. On day 2, they received [68Ga]annexin A5 PET or histofluorescence TUNEL staining. Mice had 2-deoxy-2-[18F]fluoro-d-glucose (FDG)-PET examinations on days 6 and 30 for calculation of the left ventricular ejection fraction and infarct area. [68Ga]Annexin A5 uptake was 7.4 ± 1.3 %ID/g within the infarction for the controls and 4.5 ± 1.9 %ID/g for the PTH group (p = .013). TUNEL staining revealed significantly more apoptotic cells in the infarct area on day 2 in the controls (64 ± 9%) compared to the treatment group (52 ± 4% p = .045). FDG-PET revealed a significant decrease in infarct size in the treatment group and an increase in the controls. Examinations of left ventricular ejection fraction on days 6 and 30 did not reveal treatment effects. [68Ga]Annexin A5 PET can detect the effects of PTH treatment as a marker of apoptosis 2 days after MI ex vivo examination confirmed significant rescue of myocardiocytes. FDG-PET showed a small but significant reduction in infarct size but no functional improvement.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.NEUROIMAGE.2006.11.038
Abstract: The performance of small animal PET for neuroreceptor studies in a psychopharmacological challenge paradigm is not yet well-described. Therefore, we used microPET and [(11)C]raclopride to map the availability of dopamine D(2/3) receptors in brain of anesthetized rats, first in a baseline condition, and again after challenge with saline or d- hetamine. Parametric maps of the specific binding (binding potential, pB) were calculated using a reference tissue input from cerebellum, and spatially normalized to a digitized stereotaxic coordinate system for rat brain. In volumes of interest (VOIs), the mean baseline pB (n=6) was 2.05 in dorsal striatum (caudate-putamen), and 1.34 in ventral striatum (nucleus accumbens), and did not significantly differ upon retest 2 h later. The availability of [(11)C]raclopride binding sites at baseline was 8% higher in the right striatum. Challenge with hetamine sulfate (1 mg/kg, i.v., n=4) decreased pB by 19% in both ventral and dorsal striatum. We have earlier predicted that blockade of monoamine oxidase (MAO) should potentiate the hetamine-evoked dopamine release, thus enhancing the displacement of [(11)C]raclopride binding in vivo. However, pretreatment of rats with pargyline hydrochloride (4 mg/kg, n=4 20 mg/kg, n=4) 1 day prior to PET did not potentiate the hetamine-evoked reduction in dopamine receptor availability within the extended striatum. We conclude that small animal PET can be used to investigate stimulant-induced dopamine release, but that the spatial resolution is insufficient to detect differences between relative changes in dorsal vs. ventral isions of the rat striatum. Furthermore, the present results do not reveal potentiation of the hetamine-evoked release of dopamine in rats with MAO inhibition.
Publisher: Elsevier BV
Date: 11-2002
DOI: 10.1016/S0006-8993(02)03340-1
Abstract: In rat extended striatum, most nicotinic cholinoceptors are likely to be presynaptic. A previous report suggested that DA and 5-HT afferents each account for at least 30% of nicotinic binding sites in the striatum. To explore this question further, rats received unilateral infusions of the neurotoxins 5,7-dihydroxytryptamine, 6-hydroxydopamine or vehicle into the medial forebrain bundle, and were sacrificed 3 weeks later. Denervation was quantified by [125I]RTI-55 autoradiography, using separate assay conditions that revealed DA and 5-HT transporters (i.e. DAT and SERT). Nicotinic cholinoceptors were quantified by [125I]epibatidine autoradiography. Infusion of 6-hydroxydopamine depleted DAT but not SERT labelling in all striatal areas (i.e. caudate-putamen, nucleus accumbens core and shell, olfactory tubercle). The serotonergic neurotoxin 5,7-dihydroxytryptamine depleted SERT and, to a lesser extent, DAT labelling. Both neurotoxins reduced [125I]epibatidine binding in striatal areas. Multiple linear regression analysis showed that these reductions in [125I]epibatidine binding were entirely associated with loss of DAT rather than SERT. The DAT-associated proportion of total [125I]epibatidine binding was 36+/-2% (caudate-putamen), 28+/-3% (accumbens core), 27+/-4% (accumbens shell) and 44+/-5% (olfactory tubercle). Cortical [125I]epibatidine binding was unaltered by 5,7-dihydroxytryptamine lesions that reduced SERT labelling by 46 to 73%. In all brain areas, even small (3.4 to 8.8%) SERT-associated reductions in [125I]epibatidine binding would have been detected as statistically significant. In conclusion, we report the failure to detect nAChRs on 5-HT terminals in extended striatum or cerebral cortex, using a sensitive [125I]epibatidine autoradiographic assay.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.NEUBIOREV.2007.02.003
Abstract: The use of pigs in neuroscience research has increased in the past decade, which has seen broader recognition of the potential of pigs as an animal for experimental modeling of human brain disorders. The volume of available background data concerning pig brain anatomy and neurochemistry has increased considerably in recent years. The pig brain, which is gyrencephalic, resembles the human brain more in anatomy, growth and development than do the brains of commonly used small laboratory animals. The size of the pig brain permits the identification of cortical and subcortical structures by imaging techniques. Furthermore, the pig is an increasingly popular laboratory animal for transgenic manipulations of neural genes. The present paper focuses on evaluating the potential for modeling symptoms, phenomena or constructs of human brain diseases in pigs, the neuropsychiatric disorders in particular. Important practical and ethical aspects of the use of pigs as an experimental animal as pertaining to relevant in vivo experimental brain techniques are reviewed. Finally, current knowledge of aspects of behavioral processes including learning and memory are reviewed so as to complete the summary of the status of pigs as a species suitable for experimental models of erse human brain disorders.
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.JNEUMETH.2006.08.016
Abstract: The volume of cerebral tissue perturbed in experimental models of middle cerebral artery occlusion (MCAO) can be highly variable. Thus, the territories of reduced cerebral blood flow (CBF) or oxygen consumption (CMRO(2)) following MCAO might properly be defined using statistical parametric mapping within a population. In order to establish such a method, we mapped CBF and CMRO(2) in 18 pigs with acute MCAO. Parametric maps were flipped about the axis of symmetry, and CBF and CMRO(2) in the infarcted hemisphere were calculated as percentages of the magnitudes in mirror-image pixels. There were log-linear relationships between the volumes of affected tissue and the percentages of normal CFB or CMRO(2). This graphical analysis showed that the volume of the core deficit was smaller for CBF that for CMRO(2), but expanded more rapidly with decreasing CBF deficit than did the corresponding volumes of reduced CMRO(2). Thus, acute changes in CBF and CMRO(2) following MCAO in the pig can be defined as probabilistic volumes.
Publisher: American Chemical Society (ACS)
Date: 18-07-2017
DOI: 10.1021/ACSCHEMNEURO.7B00252
Abstract: The success of positron emission tomography (PET) for observing molecular processes underlying brain function and disease is underpinned by radiotracer chemistry. From the earliest applications of PET to measure dopamine synthesis capacity and the abundance of neuroreceptors and transporters, to the more recent topic of dynamic neurochemical imaging, interrogation of brain dopamine in conditions such as neurodegenerative diseases, schizophrenia, mood disorders, and addictions has been a driving force that challenges the ingenuity of radiopharmaceutical scientists. In fact, the pursuit of new ligands and reaction methods to address longstanding challenges has often been pioneered in the context of dopamine imaging. From this viewpoint, we highlight the unique history of imaging the dopaminergic pathway with PET, and present our interpretation of how this worldwide effort shaped and continues to drive the field of molecular imaging.
Publisher: Wiley
Date: 07-01-2013
DOI: 10.1016/J.IJDEVNEU.2012.12.008
Abstract: The transition from mild sedation to deep anaesthesia is marked by the phenomenon of burst suppression (BS). FDG-PET studies show that the cerebral metabolic rate for glucose (CMRglc) declines dramatically with onset of BS in the adult brain. Global CMRglc increases substantially in the post-natal period and achieves its maximum in preadolescence. However, the impact of post-natal brain development on the vulnerability of CMRglc to the onset of BS has not been documented. Therefore, cerebral blood flow and metabolism were measured using a variant of the Kety-Schmidt method, in conjunction with quantitative regional estimation of brain glucose uptake by FDG-PET in groups of neonate and juvenile pigs, under a condition of light sedation or after induction of deep anaesthesia with thiopental. Quantification of simultaneous ECoG recordings was used to establish the correlation between anaesthesia-related changes in brain electrical activity and the observed cerebrometabolic changes. In the condition of light sedation the magnitude of CMRglc was approximately 20% higher in the older pigs, with the greatest developmental increase evident in the cerebral cortex and basal ganglia (P<0.05). Onset of BS was associated with 20-40% declines in CMRglc. Subtraction of the mean parametric maps for CMRglc showed the absolute reductions in CMRglc evoked by thiopental anaesthesia to be two-fold greater in the pre-adolescent pigs than in the neonates (P<0.05). Thus, the lesser suppression of brain energy demand of neonate brain during deep anaesthesia represents a reduced part of thiopental suppressing brain metabolism in neonates.
Publisher: Springer Science and Business Media LLC
Date: 12-04-2011
DOI: 10.1007/S00259-011-1808-Y
Abstract: To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [(18)F]NS10743, a novel diazabicyclononane derivative targeting α7 nicotinic acetylcholine receptors (α7 nAChRs). Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [(18)F]NS10743 under baseline conditions (n = 3) and after blocking of the α7 nAChR with NS6740 (3 mg·kg(-1) bolus + 1 mg·kg(-1)·h(-1) continuous infusion n = 3). Arterial plasma s les were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time-radioactivity curves was performed, and parametric maps were calculated relative to arterial input. Plasma [(18)F]NS10743 passed readily into the brain, with peak uptake occurring in α7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippoc us. The highest SUV(max) was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUV(max) 1.53 ± 0.32). Administration of NS6740 significantly decreased [(18)F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BP(ND). The baseline BP(ND) ranged from 0.39 ± 0.08 in the cerebellum to 0.76 ± 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BP(ND) in regions with high [(18)F]NS10743 binding (temporal lobe -29%, p = 0.01 midbrain: -35%, p = 0.02), without significantly altering the BP(ND) in low binding regions (cerebellum: -16%, p = 0.2). This study confirms the potential of [(18)F]NS10743 as a target-specific radiotracer for the molecular imaging of central α7 nAChRs by PET.
Publisher: Springer Science and Business Media LLC
Date: 08-2019
Publisher: Elsevier BV
Date: 08-2004
Publisher: Elsevier BV
Date: 07-1989
DOI: 10.1016/0014-2999(89)90071-X
Abstract: The mechanism by which 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) depletes forebrain dopamine is not fully understood, but a necessary step involves the formation of neurotoxic MPP+ by monoamine oxidase type B (MAO-B). The histamine neurons in the brain contain MAO-B and are a possible site for the production of MPP+. Two weeks after MPTP injections (2 X 50 mg/kg i.p.) in C-57 mice, striatal dopamine was reduced by more than 70%. However, histamine levels in neocortex, hippoc us and hypothalamus were unaffected by this neurotoxic dose of MPTP. Thus, as in Parkinson's disease, central histaminergic systems appear to be spared in the MPTP model.
Publisher: Elsevier BV
Date: 12-1997
DOI: 10.1016/S0165-0270(97)00147-7
Abstract: The kinetic behaviour of [3H]DOPA in living rat brain was investigated by compartmental modelling of measured activities from combined metabolite pools in a time-series (180 min) of static autoradiograms from right cerebral hemispheres. Two models of [3H]DOPA uptake and metabolism that incorporated the removal of the decarboxylation product, [3H]dopamine, from brain were significantly more accurate than a model in which [3H]dopamine accumulated irreversibly in situ. Present estimates of [3H]DOPA kinetic constants were compared to previously published results based on the analysis of measured activities from in idual metabolite pools separated by chromatographic fractionation of [3H]DOPA metabolites in the left cerebral hemispheres of the same rats. Autoradiographic estimates of DOPA decarboxylase activity with respect to [3H]DOPA in brain (k3DOPA) were under-estimated several-fold relative to chromatographic estimates this discrepancy is explained by post-mortem enzyme activity and omission of biological compartments from the models. However, autoradiographic estimates of the unidirectional blood-brain clearance of [3H]DOPA (K1DOPA) and monoamine oxidase activity with respect to [3H]dopamine in brain (k7DA') agreed with chromatographic estimates. This concordance represents the first empirical validation of compartmental modelling of autoradiographic data as a method for quantitatively investigating the kinetic behaviour of radiolabelled L-DOPA in living mammalian brain.
Publisher: SAGE Publications
Date: 03-2000
DOI: 10.1177/096368970000900210
Abstract: A multicenter study is under way to investigate the efficacy of allografting of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Göttingen minipigs. We are now using positron emission tomography (PET) methods for testing the physiological responses to MPTP intoxication and the time course of the response to several treatment strategies. We now report preliminary results obtained in 11 pigs employed in the initial phase of the study the completed study shall ultimately include 30 pigs. Animals were randomly assigned to one of five groups: 1) Control, 2) MPTP intoxication, 3) MPTP intoxication followed by allograft, 4) MPTP intoxication followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete glia cell line-derived neurotrophic factor (GDNF) (≈2 ng GDNF/h/10 5 cells). MPTP was administered (1 mg/kg/day, SC) for 7–10 days until the pigs had developed mild parkinsonian symptoms of muscle rigidity, hypokinesia, and impaired coordination, especially of the hind limbs. Approximately 2 weeks after the last MPTP dose, animals received a T1-weighted magnetic resonance imaging (MRI) scan, and a series of dynamic PET recordings. After the first series of PET scans, four grafts of porcine embryonic mesencephalic tissue (E28 days) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-based stereotactic techniques. Immunosuppression of some animals with cyclosporin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last scans, pigs were killed and the brains were perfused for unbiased stereological examination of cytological and histochemical markers in striatum and substantial nigra. The behavioral impairment of the animals (the “Parkinson's score”) had been evaluated throughout the 8-month period. Kinetic analysis of the first set of PET scans has indicated that the rate constant for the decarboxylation of FDOPA in catecholamine fibers was reduced by 33% in striatum of the mildly parkinsonian pigs. The rate of association of [ 11 C]NS-2214 to catecholamine uptake sites was reduced by 62% in the same groups of pigs. No significant difference was found in the binding potential of [ 11 C]raclopride to the dopamine D 2 -like receptors in striatum of the MPTP-intoxicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially denervated pig striatum.
Publisher: Wiley
Date: 22-04-2010
DOI: 10.1002/SYN.20785
Abstract: To test for alpha(2) adrenergic modulation of dopamine D(2/3) receptor availability in striatum of living mice using the high-affinity ligand [(18)F]fallypride and microPET. Groups of anesthetized mice were pretreated with saline, the alpha(2)-agonist clonidine (1 mg/kg), and the alpha(2)-antagonists RX821002 (1 mg/kg) and yohimbine (1 mg/kg). Dynamic microPET recordings lasting 120 min were then initiated upon i.v. tracer injection of [(18)F]fallypride. Parametric maps of [(18)F]fallypride binding potential (BP(ND)) were calculated using the Logan method, with cerebellum serving as the reference region. Mean striatal [(18)F]fallypride BP(ND) was 10.6 +/- 1.7 in the saline control animals, 8.9 +/- 1.7 (-16% P < 0.05) in the RX821002 group, 8.3 +/- 2.6 (-22% P < 0.05) in the yohimbine group and 10.3 +/- 2.2 (n.s.) in the clonidine group. These findings are consistent with a tonic inhibition of dopamine release by alpha(2) adrenergic receptors, such that alpha(2) blockade increased the competition from endogenous dopamine at D(2/3) receptors, thus reducing the [(18)F]fallypride BP(ND) by about 20%. Absent effects of clonidine suggest a ceiling effect in the tonic inhibition of dopamine release. This in vivo PET evidence for alpha(2)/dopaminergic interaction may be relevant to putative actions of atypical antipsychotic medications via adrenergic receptors.
Publisher: Springer Singapore
Date: 2021
Publisher: Wiley
Date: 02-1987
DOI: 10.1111/J.1471-4159.1987.TB04135.X
Abstract: The metabolism of the positron-emitting compound [18F]6-fluoro-L-3,4-dihydroxyphenylalanine (*F-DOPA) was studied in carbidopa-pretreated male hooded rats. Thirty minutes following carbidopa administration (5 mg/kg i.p.), animals received *F-DOPA (500 micrograms/kg specific activity, 175-230 Ci/mol) as an intrajugular bolus. Blood s les were taken at various times between 5 and 90 min, and the plasma was analyzed by HPLC with gamma counting of fractions. *F-DOPA disappeared rapidly from plasma in concert with the formation of the 3-O-methylated metabolite, Me-*F-DOPA. Animals were killed from 5 to 120 min after injection, and the brains were rapidly dissected. The disappearance of *F-DOPA from both vermis and striatal s les was rapid. Me-*F-DOPA, the sole metabolite observed in the vermis, was the major labeled material in the striatum at greater than or equal to 20 min after injection. Fluorodopamine was an important metabolite in the striatum, making up 25% of total radioactivity at early intervals. Striatal s les also contained fluoro-3,4-dihydroxyphenylacetic acid, which constituted approximately 10% of the total radioactivity, and traces of two radiolabeled compounds, tentatively identified as fluorohomovanillic acid and fluoro-3-methoxytyramine.
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.NUCMEDBIO.2013.12.014
Abstract: Dopamine D3 receptors are implicated in various neuropsychiatric diseases, drug abuse and alcoholism, but specific agents for D3 molecular imaging are lacking. We evaluated two in vitro selective fluorine-18-labeled radioligand candidates ([(18)F]5 and [(18)F]6) for positron emission tomography (PET) imaging of D3 receptor availability in the brain. Biodistribution was evaluated in Sprague-Dawley rats using ex vivo autoradiography and small-animal PET. Protein binding studies were conducted in human plasma and cerebrospinal fluid. [(18)F]5 showed rapid blood-brain barrier penetration and fast washout after intravenous injection, whereas the rat brain penetration of [(18)F]6 was lower. The total distribution volume (VT) of [(18)F]5 was 20-26 mL g(-1) throughout brain. Co-injection with the D3 antagonist BP897 resulted in globally increased cerebral washout of [(18)F]5 and [(18)F]6, but SUV analysis and parametric mapping of binding potential (BPND) relative to the cerebellum did not reveal specific binding of either ligand in D3-rich brain regions, i.e. the ventral striatum. However, there was substantial displaceable binding of [(18)F]5, and to a lesser extent [(18)F]6, in the pituitary. These radioligands reveal dopamine D3 receptors in the pituitary, but are not suitable for PET imaging of in brain, possibly due to low specific signal relative to the globally high VT.
Publisher: Wiley
Date: 12-01-2013
DOI: 10.1002/SYN.21630
Abstract: Positron emission tomography (PET) with the high affinity dopamine D(2/3) receptor ligand [¹⁸F]-fallypride affords estimates of the binding potential (BP(ND) ) in extra-striatal regions of low receptor abundance, but the sufficient recording time for accurate measurements in striatum has been called into question. We have earlier argued that transient equilibrium measurements are obtained in striatum with [¹⁸F]-fallypride PET recordings of 3 h duration, which may be the practical limit for clinical investigations without interrupted scanning. However, the high extraction fraction of [¹⁸F]-fallypride predicts flow-dependence of tracer delivery to brain, which may be a source of variance of the apparent BP(ND) in regions of high binding. To test this prediction, we conducted a retrospective analysis of [¹⁸F]-fallypride PET data from a group of 50 healthy volunteers (age 18-58 years [mean ± SD: 32.6 ± 10.6), who had participated in clinical studies without arterial input measurements. We used the initial 120-s integral (AUC) of the venous confluence (VC) as a surrogate marker for cerebral blood flow (CBF) and tested for correlations between regional estimates of BP(ND) calculated by the simplified reference tissue model (SRTM) and the in idual VC-AUC. The magnitude of BP(ND) in a high binding region (putamen), but not in a low binding region (thalamus) correlated positively with VC-AUC, suggesting that approximately 9% of the variance in the [¹⁸F]-fallypride BP(ND) in putamen can be attributed to in idual differences in this surrogate marker for CBF, a contribution equal in magnitude to the effects of age on BP(ND) in putamen of the present healthy control group.
Publisher: Hindawi Limited
Date: 05-2008
DOI: 10.1111/J.1600-0404.2007.00943.X
Abstract: Parkinson's disease (PD) may be associated with increased energy metabolism in overactive regions of the basal ganglia. Therefore, we hypothesized that treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine would decrease regional cerebral blood flow (rCBF) and oxygen metabolism in the basal ganglia of patients with early-stage PD. Quantitative positron emission tomography (PET) recordings were obtained with 15O]water and 15O]oxygen in 10 patients, scanned first in a baseline condition, and again 6 weeks after treatment with a daily dose of 20 mg memantine. Dynamic PET data were analyzed using volume of interest and voxel-based approaches. The treatment evoked rCBF decreases in basal ganglia, and in several frontal cortical areas. The regional cerebral metabolic rate of oxygen (rCMRO2) did not decrease in any of the a priori defined regions, and consequently the oxygen extraction fraction was increased in these regions. Two peaks of significantly decreased rCMRO2 were detected near the frontal poles in both hemispheres, using a posteriori voxel-based analysis. Although we did not find the predicted decrease in basal ganglia oxygen consumption, our data suggest that treatment with memantine actively modulates neuronal activity and/or hemodynamic response in basal ganglia of PD patients. This finding may be relevant to the putative neuroprotective properties of NMDAR antagonists.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.BIOPSYCH.2015.11.009
Abstract: There is evidence of abnormal cerebral dopamine transmission in nicotine-dependent smokers, but it is unclear whether dopaminergic abnormalities are due to acute nicotine abuse or whether they persist with abstinence. We addressed this question by conducting longitudinal positron emission tomography (PET) examination of smokers before and after 3 months of abstinence. We obtained baseline 6-[(18)F]fluoro-L-DOPA (FDOPA)-PET scans in 15 nonsmokers and 30 nicotine-dependent smokers, who either smoked as per their usual habit or were in acute withdrawal. All smokers then underwent cessation treatment, and successful abstainers were re-examined by FDOPA-PET after 3 months of abstinence (n = 15). Uptake of FDOPA was analyzed using a steady-state model yielding estimates of the dopamine synthesis capacity (K) the turnover of tracer dopamine formed in living brain (kloss) and the tracer distribution volume (Vd), which is an index of dopamine storage capacity. Compared with nonsmokers, K was 15% to 20% lower in the caudate nuclei of consuming smokers. Intrain idual comparisons of consumption and long-term abstinence revealed significant increases in K in the right dorsal and left ventral caudate nuclei. Relative to acute withdrawal, Vd significantly decreased in the right ventral and dorsal caudate after prolonged abstinence. Severity of nicotine dependence significantly correlated with dopamine synthesis capacity and dopamine turnover in the bilateral ventral putamen of consuming smokers. The results suggest a lower dopamine synthesis capacity in nicotine-dependent smokers that appears to normalize with abstinence. Further investigations are needed to clarify the role of dopamine in nicotine addiction to help develop smoking prevention and cessation treatments.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2006
DOI: 10.1007/S00259-005-0052-8
Abstract: It has been suggested that ammonia-induced enhancement of peripheral benzodiazepine receptors (PBRs) in the brain is involved in the development of hepatic encephalopathy (HE). This hypothesis is based on animal experiments and studies of post-mortem human brains using radiolabelled PK11195, a specific ligand for PBR, but to our knowledge has not been tested in living patients. The aim of the present study was to test this hypothesis by measuring the number of cerebral PBRs in specific brain regions in cirrhotic patients with an acute episode of clinically manifest HE and healthy subjects using dynamic (11)C-PK11195 brain PET. Eight cirrhotic patients with an acute episode of clinically manifest HE (mean arterial ammonia 81 micromol/l) and five healthy subjects (22 micromol/l) underwent dynamic (11)C-PK11195 and (15)O-H(2)O PET, co-registered with MR images. Brain regions (putamen, cerebellum, cortex and thalamus) were delineated on co-registered (15)O-H(2) (15)O and MR images and copied to the dynamic (15)O-H(2)O and (11)C-PK11195 images. Regional cerebral blood flow (CBF) ((15)O-H(2)O scan) and the volume of distribution of PK11195 ((11)C-PK11195 scan) were calculated by kinetic analysis. There were regional differences in the CBF, with lowest values in the cortex and highest values in the putamen in both groups of subjects (p<0.05), but no significant differences between the groups. There were no significant differences in the volume of distribution of PK11195 (V (d)) between regions or between the two groups of subjects. Mean values of V (d) ranged from 1.0 to 1.1 in both groups of subjects. The results do not confirm the hypothesis of an increased number of PBRs in patients with HE.
Publisher: Wiley
Date: 11-1992
DOI: 10.1111/J.1471-4159.1992.TB11026.X
Abstract: In vivo microdialysis was employed in order to characterize the steady-state kinetics of the turnover of specific dopamine and serotonin metabolites in the rat striatum 48 h after surgery. Inhibitors of monoamine oxidase (MAO pargyline) and catechol-O-methyltransferase (COMT Ro 40-7592) were administered, either separately or in conjunction, at doses sufficient to block these enzymes in the CNS. In some experiments, the acid metabolite carrier was blocked with probenecid. Temporal changes were then observed in the efflux of interstitial dopamine, 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). The fractional rate constants for the accumulation or disappearance of the metabolites could be determined after pharmacological blockade of catabolic enzymes or the acid metabolite carrier. Interstitial 5-HIAA was found to be cleared with a half-life of approximately 2 h. After blockade of either MAO or COMT, HVA disappeared with a half-life of 17 min. Experiments employing probenecid suggested that some of the interstitial HVA was cleared by the acid metabolite carrier, the remainder being cleared by a probenecid-insensitive process, possibly conjugation. After MAO inhibition, DOPAC disappeared with an apparent half-life of 11.3 min. The rate of 3-MT accumulation after pargyline indicated that the majority of interstitial HVA (> 95%) is formed from DOPAC rather than 3-MT. The formation of 3-MT from interstitial dopamine, calculated from the accumulation rate of 3-MT after pargyline, appeared to follow first-order kinetics (k = 0.1 min-1).
Publisher: Elsevier BV
Date: 1987
DOI: 10.1016/0014-2999(87)90137-3
Abstract: The effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on the levels of the neuropeptides somatostatin and substance P, were examined in various brain regions of C57 mice. Two weeks after injections of MPTP (2 X 30, 2 X 40 and 2 X 50 mg/kg i.p.) a dose-dependent decrease in striatal catecholamine levels was observed. There was also a dose-dependent increase in nigral somatostatin immunoreactivity and no reduction in striatonigral substance P levels. These results are in contrast with the changes observed in peptide levels in post-mortem Parkinson's brains.
Publisher: Society for Neuroscience
Date: 25-07-2007
DOI: 10.1523/JNEUROSCI.0805-07.2007
Abstract: Previous positron emission tomography (PET) studies with levodopa analogs have revealed a modestly increased capacity for dopamine synthesis in the striatum of patients with schizophrenia compared with healthy age-matched control subjects. We hypothesized that not just the synthesis but also the turnover of radiolabeled dopamine is elevated in patients. To test the hypothesis, we reanalyzed 2-h-long [ 18 F]fluorodopa (FDOPA)/PET recordings from eight unmedicated patients with schizophrenia and 15 healthy age-matched control subjects, using new methods for the quantification of [ 18 F]fluorodopamine steady-state kinetics. The fractional rate constant for the catabolism and elimination of [ 18 F]fluorodopamine was elevated nearly twofold in striatum, the largest biochemical difference in brain of schizophrenics yet reported. The magnitude of the intrinsic blood–brain FDOPA clearance with correction for this loss of [ 18 F]fluorodopamine metabolites was increased by 20% in caudate and putamen and by 50% in amygdala and midbrain of the patients. However, the magnitude of the steady-state storage of FDOPA and its decarboxylated metabolites ( V d ) was reduced by one-third in the caudate nucleus and amygdala of the schizophrenic group. Thus, reduced steady-state storage of [ 18 F]fluorodopamine occurs in the midst of accelerated synthesis in brain of untreated patients. Positive scores of the positive and negative syndrome scale correlated inversely with the magnitude of V d in amygdala, suggesting an association between positive symptoms and impaired steady-state storage of FDOPA metabolites in that structure.
Publisher: Elsevier BV
Date: 2019
Publisher: IEEE
Date: 07-2019
Publisher: SAGE Publications
Date: 23-02-2005
Abstract: Conventional methods for the graphical analysis of 6-[ 18 F]fluorodopa (FDOPA) ositron emission tomography (PET) recordings ( K app in ) may be prone to negative bias because of oversubtraction of the precursor pool in the region of interest, and because of diffusion of decarboxylated FDOPA metabolites from the brain. These effects may reduce the sensitivity of FDOPA/PET for the detection of age-related changes in dopamine innervations. To test for these biasing effects, we have used a constrained compartmental analysis to calculate the brain concentrations of the plasma metabolite 3- O-methyl-FDOPA (OMFD) during 120 mins of FDOPA circulation in healthy young, healthy elderly, and Parkinson's disease subjects. Calculated brain OMFD concentrations were subtracted frame-by-frame from the dynamic PET recordings, and maps of the FDOPA net influx to brain were calculated assuming irreversible trapping ( K app ). Comparison of K app in and K app maps revealed a global negative bias in the conventional estimates of FDOPA clearance. The present OMFD subtraction method revealed curvature in plots of K app at early times, making possible the calculation of the corrected net influx ( K) and also the rate constant for diffusion of decarboxylated metabolites from the brain ( k loss ). The effective distribution volume (EDV 2 K/ k loss ) for FDOPA, an index of dopamine storage capacity in brain, was reduced by 85% in putamen of patients with Parkinson's disease, and by 58% in the healthy elderly relative to the healthy young control subjects. Results of the present study support claims that storage capacity for dopamine in both caudate and putamen is more profoundly impaired in patients with Parkinson's disease than is the capacity for DOPA utilization, calculated by conventional FDOPA net influx plots. The present results furthermore constitute the first demonstration of an abnormality in the cerebral utilization of FDOPA in caudate and putamen as a function of normal aging, which we attribute to loss of vesicular storage capacity.
Publisher: American Medical Association (AMA)
Date: 09-2005
Publisher: Springer Science and Business Media LLC
Date: 07-12-2011
DOI: 10.1007/S10554-011-9995-Y
Abstract: There has been a lack of standardized workup guidelines for patients with congenital abnormal origin of a coronary artery from the opposite sinus (ACAOS). We aimed to evaluate the use of cardiac hybrid imaging using multi-detector row CT (MDCT) for coronary CT angiography (Coronary CTA) and stress-rest myocardial perfusion SPECT (MPS) for comprehensive diagnosis of symptomatic adult patients with ACAOS. Seventeen symptomatic patients (12 men 54 ± 13 years) presenting with ACAOS underwent coronary CTA and MPS. Imaging data were analyzed by conventional means, and with additional use of 3D image fusion to allocate stress induced perfusion defects (PD) to their supplying coronary arteries. An anomalous RCA arose from the left anterior sinus in eight patients, an abnormal origin from the right sinus was detected in nine patients (5 left coronary arteries, LCA and 4 LCx). Five of the 17 patients (29%) demonstrated a reversible PD in MPS. There was no correlation between the anatomical variants of ACAOS and the presence of myocardial ischemia. Image fusion enabled the allocation of reversible PD to the anomalous vessel in three patients (two cases in the RCA and the other in the LCA territory) PD in two patients were allocated to the territory of artery giving rise to the anomalies, rather than the anomalies themselves. In a small cohort of adult symptomatic patients with ACAOS anomaly there was no relation found between the specific anatomical variant and the appearance of stress induced myocardial ischemia using cardiac hybrid imaging.
Publisher: Society of Nuclear Medicine
Date: 05-10-2011
DOI: 10.2967/JNUMED.111.089276
Abstract: We hypothesized that (68)Ga-DOTATATE uptake of neuroendocrine tumors is sensitive to therapy with a nonradioactive somatostatin analog. (68)Ga-DOTATATE PET/CT was used to examine 105 patients, 35 of whom had been pretreated with long-acting octreotide. The maximum standardized uptake value (SUV(max)) of target tissues, as well as metastases, was compared between the groups of patients with (group 1) and without (group 2) octreotide treatment. The SUV(max) of the spleen and liver was significantly lower in group 1 than in group 2 (both P < 0.001). There were no significant group differences in SUV(max) for primary tumors (28.6 ± 6.8 vs. 32.9 ± 31.5) or metastases in the liver (27.2 ± 14.8 vs. 25.7 ± 10.7), lymph nodes (41.4 ± 19.5 vs. 25.0 ± 6.3), or skeleton (39.5 ± 22.0 vs. 15.4 ± 7.8). In 9 patients available for intrain idual comparison, tumor uptake was unaffected by treatment with somatostatin analogs (21.7 vs. 20.6 P = 0.93). Treatment with a long-acting somatostatin analog did not significantly reduce (68)Ga-DOTATATE binding in neuroendocrine tumors but tended to improve the tumor-to-background ratio.
Publisher: Proceedings of the National Academy of Sciences
Date: 22-11-1994
Abstract: The hypofrontality theory of the pathogenesis of schizophrenia predicts that cortical lesions cause psychosis. During a search for abnormalities of catecholaminergic neurotransmission in patients with complex partial seizures of the mesial temporal lobe, we discovered an increase of the rate of metabolism of an exogenous dopa tracer (6-[18F]fluoro-L-dopa) in the neostriatum of a subgroup of patients with a history of psychosis. When specifically assayed for this abnormality, patients with schizophrenia revealed the same significant increase of the rate of metabolism in the striatum. The finding is consistent with the theory that a state of psychosis arises when episodic dopamine excess is superimposed on a trait of basic dopamine deficiency in the striatum. The finding is explained by the hypothesis that cortical insufficiency, a proposed pathogenetic mechanism of both disorders, causes an up-regulation of the enzymes responsible for dopa turnover in the neostriatum as well as the receptors mediating dopaminergic neurotransmission.
Publisher: Wiley
Date: 06-1991
Abstract: The binding of the histamine autoreceptor (H3) agonist [3H]-N alpha-methyl-histamine ([3H]-N-MeHA) was examined in 25 micron thick rat forebrain sections. The specific binding was saturable and of high affinity: Scatchard analysis indicated a Kd of 2 nM and a Bmax of 25 +/- 3 fmol/section. Under similar conditions, [3H]-histamine [( 3H]-HA) bound with a Kd of 8 nM and a Bmax of 20 +/- 2 fmol/section. Competition studies indicated that both ligands bound an identical site which had the pharmacological characteristics of the H3 binding site. The high affinity binding of [3H-N-MeHA was sensitive to the presence of 5'-guanylyl-imidodiphosphate, indicating that the binding site is likely coupled to a G-protein. Autoradiographic studies indicated the [3H]-N-MeHA binding to be greatest in the nucleus accumbens, striatum, substantia nigra pars reticulata, and certain cortical areas. Striatal quinolinic acid lesions greatly reduced binding in both the striatum and ipsilateral substantia nigra, while 6-hydroxydopamine lesions of the nigrostriatal dopamine system were without effect on binding. Therefore, most of the H3 binding sites in the basal ganglia are on striatonigral projection neurons. Cortical quinolinic acid lesions greatly reduced H3 binding in cortex, indicating that the binding in cortex, as in striatum, is largely on intrinsic neurons, rather than on afferents such as histamine nerve terminals.
Publisher: Springer Science and Business Media LLC
Date: 24-09-2015
DOI: 10.1038/MP.2015.146
Publisher: Public Library of Science (PLoS)
Date: 11-09-2013
Publisher: Elsevier BV
Date: 12-1987
DOI: 10.1016/0028-3908(87)90136-5
Abstract: Local injections of p-methoxyphenol into the substantia nigra of rats led to a mildly dose-related destruction of dopamine neurons as indicated by reductions of dopamine and its metabolites in the ipsilateral striatum and by loss of tyrosine hydroxylase immunoreactivity in the injected substantia nigra. Both Nissl staining of the injected nucleus and measurement of noradrenaline and serotonin in the ipsilateral striatum indicated some selectivity of the toxic action.
Publisher: Springer Science and Business Media LLC
Date: 14-02-2013
DOI: 10.1007/S11307-013-0618-Y
Abstract: The purpose of this study is to evaluate left ventricular functional parameters in healthy mice and in different murine models of cardiomyopathy with the novel blood pool (BP) positron emission tomography (PET) tracer [68Ga]-albumin. ECG-gated microPET examinations were obtained in healthy mice, and mice with dilative (DCM) and ischemic cardiomyopathy (ICM) using the novel BP tracer [68Ga]-albumin (AlbBP), as well as [18F]-FDG microPET. Cine-magnetic resonance imaging (MRI) examination performed on a clinical 1.5-T MRI provided the reference standard measurements. When considering the combined group of healthy controls, DCM and ICM AlbBP-PET significantly overestimated the magnitudes of EDV (AlbBP, 181±86 μl cine-MRI, 125±80 μl P<0.001) and ESV (AlbBP, 136±92 μl cine-MRI, 96±77 μl P<0.001), whereas the EF (AlbBP, 31±16% cine-MRI, 33±21% P=0.910) matched closely to cine-MRI results, as did findings with [18F]-FDG. High correlations were found between the measured cardiac parameters (EDV: R=0.978, ESV: R=0.989, and LVEF: R=0.992). Measuring left ventricular function in mice with [68Ga]-albumin BP PET is feasible and showed a high correlation compared to cine-MRI, which was used as a reference standard.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2013
DOI: 10.1007/S12350-013-9673-7
Abstract: To identify predictors of left ventricular mechanical dyssynchrony (LVMD) in patients with known left bundle branch block (LBBB) using gated single-photon emission computed tomography (SPECT) phase analysis. 81 patients (74% male, 70 ± 10 years) with LBBB and suspected or known coronary artery disease underwent ECG-gated myocardial perfusion SPECT. LV perfusion and functional parameters were measured, and phase analysis was performed to quantify LV-dyssynchrony. 35/81 patients (42%) had prior myocardial infarction (MI), and the mean left ventricular ejection fraction (LVEF) was 49% ± 16%. LVMD was present in 58/81 (72%) patients. The summed thickening score (STS) (P < .001 odds ratio 1.22) emerged as independent predictor for the presence of LVMD in a multivariate regression model. In addition, prior MI, low LVEF, summed stress score, summed rest score, summed motion score, and LAD rest extent were identified as predictors of LVMD in a univariate model. Clinical baseline characteristics, cardiac risk factors, and QRS duration (P = .051) had no influence on the presence of LVMD. In patients with LBBB, the occurrence of LVMD as assessed by gated SPECT phase analysis is mainly influenced by reduced myocardial contractility as expressed by the STS. Proper discrimination between LVMD arising from known electrical conduction delay as opposed to areas of MI causing reduced regional contractility seems to be mandatory for therapy planning in patients with LVMD.
Publisher: Wiley
Date: 2001
DOI: 10.1002/SYN.1098
Abstract: Several drugs of abuse, including nicotine, are thought to exert their reinforcing effects through actions on the mesolimbic dopamine system. Animal and human studies suggest that chronic administration of addictive drugs may lead to impaired dopamine neurotransmission in the nucleus accumbens. We measured D1 receptor density in 11 smokers and 18 nonsmokers using positron emission tomography and the D1 receptor ligand [11C]SCH 23390. Ten of the smokers were scanned twice, once after overnight abstinence from cigarettes, and once while smoking at their usual rate, to account for possible acute effects of cigarette smoking on D1 receptor binding. In addition, eight control subjects were scanned twice to assess the reproducibility of the method. We used compartmental modeling to measure [11C]SCH 23390 binding potential, a measure of D1 receptor density. There were no differences in binding between abstinent and nonabstinent scans in smokers or in the two scans in controls. However, there was a significant reduction in [11C]SCH 23390 binding potential in smokers compared to nonsmokers in the striatum, most prominently in the ventral striatum. This suggests that there is a reduction in dopamine D1 receptor density in the ventral striatum of human cigarette smokers relative to nonsmokers, which implies that the postsynaptic mesolimbic dopamine system may be chronically underactive in smokers, either as an antecedent or consequence of addiction to cigarettes. Such a hypodopaminergic state may play an important role in sustaining nicotine-seeking behavior. Alternatively, an inherited reduction in dopamine receptors in the striatum may be associated with an increased risk of addictive behavior.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2008
DOI: 10.1038/NN.2222
Abstract: Dopamine is released under stress and modulates processing of aversive stimuli. We found that dopamine storage capacity in human amygdala, measured with 6-[(18)F]fluoro-L-DOPA positron emission tomography, was positively correlated with functional magnetic resonance imaging blood oxygen level-dependent signal changes in amygdala and dorsal anterior cingulate cortex that were evoked by aversive stimuli. Furthermore, functional connectivity between these two regions was inversely related to trait anxiety. Our results suggest that in idual dopamine storage capacity in amygdala subserves modulation of emotional processing in amygdala and dorsal cingulate, thereby contributing to in idual differences in anxious temperament.
Publisher: Wiley
Date: 2001
DOI: 10.1002/SYN.1071
Abstract: The activity of DOPA decarboxylase measured in homogenates from rat striatum, or calculated from the rate of tracer decarboxylation measured ex vivo, is stimulated following acute treatment with antagonists of dopamine D2-like receptors. We used compartmental kinetics to test the hypothesis that utilization of the DOPA decarboxylase substrate [(18)F]fluorodopa is potentiated in living striatum following acute treatment with a typical neuroleptic. The kinetics of the tracer uptake were determined in eight anesthetized female pigs (40 kg) and in three animals receiving an infusion of haloperidol (75 microg kg(-1) h(-1)) for 1 h prior to tracer administration and throughout the 2-h positron emission recording. The relative activity of DOPA decarboxylase in striatum was increased threefold by the treatment. This potentiation of DOPA decarboxylation after pharmacological blockade of dopamine D2-like receptors may be used to optimize the utilization of exogenous DOPA in the treatment of Parkinson's disease.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.APRADISO.2013.01.002
Abstract: (-)-[(18)F]flubatine is a promising agent for visualization by PET of cerebral α4β2 nicotinic acetylcholine receptors (nAChRs), which are implicated in psychiatric and neurodegenerative disorders. Here, we describe a substantially improved two-step radiosynthesis strategy for (-)-[(18)F]flubatine, based on the nucleophilic radiofluorination of an enantiomerically pure precursor followed by deprotection of the intermediate. An extensive leaving group rotecting group library of precursors was tested. Application of a trimethylammonium-iodide precursor with a Boc-protecting group provided the best results: labeling efficiencies of 80-95%, RCY of 60±5%, radiochemical purity of >98%, and a specific activity of >350GBq/μmol. The radiosynthesis is easily transferable to an automated synthesis module.
Publisher: Elsevier BV
Date: 09-2001
DOI: 10.1016/S0165-0270(01)00453-8
Abstract: Different methodologies for PET data analysis influence the magnitude of estimates of blood-brain transfer coefficients and rate constants for the metabolism of FDOPA in living striatum. We now test the effects on several kinetic parameters of automatic procedures for volume of interest (VOI) selection. We also tested the sensitivity of the estimates to dynamic frame sequence duration, and produced a standard method for minimizing the variations in physiological estimates for FDOPA kinetics in minipig brain. We used minipigs because our previous work has shown them to provide an appropriate animal model for study normal and pathological cerebral DOPA metabolism using PET. Time-activity curves in striatum of adult minipigs were acquired in VOIs defined manually on MR-images, or alternatively on the basis of the radioactivity concentration based on the most radioactive voxel in the last scan frame. For all frame sequences, the relative decarboxylase activity (k(3)(D)) declined significantly (P < 0.006) as the VOI threshold declined from 95 to 70% of the most radioactive voxel. Irrespective of VOI size, the magnitude of k(3)(D) declined significantly (P < 0.001) from 0.074+/-0.008 to 0.045+/-0.005 per min (mean+/-S.E.M.) as total sequence length increased from 60 to 120 min circulation. The method of VOI selection had no significant effect on the striatum decarboxylation index of FDOPA calculated relative to the radioactivity in cerebellum (k(3)(S)).
Publisher: Wiley
Date: 13-01-2010
DOI: 10.1111/J.1468-1331.2009.02807.X
Abstract: Previous volumetric magnetic resonance imaging (MRI) studies of Parkinson's disease (PD) utilized primarily voxel-based morphometry (VBM), and investigated mostly patients with moderate- to late-stage disease. We now use deformation-based morphometry (DBM), a method purported to be more sensitive than VBM, to test for atrophy in patients with early-stage PD. T1-weighted MRI images from 24 early-stage PD patients and 26 age-matched normal control subjects were compared using DBM. Two separate studies were conducted, where two minimally-biased nonlinear intensity-average were created one for all subjects and another for just the PD patients. The DBM technique creates an average population-based MRI-average in an iterative hierarchical fashion. The nonlinear transformations estimated to match each subject to the MRI-average were then analysed. The DBM comparison between patients and controls revealed significant contraction in the left cerebellum, and non-significant trends towards frontal, temporal and cingulate sulcal expansions with frontal and temporal white matter contractions. Within the patient group, the unified PD rating scores were highly correlated with local expansions in or near sulci bordering on frontal and temporal cortex. Our results suggest that DBM could be a sensitive method for detecting morphological changes in early-stage PD.
Publisher: Public Library of Science (PLoS)
Date: 23-02-2015
Publisher: Wiley
Date: 24-08-2018
DOI: 10.1002/SYN.22064
Abstract: In addition to probing regional differences in receptor availability, molecular positron emission tomography (PET) is proving useful for investigating perturbations in neurotransmitter networks using interregional correlation analyses. In a multi-modal imaging study, we examined interregional correlations of dopamine D
Publisher: Elsevier BV
Date: 11-0011
DOI: 10.1016/0006-8993(94)91985-2
Abstract: To map the unknown distribution of histamine H3 binding sites, we compared autoradiographs of the binding of the H3 agonist N alpha-[3H]methylhistamine ([3H]NAMH) in the forebrain of mouse and guinea pig. Saturation binding revealed the presence of a single site with apparent affinity of 0.75 nM in the mouse and 1.2 nM in the guinea pig. Binding constants were nearly identical in male and female mice. The rank order of [3H]NAMH binding in mouse brain was striatum > insular cortex > neocortex, as previously observed in the rat. In the guinea pig, the rank order was insular cortex > striatum approximately neocortex. The Bmax of [3H]NAMH in insular cortex of both species was close to 60 fmol/mg. Thus, the guinea pig differs from the rodent in that the highest density of H3 binding was present in cortical rather than subcortical structures.
Publisher: Elsevier BV
Date: 1988
DOI: 10.1016/0006-2952(88)90725-3
Abstract: The metabolisms of L-18F-2-fluoro-DOPA (L-2-18F-DOPA) and L-18F-6-fluoro-DOPA (L-6-18F-DOPA) were compared in vitro and in vivo in the carbidopa-pretreated male hooded rat. In vivo, the sole metabolites in plasma were O-methylated derivatives. The peripheral formation of the O-methylated derivative of L-2-18F-DOPA was approximately twice as great as that for the 6-isomer. Animals were killed at 10 and 60 min after administration of the 18F-DOPAs, and s les of striatum and vermis were analyzed by HPLC. L-2-18F-DOPA passed less readily into brain than did L-6-18F-DOPA. Whereas significant amounts of 6-18F-fluorodopamine and metabolites were formed in the striatum, no decarboxylated derivatives of L-2-18F-DOPA were found. Determination of the Michaelis-Menten kinetic constants for aromatic amino acid decarboxylase AADC, EC 4.1.1.26) indicated that the Km for L-2-18F-DOPA (982 +/- 115 microM) was considerably higher than that for L-6-18F-DOPA (101 +/- 22 microM). The low substrate affinity for AADC and the relatively more rapid rate of O-methylation in the periphery account for the lack of formation of 2-18F-fluorodopamine in vivo. The ratio of total radioactivity between striatum and other brain regions is related to the decarboxylation of radiolabeled tracer and the relative persistence of the decarboxylated derivatives in the striatum. Since L-2-18F-DOPA is not decarboxylated in rat striatum, it is not a promising agent for the study of cerebral DOPA metabolism in humans by means of positron emission tomography.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2005
DOI: 10.1007/S00221-004-2026-7
Abstract: A screening procedure was developed to provide quantitative estimates of structural parameters, regional volumes and neuron number, in a neurotoxicologic study of the Göttingen minipig brain. The study material consisted of normal controls and brains collected from young minipigs which had been exposed in utero to the mitotic inhibitor methylazoxymethanol acetate (MAM). Based on stereological principles and systematic s ling techniques, volumetric data from pre-selected regions of the pig brain was obtained using Cavalieri's principles and point-counting. Secondarily, estimates of total hemispheric neocortical cell numbers were obtained from pre-selected groups to test the potential effect of MAM on neuron number. No significant differences were observed in volume of the pre-selected regions of MAM intoxicated pigs nor in estimates of total neocortical neuron number.
Publisher: MDPI AG
Date: 22-04-2021
DOI: 10.3390/MOLECULES26092451
Abstract: Hallucinogens are a loosely defined group of compounds including LSD, N,N-dimethyltryptamines, mescaline, psilocybin silocin, and 2,5-dimethoxy-4-meth hetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with N1-([11C]-methyl)-2-bromo-LSD ([11C]-MBL) displacement with the non-radioactive competitor ketanserin confirmed that the majority of [11C]-MBL specific binding was to serotonin 5-HT2A receptors. However, interactions at serotonin 5HT1A and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood–brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry and molecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT2A/2C agonist N-(2[11CH3O]-methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine ([11C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([15O]-water) or metabolism ([18F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research.
Publisher: SAGE Publications
Date: 07-05-2014
Abstract: The success of serotonin-selective reuptake inhibitors has lent support to the monoamine theory of major depressive disorder (MDD). This issue has been addressed in a number of molecular imaging studies by positron emission tomography or single-photon emission computed tomography of serotonin reuptake sites (5-HTT) in the brain of patients with MDD, with strikingly disparate conclusions. Our meta-analysis of the 18 such studies, totaling 364 MDD patients free from significant comorbidities or medication and 372 control subjects, revealed reductions in midbrain 5-HTT (Hedges' g = −0.49 95% CI: (−0.84, −0.14)) and amygdala (Hedges' g = −0.50 95% CI: (−0.78, −0.22)), which no in idual study possessed sufficient power to detect. Only small effect sizes were found in other regions with high binding (thalamus: g = −0.24, striatum: g = −0.32, and brainstem g = −0.22), and no difference in the frontal or cingulate cortex. Age emerged as an important moderator of 5-HTT availability in MDD, with more severe reductions in striatal 5-HTT evident with greater age of the study populations ( P .01). There was a strong relationship between severity of depression and 5-HTT reductions in the amygdala ( P = 0.01). Thus, molecular imaging findings indeed reveal widespread reductions of ˜10% in 5-HTT availability in MDD, which may predict altered spatial-temporal dynamics of serotonergic neurotransmission.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Hindawi Limited
Date: 09-2004
Publisher: SAGE Publications
Date: 05-1998
DOI: 10.1097/00004647-199805000-00004
Abstract: Tyrosine hydroxylase of catecholamine neurons catalyzes the synthesis of 3,4-dihydroxphenylalanine (DOPA), which is subsequently metabolized to dopamine by DOPA decarboxylase (DDC). However, DOPA is not committed to decarboxylation in vivo because export of DOPA from brain and metabolism of DOPA other than decarboxylation are possible. To estimate the relative magnitudes of the several fates of DOPA, the kinetics of the uptake and metabolism of l-[ 3 H]tyrosine ([ 3 H]Tyr, intravenous infusion) was measured in brain of rats pretreated with NSD 1015, an inhibitor of DDC. Some rats were pretreated with haloperidol before the blockade of DDC. The [ 3 H]Tyr was incorporated into brain protein at a rate constant of 0.03 min −1 . The relative tyrosine hydroxylase activity in striatum was 0.005 min −1 at 30 minutes after NSD 1015, 0.011 min −1 3 hours later, and 0.020 min −1 after haloperidol treatment. The rate constant for the clearance of DOPA from brain (0.06 min −1 ) and earlier estimates of the rate constant of DDC activity in striatum (0.26 min −1 ) together predict that 80% of DOPA formed in normal rat striatum normally is available for dopamine synthesis. It follows that modulation of DDC activity can influence the rate of DA synthesis by affecting the relative magnitude of the several fates of DOPA in living brain.
Publisher: Elsevier BV
Date: 2013
Publisher: Elsevier BV
Date: 07-2016
Publisher: Wiley
Date: 30-05-2001
DOI: 10.1002/SYN.1077
Abstract: The decarboxylation of 6-[(18)F]fluorodopa (FDOPA) and retention of the product [(18)F]fluorodopamine within vesicles of catecholamine fibers results in the labeling of dopamine-rich brain regions during FDOPA/PET studies. However, this metabolic trapping is not irreversible due to the eventual diffusion of [(18)F]fluorodopamine metabolites from brain. Consequently, time-radioactivity recordings of striatum are progressively influenced by metabolite loss. In linear analyses, the net blood-brain clearance of FDOPA (K(D)(i), ml g(-1) min(-1)) can be corrected for this loss by the elimination rate constant k(Lin)(cl) (min(-1)). Similarly, the DOPA decarboxylation rate constant (k(D)(3), min(-1)) calculated by compartmental analysis can also be corrected for metabolite loss by the elimination rate constant k(DA)(9) (min(-1)). To compare the two methods, we calculated the two elimination rate constants using data recorded during 240 min of FDOPA circulation in normal monkeys and in monkeys with unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesions. Use of the extended models increased the magnitudes of K(D)(i) and k(D)(3) in striatum in the case of k(D)(3), variance of the estimate was substantially improved upon correction for metabolite loss. The rate constants for metabolite loss were higher in MPTP-lesioned monkey striatum than in normal striatum. The high correlation between in idual estimates of k(Lin)(cl) and k(DA)(9) suggests that both rate constants reveal loss of decarboxylated metabolites from brain.
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.NEUROIMAGE.2005.09.044
Abstract: The binding of three tracers for monoaminergic terminals was mapped in the brain of healthy young (N=6) and healthy old rhesus monkeys (N=4), aged monkeys with mild unilateral intracarotid MPTP lesions (N=3), and monkeys of intermediate age with severe systemic MPTP lesions (N=6). The ligand for monoaminergic vesicles (+)-[(11)C]dihydrotetrabenazine (+DTBZ) had a mean binding potential (pB) of 1.4 in striatum of the healthy young monkeys, which was reduced by 20% in putamen of the old monkeys. The catecholamine transporter ligand (+)-[(11)C]methylphenidate (+MP) had a mean pB of 1.3 in striatum of the young monkeys, which was reduced by 40% in caudate and putamen of the old monkeys. The DOPA decarboxylase substrate [(18)F]fluoro-l-DOPA (FDOPA) had a mean decarboxylation coefficient (k(3)(S)) of 0.4 h(-1) in striatum of the young group, and was not significantly reduced in the aged group. Of the three ligands, only +DTBZ pB was significantly reduced in striatum of the small group of animals with mild unilateral lesions. In the group with systemic MPTP lesions, the mean reduction of the binding of the three ligands was 80% in the caudate and putamen. However, the decline in +MP pB in the ventral striatum (-75%) exceeded the declines of +DTBZ pB and FDOPA k(3)(S) in that region (-65%), suggesting that compensatory down-modulation of uptake sites may occur in the striatal regions with the least dopamine depletion. Binding of all three ligands was reduced by 50% in the anterior cingulate cortex and in the thalamus, suggesting toxicity of MPTP for extrastriatal catecholamine innervations. +DTBZ binding in the hypothalamus, presumably mainly in serotonin fibers, was unaffected by systemic MPTP treatment. Of the three tracers, +DTBZ was most sensitive for detecting MPTP-induced dopamine depletion in monkey striatum.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.NEUROBIOLAGING.2008.05.005
Abstract: Conventional indices of the utilization of FDOPA in living human brain have not consistently revealed important declines in dopamine function with normal aging. However, most methods of kinetic analysis have assumed irreversible trapping of decarboxylated FDOPA metabolites in brain, an assumption that is violated even in PET recordings of short duration. Therefore, we have developed methods for the calculation of steady-state storage of FDOPA together with its decarboxylated metabolites (V(d), mlg(-1)), based upon improved kinetic analysis of 120-min emission recordings. In a group of 28 normal male subjects, of age ranging from 23 to 73 years, the magnitude of V(d) in the striatum and in extrastriatal regions declined by approximately 10% with each decade. The utilization of FDOPA was also calculated by several conventional methods assuming irreversible trapping, i.e. the net blood brain clearance (K(in)(app), mlg(-1)min(-1)), the DOPA decarboxylase activity relative to a reference tissue input (k(3)(S), min(-1)), and relative to the arterial input (k(3)(D), min(-1)). None of these methods revealed an age-related decline in FDOPA utilization in the extended striatum, although the magnitude of K(in)(app) did decline in cerebral cortex. Thus, the capacity to synthesize [(18)F]fluorodopamine remained largely intact in striatum of the elderly subjects, but in the presence of a substantially increased rate of washout (k(loss)), which was evident in all brain regions examined. Consequently, the magnitude of V(d) declined with healthy aging, possibly reflecting impaired vesicular storage capacity, resulting in enhanced exposure of cytosolic [(18)F]fluorodopamine to monoamine oxidase.
Publisher: Elsevier BV
Date: 02-2021
Publisher: American Psychiatric Association Publishing
Date: 08-2005
DOI: 10.1176/APPI.AJP.162.8.1515
Abstract: In abstinent alcoholic patients, a low availability of dopamine D2/3 receptors in the ventral striatum and adjacent putamen was associated with a high level of craving for alcohol. Alcohol craving may also depend on presynaptic dysfunction of striatal dopamine production, which may contribute to the risk of relapse. In this study, positron emission tomography (PET) was used to compare dopamine synthesis capacity in the striatum in alcoholic patients and healthy comparison subjects. Positron emission tomography (PET) was used to map the net blood-brain clearance of the dopa decarboxylase substrate 6-[18F]fluoro-l-dopa, an index of dopamine synthesis capacity, in the striatum of 12 detoxified male alcoholic patients and 13 age-matched healthy men. The parametric maps were correlated with results of an earlier [18F]desmethoxyfallypride PET study of dopamine D2/3 receptor availability in the same 12 alcoholic patients and in 12 of the healthy volunteers. Alcohol craving was measured with the Alcohol Craving Questionnaire. Patients were followed for 6 months, and alcohol intake was recorded. The magnitude of net blood-brain clearance in the striatum did not differ significantly between detoxified alcoholic patients and the comparison subjects. However, a voxel-wise correlation analysis of net blood-brain clearance in the alcoholic patients linked low levels of dopamine synthesis capacity in the bilateral putamen with high levels of alcohol craving. After normalization of net blood-brain clearance maps to the voxel-wise estimates of dopamine D2/3 receptor availability, there was still a negative correlation with alcohol craving. Alcohol craving at the time of scanning was associated with high level of alcohol intake in the 6-month follow-up period. Simultaneous assay by PET of pre- and postsynaptic markers of dopamine neurotransmission indicated that a striatal dopamine deficit correlated with alcohol craving, which was associated with a high relapse risk.
Publisher: Elsevier BV
Date: 09-1995
DOI: 10.1016/0006-2952(95)00216-M
Abstract: 6-[18F]fluoro-L-DOPA (FDOPA) has been used as a tracer for the cerebral activity of L-3,4-dihydroxyphenylalanine (DOPA)-decarboxylase in studies of positron emission tomography (PET). However, the substitution of fluorine on the aromatic ring may alter the disposition and metabolism of FDOPA from that of endogenous DOPA. In the present study, the kinetics of the peripheral metabolism and the facilitated unidirectional blood-brain clearance of [3H]DOPA and FDOPA were compared in Wistar rats pretreated with carbidopa. In arterial plasma, FDOPA was O-methylated with an apparent rate constant (0.031 min-1) 3-fold that of [3H]DOPA in the same rats. The O-methylated metabolite of FDOPA (OMe-FDOPA) was eliminated from plasma at a rate constant (0.018 min-1) 3-fold that of OMe-[3H]DOPA. The mean unidirectional blood-brain clearance of FDOPA (4.5 mL.hg-1.min-1) in six brain regions was 60% higher than that of [3H]DOPA.
Publisher: Wiley
Date: 17-02-2012
DOI: 10.1002/HBM.22000
Abstract: Fluid intelligence represents the capacity for flexible problem solving and rapid behavioral adaptation. Rewards drive flexible behavioral adaptation, in part via a teaching signal expressed as reward prediction errors in the ventral striatum, which has been associated with phasic dopamine release in animal studies. We examined a s le of 28 healthy male adults using multimodal imaging and biological parametric mapping with (1) functional magnetic resonance imaging during a reversal learning task and (2) in a subs le of 17 subjects also with positron emission tomography using 6‐[ 18 F]fluoro‐ L ‐DOPA to assess dopamine synthesis capacity. Fluid intelligence was measured using a battery of nine standard neuropsychological tests. Ventral striatal BOLD correlates of reward prediction errors were positively correlated with fluid intelligence and, in the right ventral striatum, also inversely correlated with dopamine synthesis capacity (FDOPA K ). When exploring aspects of fluid intelligence, we observed that prediction error signaling correlates with complex attention and reasoning. These findings indicate that in idual differences in the capacity for flexible problem solving relate to ventral striatal activation during reward‐related learning, which in turn proved to be inversely associated with ventral striatal dopamine synthesis capacity. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
Publisher: Society for Neuroscience
Date: 23-10-2013
DOI: 10.1523/JNEUROSCI.1398-13.2013
Abstract: Cerebral dopamine (DA) transmission is thought to be an important modulator for the development and occurrence of aggressive behavior. However, the link between aggression and DA transmission in humans has not been investigated using molecular imaging and standardized behavioral tasks. We investigated aggression as a function of DA transmission in a group of ( N = 21) healthy male volunteers undergoing 6-[ 18 F]-fluoro- l -DOPA (FDOPA)-positron emission tomography (PET) and a modified version of the Point Subtraction Aggression Paradigm (PSAP). This task measures aggressive behavior during a monetary reward-related paradigm, where a putative adversary habitually tries to cheat. The participant can react in three ways (i.e., money substraction of the putative opponent [aggressive punishment], pressing a defense button, or continuing his money-making behavior). FDOPA-PET was analyzed using a steady-state model yielding estimates of the DA-synthesis capacity ( K ), the turnover of tracer DA formed in living brain ( k loss ), and the tracer distribution volume ( V d ), which is an index of DA storage capacity. Significant negative correlations between PSAP aggressive responses and the DA-synthesis capacity were present in several regions, most prominently in the midbrain ( r = −0.640 p = 0.002). Lower degrees of aggressive responses were associated with higher DA storage capacity in the striatum and midbrain. Additionally, there was a significant positive correlation between the investment into monetary incentive responses on the PSAP and DA-synthesis capacity, notably in the midbrain ( r = +0.618, p = 0.003). The results suggest that in iduals with low DA transmission capacity are more vulnerable to reactive/impulsive aggression in response to provocation.
Publisher: Wiley
Date: 14-07-2015
DOI: 10.1002/SYN.21838
Abstract: Aim of this study was to quantify the binding of [(123) I]FP-CIT in striatum of healthy tree shrews. [(123) I]FP-CIT is widely used in clinical SPECT imaging to reveal nigrostriatal degeneration in aid of the diagnosis of clinically uncertain parkinsonian syndromes. Despite its wide clinical use, the saturation binding parameters of [(123) I]FP-CIT for the dopamine transporter (DAT) have not yet been determined in any mammalian brain. Tree shrews are genetically and neuroanatomically more similar to humans than are rodents and might therefore be a valuable animal model for research of neurological disorders involving brain dopamine. Quantitative in vitro autoradiography with [(123) I]FP-CIT was performed with brains of healthy tree shrews and, for comparison, brains of healthy rats. Dopamine D2/3 receptor autoradiography with [(3) H]raclopride was also performed. Saturation analysis revealed high specificity of [(123) I]FP-CIT for DAT in the striatum with considerably higher affinity in tree shrews than in rats (KD = 10.3 versus 36.4 nM). The density of DAT binding sites also was higher in tree shrews than in rats (Bmax = 2499 versus 1495 pmol/g wet weight (ww)). [(3) H]raclopride revealed D2/3 receptors in the tree shrew striatum with about the same density as in rats (Bmax = 78.4 versus 84.1 pmol/g ww), but with slightly lower affinity in tree shrews (KD = 1.27 versus 0.59 nM). The higher affinity in combination with the higher abundance of DAT binding sites compared to rat striatum predicts substantially higher binding of [(123) I]FP-CIT in SPECT studies of living tree shrews.
Publisher: Wiley
Date: 10-1993
Abstract: Paroxetine, an antidepressant with a high affinity for serotonin (5-HT) re-uptake sites, is a potential tracer of these sites. We determined the kinetic properties of [3H]paroxetine in rat brain in vivo. Relative to [14C]iodo-antipyrine, the brain uptake index (BUI) of [3H]paroxetine was 60-70%. The unidirectional blood clearance of [3H]paroxetine were 0.05-0.12 ml g-1 min-1, lower than expected from the BUI values. The steady state volume of distribution was 3.5 ml hg-1 in the diencephalon and 1.8 ml g-1 in the cerebellum, suggesting a binding potential of unity. Autoradiographs at four hours after [3H]paroxetine injection (300 microCi, i.p.) revealed heterogeneous binding consistent with the calculated binding potentials. Binding was nearly absent from cerebellum and was highest in the dorsal raphe, superior colliculus, dorsal hypothalamus, and entorhinal cortex, but did not reach equilibrium in four hours of tracer circulation. The specific binding relative to vermis was displaced by pretreatment with fluoxetine (10 mg/kg, i.p.).
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.NEUROIMAGE.2007.12.057
Abstract: In positron emission tomography (PET) studies of cerebral blood flow (CBF) and metabolism, the large interin idual variation commonly is minimized by normalization to the global mean prior to statistical analysis. This approach requires that no between-group or between-state differences exist in the normalization region. Given the variability typical of global CBF and the practical limit on s le size, small group differences in global mean easily elude detection, but still bias the comparison, with profound consequences for the physiological interpretation of the results. Quantitative [15O]H2O PET recordings of CBF were obtained in 45 healthy subjects (21-81 years) and 14 patients with hepatic encephalopathy (HE). With volume-of-interest (VOI) and voxel-based statistics, we conducted regression analyses of CBF as function of age in the healthy group, and compared the HE group to a subset of the controls. We compared absolute CBF values, and CBF normalized to the gray matter (GM) and white matter (WM) means. In additional simulation experiments, we manipulated the cortical values of 12 healthy subjects and compared these to unaltered control data. In healthy aging, CBF was shown to be unchanged in WM and central regions. In contrast, with normalization to the GM mean, CBF displayed positive correlation with age in the central regions. Very similar artifactual increases were seen in the HE comparison and also in the simulation experiment. Ratio normalization to the global mean readily elevates CBF in unchanged regions when a systematic between-group difference exists in gCBF, also when this difference is below the detection threshold. We suggest that the routine normalization to the global mean in earlier studies resulted in spurious interpretations of perturbed CBF. Normalization to central WM yields less biased results in aging and HE and could potentially serve as a normalization reference region in other disorders as well.
Publisher: Springer Science and Business Media LLC
Date: 11-04-2012
DOI: 10.1007/S00259-012-2109-9
Abstract: Since differentiation between low-grade glioma (LGG) and high-grade glioma (HGG) remains challenging according to MRI criteria alone, we investigated the discriminative value of additional dynamic FET PET in patients with MRI-suspected LGG. Included in this retrospective study were 127 patients with newly diagnosed MRI-suspected LGG and dynamic FET PET prior to histopathological assessment. FET PET lesions were visually classified as having reduced, normal, or increased tracer uptake. Maximal tumour uptake scaled to the mean background uptake (SUV(max)/BG), mean tumour uptake (SUV(mean)/BG), biological tumour volume and kinetics were evaluated and correlated with in idual histopathological findings. Histopathological analysis revealed 71 patients with LGG, 47 patients with HGG (including 5 glioblastoma multiforme), 2 patients with low-grade ganglioglioma and 7 patients with non-neoplastic lesions. Of the 127 patients, 97 had lesions with increased FET uptake, of which 93 were neoplastic. Increased uptake was found in 49/71 LGG (69 %) and 42/47 HGG (89 %). None of the conventional uptake parameters differed significantly between the HGG and LGG groups. Kinetic analysis reliably identified HGG (sensitivity 95 %, specificity 72 %, PPV 74 %, NPV 95 %). Normal tracer uptake was observed in 19 patients (15 with LGG, 1 with HGG and 3 with non-neoplastic lesions) and reduced uptake in 11 patients (7 with LGG and 4 with HGG). Among the MRI-suspected LGG, kinetic but not conventional analysis of FET uptake enabled remarkably high sensitivity for detection of HGG. This held true even for lesions with low or diffuse tracer uptake. Lesions with reduced tracer uptake must be interpreted with caution, as they can also harbour HGG tissue.
Publisher: Wiley
Date: 05-1991
DOI: 10.1111/J.1471-4159.1991.TB02083.X
Abstract: The intracerebral microdialysis technique, coupled with a sensitive radioenzymatic assay, was employed to study histamine release in the striatum and in the bed nucleus of the stria terminalis (BNST) in conscious, freely moving rats. In these brain regions, extracellular histamine concentrations decreased by 20% when calcium was omitted from the perfusion solution. Extracellular histamine was insensitive to the addition of tetrodotoxin to the perfusion medium. In striatum, extracellular histamine concentrations declined in an apparent biexponential manner after the administration of alpha-fluoromethylhistidine, an inhibitor of histamine synthesis. The half-lives for the disappearance of histamine were 32 min and 7.7 h, indicating the presence of at least two histamine pools. Histidine loading resulted in a nearly twofold increase in histamine outflow in striatum. In the BNST, yohimbine increased the extracellular histamine content by 50%, suggesting that histamine release is subject to alpha 2-adrenergic regulation in vivo. The extent to which histamine detected in cerebral microdialysis s les is of neurogenic origin remains to be established.
Publisher: SAGE Publications
Date: 03-08-2006
Abstract: Conventional graphical analysis of positron emission tomography (PET) recordings of the cerebral uptake of the DOPA decarboxylase substrate [ 18 F]fluorodopa (FDOPA) assumes irreversible trapping of [ 18 F]fluorodopamine formed in the brain. However, 4-h long PET recordings allow the estimation of a rate constant for elimination of [ 18 F]fluorodopamine from the brain ( k loss ), from which can be calculated an effective distribution volume ( EDV 1 ), which is an index of [ 18 F]fluorodopamine storage capacity. We earlier developed a method employing 2-h long FDOPA recordings for the estimation of k loss and EDV, here defined as EDV 2 . This method is based on subtraction of the calculated brain concentrations of the FDOPA metabolite O-methyl-FDOPA, rather than the subtraction of the entire radioactivity in a reference region. We now extend this method for the parametric mapping of these parameters in the brain of healthy aged volunteers and patients with Parkinson's disease (PD), with asymmetry of motor symptoms. For parametric mapping, we use a novel application of a multilinear solution for the two-tissue compartment FDOPA model. We also test a new application of the Logan graphical analysis for mapping of the FDOPA distribution volume at equilibrium. The estimates of k loss and EDV 2 were more sensitive for the discrimination of biochemical abnormality in the putamen of patients with early PD relative to healthy aged subjects, than was the conventional net influx estimate. Of the several methods, multilinear estimates of EDV 2 were most sensitive for discrimination of PD and normal putamen. However, k loss was most sensitive for detecting biochemical asymmetry in the putamen of PD patients, and only k loss also detected in the caudate of PD patients a decline in the retention of [ 18 F]fluorodopamine relative to healthy aged control subjects.
Publisher: Elsevier BV
Date: 11-2001
Publisher: Elsevier
Date: 2005
Publisher: Wiley
Date: 11-07-2019
DOI: 10.1002/SYN.22121
Abstract: Genetic research has implicated dopamine neurotransmission in the expression of the self-transcendence trait in humans. However, molecular imaging of dopaminergic markers is undocumented in relation to this personality trait. In this multimodal imaging study, we first investigated the relationship between the self-transcendence trait and in vivo dopamine D
Publisher: Society of Nuclear Medicine
Date: 15-01-0011
DOI: 10.2967/JNUMED.109.070672
Abstract: We measured the uptake of the somatostatin receptor ligand (68)Ga-[1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]-D-Phe(1),Tyr(3)-octreotate (DOTATATE) in the left anterior descending coronary artery (LAD) in association with calcified plaques (CPs) and cardiovascular risk factors. Seventy consecutive tumor patients were examined by whole-body (68)Ga-DOTATATE contrast-enhanced PET/CT. Blood-pool-corrected standardized uptake value (target-to-background ratio) was measured in the LAD, and CT images were used to detect CP. Cardiovascular risk factors and history of prior cardiovascular events were recorded. (68)Ga-DOTATATE uptake was detectable in the LAD of all patients. Target-to-background ratio in the LAD correlated significantly with the presence of CP (R = 0.34 P < 0.01), prior vascular events (R = 0.26 P < 0.05), and male sex (R = 0.29 P < 0.05), whereas CP correlated with these parameters but also with age (R = 0.34 P < 0.01) and hypertension (R = 0.25 P < 0.05). In a series of oncologic patients, those with prior cardiovascular events and calcified atherosclerotic plaques showed significantly increased (68)Ga-DOTATATE uptake in the LAD, suggesting a potential role of this tracer for plaque imaging in the coronary arteries.
Publisher: MDPI AG
Date: 16-10-2020
DOI: 10.3390/MOLECULES25204749
Abstract: Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and ersity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.
Publisher: Wiley
Date: 05-1998
DOI: 10.1046/J.1471-4159.1998.70051979.X
Abstract: We tested the hypothesis that blockade of NMDA glutamate receptors in brain enhances dopamine turnover. We blocked this class of glutamate receptors in the rat brain in vivo with dizocilpine (MK-801) and measured the accumulation of radiolabeled DOPA and its metabolites as functions of time after intravenous bolus injection. Using the time courses of the accumulated metabolites, we calculated the turnover constants of enzymes mediating dopamine synthesis and catabolism. Dizocilpine treatment for 8 days enhanced the rates of DOPA decarboxylation and dopamine oxidation (monoamine oxidation) 4- and 16-fold, respectively, in neostriatum and 10- and 3-fold, respectively, in frontal cortex. The findings are not inconsistent with the hypothesis that the psychotomimetic properties of dizocilpine may be the manifestation of denervation hypersensitivity linked to activation of key enzymes of dopamine turnover in striatum.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.EURONEURO.2013.01.009
Abstract: We carried out dynamic [(18)F]fallypride PET scans to measure cerebral dopamine D2/3 receptor availability in a 23-year old patient experiencing a severe withdrawal syndrome upon voluntary abstinence from "Spice", a pre-packaged herbal smoking thought to contain synthetic cannabinoids. Upon admission to the clinic, the patient experienced craving, affective symptoms and a range of somatic complaints, which resolved after several days' monitored abstinence. PET scans were performed on the day of admission, and one week later. Estimates of [(18)F]fallypride binding potential (BPND) were obtained in striatal and extrastriatal brain regions, and compared to results of age-matched healthy control subjects. Upon admission, [(18)F]fallypride BPND was reduced by 20% in the patient's striatum and also in extra-striatal regions. During short-term follow-up upon detoxification, the BPND increased to normal values. This study shows substantial short-term alterations of dopamine D2/3 receptor availability in a patient before and after acute detoxification from "Spice Gold", thus providing first evidence of reversible effects on dopamine receptors of heavy use of a herbal smoking blend.
Publisher: Elsevier BV
Date: 04-1994
DOI: 10.1016/0006-8993(94)90146-5
Abstract: The distribution of high-affinity binding sites for the histamine H3 agonist [3H]-N alpha-methylhistamine ([3H]NAMH, 4 nM) in the rat brain was examined by autoradiography. Binding in all brain regions was displaceable with the H3 antagonist thioperamide (2 microM). The pattern of H3 binding was heterogeneous: highest levels were in the striatum and substantia nigra, which receives sparse histaminergic innervations. Intermediate H3 binding was present in neocortex and diencephalon, while low binding was evident in the medial septum and dorsal hippoc us. Hitherto unreported H3 binding sites were noted in the dorsolateral tegmentum and in the nucleus of the solitary tract (NTS). Because the NTS receives a dense histaminergic innervation, [3H]NAMH binding in the NTS was further studied by Scatchard analysis. The presence of saturable binding (Bmax = 10 +/- 4 fmol/mg, Kd = 0.6 +/- 0.3 nM, n = 3) suggested that histamine may act via H3 receptors in the NTS.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2014
DOI: 10.1186/S13550-014-0043-5
Abstract: The α7 nicotinic acetylcholine receptor (nAChR) is an important molecular target in neuropsychiatry and oncology. Development of applicable highly specific radiotracers has been challenging due to comparably low protein expression. To identify novel ligands as candidates for positron emission tomography (PET), a library of diazabicyclononane compounds was screened regarding affinity and specificity towards α7 nAChRs. From these, [ 18 F]NS14490 has been shown to yield reliable results in organ distribution studies however, the radiosynthesis of [ 18 F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets. Automated radiosynthesis of [ 18 F]NS14490 has been performed by [ 18 F]fluorination with the tosylate precursor in the TRACERlab™ FX F-N synthesis module (Waukesha, WI, USA). After optimization, the radiochemical yield of [ 18 F]NS14490 was consistently approximately 35%, and the total synthesis time was about 90 min. The radiotracer was prepared with % radiochemical purity, and the specific activity at the end of the synthesis was 226 ± 68 GBq μmol −1 . PET measurements were performed in young pigs to investigate the metabolic stability and cerebral binding of [ 18 F]NS14490 without and with administration of the α7 nAChR partial agonist NS6740 in baseline and blocking conditions. The total distribution volume relative to the metabolite-corrected arterial input was 3.5 to 4.0 mL g −1 throughout the telencephalon and was reduced to 2.6 mL g −1 in animals treated with NS6740. Assuming complete blockade, this displacement indicated a binding potential (BP ND ) of approximately 0.5 in the brain of living pigs. In addition, evidence for specific binding in major brain arteries has been obtained. [ 18 F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of α7 nAChR in brain but also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.
Publisher: Wiley
Date: 05-1998
DOI: 10.1002/(SICI)1098-2396(199805)29:1<37::AID-SYN4>3.0.CO;2-C
Abstract: Developing prediction tools for immunotherapy approaches is a clinically important and rapidly emerging field. The routinely used prediction biomarker is inaccurate and may not adequately utilize large amounts of medical data. Machine learning is a promising way to predict the benefit of immunotherapy from in idual data by in iduating the most important features from genomic data and clinical characteristics. Machine learning was applied to identify a list of candidate genes that may predict immunotherapy benefits using data from the published cohort of 853 patients with NSCLC. We used XGBoost to capture nonlinear relations among many mutation genes and ICI benefits. The value of the derived machine learning-based mutation signature (ML-signature) on immunotherapy efficacy was evaluated and compared with the tumor mutational burden (TMB) and other clinical characteristics. The predictive power of ML-signature was also evaluated in independent cohorts of patients with NSCLC treated with ICI. We constructed the ML-signature based on 429 (training/validation = 8/2) patients who received immunotherapy and extracted 88 eligible predictive genes. Additionally, we conducted internal and external validation with the utility of the OAK+POPLAR dataset and independent cohorts, respectively. This ML-signature showed the enrichment in immune-related signaling pathways and compared to TMB, ML-signature was equipped with favorable predictive value and stratification. Previous studies proposed no predictive difference between original TMB and modified TMB, and original TMB contains some genes with no predictive value. To demonstrate that fewer genetic tests are sufficient to predict immunotherapy efficacy, we used machine learning to screen out gene panels, which are used to calculate TMB. Therefore, we obtained the 88-gene panel, which showed the favorable prediction performance and stratification effect compared to the original TMB.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.IJROBP.2005.02.044
Abstract: To explore conflicting results obtained when tumor hypoxia is assessed with Eppendorf electrode Po(2) measurements and with positron emission tomography (PET) by use of [(18)F]fluoromisonidazole (FMISO). We compared the 2 methods in conjunction with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) PET, dual-tracer ex vivo autoradiography (FMISO and 2-deoxy-D-[1-(14)C]glucose (2DG)), and histology in 2 murine tumor models, the C3H mammary carcinoma and the SCCVII squamous cell carcinoma. 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-PET showed tumor-to-reference tissue ratios of 3.5 in both tumor models after 2 hours. C3H mammary carcinoma reached an FMISO PET ratio of 11 after 3.5 hours. Autoradiography showed large confluent areas of FMISO and 2DG uptake. Median Po(2) was 7 mm Hg and necrotic fraction was 10% to 30%. SCCVII squamous-cell carcinoma reached an FMISO PET tumor-to-reference tissue ratio of 2 after 2.5 hours. Autoradiography showed homogeneous 2DG uptake and scattered foci of high FMISO uptake. Median Po(2) was 1 mm Hg and necrotic fraction was below 5%. Ex vivo dual-tracer autoradiography documented the ability of in vivo FMISO PET to distinguish between confluent areas of either viable tissue or necrosis. Electrode Po(2) measurements could not be ascribed to specific areas in the tumors. Less uptake of FMISO in SCCVII squamous-cell carcinoma than in C3H mammary carcinoma could be caused by scattered foci versus confluent areas of viable hypoxic tissue in the 2 tumors, respectively.
Publisher: Springer Science and Business Media LLC
Date: 19-06-2012
DOI: 10.1007/S00259-012-2162-4
Abstract: Age-related decline in cognitive speed has been associated with prefrontal dopamine D1 receptor availability, but the contribution of presynaptic dopamine and noradrenaline innervation to age-related changes in cognition is unknown. In a group of 16 healthy participants aged 22-61 years, we used PET and the radioligand FDOPA to measure catecholamine synthesis capacity (K (in) (app) millilitres per gram per minute) and the digit symbol substitution test to measure cognitive speed, a component of fluid IQ. Cognitive speed was associated with the magnitude of K (in) (app) in the prefrontal cortex (p < 0.0005). Both cognitive speed (p = 0.003) and FDOPA K (in) (app) (p < 0.0005) declined with age, both in a standard voxel-wise analysis and in a volume-of-interest analysis with partial volume correction, and the correlation between cognitive speed and K (in) (app) remained significant beyond the effects of age (p = 0.047). MR-based segmentation revealed that these age-related declines were not attributable to age-related alterations in grey matter density. Our findings indicate that age-related changes in the capacity of the prefrontal cortex to synthesize catecholamines, irrespective of cortical atrophy, may underlie age-related decline in cognitive speed.
Publisher: SAGE Publications
Date: 11-2002
DOI: 10.3727/000000002783985314
Abstract: The functional restoration of the dopamine innervation of striatum in MPTP-poisoned Göttingen minipigs was assessed for 6 months following grafting of fetal pig mesencephalic neurons. Pigs were assigned to a normal control group and a MPTP-poisoned group, members of which received no further treatment, or which received bilateral grafts to the striatum of tissue blocks harvested from E28 fetal pig mesencephalon with and without immunosuppressive treatment after grafting, or with additional co-grafting with immortalized rat neural cells transfected to produce GDNF. In the baseline condition, and again at 3 and 6 months postsurgery, all animals were subjected to quantitative [ 18 F]fluorodopa PET scans and testing for motor impairment. At the end of 6 months, tyrosine hydroxylase (TH)-containing neurons were counted in the grafts by stereological methods. The MPTP poisoning persistently reduced the magnitude of k 3 D, the relative activity of DOPA decarboxylase in striatum, by 60%. Grafting restored the rate of [ 18 F]fluorodopa decarboxylation to the normal range, and normalized the scores in motor function. The biochemical and functional recovery was associated with survival of approximately 100,000 TH-positive graft neurons in each hemisphere. Immunosuppression did not impart a greater recovery of [ 18 F]fluorodopa uptake, nor were the number of TH-positive graft neurons or the volumes of the grafts increased in the immunosuppressed group. Contrary to expectation, co-grafting of transfected GDNF-expressing HiB5 cells, a rat-derived neural cell line, tended to impair the survival of the grafts with the lowest values for graft volumes, TH-positive cell numbers, behavioral scores, and relative DOPA decarboxylase activity. From the results we conclude that pig ventral mesencephalic allografts can restore functional dopamine innervation in adult MPTP-lesioned minipigs.
Publisher: Wiley
Date: 04-2010
DOI: 10.1002/SYN.20730
Abstract: Molecular imaging studies with benzamide radioligands can reveal competition from endogenous binding at D(2/3)-receptors in living brain. However, single photon emission computed tomography (SPECT) methods suffer from limited spatial resolution, and [(11)C]-labeled ligands are only available at positron emission tomography (PET) research sites with cyclotron-radiochemistry facilities, whereas [(18)F] can be transported, due to its longer physical half-life. Therefore, we endeavored to characterize the vulnerabilities of the benzamide antagonist [(18)F]desmethoxyfallypride (DMFP) and its high-affinity congener [(18)F]fallypride (FP) to competition from endogenous dopamine in living mouse brain. Groups of awake mice were pretreated with saline, hetamine (10 mg/kg), or reserpine (5 mg/kg), followed by i.v. tracer injections. Mice were killed at 2.5-90 min (DMFP) or 2.5-180 min (FP) circulation times. Brains were dissected and regional radioactivity concentration measured by gamma counting. Other groups of mice were anesthetized for dynamic microPET recordings with DMFP or FP. Binding potentials (BP(ND)) were calculated using cerebellum as reference region. With 90-min circulation, DMFP BP(ND) in striatum was 2.4 by dissection and 2.2 by microPET, which showed a 62% decrease in response to hetamine-evoked dopamine release and a 33% increase after reserpine-evoked dopamine depletion. With 120-min circulation, FP BP(ND) in striatum was 24.1 by dissection and 9.2 by microPET, which showed a 31% decrease in the hetamine group, but no effect of reserpine. Dissection showed similar sensitivities for FP binding, but only a 29% hetamine-evoked reduction for DMFP. Relative to gold standard ex vivo results, microPET estimates of DMFP BP(ND) were unbiased, whereas FP BP(ND) in striatum was substantially underestimated. Both tracers proved suitable for revealing pharmacologically evoked changes in competition at D(2/3)-receptors in striatum of living mice.
Publisher: Wiley
Date: 16-10-2016
DOI: 10.1111/JNC.13759
Abstract: Read the highlighted article 'Mapping the alterations in glutamate with GluCEST MRI in a mouse model of dopamine deficiency' on page 432.
Publisher: Georg Thieme Verlag KG
Date: 30-01-2013
Abstract: Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.
Publisher: Elsevier BV
Date: 2019
Publisher: ECO-Vector LLC
Date: 07-10-2022
Abstract: INTRODUCTION: Spinal muscular atrophy (SMA) is a rare hereditary disabling disease and the most common hereditary cause of infant deaths. The timely comprehensive diagnosis of SMA permits to plan therapeutic tactics and preserve the quality of patients life. One of the objectives of the given work is a review of the actual literature data on etiopathogenesis, clinical presentation, valid diagnosis and modern effective tactics of SMA management. AIM: To evaluate the management tactics of patients with SMA taking into account neuropsychiatric symptoms, to analyze problems of proposal and organization of measures aimed at improvement of the quality of medical care, on the basis of the practical experience of the Samara region and with consideration of the current state of the problem. MATERIALS AND METHODS: In the work, the data of the archive of Seredavin Samara Regional Clinical Hospital were analyzed, 132 medical histories of 77 patients were processed with discharge dates from January 2008 to February 2022 with the following diagnoses (according to the code of the International Classification of Diseases and Health Related Problem, 10th revision (ICD-10)): G12.0 (spinal muscular atrophy, type I [WerdnigHoffmann disease], G12.1 (other hereditary SMA), G12.8 (other SMA and related syndromes) and G12.9 (unspecified SMA). The analysis of the results of clinical, laboratory, instrumental and neuropsychiatric diagnostic methods was performed in comparison with the tactics of therapeutic management of these patients. For statistical processing of the data, methods of descriptive statistics were used. RESULTS: Socio-demographic data. As of February 2022, 58 patients were registered (mean age 38.4 (41.3) years, of them 32 (55.2%) were in iduals of female gender including 21 children (mean age 12.3 (7.4) years, 14 (24.1%) girls), with the following diagnoses according to ICD-10: G12.0 (n = 7 12.0% only children), G12.1 (children: n = 14 24.1% adults: n = 29 50.0%), G12.8 (n = 6 10.3% only adults), G12.9 (n = 2 3.4% only adults). Clinical data. Motor disorders from a mild proximal lower paraparesis (n = 13 22.4%) to pronounced tetraparesis (n = 7 12.0%). The study of mental status was limited to evaluation of the state of consciousness and effectiveness of contact. Data on therapy. Until 2021, symptomatic therapy of SMA was conducted in the region, since March 2021, 8 children (13.8% of the total s le) aged 7.3 (8.8) years received nusinersen, another 8 children (13.8%) aged 9.5 (6.9) years received risdiplam parents of 3 more children (5.2%) refused taking drugs. Of adult patients (n = 37 63.8% 35.3 (23.6) years) with confirmed SMA 5q (n = 10 17.2%, 35.3 (19.0) years), 1 patient received nusinersen, the rest 9 patients (15.5%) did not receive therapy, 3 (5.2%) were achieving the right to receive drugs (at the moment of the analysis). CONCLUSION: The data analysis revealed deficit of early SMA diagnosis (at the moment of the diagnosis, all the patients were already having pronounced symptoms), of assessment of affective and cognitive disorders, monitoring of treatment effectiveness (absence of validated scales for motor skills assessment), and also showed low availability of treatment for adult patients, which requires reorganization of care of patients with SMA in the region taking into account the revealed factors).
Publisher: Wiley
Date: 15-12-1999
DOI: 10.1002/(SICI)1098-2396(19991215)34:4<313::AID-SYN7>3.0.CO;2-1
Publisher: Wiley
Date: 2004
DOI: 10.1002/SYN.20053
Abstract: Positron emission tomography (PET) studies with radiolabeled dopamine D2-like receptor ligands reveal d- hetamine-evoked increases in the competition from endogenous dopamine. However, the corresponding effects of methylenedioxymeth hetamine (MDMA, "Ecstasy"), which releases catecholamines and also serotonin, are unknown. Using PET, we measured the binding potentials (pBs) of the benzamide [11C]raclopride and the butyrophenone N-[11C]methylspiperone ([11C]NMSP) in brain of living pigs first in a baseline condition and at 45 and 165 min after infusion of (+/-)-MDMA-HCl (1 mg/kg, i.v.). Concomitant studies of cerebral blood flow did not reveal significant perfusion changes in the cerebellum reference region or in striatum, supporting the present use of reference tissue methods for the mapping of MDMA-evoked pB changes. Relative to the baseline pB of [11C]raclopride for dopamine D(2/3) receptors in striatum (pB = 1.5-2.2), MDMA-treatment reduced pB by 35% in the first posttreatment scan and by 22% in the second posttreatment scan, comparable to changes typically evoked by d- hetamine at a similar dose. In most previous studies, the in vivo binding of butyrophenones has been nearly insensitive to d- hetamine-evoked dopamine release. However, we found the baseline pB of [11C]NMSP for dopamine D2-like receptors in striatum (pB = 4-5) was decreased by 30% in the first post-MDMA scan and by 50% in the second post-MDMA scan, irrespective of assumptions about the extent of equilibrium binding attained during the 90-min-long PET recordings. Distinct properties of MDMA such as simultaneous release of dopamine and serotonin in brain may account for the present finding of progressive decline in the availability of [11C]NMSP binding sites in striatum.
Publisher: Wiley
Date: 2004
DOI: 10.1002/SYN.20052
Abstract: 3,4-Methylenedioxymeth hetamine (MDMA) acutely releases intraneuronal dopamine and serotonin and evokes hyperthermia which is linked to toxicity for serotonin fibers. The acute effects of MDMA on cerebral blood flow (CBF) in living brain have not been described in an animal model of MDMA intoxication. We predicted that MDMA-induced hyperthermia should correlate with increased CBF in the hypothalamus, a serotonin-rich brain region subserving thermoregulation. To test this prediction, we used positron emission tomography with statistical parametric mapping for exploratory analysis of the focal changes in the magnitude of CBF in the anesthetized female Landrace pig (n = 9) at 30 and 150 min after acute challenge with MDMA-HCl (1 mg/kg, i.v.). The MDMA treatment was followed by increased CBF in the occipital cortex and in the medial mesencephalon overlapping the dorsal raphé nucleus, and reduced CBF in the cerebellar vermis and in a cluster in the medulla encompassing the left locus coeruleus. The in idual increase of body temperature correlated positively with increased CBF in the vicinity of the raphé nucleus, in the hypothalamus (regions linked to thermoregulation), and also in the medial frontal cortex, which together comprise the regions receiving the most dense serotonin innervations in pig brain. Thus, in idual differences in the susceptibility to MDMA-induced hyperthermia in this population correlated with the magnitude of focal increases in CBF within specific brain regions endowed with a dense serotonin innervation, including regions linked to thermoregulation.
Publisher: Wiley
Date: 08-1991
DOI: 10.1111/J.1471-4159.1991.TB03802.X
Abstract: Previous ex vivo studies have provided indirect evidence that the dopamine (DA) metabolite 3-methoxytyramine (3-MT) may be a useful index of DA release in vivo. In the present study, in vivo microdialysis was utilized to assess directly the relationship between extracellular DA and 3-MT in the striatum of rats following a variety of pharmacological manipulations. Apomorphine, a DA receptor agonist, produced a rapid, transient decrease in both DA and 3-MT. Conversely, the DA receptor antagonist haloperidol produced a concomitant increase in extracellular DA and 3-MT. Increases in DA and 3-MT were also noted following the administration of the DA uptake inhibitor, bupropion. Local application of tetrodotoxin resulted in the complete elimination of measurable amounts of DA and 3-MT in the dialysate, gamma-Butyrolactone also greatly decreased DA and 3-MT. Finally, d- hetamine produced a large increase in DA and 3-MT in animals that had been treated previously with gamma-butyrolactone. The Pearson correlation coefficients for DA and 3-MT following these manipulations ranged from 0.87 to 0.97. These data indicate that interstitial 3-MT is an accurate index of DA release. However, when compared with previous ex vivo findings, the present results also suggest that changes in tissue concentrations of 3-MT may not reliably reflect DA release following certain pharmacological manipulations.
Publisher: SAGE Publications
Date: 09-04-2014
Abstract: To date there is no validated, 18 F-labeled dopamine transporter (DAT) radiotracer with a rapid kinetic profile suitable for preclinical small-animal positron emission tomography (PET) studies in rodent models of human basal ganglia disease. Herein we report radiosynthesis and validation of the phenyltropane 18 F-FP-CMT. Dynamic PET recordings were obtained for 18 F-FP-CMT in six untreated rats, and six rats pretreated with the high-affinity DAT ligand GBR 12909 mean parametric maps of binding potential ( BP ND ) relative to the cerebellum reference region, and maps of total distribution volume ( V T ) relative to the metabolite-corrected arterial input were produced. 18 F-FP-CMT BP ND maps showed peak values of ˜4 in the striatum, versus ˜0.4 in the vicinity of the substantia nigra. Successive truncation of the PET recordings indicated that stable BP ND estimates could be obtained with recordings lasting only 45 minutes, reflecting rapid kinetics of 18 F-FP-CMT. Pretreatment with GBR 12909 reduced the striatal binding by 72% to 76%. High-performance liquid chromatography analysis revealed rapid metabolism of 18 F-FP-CMT to a single, non-brain penetrant hydrophilic metabolite. Total distribution of volume calculated relative to the metabolite-corrected arterial input was 4.4 mL/g in the cerebellum. The pharmacological selectivity of 18 F-FP-CMT, rapid kinetic profile, and lack of problematic metabolites constitute optimal properties for quantitation of DAT in rat, and may also predict applicability in human PET studies.
Publisher: Hindawi Limited
Date: 07-1999
DOI: 10.1111/J.1600-0404.1999.TB00722.X
Abstract: We tested the hypothesis that N-methylspiperone binding to dopamine D2 receptors must be reduced when L-dopa therapy of parkinsonism augments the binding of dopamine to the receptors and improves the clinical state expressed by the Hoehn & Yahr stage. A patient with MPTP-induced parkinsonism underwent two positron emission tomographic studies of the D2-like dopamine receptors with N-[11C]methylspiperone (NMSP). The first study took place 3 days after cessation of the L-dopa medication, the second 5 days after its resumption. Noticeable clinical deterioration occurred during both studies, consistent with significant dopamine receptor blockade by NMSP and elevated NMSP binding in both scans. The dopa treatment did not reduce the NMSP binding. On the contrary, the rate of binding of NMSP (k3) was increased on-dopa, compared to off-dopa. The increase was consistent with the slightly greater dopamine receptor density estimated after resumption of the dopa therapy. The NMSP binding to serotonin receptors suggested lower synaptic serotonin on-dopa than off-dopa. The results are consistent with negative correlation between the Hoehn & Yahr stage and the amount of dopamine bound to dopamine D2 receptors. Low synaptic serotonin may explain the depression seen in some patients on dopa for Parkinson's disease.
Publisher: Springer Science and Business Media LLC
Date: 04-1999
Publisher: Springer Science and Business Media LLC
Date: 09-2009
DOI: 10.1038/IJO.2009.168
Publisher: Wiley
Date: 25-07-2011
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.NEUROIMAGE.2009.11.035
Abstract: PET studies with the DOPA decarboxylase substrate 6-[(18)F]fluoro-l-DOPA (FDOPA) reveal the storage of [(18)F]-fluorodopamine within synaptic vesicles, mainly of dopamine fibres. As such, FDOPA PET is a sensitive indicator of the integrity of the nigrostriatal dopamine innervation. Nonetheless, there have been several reports of focal elevations of FDOPA utilization in brain of patients with Parkinson's disease (PD), all based on reference tissue methods. To investigate this phenomenon further, we used voxel-wise steady-state kinetic analysis to search for regions of elevated FDOPA utilization (K ml g(-1) min(-1)) and steady-state trapping (V(d) ml g(-1)) in a group of well-characterized patients with early, asymmetric PD, who were contrasted with an age-matched control group. Subtraction of the population mean parametric maps revealed foci of increased FDOPA utilization K (+25%) in the bilateral medial nucleus accumbens, whereas the expected declines in the trapping of FDOPA were seen in the caudate and putamen. This observation suggests hyperfunction of catecholamine fibres innervating specifically the limbic striatum, which could guide the design of future prospective FDOPA-PET studies of the impulse control disorders occurring in some PD patients under treatment with dopamine agonists. A focus of increased FDOPA influx and also V(d) was detected in the periaqueductal grey, consistent with some earlier reports based on reference tissue analysis. Increased FDOPA trapping in the periaqueductal grey of PD patients seems consistent with recent reports of increased activity of serotonin neurons in a rat model of parkinsonism.
Publisher: Radiological Society of North America (RSNA)
Date: 09-2009
DOI: 10.1148/RADIOL.2531082137
Abstract: To evaluate the incremental prognostic value of coronary artery calcification (CAC) scoring over single photon emission computed tomographic (SPECT) myocardial perfusion imaging in long-term prognosis and survival of patients with stable coronary artery disease (CAD). All patients provided written informed consent to undergo CAC scoring according to a protocol that was approved by the local clinical institutional review board. Over a median follow-up time of 5.4 years, 260 patients with stable CAD were followed up for severe cardiac events (cardiac death or nonfatal myocardial infarction). CAC scanning and SPECT myocardial perfusion imaging were performed at enrollment. Patients were stratified on the basis of well-established cutoff points for CAC score, summed stress score (SSS), and summed rest score (SRS). Kaplan-Meier survival curves and the Cox proportional hazards model were used. CAC score and SRS were identified as the only independent predictors of event-free survival. Patients with perfusion abnormalities at rest (SRS > or = 2), a CAC score greater than 400, or severe perfusion abnormalities under stress (SSS > or = 13) were identified as having significantly increased risk for subsequent severe cardiac events (P = .023, .0095, and .007, respectively). In addition, a CAC score greater than 400 offered incremental prognostic value over the scintigraphic scores alone (P = .028 with an SSS > 8 P = .008 with an SRS > or = 2). CAC score and SRS were identified as independent predictors of severe cardiac events during long-term follow-up of patients with known CAD. CAC scores imparted superior risk stratification information as compared with SPECT myocardial perfusion imaging results alone.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 05-2017
Publisher: MDPI AG
Date: 30-05-2021
DOI: 10.3390/LIFE11060506
Abstract: Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [11C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of mGluR5 availability, and to investigate their functional significance relating to neural systems-level changes. Twelve prolonged abstinent male subjects with alcohol dependence (median abstinence duration: six months) and ten healthy male controls underwent [11C]ABP688 PET imaging and 3-Tesla MRI. For mGluR5 availability, binding potential (BPND) was calculated using the simplified reference tissue model with cerebellar gray matter as the reference region. The initial region-of-interest (ROI)-based analysis yielded no significant group differences in mGluR5 availability. The voxel-based analysis revealed significantly lower [11C]ABP688 BPND in the middle temporal and inferior parietal cortices, and higher BPND in the superior temporal cortex in the alcohol dependence group compared with controls. Functional connectivity analysis of the rs-fMRI data employed seed regions identified from the quantitative [11C]ABP688 PET analysis, which revealed significantly altered functional connectivity from the inferior parietal cortex seed to the occipital pole and dorsal visual cortex in the alcohol dependence group compared with the control group. To our knowledge, this is the first report on the combined analysis of mGluR5 PET imaging and rs-fMRI in subjects with alcohol dependence. These preliminary results suggest the possibility of region-specific alterations of mGluR5 availability in vivo and related functional connectivity perturbations in prolonged abstinent subjects.
Publisher: Elsevier BV
Date: 1997
DOI: 10.1016/S0006-8993(96)01227-9
Abstract: We used quantitative autoradiography to measure the contribution of the 5-hydroxytryptamine (5-HT, serotonin) innervation of rat telencephalon to the synthesis of dopamine (DA) from exogenous L-DOPA. One week after stereotaxic infusions of 5,7-dihydroxy-tryptamine (5,7-DHT, 1.6 micrograms) into the right medial forebrain bundle (MFB), rats received [3H]DOPA (200 microCi,i.v.), which circulated for 90 min. The specific bindings in vitro of the 5-HT uptake site ligand [3H]citalopram and the DA uptake site ligand [125I]RTI-55 were measured in cryostat sections from the prosencephalon. In most structures ipsilateral to the lesion, [3H]citalopram specific binding was substantially reduced (50-90%). In the lateral habenula specific binding declined by only 30-40%, reflecting the presence of a 5-HT pathway deviating from the MFB at the mesencephalic flexure. [125I]RTI-55 binding in the basal ganglia was reduced by 50% on the side of the 5,7-DHT lesion, but was unperturbed in rats pretreated with desmethylimipramine (DMI). 5,7-DHT infusions decreased the synthesis of [3H]DA from [3H]DOPA in vivo in the basal ganglia by (40-90%). Pretreatment with DMI protected [3H]DA synthesis in the basal ganglia, but not in the olfactory tubercle and amygdala ipsilateral to the lesion. Whereas the 5-HT innervation does not contribute greatly to [3H]DA synthesis in the basal ganglia, a substantial proportion of [3H]DA synthesis in olfactory tubercle and amygdala requires an intact 5-HT innervation.
Publisher: Wiley
Date: 12-1998
DOI: 10.1002/(SICI)1098-2396(199812)30:4<351::AID-SYN2>3.0.CO;2-2
Publisher: Hindawi Limited
Date: 05-2001
DOI: 10.1034/J.1600-0404.2001.103005309.X
Abstract: As part of the DaNeX study, the uptake and binding of several positron emitting tracers was recorded in brain of healthy Göttingen minipigs, in minipigs with a syndrome of parkinsonism due to MPTP intoxication, and in parkinsonian minipigs which had received intrastriatal grafts of mesencephalic neurons from fetal pigs. The specific binding of [11C]NS 2214 to catecholamine uptake sites was reduced by two thirds in striatum of the intoxicated animals, while the rate constant for the decarboxylation of [18F]fluorodopa was reduced by 50% in the intoxicated animals. Several months after grafting, both pre-synaptic markers of dopamine fibres were normal in striatum. Dopamine depletion or grafting were without effect on the cerebral perfusion rate, measured with [15O]-water, did not alter the rate of oxygen metabolism (CMRO2) in brain, and did not alter the binding potential of tracers for dopamine D1 or D2 receptors in pig striatum. However, the grafting was associated with a local increase in the binding of [11C]PK 11195, a tracer for reactive gliosis, suggesting that an immunological reaction occurs at the site of graft, which might potentially have reduced the graft patency. However, this apparent immunological response did not preclude the re-establishment of normal [18F]fluorodopa and [11C]NS 2214 uptake in the allografted striatum.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.BRAINRESBULL.2005.02.033
Abstract: The analysis of physiological processes in brain by position emission tomography (PET) is facilitated when images are spatially normalized to a standard coordinate system. Thus, PET activation studies of human brain frequently employ the common stereotaxic coordinates of Talairach. We have developed an analogous stereotaxic coordinate system for the brain of the Gottingen miniature pig, based on automatic co-registration of magnetic resonance (MR) images obtained in 22 male pigs. The origin of the pig brain stereotaxic space (0, 0, 0) was arbitrarily placed in the centroid of the pineal gland as identified on the average MRI template. The orthogonal planes were imposed using the line between stereotaxic zero and the optic chiasm. A series of mean MR images in the coronal, sagittal and horizontal planes were generated. To test the utility of the common coordinate system for functional imaging studies of minipig brain, we calculated cerebral blood flow (CBF) maps from normal minipigs and from minipigs with a syndrome of parkisonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-poisoning. These maps were transformed from the native space into the common stereotaxic space. After global normalization of these maps, an undirected search for differences between the groups was then performed using statistical parametric mapping. Using this method, we detected a statistically significant focal increase in CBF in the left cerebellum of the MPTP-lesioned group. We expect the present approach to be of general use in the statistical parametric mapping of CBF and other physiological parameters in living pig brain.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2012
DOI: 10.1007/S00259-012-2157-1
Abstract: Left ventricular (LV) mechanical dyssynchrony (LVMD) was assessed by gated single-photon emission CT myocardial perfusion imaging (MPI) as an independent predictor of death from any cause in patients with known coronary artery disease (CAD) and reduced LV function. Between 2001 and 2010, 135 patients (64 ± 11 years of age, 84 % men) with known CAD, reduced LV ejection fraction (LVEF, 38 ± 15 %) and without an implanted cardiac resynchronization therapy device underwent gated MPI at rest. LV functional evaluation, which included phase analysis, was conducted to identify patients with LVMD. Kaplan-Meier survival curves were calculated for death of any cause during a mean follow-up of 2.0 ± 1.7 years. Uni- and multivariate Cox proportional hazards regression models were calculated to identify independent predictors of death from any cause. Of the 135 patients, 30 (22 %) died during follow-up (18 cardiac deaths and 12 deaths from other causes). Kaplan-Meier curves showed a significantly shorter survival time in the patients with severely reduced LVEF (<30 %, n = 45) or with LVMD (n = 81, log-rank test P <0.005). Cox models identified LVMD, LVEF < 30 % and a total perfusion deficit at rest of ≥ 20 % as independent predictors of death from any cause. While patients with LVEF <30 % in conjunction with LVMD had similar survival times irrespective of whether they had early revascularization or medical therapy, those patients with LVEF ≥ 30% and LVMD who underwent revascularization had significantly longer survival. In patients with known CAD and reduced LV function, dyssynchrony of the LV is an independent predictor of death from any cause.
Publisher: Oxford University Press (OUP)
Date: 22-10-2012
Publisher: Society of Nuclear Medicine
Date: 18-08-2010
DOI: 10.2967/JNUMED.110.075002
Abstract: We aimed to evaluate (68)Ga-DOTATATE PET/CT for the early prediction of time to progression and clinical outcome after a first cycle of peptide receptor radionuclide treatment (PRRT) in a cohort of patients with well-differentiated neuroendocrine tumors. Thirty-three consecutive patients (22 men and 11 women mean age +/- SD, 57.8 +/- 12.1 y) were investigated at baseline and again 3 mo after initiation of the first cycle of PRRT. (68)Ga-DOTATATE receptor expression was assessed using 2 measures of standardized uptake value (SUV): maximum SUV (SUV(max)) and tumor-to-spleen SUV ratio (SUV(T/S)). Percentage change in SUV scores after PRRT relative to baseline (DeltaSUV) was calculated. After completing 1-3 cycles of PRRT, patients entered the follow-up study, for estimation of time to progression. According to the Response Evaluation Criteria in Solid Tumors, progression was defined on the basis of contrast-enhanced CT. Clinical symptoms, as well as the tumor markers chromogranin A and neuron-specific enolase, were also recorded during regular follow-up visits. The 23 of 31 patients with decreased SUV(T/S) after the first PRRT cycle had longer progression-free survival than did the 8 of 31 patients with stable or increased scores (median survival not reached vs. 6 mo, P = 0.002). For the 18 of 33 patients showing a reduction in SUV(max), there was no significant difference in progression-free survival (median survival not reached vs. 14 mo, P = 0.22). Multivariate regression analysis identified SUV(T/S) as the only independent predictor for tumor progression during follow-up. In the 17 of 33 patients with clinical symptoms before PRRT, DeltaSUV(T/S) correlated with clinical improvement (r = 0.52, P < 0.05), whereas DeltaSUV(max) did not (r = 0.42, P = 0.10). Changes in the tumor markers (chromogranin A and neuron-specific enolase) did not predict DeltaSUV scores, clinical improvement, or time to progression. Decreased (68)Ga-DOTATATE uptake in tumors after the first cycle of PRRT predicted time to progression and correlated with an improvement in clinical symptoms among patients with well-differentiated neuroendocrine tumors DeltaSUV(T/S) was superior to DeltaSUV(max) for prediction of outcome.
Publisher: Wiley
Date: 03-2004
DOI: 10.1017/S0012162204000313
Abstract: Attention-deficit-hyperactivity disorder (ADHD), while largely thought to be a genetic disorder, has environmental factors that appear to contribute significantly to the aetiopathogenesis of the disorder. One such factor is pretern birth with vulnerable cerebrovascular homeostasis. We hypothesised that cerebral ischaemia at birth could contribute to persistent deficient dopaminergic neurotransmission, which is thought to be the pathophysiological basis of the disorder. We examined dopamine D(2/3) receptor binding with positron emission tomography (PET) using [11C] raclopride as a tracer, and continuous reaction times (RT) with a computerized test of variables (TOVA) in six adolescents (12-14 years of age, one female) who had been examined with cerebral blood flow (CBF) measurements at preterm birth and had a subsequent history of attention deficit. We found that high dopamine receptor availability ('empty receptors') was linked with increased RT and RT variability, supporting the concept of a dopaminergic role in symptomatology. High dopamine receptor availability was predicted by low neonatal CBF, supporting the hypothesis of cerebral ischaemia as a contributing factor in infants susceptible to ADHD.
Publisher: Elsevier BV
Date: 12-1986
DOI: 10.1016/0024-3205(86)90403-0
Abstract: An investigation of the metabolism of [18F]-6-fluorodopa (FDOPA) given to carbidopa treated subjects for scanning by positron emission tomography (PET) has been carried out by analysis of plasma. Reverse phase ion pair HPLC and alumina extraction were employed to fractionate and identify the [18F]-labelled compounds of plasma over a two hour period. During this time, the plasma levels of both total 18F and FDOPA decreased as a bi-exponential function of time. The rates of 18F, but not FDOPA, elimination were observed to decrease with age. In addition to FDOPA, only one other major peak of radioactivity was resolved by HPLC. Identification of this compound as the O-methylated derivative of FDOPA (MeFDOPA) is based on its shared HPLC elution time with in vitro synthesized O-[methyl-14C]-FDOPA. The ratio of the concentration of MeFDOPA to FDOPA (MeFDOPA/FDOPA) in plasma increased linearly with time, and the slope of this linear relationship decreased with the age of the in idual.
Publisher: Georg Thieme Verlag KG
Date: 2010
DOI: 10.3413/NUKMED-0299
Abstract: Aim: Fluorine-labelled choline derivatives were recently suggested as agents for visualizing vulnerable atherosclerotic plaques. We therefore aimed to evaluate the association between18F-fluoroethylcholine (FEC) uptake in the wall of large arteries, where calcification was also measured, with the presence of cardiovascular risk factors and occurrence of prior cardiovascular events. Patients, methods: Detailed clinical information, including common cardiovascular risk factors, was obtained retrospectively in 60 prostate cancer patients examined with whole-body FEC PETCT. In each patient, we calculated the mean blood pool-corrected SUV, as well as the mean target-to-background ratio (TBR), in addition to the sum of calcified plaques (CPsum) from six major vessels: ascending and descending aorta, aortic arch, abdominal aorta, and both iliac arteries. Results: As reported previously, the CPsum correlated significantly with cardiovascular risk factors, in contrast to mean SUV or TBR scores, which did not show any significance with the presence of cardiovascular risk factors. There was no correlation between CPsum, mean TBR or SUV, nor was there any significant association of CPsum, mean TBR or SUV with the prior occurrence of cardio- or cerebrovascular events. Conclusion: Contrary to a recent report, we found in our rather large cohort of elderly prostate cancer patients no significant association between FEC uptake in large vessels and atherosclerotic plaque burden, or the presence of cardiovascular risk factors. In line with prior reports on structural changes in vessels, increased calcified atherosclerotic plaque burden was strongly associated with the occurrence of common cardiovascular risk factors.
Publisher: Springer Science and Business Media LLC
Date: 09-06-2015
DOI: 10.1038/MP.2015.74
Publisher: Springer Science and Business Media LLC
Date: 07-11-2014
DOI: 10.1007/S00213-014-3794-9
Abstract: Many aspects of the neurobiology of schizophrenia, especially the physiological basis of the negative symptoms and associated cognitive deficits, remain inadequately understood. Tandon and Greden (1989) postulated a central role of dopaminergic/cholinergic imbalance in schizophrenia. In light of this hypothesis, we elected to investigate the effects of anticholinergic challenge on psychopathology, cognition and attention in 12 unmedicated patients with schizophrenia and 12 healthy controls. The first examination occurred before any pharmacological intervention the second examination was carried out immediately following an intravenous infusion of 5 mg biperiden, a centrally acting antimuscarinergic agent. The biperiden challenge provoked a considerable increase in PANSS scores in both groups which was significantly more pronounced in patients (repeated measures analysis of variance (ANOVA) (rmANOVA): F(df) = 6.4(1,22) p = 0.019). The increase in the PANSS scores showed a significant negative correlation with age in patients. Biperiden caused considerable cognitive impairments in both groups. A significant group difference (rmANOVA) could be observed for TMT-B (F(df) = 11.29(1,22) p = 0.003). The anticholinergic intervention caused more pronounced psychopathological and cognitive deteriorating effects in patients suffering from schizophrenia than in healthy volunteers. This could be related to the disrupted cholinergic transmission in schizophrenia. Our findings speak on behalf of the need of a more restrictive use of anticholinergics in psychiatric patients. The age-related attenuation of PANSS score increases in patients could be related to the age-dependent changes in dopamine dynamics and also to the age-associated decline of the availability of muscarinic receptors. Our results emphasise the need for further investigation of cholinergic disturbances in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 05-2018
DOI: 10.1007/S00213-018-4916-6
Abstract: A considerable body of research links cognitive function to dopaminergic transmission in the prefrontal cortex, but less is known about cognition in relation to striatal dopamine D We investigated this association by obtaining PET recordings with the high-affinity D The patients' performance in cognitive tests was significantly impaired in almost all domains. Irrespective of medication history, the mean [ The association between better cognitive performance and greater BP
Publisher: Springer Science and Business Media LLC
Date: 30-10-2002
Publisher: Georg Thieme Verlag KG
Date: 09-2008
Abstract: Dopamine transmission remains central to our understanding of neurocircuitry models of schizophrenia, and to the mechanism of action of typical antipsychotic medications, which preferentially block D (2)-receptors in striatum. In cerebral cortex, D (2)- and D (1)- mediated transmission modulates information processing, and tunes the activity of the cortico-striato-thalamic loops, in which dopaminergic, glutamatergic, GABAergic and serotonergic projections are integrated and interconnected. Molecular imaging techniques, especially positron emission tomography, have been used to investigate the spatial pattern of the binding properties of antipsychotic medications. We now summarize the state of development of molecular imaging, integrated into a model of schizophrenia emphasizing dysfunction of a complex loop, rather than a discrete abnormality in the basal ganglia, as had been implicitly assumed in the classic dopamine model of psychosis. Finally, hypotheses are proposed to explain differences between first- and second generation antipsychotics with respect of regional selectivity for dopamine and serotonin neurons.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-02-2010
Abstract: Sensation seeking is a core personality trait that declines with age in both men and women, as do also both density and availability of the dopamine D 2/3 receptors in striatum and cortical regions. In contrast, novelty seeking at a given age relates inversely to dopamine receptor availability. The simplest explanation of these findings is an inverted-U-shaped correlation between ratings of sensation seeking on the Zuckerman scale and dopamine D 2/3 receptor availability. To test the claim of an inverted-U-shaped relation between ratings of the sensation-seeking personality and measures of dopamine receptor availability, we used PET to record [ 11 C]raclopride binding in striatum of 18 healthy men. Here we report that an inverted-U shape significantly matched the receptor availability as a function of the Zuckerman score, with maximum binding potentials observed in the midrange of the scale. The inverted-U shape is consistent with a negative correlation between sensation seeking and the reactivity (“gain”) of dopaminergic neurotransmission to dopamine. The correlation reflects Zuckerman scores that are linearly linked to dopamine receptor densities in the striatum but nonlinearly linked to dopamine concentrations. Higher dopamine occupancy and dopamine concentrations explain the motivation that drives afflicted in iduals to seek sensations, in agreement with reduced protection against addictive behavior that is characteristic of in iduals with low binding potentials.
Publisher: Wiley
Date: 15-09-1999
DOI: 10.1002/(SICI)1098-2396(19990915)33:4<247::AID-SYN1>3.0.CO;2-6
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.NEUINT.2010.01.010
Abstract: There has arisen considerable interest in the study of dopamine D(2/3) agonist binding sites by positron emission tomography (PET), based on the claim that agonist sites represent a functional subset of the total number of sites labeled by more conventional antagonist ligands. To test the basis of this claim, we used quantitative autoradiography to measure the abundance of binding sites of a dopamine D(2/3) agonist ([(3)H]NPA) and an antagonist ([(3)H]raclopride) in cryosections of rat brain. Saturation binding studies revealed that the B(max) for [(3)H]NPA was nearly identical to that of [(3)H]raclopride in dorsal brain regions, but was 25% less in the ventral striatum and 56% less in the olfactory tubercle. We also tested the displacement of the two ligands by the hallucinogen LSD, which is known to have dopamine agonist properties. Whereas displacement of [(3)H]raclopride by increasing LSD concentrations was monophasic, displacement of [(3)H]NPA was biphasic, suggesting an action of LSD via a subset of dopamine D(2/3) agonist binding sites. Addition of the stable GTP analogue Gpp(NH)p to the medium abolished 90% of the [(3)H]NPA binding, and increased [(3)H]raclopride binding by 10%, with a shift to the right in the LSD competition curve, suggesting retention of endogenous dopamine in washed cryostat sections. Thus [(3)H]NPA and [(3)H]raclopride binding sites have nearly identical abundances in rat dorsal striatum, but are distinct in the ventral striatum, and with respect to their displacement by LSD.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2008
DOI: 10.1007/S00259-007-0683-Z
Abstract: Dopaminergic neurotransmission in the ventral striatum may interact with limbic processing of affective stimuli, whereas dorsal striatal dopaminergic neurotransmission can affect habitual processing of emotionally salient stimuli in the pre-frontal cortex. We investigated the dopaminergic neurotransmission in the ventral and dorsal striatum with respect to central processing of affective stimuli in healthy subjects. Subjects were investigated with positron emission tomography and [(18)F]DOPA for measurements of dopamine synthesis capacity and [(18)F]DMFP for estimation of dopamine D2 receptor binding potential. Functional magnetic resonance imaging was used to assess the blood-oxygen-level-dependent (BOLD) response to affective pictures, which was correlated with the ratio of [(18)F]DOPA net influx constant K(app)(in)/[(18)F]DMFP-binding potential (BP_ND) in the ventral and dorsal striatum. The magnitude of the ratio in the ventral striatum was positively correlated with BOLD signal increases elicited by negative versus neutral pictures in the right medial frontal gyrus (BA10), right inferior parietal lobe and left post-central gyrus. In the dorsal striatum, the ratio was positively correlated with BOLD signal activation elicited by negative versus neutral stimuli in the left post-central gyrus. The BOLD signal elicited by positive versus neutral stimuli in the superior parietal gyrus was positively correlated with the dorsal and ventral striatal ratio. The correlations of the ratio in the ventral and dorsal striatum with processing of affective stimuli in the named cortical regions support the hypothesis that dopamine transmission in functional isions of the striatum modulates processing of affective stimuli in specific cortical areas.
Publisher: Elsevier BV
Date: 08-1987
DOI: 10.1016/0006-2952(87)90526-0
Abstract: [18F]-6-Fluoro-L-DOPA ([18F]DOPA), a tracer for cerebral dopamine in studies utilizing positron emission tomography (PET), is rapidly metabolized by catechol-O-methyltransferase (COMT) in the periphery following intravenous injection to carbidopa-pretreated humans and rats. Experiments were performed to determine the effect of pretreatment with 3',4'-dihydroxy-2-methyl-propiophenone (U-0521), a competitive inhibitor of COMT, on [18F]DOPA metabolism in the carbidopa-pretreated hooded rat. U-0521 (25 mg/kg, i.p.), administered 10 min prior to the [18F]DOPA, served to increase the persistence of [18F]DOPA in plasma over a 2-hr period by decreasing the rate of formation of the peripheral metabolite 3-O-methyl-6-fluorotyrosine (Me[18F]DOPA). This compound passes readily into brain and was the sole [18F]DOPA metabolite observed in cortex and cerebellum. U-0521 produced a short-lasting decrease in Me[18F]DOPA levels in these two tissues. In striatum, decreases in Me[18F]DOPA were found to last at least 90 min. Associated with the elevated availability of [18F]DOPA in plasma produced by U-0521 were 50% increases in striatal [18F]dopamine ([18F]DA) levels and 40% increases in the levels of [18F]dihydroxyphenylacetic acid ([18F]DOPAC) at times between 30 and 90 min following [18F]DOPA injection. Increased decarboxylation of [18F]DOPA in the striatum of U-0521-treated rats resulted in heightened radiocontrast between striatum and other cerebral tissues.
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.NEUROIMAGE.2005.11.014
Abstract: In animal studies, acute antipsychotic treatment was shown to enhance striatal DOPA-decarboxylase (DDC) activity. However, this phenomenon has not been demonstrated in humans by positron emission tomography (PET). Therefore, we investigated acute haloperidol effects on DDC activity in humans using [18F]fluorodopa (FDOPA) PET. Nine healthy volunteers were scanned with FDOPA in drug-free baseline conditions and after 3 days of haloperidol treatment (5 mg/day). A continuous performance test (CPT) was administered in both conditions. The net blood-brain clearance of FDOPA (K(in)app) in striatum, mesencephalon, and medial prefrontal cortex was calculated by volume-of-interest analysis. The macroparameter K(in)app is a composite of several kinetic terms defining the distribution volume of FDOPA in brain (V(e)D) and the relative activity of DOPA decarboxylase (k3D). Therefore, compartmental kinetic analysis was used to identify the physiological basis of the observed changes in K(in)app period. The magnitude of K(in)app was significantly increased in the putamen (18%) and mesencephalon (36%). Furthermore, V(e)D in the brain was increased by 15%. Increments of k3(D) in the basal ganglia did not attain statistical significance. The significant worsening of CPT results did not correlate with changes in FDOPA utilization. The present PET results indicate potentiation of FDOPA utilization in human basal ganglia by acute haloperidol treatment, apparently due to increased availability throughout the brain. The stimulation of DDC cannot be excluded due to insufficient statistical power in the estimation of k3(D) changes.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.NEUBIOREV.2012.01.009
Abstract: Positron emission tomography (PET) provides dynamic images of the biodistribution of radioactive tracers in the brain. Through application of the principles of compartmental analysis, tracer uptake can be quantified in terms of specific physiological processes such as cerebral blood flow, cerebral metabolic rate, and the availability of receptors in brain. Whereas early PET studies in animal models of brain diseases were h ered by the limited spatial resolution of PET instruments, dedicated small-animal instruments now provide molecular images of rodent brain with resolution approaching 1mm, the theoretic limit of the method. Major applications of PET for brain research have consisted of studies of animal models of neurological disorders, notably Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD), stroke, epilepsy and traumatic brain injury these studies have particularly benefited from selective neurochemical lesion models (PD), and also transgenic rodent models (AD, HD). Due to their complex and uncertain pathophysiologies, corresponding models of neuropsychiatric disorders have proven more difficult to establish. Historically, there has been an emphasis on PET studies of dopamine transmission, as assessed with a range of tracers targeting dopamine synthesis, plasma membrane transporters, and receptor binding sites. However, notable recent breakthroughs in molecular imaging include the development of greatly improved tracers for subtypes of serotonin, cannabinoid, and metabotropic glutamate receptors, as well as noradrenaline transporters, amyloid-β and neuroinflammatory changes. This article reviews the considerable recent progress in preclinical PET and discusses applications relevant to a number of neurological and neuropsychiatric disorders in humans.
Publisher: MDPI AG
Date: 24-12-2021
DOI: 10.3390/BIOMEDICINES10010034
Abstract: Adiponectin is an adipokine that mediates cellular cholesterol efflux and plays important roles in neuroinflammatory processes. In this study, we undertook positron emission tomography (PET) with the translocator protein (TSPO) ligand [11C]PK11195 and measured serum adiponectin levels in groups of treatment-naïve young adult patients with major depressive disorder (MDD) and matched healthy controls. Thirty treatment-naïve MDD patients (median age: 24 years) and twenty-three healthy controls underwent [11C]PK11195 PET. We quantified TSPO availability in brain as the [11C]PK11195 binding potential (BPND) using a reference tissue model in conjunction with the supervised cluster analysis (SVCA4) algorithm. Age, sex distribution, body mass index, and serum adiponectin levels did not differ between the groups. Between-group analysis using a region-of-interest approach showed significantly higher [11C]PK11195 BPND in the left anterior and right posterior cingulate cortices in MDD patients than in controls. Serum adiponectin levels had significant negative correlations with [11C]PK11195 BPND in the bilateral hippoc us in MDD patients, but significant positive correlations in the bilateral hippoc us in the control group. Our results indicate significantly higher TSPO binding in the anterior and posterior cingulate cortices in treatment-naïve young MDD patients, suggesting microglial activation in these limbic regions, which are involved in cognitive and emotional processing. The opposite correlations between [11C]PK11195 BPND in the hippoc us with serum adiponectin levels in MDD and control groups suggest that microglial activation in the hippoc us may respond differentially to adiponectin signaling in MDD and healthy subjects, possibly with respect to microglial phenotype.
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.NEUROIMAGE.2013.09.017
Abstract: We previously investigated the progression of β-amyloid deposition in brain of mice over-expressing amyloid-precursor protein (APP-Swe), a model of Alzheimer's disease (AD), in a longitudinal PET study with the novel β-amyloid tracer [(18)F]-florbetaben. There were certain discrepancies between PET and autoradiographic findings, which seemed to arise from partial volume effects (PVE). Since this phenomenon can lead to bias, most especially in the quantitation of brain microPET studies of mice, we aimed in the present study to investigate the magnitude of PVE on [(18)F]-florbetaben quantitation in murine brain, and to establish and validate a useful correction method (PVEC). Phantom studies with solutions of known radioactivity concentration were performed to measure the full-width-at-half-maximum (FWHM) resolution of the Siemens Inveon DPET and to validate a volume-of-interest (VOI)-based PVEC algorithm. Several VOI-brain-masks were applied to perform in vivo PVEC on [(18)F]-florbetaben data from C57BL/6(N=6) mice, while uncorrected and PVE-corrected data were cross-validated with gamma counting and autoradiography. Next, PVEC was performed on longitudinal PET data set consisting of 43 PET scans in APP-Swe (13-20months) and age-matched wild-type (WT) mice using the previously defined masks. VOI-based cortex-to-cerebellum ratios (SUVR) were compared for uncorrected and PVE-corrected results. Brains from a subset of transgenic mice were ultimately examined by autoradiography ex vivo and histochemistry in vitro as gold standard assessments, and compared to VOI-based PET results. The phantom study indicated a FWHM of 1.72mm. Applying a VOI-brain-mask including extracerebral regions gave robust PVEC, with increased precision of the SUVR results. Cortical SUVR increased with age in APP-Swe mice compared to baseline measurements (16months: +5.5%, p<0.005 20months: +15.5%, p<0.05) with uncorrected data, and to a substantially greater extent with PVEC (16months: +12.2% p<0.005 20months: +36.4% p<0.05). WT animals showed no binding changes, irrespective of PVEC. Relative to autoradiographic results, the error [%] for uncorrected cortical SUVR was 18.9% for native PET data, and declined to 4.8% upon PVEC, in high correlation with histochemistry results. We calculate that PVEC increases by 10% statistical power for detecting altered [(18)F]-florbetaben uptake in aging APP-Swe mice in planned studies of disease modifying treatments on amyloidogenesis.
Publisher: Wiley
Date: 2010
DOI: 10.1002/SYN.20706
Abstract: We earlier reported an anomalous 50% decrease in [(11)C]N-methylspiperone ([(11)C]NMSP) binding to dopamine D(2)-like receptors in living pig striatum after challenge with 3,4-methylenedioxymeth hetamine (MDMA, "Ecstasy"), suggesting either (1) a species peculiarity in the vulnerability of butyrophenone binding to competition from dopamine or (2) a novel consequence of synergistic actions of serotonin and dopamine at dopamine receptors. To distinguish these possibilities, we used microPET to test the vulnerability of [(11)C]NMSP binding in striatum of rats with unilateral telencephalic serotonin lesions, later verified by [(125)I]RTI-55 autoradiography. Baseline [(11)C]NMSP microPET recordings were followed by either saline or MDMA-HCl (4 mg/kg) injections (i.v.), and a second [(11)C]NMSP recording, culminating with injection of [(3)H]raclopride for autoradiography ex vivo. Neither MDMA-challenge nor serotonin lesion had any detectable effect on [(11)C]NMSP binding. In contrast, MDMA challenge increased receptor occupancy by [(3)H]raclopride ex vivo (relative to the B(max) in vitro) from 8% to 12%, and doubled the free ligand concentration in cerebral cortex, apparently by blocking hepatic CYP2D6. Assuming a single binding-site model, the increased [(3)H]raclopride binding indicated doubling of the apparent equilibrium dissociation constant in vivo (K(app) (d)), revealing a 2-fold increase in competition from endogenous dopamine at [(3)H]raclopride binding sites. The results favor hypothesis (1) that the remarkable vulnerability of [(11)C]NMSP binding in pig striatum to MDMA challenge does not generalize to the rodent.
Publisher: Wiley
Date: 08-2006
DOI: 10.1111/J.1460-9568.2006.04975.X
Abstract: Increased binding of the peripheral benzodiazepine binding site (PBBS) ligand [(3)H]PK11195 in the central nervous system of patients suffering from acute and chronic neuropathology has been associated with reactive microgliosis. However, it remains uncertain which stages of microglial activation occur in conjunction with the increased [(3)H]PK11195 binding. We used quantitative autoradiography for [(3)H]PK11195 and quantitative polymerase chain reaction for PBBS mRNA and markers of early and late microglial activation to investigate the time-course of cellular responses in the hippoc us of mice with degeneration of the entorhinal-hippoc al perforant path. The axonal lesion evoked an increase in the B(max) for [(3)H]PK11195 in hippoc us which peaked at 2 days post-lesion, remained elevated at day 5 and began to decline at 10 days post-lesion. These changes occurred in the absence of significant changes in affinity in vitro. Quantitative polymerase chain reaction analysis of isolated hippoc i using exon-specific primers indicated the presence of several splice variants of PBBS mRNA, which appeared to be affected differentially by the lesion. The changes in PBBS mRNA and CD11b mRNA levels correlated with the B(max) for [(3)H]PK11195 during 10 days post-lesion, suggesting that microglial activation couples with increases in mRNA levels for these markers. In addition, the onset of changes in PBBS mRNA levels coincided with the significantly elevated tumor necrosis factor mRNA levels present during early microglial activation at 2 days post-lesion. We conclude that up-regulation of [(3)H]PK11195 binding and PBBS mRNA levels coincided with early microglial activation, characterized by concomitantly increased microglial tumor necrosis factor mRNA levels, and persisted throughout the period with reactive microgliosis.
Publisher: Wiley
Date: 23-05-2003
DOI: 10.1002/SYN.10222
Abstract: In vitro, the novel diazabicyclononane NS 4194 has several thousand-fold selectivity for blocking the transport into rat brain synaptosomes of [(3)H]-serotonin in comparison to [(3)H]-dopamine or [(3)H]-noradrenaline. We have prepared [(11)C]-NS 4194 in order to test its properties for PET imaging of brain serotonin transporters in comparison with the well-documented tracer [(11)C]-DASB. Both compounds had rapid clearance from blood to brain of living pigs. The apparent equilibrium distribution volumes in cerebellum were 35 ml g(-1) for [(11)C]-NS 4194 and 11 ml g(-1) for [(11)C]-DASB. Pretreatment of pigs with citalopram did not reduce the uptake of either tracer in cerebellum, validating the use of that tissue as a nonbinding reference tissue for kinetic analysis of specific binding. The binding potential (pB) calculated for [(11)C]-NS 4194 using arterial input models was close to 0.5 in the telencephalon, and was 60% displaced by citalopram. However, the reference tissue method of Lammertsma was unsuited to calculate pB for this tracer, apparently due to its excessive nonspecific binding. In contrast to the relatively homogeneous binding of [(11)C]-NS 4194, the pB of [(11)C]-DASB ranged from 0.6 in frontal cortex to 2 in the mesencephalon when calculated by the method of Lammertsma. Parametric maps of the pB of [(11)C]-DASB showed a pattern consistent with the known distribution of serotonin transporters in pig brain in vitro, and there was a uniform displacement of 80% of the specific binding after citalopram treatment in vivo. In conclusion, [(11)C]-DASB is in several respects superior to [(11)C]-NS 4194 for the detection of serotonin uptake sites by PET.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2012
Abstract: We performed an initial evaluation of non-invasive ECG-gated [ 18 F]FDG-positron emission tomography (FDG-PET) for serial measurements of left ventricular volumes and function in murine models of dilated (DCM) and ischemic cardiomyopathy (ICM), and then tested the effect of erythropoietin (EPO) treatment on DCM mice in a preliminary FDG-PET therapy monitoring study. Mice developed DCM 8 weeks after injection with Coxsackievirus B3 (CVB3), whereas ICM was induced by ligation of the left anterior descending artery. LV volumes (EDV and ESV) and the ejection fraction (LVEF) of DCM, ICM and healthy control mice were measured by FDG-PET and compared with reference standard results obtained with 1.5 T magnetic resonance imaging (MRI). In the subsequent monitoring study, LVEF of DCM mice was evaluated by FDG-PET at baseline, and after 4 weeks of treatment, with EPO or saline. LV volumes and the LVEF as measured by FDG-PET correlated significantly with the MRI results. These correlations were higher in healthy and DCM mice than in ICM mice, in which LVEF measurements were somewhat compromised by absence of FDG uptake in the area of infarction. LV volumes (EDV and ESV) were systematically underestimated by FDG-PET, with net bias such that LVEF measurements in both models of heart disease exceeded by 15% to 20% results obtained by MRI. In our subsequent monitoring study of DCM mice, we found a significant decrease of LVEF in the EPO group, but not in the saline-treated mice. Moreover, LVEF in the EPO and saline mice significantly correlated with histological scores of fibrosis. LVEF estimated by ECG-gated FDG-PET significantly correlated with the reference standard MRI, most notably in healthy mice and mice with DCM. FDG-PET served for longitudinal monitoring of effects of EPO treatment in DCM mice.
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.EURONEURO.2014.12.010
Abstract: Altered SERT and DAT availabilities during treatment with escitalopram were investigated with [(123)I]2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) SPECT in a series of patients fulfilling the criteria for unipolar major depressive disorder (MDD). 27 patients (10m, 42±16y) with diagnosis of MDD were recruited for the study. All patients underwent neuropsychiatric testing for assessment of Hamilton Depression (HAM-D) and Beck Depression Inventory (BDI) scores. At baseline, [(123)I]β-CIT SPECT recordings were acquired 4h (SERT-weighted) and 20-24h p.i (DAT-weighted). Follow-up scans and neuropsychiatric testing were performed after six weeks of stable escitalopram medication. Voxel-wise parametric maps of specific/ non-specific ratios-1 (~BPND) were calculated. At baseline, DAT-weighted BPND was 5.06±0.81 in striatum and SERT-weighted BPND was 0.94±0.18 in thalamus. There were significant negative correlations with age for DAT in striatum (R=-0.60 p<0.01) and SERT in thalamus (R=-0.45 p<0.05). Under SSRI treatment there was an apparent 42% occupancy of SERT in thalamus (p<0.0001), whereas DAT availability increased significantly by 20% in striatum (p<0.001) higher apparent SERT occupancy in thalamus was associated with lesser DAT increase in striatum (R=-0.62 p<0.005). The low apparent SERT occupancy may be confounded by alterations in SERT expression during treatment. Thus, [(123)I]β-CIT SPECT revealed age-dependent declines in DAT and SERT availabilities in un-medicated MDD patients, comparable to that seen previously in healthy controls. At follow-up, the SSRI-evoked increase in DAT was less pronounced in the older patients, even though apparent SERT occupancy and clinical improvement were not age-dependent. Present findings may have implications for escitalopram dosage and side effect profile in younger MDD patients.
Publisher: MDPI AG
Date: 19-11-2019
DOI: 10.3390/MOLECULES24224190
Abstract: The discovery of endogenous peptide ligands for morphine binding sites occurred in parallel with the identification of three subclasses of opioid receptor (OR), traditionally designated as μ, δ, and κ, along with the more recently defined opioid-receptor-like (ORL1) receptor. Early efforts in opioid receptor radiochemistry focused on the structure of the prototype agonist ligand, morphine, although N-[methyl-11C]morphine, -codeine and -heroin did not show significant binding in vivo. [11C]Diprenorphine ([11C]DPN), an orvinol type, non-selective OR antagonist ligand, was among the first successful PET tracers for molecular brain imaging, but has been largely supplanted in research studies by the μ-preferring agonist [11C]carfentanil ([11C]Caf). These two tracers have the property of being displaceable by endogenous opioid peptides in living brain, thus potentially serving in a competition-binding model. Indeed, many clinical PET studies with [11C]DPN or [11C]Caf affirm the release of endogenous opioids in response to painful stimuli. Numerous other PET studies implicate μ-OR signaling in aspects of human personality and vulnerability to drug dependence, but there have been very few clinical PET studies of μORs in neurological disorders. Tracers based on naltrindole, a non-peptide antagonist of the δ-preferring endogenous opioid enkephalin, have been used in PET studies of δORs, and [11C]GR103545 is validated for studies of κORs. Structures such as [11C]NOP-1A show selective binding at ORL-1 receptors in living brain. However, there is scant documentation of δ-, κ-, or ORL1 receptors in healthy human brain or in neurological and psychiatric disorders here, clinical PET research must catch up with recent progress in radiopharmaceutical chemistry.
Publisher: Wiley
Date: 2006
DOI: 10.1002/SYN.20262
Abstract: We have developed [(11)C]mirtazapine as a ligand for PET studies of antidepressant binding in living brain. However, previous studies have determined neither optimal methods for quantification of [(11)C]mirtazapine binding nor the pharmacological identity of this binding. To obtain that information, we have now mapped the distribution volume (V(d)) of [(11)C]mirtazapine relative to the arterial input in the brain of three pigs, in a baseline condition and after pretreatment with excess cold mirtazapine (3 mg/kg). Baseline V(d) ranged from 6 ml/ml in cerebellum to 18 ml/ml in frontal cortex, with some evidence for a small self-displaceable binding component in the cerebellum. Regional binding potentials (pBs) obtained by a constrained two-compartment model, using the V(d) observation in cerebellum, were consistently higher than pBs obtained by other arterial input or reference tissue methods. We found that adequate quantification of pB was obtained using the simplified reference tissue method. Concomitant PET studies with [(15)O]-water indicated that mirtazapine challenge increased CBF uniformly in cerebellum and other brain regions, supporting the use of this reference tissue for calculation of [(11)C]mirtazapine pB. Displacement by mirtazapine was complete in the cerebral cortex, but only 50% in diencephalon, suggesting the presence of multiple binding sites of differing affinities in that tissue. Competition studies with yohimbine and RX 821002 showed decreases in [(11)C]mirtazapine pB throughout the forebrain use of the multireceptor version of the Michaelis-Menten equation indicated that 42% of [(11)C]mirtazapine binding in cortical regions is displaceable by yohimbine. Thus, PET studies confirm that [(11)C]mirtazapine affects alpha(2)-adrenoceptor binding sites in living brain.
Publisher: Wiley
Date: 2005
DOI: 10.1002/SYN.20141
Abstract: The psychoactive properties of the hallucinogen LSD have frequently been attributed to high affinity interactions with serotonin 5HT2 receptors in brain. Possible effects of LSD on dopamine D2/3 receptor availability have not previously been investigated in living brain. Therefore, we used PET to map the binding potential (pB) of [11C]raclopride in brain of three pigs, first in a baseline condition, and again at 1 and 4 h after administration of LSD (2.5 microg/kg, i.v.). There was a progressive treatment effect in striatum, where the pB was significantly reduced by 19% at 4 h after LSD administration. Concomitant maps of cerebral blood flow did not reveal significant changes in perfusion during this interval. Subsequent in vitro studies showed that LSD displaced [3H]raclopride (2 nM) from pig brain cryostat sections with an IC50 of 275 nM according to a one-site model. Fitting of a two-site model to the data suggested the presence of a component of the displacement curves with a subnanomolar IC50, comprising 20% of the total [3H]raclopride binding. In microdialysis experiments, LSD at similar and higher doses did not evoke changes in the interstitial concentration of dopamine or its acidic metabolites in rat striatum. Together, these results are consistent with a direct interaction between LSD and a portion of dopamine D2/3 receptors in pig brain, possibly contributing to the psychopharmacology of LSD.
Publisher: SAGE Publications
Date: 11-2012
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.NEUROIMAGE.2015.10.031
Abstract: A recent [(18)F]FDOPA-PET study reports negative correlations between dopamine synthesis rates and aggressive behavior. Since dopamine is among the substrates for monoamine oxidase A (MAOA), this investigation examines whether functional allelic variants of the MAOA tandem repeat (VNTR) promotor polymorphism, which is known to modulate aggressive behavior, influences dopamine release and aggression in response to violent visual stimuli. We selected from a genetic prescreening s le, strictly case-matched groups of 2×12 healthy male subjects with VNTRs predictive of high (MAOA-High) and low (MAOA-Low) MAOA expression. Subjects underwent pairs of PET sessions (dopamine D2/3 ligand [(18)F]DMFP) while viewing a movie of neutral content, versus violent content. Directly afterwards, aggressive behavior was assessed by the Point Subtraction Aggression Paradigm (PSAP). Finally, PET data of 23 participants and behavioral data of 22 participants were analyzed due to post hoc exclusion criteria. In the genetic prescreening s le MAOA-Low carriers had significantly increased scores on the Buss-Perry Aggression Questionnaire. In the PET-study-group, aggressive behavior under the emotional neutral condition was significantly higher in the MAOA-Low group. Interestingly, the two MAOA-groups showed inverse dopaminergic and behavioral reactions to the violent movie: The MAOA-High group showed higher dopamine release and increased aggression after the violent movie MAOA-Low subjects showed decreases in aggressive behavior and no consistent dopamine release. These results indicate a possible impact of the MAOA-promotor polymorphism on the neurobiological modulation of aggressive behavior. However, the data do not support approaches stating that MAOA-Low fosters aggression by a simple pro-dopaminergic mechanism.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.NEUROIMAGE.2006.10.013
Abstract: Molecular and functional imaging techniques reveal evidence for lateralization of human cerebral function. Based on animal data, we hypothesized that asymmetry in dopamine neurotransmission declines during normal aging. In order to test this hypothesis, we measured dopamine D2/3 receptor availability with [18F]desmethoxyfallypride-PET (DMFP) in putamen and caudate nucleus (NC) of 21 healthy, right-handed males (24-60 years 35+/-10). For volumetric analysis, high-resolution T1-weighted MR-images were obtained in 18 of the PET-subjects in order to assess possible age-related decreases in NC and putamen volume. The calculated DMFP binding potentials (BP) showed a right-ward asymmetry in NC of young subjects that decreased with age (r = 0.577, p = 0.006 Pearson correlation two-tailed). An age-independent analysis showed a right-ward asymmetry in NC of the whole subject group (left: 1.49+/-0.35 right: 1.65+/-0.43 [mean+/-S.D.] p = 0.020). No such side lateralization or age-effects could be found in the putamen. Volumes tended to be asymmetric in the putamen (right: 4.85+/-0.56 cm3 left: 4.64+/-0.86 cm3 [mean+/-S.D.] p = 0.063), but not in NC. The decline of putamen volume during aging was significant in the right putamen (r = -0.613 p = 0.007 Pearson correlation two-tailed). There were no other significant correlations between striatal volumes and age or BP. Because ventral striatal dopamine neurotransmission is involved in cognitive processes, this loss of physiological asymmetry in NC dopamine transmission during aging might be involved in age-related declines of cognitive performance.
Publisher: Elsevier BV
Date: 2018
Publisher: Wiley
Date: 11-1994
DOI: 10.1046/J.1471-4159.1994.63051675.X
Abstract: A previous study of the metabolism of 6-[18F]-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) in rats pretreated with carbidopa contained information amenable to kinetic analysis. Using these data, tracer transfer coefficients and metabolic rate constants were estimated. After intravenous injection, FDOPA in circulation was O-methylated (k0D = 0.055 min-1), and the metabolite (O-methyl-FDOPA) escaped from plasma with a rate constant (k-1M) of 0.01 min-1. The initial clearance of FDOPA to striatum (K1D) was 0.07 ml g-1 min-1, and the equilibrium distribution volume (VeD) was 0.67 ml g-1. The initial clearance of O-methyl-FDOPA to striatum (K1M) was 0.08 ml g-1 min-1, and the equilibrium distribution volume (VeM) was 0.75 ml g-1. The rate constant of FDOPA decarboxylation (k3D) was 0.17 min-1 in striatum. The elimination of 6-[18F]fluorodopamine (FDA) from striatum suggested an apparent rate constant for monoamine oxidase activity (k7') of 0.055 min-1. 6-[18F]Fluorohomovanillic acid (FHVA) was formed from 6-[18F]fluoro-L-3,4-dihydroxyphenylacetic acid with a rate constant (k11) of 0.083 min-1, and FHVA was eliminated from striatum (k9) with a rate constant of 0.12 min-1. The steady-state concentration ratios of FDA and its metabolites were shown to be functions of these rate constants.
Publisher: Wiley
Date: 03-10-2011
DOI: 10.1111/J.1369-1600.2011.00355.X
Abstract: Positron emission tomography (PET) shows reduced binding of the dopamine D(2/3) antagonist [(11) C]raclopride in striatum of withdrawn psychostimulant abusers, but not consistently in patients with alcohol dependence (AD). We make first use of the high affinity ligand [(18) F]fallypride to obtain serial measures of D(2/3) receptor availability in striatal and extrastriatal regions of AD patients undergoing detoxification. Seventeen patients (mean age 44 ± 5y) with AD and 14 age-matched healthy volunteers participated. Each patient underwent [(18) F]fallypride PET upon hospital admission, and again 1-2 weeks later two patients achieving abstinence, and two with substantial harm reduction had additional PET follow-up at 1 year. Dynamic 180-minute PET recordings were used for volume of interest (VOI)-based and voxel-wise analysis of [(18) F]fallypride binding potential (BP(ND) ). Mean baseline BP(ND) in striatum of the AD patients (15.7 ± 3.6) was unaltered during short-term follow-up, and did not differ from that in healthy controls (16.8 ± 3.0) however, BP(ND) was 10-20% lower in thalamus, hippoc us, and insular and temporal cortex of the AD patients (P < 0.05). Age-dependent declines in BP(ND) were very small in controls, but more pronounced and widespread in the AD group. Striatal and thalamic BP(ND) increased by 30% in four patients with long-term abstinence or reduced alcohol consumption. VOI-based [(18) F]fallypride PET analyses revealed group differences in D(2/3) receptor availability primarily in extra-striatal regions. Age-related loss of dopamine D(2/3) receptors was more pronounced in AD patients. Receptor availability was unaltered by acute withdrawal, but increased in the subgroup of patients with long-term follow-up, suggesting reversibility of receptor changes.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2019
Publisher: Society of Nuclear Medicine
Date: 09-08-2012
DOI: 10.2967/JNUMED.112.105387
Abstract: In this era of systems biology, the tide of information derived from "omic" technologies (genomics, proteomics, etc.) has sparked a revolution in drug design, with many industrial and academic programs now embracing the concepts of molecular medicine (i.e., targeting changes in specific proteins or pathways) as measures of treatment efficacy and outcome. This approach has yielded a plethora of new preclinical therapeutics directed at novel targets within oncology. In many ways, the evolution of molecular imaging agents as diagnostic probes mirrors that of chemotherapeutics yet despite an increasing number of PET and SPECT radiotracers being evaluated in human trials, relatively few agents have found widespread use in clinical oncology. In light of this observation, is it time to reevaluate our strategies for radiopharmaceutical design and use? In this article, we argue that PET has enormous potential to deliver clinically relevant information on disease dynamics that extends beyond mapping the density and spatial distribution of a target. Recent developments in targeting pharmacodynamic biomarkers aim to exploit better the advantages of functional PET by detecting changes in signal transduction pathways, particularly in response to disease progression or treatment in cancer.
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.RESUSCITATION.2009.03.005
Abstract: To assess the regional vulnerability to ischemic damage and perfusion/metabolism mismatch of reperfused brain following restoration of spontaneous circulation (ROSC) after cardiac arrest. We used positron emission tomography (PET) to map cerebral metabolic rate of oxygen (CMRO(2)), cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in brain of young pigs at intervals after resuscitation from cardiac arrest. After obtaining baseline PET recordings, ventricular fibrillation of 10 min duration was induced, followed by mechanical closed-chest cardiopulmonary resuscitation (CPR) in conjunction with i.v. administration of 0.4 U/kg of vasopressin. After CPR, external defibrillatory shocks were applied to achieve restoration of spontaneous circulation (ROSC). CBF and CMRO(2) were mapped and voxelwise maps of OEF were calculated at times of 60, 180, and 300 min after ROSC. There was hypoperfusion throughout the telencephalon at 60 min, with a return towards baseline values at 300 min. In contrast, there was progressively increasing CBF in cerebellum throughout the observation period. The magnitude of CMRO(2) decreased globally after ROSC, especially in cerebral cortex. The magnitude of OEF in cerebral cortex was 60% at baseline, tended to increase at 60 min after ROSC, and declined to 50% thereafter, thus suggesting transition to an ischemic state. The cortical regions tended most vulnerable to the ischemic insult with an oligaemic pattern and a low CMRO(2) whereas the cerebellum instead showed a pattern of luxury perfusion.
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.BBR.2005.06.008
Abstract: Behavioral response to novelty in rats has been linked both to dopamine transmission in the ventral striatum, and to propensity to self-administer psychostimulant drugs. In order to probe the relationship between behavioral response to novelty and dopamine systems we have developed a behavioral model for correlation with positron emission tomography (PET) of dopamine transmission in brain of Göttingen minipigs. In the present study, we measured exploration of a novel object by recording the number of contacts, and duration of contact with a novel object, in groups of six male and six female adult minipigs. We hypothesized that these novelty scores would correlate with the hetamine-evoked dopamine release in ventral striatum, measured 2 weeks later in a PET study of the availability of binding sites for the dopamine D2/3 antagonist [11C]raclopride. There were significant correlations between duration of contact with a novel object and the hetamine-evoked reductions in binding potential (DeltapB) in the left ventral striatum of the 12 animals Comparison of results by gender revealed that the correlation was driven mainly by the male group, and was not present in the female group. We interpret these results to show that propensity to explore an unfamiliar object is relatively elevated in pigs with low basal occupancy of dopamine D2/3 receptors by endogenous dopamine, and with high hetamine-induced occupancy of released dopamine in the male pigs.
Publisher: Wiley
Date: 2006
DOI: 10.1002/SYN.20257
Abstract: The cerebral distribution of peripheral-type benzodiazepine binding sites (PBBS) in human brain has been investigated by positron emission tomography (PET) with the specific radioligand [11C]PK11195 in erse neuropathological conditions. However, little is known about the pattern of PK11195 binding sites in healthy brain. Therefore, we used quantitative autoradiography to measure the saturation binding parameters for [3H]PK11195 in cryostat sections from young Landrace pigs. Specific binding was lowest in the cerebellar white matter (85 fmol mg(-1)) and highest in the caudate nucleus (370 fmol mg(-1)), superior colliculus (400 fmol mg(-1)), and anterior thalamic nucleus (588 fmol mg(-1)). The apparent affinity was in the range of 2-6 nM in vitro, predicting high specific binding in PET studies of living brain. However, the distribution volume (V(d), ml g(-1)) of high specific activity [11C]PK11195 was nearly homogeneous (3 ml g(-1)) throughout brain of healthy Landrace pigs, and was nearly identical in studies with lower specific activity, suggesting that factors in vivo disfavor the detection of PBBS in Landrace pigs with this radioligand. In young, adult Göttingen minipig brain, the magnitude of V(d) for [11C]PK11195 was in the range 5-10 ml g(-1), and had a heterogeneous distribution resembling the in vitro findings in Landrace pigs. There was a trend toward globally increased V(d) in a group of minipigs with acute MPTP-induced parkinsonism, but no increase in V(d) was evident in the same pigs rescanned at 2 weeks after grafting of fetal mesencephalon to the partially denervated striatum. Thus, [11C]PK11195 binding was not highly sensitive to constituitively expressed PBBS in brain of young Landrace pigs, and did not clearly demonstrate the expected microglial activation in the MPTP/xenograft model of minipigs.
Publisher: MDPI AG
Date: 03-02-2023
DOI: 10.3390/BIOM13020290
Abstract: Hyperphosphorylated tau aggregates, also known as neurofibrillary tangles, are a hallmark neuropathological feature of Alzheimer’s disease (AD). Molecular imaging of tau by positron emission tomography (PET) began with the development of [18F]FDDNP, an amyloid β tracer with off-target binding to tau, which obtained regional specificity through the differing distributions of amyloid β and tau in AD brains. A concerted search for more selective and affine tau PET tracers yielded compounds belonging to at least eight structural categories 18F-flortaucipir, known variously as [18F]-T807, AV-1451, and Tauvid®, emerged as the first tau tracer approved by the American Food and Drug Administration. The various tau tracers differ concerning their selectivity over amyloid β, off-target binding at sites such as monoamine oxidase and neuromelanin, and degree of uptake in white matter. While there have been many reviews of molecular imaging of tau in AD and other conditions, there has been no systematic comparison of the fitness of the various tracers for discriminating between AD patient and healthy control (HC) groups. In this narrative review, we endeavored to compare the binding properties of the various tau tracers in vitro and the effect size (Cohen’s d) for the contrast by PET between AD patients and age-matched HC groups. The available tracers all gave good discrimination, with Cohen’s d generally in the range of two–three in culprit brain regions. Overall, Cohen’s d was higher for AD patient groups with more severe illness. Second-generation tracers, while superior concerning off-target binding, do not have conspicuously higher sensitivity for the discrimination of AD and HC groups. We suppose that available pharmacophores may have converged on a maximal affinity for tau fibrils, which may limit the specific signal imparted in PET studies.
Publisher: Wiley
Date: 2007
DOI: 10.1002/SYN.20377
Abstract: The psychostimulant 3,4-methylendioxymeth hetamine (MDMA, "ecstasy") evokes degeneration of telencephalic serotonin innervations in rodents, nonhuman primates, and human recreational drug users. However, there has been no alternative to nonhuman primates for studies of the cognitive and neurochemical consequences of serotonin depletion in a large-bodied animal. Therefore, we used positron emission tomography (PET) with [(11)C]DASB to map the distribution of plasma membrane serotonin transporters in brain of Göttingen minipigs, first in a baseline condition, and again at 2 weeks after treatment with MDMA (i.m.), administered at a range of doses. In parallel PET studies, [(11)C]WAY-100635 was used to map the distribution of serotonin 5HT(1A) receptors. The acute MDMA treatment in awake pigs evoked 1 degrees C of hyperthermia. MDMA at total doses greater than 20 mg/kg administered over 2-4 days reduced the binding potential (pB) of [(11)C]DASB for serotonin transporters in porcine brain. A mean total dose of 42 mg/kg MDMA in four animals evoked a mean 32% decrease in [(11)C]DASB pB in mesencephalon and diencephalon, and a mean 53% decrease in telencephalic structures. However, this depletion of serotonin innervations was not associated with consistent alterations in the binding of [(11)C]WAY-100635 to serotonin 5HT(1A) receptors. Stereological cell counting of serotonin-positive neurons, which numbered 95,000 in the dorsal raphé nucleus of normal animals, was unaffected in MDMA-treated group. group.
Publisher: Wiley
Date: 2006
DOI: 10.1002/SYN.20258
Abstract: The activity of both isozymes of monoamine oxidase (MAO) is reduced by 50% in the brain of human smokers. We hypothesized that this is not an epiphenomenon, but should bring about potentiation of the action of psychostimulant drugs. To test this hypothesis, we carried out serial positron emission tomography (PET) studies in Göttingen miniature pigs to measure the binding of the MAO-A ligand [11C]harmine and to measure the changes in [11C]raclopride binding evoked by a low dose of hetamine (0.7 mg/kg as free base, i.v.), first in a baseline condition, and, one month later, after acute treatment with pargyline (2 x 3 mg/kg as free base, i.m.). In the baseline, the distribution volume of [11C]harmine relative to the arterial input (V(d), ml g(-1)) ranged from 74 ml g(-1) in cerebellum to 139 ml g(-1) in the medial hypothalamus. Pargyline treatment reduced the magnitude of V(d) globally to 34-54 ml g(-1). Nearly complete displacement of [11C]harmine binding was detected in neocortex and striatum, but there was evidence for pargyline-resistant binding in the pituitary gland and diencephalon. In the baseline condition, the low dose of hetamine evoked a 14% decline in the binding potential (BP) (pB) of [11C]raclopride in striatum (P = 0.026). After pargyline treatment, the hetamine effect was of similar magnitude (-11%), although not statistically significant (P = 0.054). However, the second hetamine challenge evoked a 24% reduction in [11C]raclopride pB relative to the original baseline condition (P = 0.018). Present results do not strongly support our hypothesis that MAO inhibition should potentiate the hetamine-evoked dopamine release as measured in the [11C]raclopride competition paradigm.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1999
Publisher: SAGE Publications
Date: 21-01-2015
Abstract: 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.
Publisher: MDPI AG
Date: 24-08-2023
Abstract: We have established a method for nucleophilic one-pot, two-step radiosynthesis of the popular opioid receptor radioligand 6-O-(2-[18F]fluoroethyl)-6-O-desmethyl-diprenorphine ([18F]FE-DPN) from the novel precursor 6-O-(2-tosyloxyethyl)-6-O-desmethyl- 3-O-trityl-diprenorphine (TE-TDDPN), which we designate as the Henriksen precursor. We undertook an optimization of the synthesis conditions, aiming to enhance the accessibility of [18F]FE-DPN for positron emission tomography (PET) studies of μ-opioid receptors. Herein, we report an optimized direct nucleophilic 18F-fluorination and the deprotection conditions for a fully automated radiosynthesis of [18F]FE-DPN on a modified GE Tracerlab FX FE synthesis panel. Starting from 1–1.5 GBq of [18F]fluoride and applying an Oasis Max 1cc cartridge for fluorine-18 trapping with a reduced amount of K2CO3 (5.06 μmol K+ ion), [18F]FE-DPN ([18F]11) was produced with 44.5 ± 10.6 RCY (decay-corrected), high radiochemical purity ( %), and a molar activity of 32.2 ± 11.8 GBq/μmol in 60–65 min.
Publisher: Springer Berlin Heidelberg
Date: 2011
Abstract: The main motor symptoms of Parkinson's disease (PD) are linked to degeneration of the nigrostriatal dopamine (DA) fibers, especially those innervating the putamen. This degeneration can be assessed in molecular imaging studies with presynaptic tracers such as [(18)F]-fluoro-L-DOPA (FDOPA) and ligands for DA transporter ligands. However, the pathologies of PD are by no means limited to nigrostriatal loss. Results of post mortem and molecular imaging studies reveal parallel degenerations of cortical noradrenaline (NA) and serotonin (5-HT) innervations, which may contribute to affective and cognitive changes of PD. Especially in advanced PD, cognitive impairment can come to resemble that seen in Alzheimer's dementia, as can the degeneration of acetylcholine innervations arising in the basal forebrain. The density of striatal DA D(2) receptors increases in early untreated PD, consistent with denervation upregulation, but there is an accelerated rate of DA receptor loss as the disease advances. Animal studies and post mortem investigations reveal changes in brain opioid peptide systems, but these are poorly documented in imaging studies of PD. Relatively minor changes in the binding sites for GABA are reported in cortex and striatum of PD patients. There remains some controversy about the expression of the 18 kDa translocator protein (TSPO) in activated microglia as an indicator of an active inflammatory component of neurodegeneration in PD. A wide variety of autonomic disturbances contribute to the clinical syndrome of PD the degeneration of myocardial sympathetic innervation can be revealed in SPECT studies of PD patients with autonomic failure. Considerable emphasis has been placed on investigations of cerebral blood flow and energy metabolism in PD. Due to the high variance of these physiological estimates, researchers have often employed normalization procedures for the sensitive detection of perturbations in relatively small patient groups. However, a widely used normalization to the global mean must be used with caution, as it can result in spurious findings of relative hypermetabolic changes in subcortical structures. A meta-analysis of the quantitative studies to date shows that there is in fact widespread hypometabolism and cerebral blood flow in the cerebral cortex, especially in frontal cortex and parietal association areas. These changes can bias the use of global mean normalization, and probably represent the pathophysiological basis of the cognitive impairment of PD.
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.EJPHAR.2007.01.087
Abstract: The relationship between the abundances of agonist and antagonist-binding sites for monoamine receptors is poorly established. Therefore, we used quantitative autoradiography to investigate the distribution and concentration of binding sites for histamine H(3) receptor ligands in cryostat sections of pig brain. As in other species, binding of the histamine H(3) receptor agonist [(3)H]N(alpha)-methylhistamine was highly heterogeneous in the pig brain, with highest B(max) in the substantia nigra, followed by the nucleus accumbens and caudate, intermediate binding in frontal cortex, diencephalon, and mesencephalon, and absent specific binding in cerebellum: the affinity of [(3)H]N(alpha)-methylhistamine was close to 1 nM in all regions of pig brain. Thus, the saturation binding parameters for this H(3) receptor agonist in pig brain were similar to the earlier reports in rat, guinea pig, and human. The distribution of histamine H(3) receptors labeled with the receptor antagonist [(125)I]iodophenpropit in adjacent cryostat sections from the same group of pigs was very similar to that of [(3)H]N(alpha)-methylhistamine. However, the B(max) of the receptor antagonist was 40% higher in the basal ganglia than was the B(max) of the receptor agonist. The K(d) for the receptor antagonist ligand was close to 0.9 nM in all regions. These results suggest that histamine H(3) receptor agonist-binding sites, i.e. those linked to intracellular G-protein, comprise a subset of the total receptor antagonist-binding sites in the basal ganglia, as has been reported for dopamine D(2) receptors.
Publisher: Wiley
Date: 07-2006
DOI: 10.1111/J.1460-9568.2006.04903.X
Abstract: Dopaminergic neurotransmission in the ventral and dorsal striatum interact with central processing of rewarding and reward-indicating stimuli, and may affect frontocortical-striatal-thalamic circuits regulating goal-directed behaviour. Thirteen healthy male volunteers were investigated with multimodal imaging, using the radioligand 6-[(18)F]fluoro-l-DOPA (FDOPA) for positron emission tomography (PET) measurements of dopamine synthesis capacity, and also functional magnetic resonance imaging (fMRI) in a cognitive activation paradigm. We calculated the correlation between FDOPA net blood-brain influx ( ml/g/min) in the ventral and associative dorsal striatum and BOLD signal changes elicited by standardized affectively positive, negative and neutral visual stimuli. The magnitude of in the ventral striatum was positively correlated with BOLD signal increases in the left anterior cingulate cortex and right insular operculum elicited by positive vs. neutral stimuli, but not negative vs. neutral stimuli. In the dorsal striatum, the magnitude of was positively correlated with processing of positive and negative stimuli in the left dorsolateral prefrontal cortex. These findings suggest that dopamine synthesis capacity in the ventral striatum correlates with the attentional processing of rewarding positive stimuli in the anterior cingulate cortex of healthy subjects. Dopaminergic neurotransmission in the associative dorsal striatum has been associated previously with habit learning. The observed correlation between dopamine synthesis capacity in the dorsal striatum and BOLD signal changes in the dorsolateral prefrontal cortex suggests dopaminergic modulation of processing of emotional stimuli in brain areas associated with motor planning and executive behaviour control.
Publisher: Elsevier BV
Date: 07-2014
Publisher: Wiley
Date: 28-11-2007
DOI: 10.1002/HBM.20325
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.NEUINT.2010.12.007
Abstract: It has been argued that agonist ligands for dopamine D(2/3) receptors recognize a privileged subset of the receptors in living striatum, those which are functionally coupled to intracellular G-proteins. In support of this claim, the D(2/3) agonist [(3)H]-N-propylnorapomorphine ([(3)H]NPA) proved to be more vulnerable to competition from endogenous dopamine than was the antagonist ligand [(11)C]raclopride, measured ex vivo in mouse striatum, and subsequently in multi-tracer PET studies of analogous design. Based on these results, we predicted that prolonged dopamine depletion would result in a preferential increase in agonist binding, and a lesser competition from residual dopamine to the agonist binding. To test this hypothesis we used autoradiography to measure [(3)H]NPA and [(3)H]raclopride binding sites in hemi-parkinsonian rats with unilateral 6-OHDA lesions, with and without hetamine challenge. Unilateral lesions were associated with a more distinct increase in [(3)H]NPA binding ex vivo than was seen for [(3)H]raclopride binding in vitro. Furthermore, this preferential asymmetry in [(3)H]NPA binding was more pronounced in hetamine treated rats. We consequently predict that agonist ligands should likewise be fitter than antagonists for detecting responses to denervation in positron emission tomography studies of idiopathic Parkinson's disease. Agonist binding increases in vivo are likely to reflect the composite of a sensitization-like phenomenon, and relatively less competition from endogenous dopamine, as seen in the lesioned side of 6-OHDA induced hemi-parkinsonism.
Publisher: Elsevier BV
Date: 1993
DOI: 10.1016/0006-8993(93)90240-N
Abstract: Groups of 6 rats were treated for 5 days with either reserpine hydrochloride (5 mg/kg i.p., per diem), or saline. Regional binding of the histamine H3 agonist N alpha-[3H]methyl-histamine ([3H]NAMH) was determined in forebrain sections by quantitative autoradiography and Scatchard analysis. Highest maximal binding was in nucleus accumbens (107 +/- 18 fmol/mg) and corpus striatum (58 +/- 9 fmol/mg), where the apparent affinity was close to 4 nM. Maximal binding of [3H]NAMH in the insular cortex (39 +/- 6 fmol/mg) was higher than in other cortical areas examined. Reserpine treatment produced a 50% decrease in both the Bmax and the apparent Kd in the corpus striatum and nucleus accumbens, but binding parameters in the cortex and septum were unaltered. Therefore, the response of H3 receptors in rat forebrain to reserpine treatment for 5 days was regionally heterogenous such that maximal [3H]NAMH binding was typically higher in insular cortex (36 +/- 6 fmol/mg) than in corpus striatum (24 +/- 3 fmol/mg) of reserpine-treated rats.
Publisher: SAGE Publications
Date: 05-2002
DOI: 10.1097/00004647-200205000-00011
Abstract: According to the ternary complex model of G-protein linkage to receptors, agonists increase the affinity of the receptors for the G protein. The model predicts that an endogenous agonist's constant of inhibition toward an agonist radioligand is lower than that toward an antagonistic radioligand. The authors hypothesized that competition from endogenous dopamine in striatum of living mice should have a greater effect on the binding of the D 2,3 partial agonist N-[ 3 H]propylnorapomorphine than on the binding of the D 2,3 antagonist [ 11 C]raclopride. The baseline binding potential ( p B(0) ), defined as the ratio of bound-to-unbound ligand in the absence of competition from endogenous dopamine, was simultaneously measured in mouse striatum for [ 11 C]raclopride ( p B(0) = 8.5) and N-[ 3 H]propylnorapomorphine ( p′ B(0 ) = 5.3). The baseline was established by treatment with α-methyl- p-tyrosine and reserpine. Relative to these baseline values in saline-treated mice, the p B of N-[ 3 H]propylnorapomorphine decreased 52% whereas the p B of [ 11 C]raclopride decreased only 30%, indicating greater sensitivity of the former compound to inhibition by synaptic dopamine. Furthermore, hetamine decreased the p B of N-[ 3 H]propylnorapomorphine to a greater extent (73%) than that of [ 11 C]raclopride (43%) relative to the reserpine condition. For both radioligands, the occupancy of the dopamine receptors by endogenous agonist obeyed Michaelis-Menten kinetics over a wide range of agonist concentrations established by the pharmacologic treatments. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and decreased to a value 1.66 times greater for N-[ 3 H]propylnorapomorphine than for [ 11 C]raclopride at its highest occupancies. The results are consistent with the hypothesis that agonist binding is more sensitive than antagonist binding to competition from endogenous dopamine. Therefore, dopamine agonist ligands may be superior to benzamide antagonist ligands for the estimation of dopamine receptor occupancy by endogenous synaptic dopamine. The analysis of the effect of dopamine occupancy on the inhibition of N-[ 3 H]propylnorapomorphine binding indicated a limited supply of G protein with a maximum ternary complex fraction of 40% of maximum agonist binding capacity.
Publisher: Wiley
Date: 03-2009
DOI: 10.1111/J.1528-1167.2009.02272.X
Abstract: Alterations in dopamine neurotransmission in animal models of epilepsies have been frequently demonstrated using invasive neuroscience or ex vivo techniques. We aimed to test whether corresponding alterations could be detected by noninvasive in vivo brain imaging with positron emission tomography (PET) in the chronic phase of the rat pilocarpine model of temporal lobe epilepsy. Six pilocarpine-treated Wistar rats exhibiting spontaneous recurrent seizures and nine control rats were studied with PET using [(18)F]-fallypride, a high-affinity dopamine D(2/3) receptor ligand. Parametric images of [(18)F]-fallypride specific binding were calculated using a reference tissue method, and the two groups were contrasted by whole-brain voxel-based analysis implemented in statistical parametric mapping (SPM5). Dopamine D(2/3) receptor availability was 27% lower in the bilateral anterior caudate-putamen of pilocarpine-treated rats as compared to controls (p < 0.05), but binding was unaffected in other striatal or extrastriatal regions. The finding of substantially reduced availability of dopamine D(2/3) receptors in the anterior caudate-putamen of rats during the chronic phase of the pilocarpine model is in agreement with results of invasive (microinjection, microdialysis) animal studies that have revealed increased dopamine tonus and a D(2/3) receptor-mediated anticonvulsant action of dopamine in the anterior segment of the rat striatum. The present PET approach could be prospectively applied for monitoring dopamine receptor changes longitudinally, that is, at different phases of the epileptogenic process, and opens perspectives for testing dopaminergic agents as potential antiepileptogenic drugs.
Publisher: SAGE Publications
Date: 07-1993
Abstract: Like native DOPA, [ 18 F]-6-fluoro-l-3,4-dihydroxyphenylalanine ([ 18 F]FDOPA) is subject to methylation and decarboxylation. To determine the rates of formation and elimination of [ 18 F]FDOPA metabolites, plasma from human subjects undergoing positron emission tomographic (PET) studies was analyzed by high-performance liquid chromatography (HPLC). In addition to the principal metabolite O-methyl-[ 18 F]FDOPA (OMe-[ 18 F]FDOPA), two decarboxylated metabolites were detected in plasma from carbidopa pretreated subjects. The concentrations of each metabolite during 90 min following tracer injection could be described as a function of the concentration of [ 18 F]FDOPA, and two rate constants k 0 , the rate of formation, and k –1 , the rate of clearance. Plasma metabolite time series generated from total plasma activity curves and measured rate constants were in close agreement with the actual concentrations determined by HPLC fractionation. Population means for k 0 (0.011 ± 0.002 min −1 ) and k –1 , (0.010 ± 0.003 min −1 ) were used to generate “simulated” plasma curves. The measured and generated plasma curves were used as inputs for estimation of partition and decarboxylation coefficients of [ 18 F]FDOPA in brain. The use of generated input functions from normal population means of transfer coefficients did not introduce a systematic error into the estimate of the enzyme activity. However, the high variability of these estimates in patients precludes the use of this technique as an alterative to in idual HPLC measurements.
Publisher: Society for Neuroscience
Date: 29-10-2014
DOI: 10.1523/JNEUROSCI.1560-14.2014
Abstract: Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D 2/3 -receptors, thus indirectly revealing presynaptic dopamine release. We used [ 18 F]fluorodopamine ([ 18 F]FDOPA)-PET in conjunction with the inlet–outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [ 18 F]FDOPA PET scans (124 min slow bolus-injection arterial blood s ling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [ 18 F]FDOPA ( K dopamine synthesis capacity) as well as the [ 18 F]fluorodopamine washout rate ( k loss , index of dopamine turnover). MPH substantially decreased k loss in putamen (−22% p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, in idual k loss changes correlated with altered cognitive performance under MPH. [ 18 F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females.
Publisher: Springer Science and Business Media LLC
Date: 24-12-2014
DOI: 10.1007/S11307-014-0811-7
Abstract: Post-synaptic dopamine D2/3 receptors are reduced in animal models of obesity, and in obese humans, concordant with similar findings in habitual drug users. However, corresponding pre-synaptic changes in brain dopamine are less documented in obesity models. Therefore, we used positron emission tomography (PET) with the dopamine transporter (DAT) ligand N-(3-[(18)F]fluoropropyl)-2-β-carbomethoxy-3-β-(4'-methylphenyl) tropane ([(18)F]FP-CMT) to test the hypothesis that DAT availability is attenuated in adult fatty Zucker (FZ) rats versus lean littermates (LZ). Groups of nine FZ and LZ rats were examined by [(18)F]FP-CMT PET at approximately 6 weeks and at 6 months of age. The baseline mean striatal binding potential (BPND) of [(18)F]FP-CMT did not differ between groups (LZ 2.4 FZ 2.5), although FZ rats already had higher body weight and elevated blood triglycerides, cholesterol, and insulin. At follow-up, a mixed effects multiple regression model showed that the maturation of DAT availability was attenuated in FZ rats, such that the mean BPND in striatum was 17 % lower (LZ 4.0 FZ 3.3 p = 0.01). Body weight was twofold higher in the adult FZ rats, and triglycerides fourfold increased, but glucose remained normal despite doubling of insulin levels. Maturation of the striatal dopamine innervation is impaired in this model of obesity/hyperlipidaemia without diabetes, implying an acquired trait of reduced dopamine reuptake capacity.
Publisher: Wiley
Date: 12-1997
DOI: 10.1111/J.1749-6632.1997.TB48637.X
Abstract: Environmental enrichment (EE) is an environmental paradigm encompassing sensory, cognitive, and physical stimulation at a heightened level. Previous studies have reported the beneficial effects of EE in the brain, particularly in the hippoc us. EE improves cognitive function as well as ameliorates depressive and anxiety-like behaviors, making it a potentially effective neuroprotective strategy against neurodegenerative diseases such as Alzheimer's disease (AD). Here, we summarize the current evidence for EE as a neuroprotective strategy as well as the potential molecular pathways that can explain the effects of EE from a biochemical perspective using animal models. The effectiveness of EE in enhancing brain activity against neurodegeneration is explored with a view to differences present in early and late life EE exposure, with its potential application in human being discussed. We discuss EE as one of the non pharmacological approaches in preventing or delaying the onset of AD for future research.
Publisher: Elsevier BV
Date: 2001
DOI: 10.1016/S0969-8051(00)00187-6
Abstract: Most radioligands are substantially metabolised in peripheral organs during the course of positron emission tomography (PET) recordings. Accurate determination of plasma concentrations of unmetabolised radioligands is often important for quantification of data from PET studies. The fractions of untransformed radioligand and radioactive metabolites in plasma extracts must then be measured. Temporal changes in these fractions are influenced by the rate constant of appearance of total radioactive metabolites in plasma (apparent rate constant of metabolism in plasma, k(0)) and the net rate constant of elimination of all radioactive metabolites from plasma (k(-1)). In order to clarify the relationship between radioligand fractions and rate constants, plasma s les collected from Göttingen minipigs during PET recordings using four different binding site ligands were analysed by radio high performance liquid chromatography. The calculated plasma concentrations of parent compounds and their radioactive metabolites were used to calculate k(0) and k(-1) for 11C-labelled NNC 112, NS 2214, PK 11195 and raclopride in minipigs using a novel application of the tissue-slope intercept plot. In general, the apparent rate constant of metabolism in plasma was found to be greater in the minipig than in man. The reported kinetic analysis enables the apparent metabolism of PET radioligands in plasma to be quantified.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2018
DOI: 10.1038/S41380-018-0114-5
Abstract: Antipsychotic drugs are effective interventions in schizophrenia. However, the efficacy of these agents often decreases over time, which leads to treatment failure and symptom recurrence. We report that antipsychotic efficacy in rat models declines in concert with extracellular striatal dopamine levels rather than insufficient dopamine D2 receptor occupancy. Antipsychotic efficacy was associated with a suppression of dopamine transporter activity, which was reversed during failure. Antipsychotic failure coincided with reduced dopamine neuron firing, which was not observed during antipsychotic efficacy. Synaptic field responses in dopamine target areas declined during antipsychotic efficacy and showed potentiation during failure. Antipsychotics blocked synaptic vesicle release during efficacy but enhanced this release during failure. We found that the pharmacological inhibition of the dopamine transporter rescued antipsychotic drug treatment outcomes, supporting the hypothesis that the dopamine transporter is a main target of antipsychotic drugs and predicting that dopamine transporter blockers may be an adjunct treatment to reverse antipsychotic treatment failure.
Publisher: No publisher found
Date: 2010
DOI: 10.1111/J.1528-1167.2010.02671.X
Abstract: Based on experimental findings, overexpression of P-glycoprotein at the blood-brain barrier has been suggested to be a contributor to pharmacoresistance of the epileptic brain. We test a technique for evaluation of interin idual differences of elevated transporter function, through microPET analysis of the impact of the P-glycoprotein modulator tariquidar. The preclinical study is intended for eventual translation to clinical research of patients with pharmacoresistant seizure disorders. We made a microPET evaluation of the effects of tariquidar on the brain kinetics of the P-glycoprotein substrate [(18) F]MPPF in a rat model with spontaneous recurrent seizures, in which it has previously been demonstrated that phenobarbital nonresponders exhibit higher P-glycoprotein expression than do phenobarbital responders. Mean baseline parametric maps of the [(18) F]MPPF unidirectional blood-brain clearance (K(1) ml/g per min) and the efflux rate constant (k(2) per min) did not differ between the nonresponder and responder group. Tariquidar pretreatment increased the magnitude of [(18) F]MPPF K(1) in hippoc us by a mean of 142% in the nonresponders, which significantly exceeded the 92% increase observed in the responder group. The same treatment decreased the mean magnitude of [(18) F]MPPF k(2) in hippoc us by 27% in nonresponders, without comparable effects in the responder group. These results constitute a proof-of-concept for a novel imaging approach to evaluate blood-brain barrier P-glycoprotein function in animals. By extension, [(18) F]MPPF positron emission tomography (PET) with tariquidar pretreatment may be amenable for clinical applications exploring further the relevance of P-glycoprotein overexpression, and for enabling the rational design of pharmacotherapy according to in idual differences in P-glycoprotein expression.
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.NEUROIMAGE.2004.11.031
Abstract: Abnormal central dopamine (DA) neurotransmission has been implicated in the impulsivity, inattention, and hyperactivity of attention deficit hyperactivity disorder (ADHD). We hypothesized that a pharmacological challenge with methylphenidate (MP) at a therapeutic dose increases extracellular DA concentrations in proportion to the severity of these specific ADHD symptoms. To test this hypothesis, we measured by PET the effect of acute challenge with MP on the availability of striatal binding sites for [11C]raclopride (pB), an index of altered interstitial DA concentration, in nine unmedicated adolescents (1 female, 8 males age 13.7 +/- 1.8 years) with a current diagnosis of ADHD. We estimated the pB of [11C]raclopride for brain dopamine D2/3 receptors first in a baseline resting condition, and again after an acute challenge with MP (0.3 mg/kg, p.o.), and calculated the percentage change in (%DeltapB) in left and right striatum. On another day, measurements of impulsivity and inattention were performed using a computerized continuous performance test. There was a significant correlation between the magnitude of %DeltapB in the right striatum and the severity of inattention and impulsivity. MP-evoked %DeltapB correlated with standard scores for impulse control (r = 0.68 P = 0.02), attention (r = 0.81 P = 0.005), information processing (r = 0.66 P = 0.02), and consistency of attention, or variability (r = 0.60 P = 0.04). In conclusion, the results link inattention and impulsivity with sensitivity of brain DA receptor availability to an MP challenge, corroborating the hypothesis that MP serves to potentiate decreased DA neurotransmission in ADHD.
Publisher: Society of Nuclear Medicine
Date: 13-12-2010
DOI: 10.2967/JNUMED.110.078709
Abstract: The present study aimed to distinguish responders to cardiac resynchronization therapy (CRT) from nonresponders, using electrocardiogram-gated 18F-FDG PET/CT. Seven consecutive CRT nonresponders were included in the study, along with 7 age- and sex-matched CRT responders, serving as reference material. Therapy response was defined as clinical improvement (≥1 New York Heart Association class) and evidence of reverse remodeling. Besides PET/CT, we measured brain natriuretic peptide levels and assessed dyssynchrony using transthoracic echocardiography. Compared with nonresponders, CRT responders showed significant differences in the declines of left-ventricular end-systolic volume and brain natriuretic peptide and in left-ventricular dyssynchrony (global left-ventricular entropy), extent of the myocardial scar burden, and biventricular pacemaker leads positioned within viable myocardial regions. Among the nonresponders, further therapy management was guided by the PET/CT results in 4 of 7 patients. Cardiac hybrid imaging using gated 18F-FDG PET/CT enabled the identification of potential reasons for nonresponse to CRT therapy, which can guide subsequent therapy.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2009
DOI: 10.1007/S10554-009-9510-X
Abstract: To evaluate the accuracy of myocardial perfusion SPECT (MPI) in the detection and allocation of vessel specific perfusion defects (PD) using standard distribution territories in a routine clinical procedure of patients with multivessel disease (MVD). Combined quantitative coronary angiography and fractional flow reserve (QCA/FFR) measurements were used as invasive reference standard. 216 vessels in 72 MVD patients (67 +/- 10 years, 28 female) were investigated using MPI and QCA. FFR of 93 vessels with intermediate stenoses was determined. MPI detected significant stenoses according to QCA/FFR findings with a sensitivity of 85%. However, vessel-based evaluation using standard myocardial distribution territories delivered a sensitivity of only 62% (28 MPI+ out of 45 (QCA/FFR)+ findings), with specificity, PPV and NPV of 90, 62 and 90%. 7/17 false positive and 7/17 false negative findings (41%) could be attributed to incorrect allocation of reversible PD to their respective coronary arteries. 6/17 (35%) perfusion territories were classified as false negative when additional fixed PD were present. MPI had reasonable sensitivity for the detection of significant coronary artery disease in patients with multivessel disease. However, sensitivity decreased markedly, when the significance of each in idual stenosis was evaluated using standard myocardial supplying territories. In this setting, 41% of false negative and false positive MPI findings resulted from incorrect allocation of reversible perfusion defects to their determining supplying vessel.
Publisher: Springer Science and Business Media LLC
Date: 19-03-2010
DOI: 10.1007/S00259-010-1432-2
Abstract: Measurements of [(18)F]fluorodeoxyglucose (FDG) uptake as a potential marker of the inflammatory activity of the vessel wall could be useful to identify vulnerable atherosclerotic plaques. The purpose of this study was to correlate the FDG uptake in the left anterior descending coronary artery (LAD) with cardiovascular risk factors, pericardial fat volume (PFV) and calcified plaque burden (CPB). A total of 292 consecutive tumour patients were examined by whole-body FDG PET and contrast-enhanced CT. The blood pool-corrected standardized uptake value (target to background ratio, TBR) was measured in the LAD, and the contrast-enhanced CT images were used to measure the PFV and the CPB. The Spearman correlation coefficient and the unpaired t test were used for statistical comparison between image-based results and cardiovascular risk factors. Vascular FDG uptake could be measured for 161 of 292 (55%) patients without myocardial uptake, but the vessel uptake could not be distinguished in the other patients, due to pervasive myocardial uptake. The TBR of the LAD showed significant correlations with hypertension (R = 0.18 p < 0.05), coronary heart disease (R = 0.19 p < 0.05), body mass index (BMI) (R = 0.19 p < 0.05), CPB (R = 0.36 p < 0.001) and PFV (R = 0.20 p < 0.05), but not with other risk factors. Patients with a TBR in the upper tertile had a larger CPB and a higher PFV than patients with a TBR in the lower tertile (9.1 vs 3.5 p < 0.001 for CPB and 92.2 vs 71.5 mm(3) p < 0.05 for PVF). FDG uptake measurement in the LAD correlates with hypertension, coronary heart disease, BMI, PFV and CPB. However, due to myocardial FDG uptake these measurements are only feasible in one half of the patients.
Publisher: Wiley
Date: 2000
Publisher: Elsevier BV
Date: 04-1994
DOI: 10.1016/0006-8993(94)90147-3
Abstract: Histamine H3 antagonists have been reported to discriminate subclasses of histamine H3 agonist binding in rat cortical membranes. This phenomenon was investigated by autoradiography of cryostat sections of rat forebrain labelled with [3H]N alpha-methylhistamine ([3H]NAMH, 4 nM). Displacement curves with thioperamide detected a single site in cortex and striatum (pIC50 = 8.18 +/- 0.03). However, Hill coefficients (nH = 0.51 +/- 0.12) suggested the possible presence of multiple binding sites. Displacement with burimamide was consistent with two site models in all brain regions examined (pIC50(A) = 7.9 +/- 1.5 pIC50(B) = 5.6 +/- 0.7), except for the medial septum where a single site was detected. Elsewhere, the relative abundance of the two sites displaced by burimamide (H3A:H3B) appeared to be 1:2. Thioperamide may have failed to discriminate two sites because the IC50s were too similar to be distinguished in the present autoradiographic study.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.BRAINRESBULL.2004.08.007
Abstract: The availability of dopamine D(2/3) binding sites in brain of six male and six female Göttingen minipigs was measured in a baseline condition and after challenge with hetamine sulfate (1mg/kg, i.v.) in PET studies with [(11)C]raclopride. Maps of the binding potential (pB B(max)/K(d)) of [(11)C]raclopride were spatially normalized and co-registered to a common stereotaxic coordinate system for pig brain. The pB maps were then analyzed by volume of interest and voxel-wise comparisons of gender and condition. The mean baseline pB tended to be 10-20% higher in striatum of the female group, but this gender difference was not significant. Variance of the mean baseline pB was higher in the males (44%) than in females (30%), but there was no correlation between pB and in idual plasma cortisol or testosterone concentrations. Using statistical parametric mapping, we detected a focus in the right posterior putamen where the magnitude of the hetamine-evoked decrease in pB was greater in the male than in the female group. Thus, the spatial pattern of reactivity of dopamine D(2/3) receptor availability to hetamine challenge is not identical in male and female pigs. Within the entire population, the decline in pB evoked by hetamine (Delta pB) was greater in the ventral striatum (-28%) than in the caudate nucleus (-17%), consistent with earlier reports in monkeys and humans. The magnitude of Delta pB correlated highly with the baseline pB values in all isions of the striatum. Based upon the principles of competitive binding, the slope of this empirical relationship, f(i), is equal to the fraction of [(11)C]raclopride binding sites sensitive to endogenous dopamine the magnitude of this fraction ranged from 0.29 in the caudate to 0.36 in the ventral striatum.
Publisher: Elsevier BV
Date: 02-2016
Publisher: Oxford University Press (OUP)
Date: 15-04-2010
Publisher: SAGE Publications
Date: 2018
Abstract: The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain’s resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X 7 and P2Y 12 , the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.NEUROIMAGE.2007.12.045
Abstract: The telencephalic dopamine innervations contribute to the modulation of cognitive processing. However, the relationship between cognitive effects of D(2/3)-receptor antagonism and dopamine transmission is not described in healthy subjects. We therefore tested effects of acute haloperidol (5 mg/d over 3 days) on continuous performance task (CPT) performance and 6-[(18)F]-fluoro-l-DOPA (FDOPA) PET parameters. Nine physically and mentally healthy male men performed two FDOPA-PET scans including arterial plasma withdrawal. Over 3 days before the second scan, all subjects were treated with 5 mg/d haloperidol orally. Using our novel steady-state analysis, we calculated the intrinsic rate of the cerebral FDOPA utilization (K), the turnover of [(18)F]fluorodopamine formed in brain (k(loss)) and the storage for FDOPA and its brain metabolites (V(d)). Furthermore, a ds-CPT and EPS-screening was performed before every PET scan. We found that FDOPA kinetics in those normal subjects with relatively high baseline K showed a more pronounced sensitivity to haloperidol treatment, manifesting in reduced storage capacity and elevated turnover of [(18)F]fluorodopamine, whereas subjects with lower K showed the opposite pattern of responses. Furthermore, low baseline K predicted improvements in the CPT task after haloperidol, whereas participants with higher baseline K showed a decline in cognitive performance. We conclude that the initial increase of [(18)F]fluorodopamine turnover after acute haloperidol challenge is associated with an over-stimulation in in iduals with initially more pharmacologically responsive dopamine systems, but optimizes cognitive performance in those with lower normal FDOPA utilization at baseline. We hypothesize that these effects may be driven by D(1)-receptor mediated transmission during D(2) blockade.
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.NEUROIMAGE.2008.12.001
Abstract: Potentiation of serotonergic transmission increases cognitive flexibility, but can in other circumstances increase sensitivity to stressful environmental cues. The personality trait Openness to Experience reflects and is also associated with an increased risk for mood disorders. We hypothesized that the personality trait has an association with a biomarker of serotonergic transmission, the plasma membrane serotonin transporter (5-HTT). In 50 healthy volunteers, we tested for correlations between scores on the NEO-PI-R scale Openness to Experience and its subscales, and cerebral binding of the 5-HTT selective PET radioligand [11C]DASB. Subjects were genotyped for the 5-HTT long/short polymorphism, and for a single nucleotide polymorphism in the long allele, designated LA/LG. Midbrain [11C]DASB binding correlated negatively with scores for Openness to Experience and its two subscales, Openness to Actions and Openness to Values. The latter subscore was negatively correlated with [11C]DASB binding in all brain regions in which [11C]DASB binding was quantified. Genetic analysis showed that homozygote LA carriers had significantly higher [11C]DASB binding in the caudate nucleus, but no significant differences in openness scores. Thus, high scores in personality facets indicative of cognitive flexibility and openness to change are associated with lower [11C]DASB binding. Lower abundance of 5-HTT sites may result in potentiation of serotonergic signaling, which occurs during treatment with SSRIs. We speculate that the set-point of serotonergic signaling in an in idual represents a trade-off between flexibility and vulnerability when exposed to environmental stress.
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.NEUROIMAGE.2008.07.042
Abstract: Recent studies of Parkinson's disease (PD) report subcortical increases of cerebral blood flow (CBF) or cerebral metabolic rate of glucose (CMRglc), after conventional normalization to the global mean. However, if the global mean CBF or CMRglc is decreased in the PD group, this normalization necessarily generates artificial relative increases in regions unaffected by the disease. This potential bias may explain the reported subcortical increases in PD. To test this hypothesis, we performed simulations with manipulation and subsequently analysis of sets of quantitative CBF maps by voxel-based statistics. CBF images from 49 healthy volunteers were randomly assigned to four sets of two groups of 20 subjects. For each set, CBF images in one group were manipulated, while the other group served as controls. In the first simulation, an isolated cortical decrease was simulated. In the second simulation, focal increases in the globus pallidus and thalamus motor nuclei were simulated in addition to cortical decreases, thus emulating the putative metabolic pattern in PD. The data were analyzed with both the SSM method and a univariate statistical approach with normalization to either the global mean or to the white matter mean. In Simulation I, global normalization robustly created artefactual subcortical increases, irrespective of analysis methodology. Simulation II demonstrated that an increased signal from the small subcortical structures involved in PD can probably not be detected with present instrumentation and typically-used s le sizes. Imposing focal decreases on cortical CBF in conjunction with global mean normalization gives rise to spurious relative CBF increases in all of the regions reported to be hyperactive in PD. Since no PET study has reported absolute increases of CBF or CMRglc in any subcortical region in PD, we conclude that the relative increases reported in some studies most likely arise from biased normalization to the global mean.
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/S0924-977X(03)00039-7
Abstract: The [18F]fluoromethyl analogue of (+)-McN5652 ([18F]FMe-McN) has recently been developed as a radioligand for imaging the neuronal serotonin transporter (SERT) with positron emission tomography (PET). We describe here the autoradiographic evaluation of [18F]FMe-McN in the brain of rats and pigs. Autoradiographic studies of [18F]FMe-McN performed on rat and pig brain in vitro showed a high accumulation of radioactivity in the regions rich in SERT, such as amygdala, hypothalamus, superficial gray layer of the superior colliculus, various nuclei of thalamus and substantia nigra. The binding of [18F]FMe-McN was reduced by citalopram, a highly selective inhibitor for SERT. Similar regional specific binding densities of [18F]FMe-McN were observed in both species. The regional distribution and specific binding of this radiotracer correlates well with the distribution and regional brain binding of [3H]citalopram. Region-to-cerebellum ratios of [18F]FMe-McN in vitro reached a maximum value of 20.6 in the rat and 14.5 in the pig. In addition, ex vivo autoradiography of the rat brain was performed 90 min after i.v. administration of [18F]FMe-McN. The highest regional uptake of [18F]FMe-McN was observed in the hypothalamic area, substantia nigra and amygdaloid area. There is a high correlation between the in vitro and in vivo binding. The region-to-cerebellum ratio in vivo reached a maximum value of 5.1 in the substantia nigra, the highest yet reported for an 18F-labelled SERT tracer in vivo in this region. Furthermore, the distribution volume of [18F]FMe-McN calculated from the PET data in various regions of the porcine brain is highly correlated with the SERT density as determined by in vitro autoradiography with [3H]citalopram. Thus, [18F]FMe-McN has a clear potential as a radiotracer for studies of the SERT distribution in man with PET.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2016
Publisher: MDPI AG
Date: 13-12-2022
Abstract: Antipsychotics (AP) induced prolongation of the QT interval in patients with schizophrenia (Sch) is an actual interdisciplinary problem as it increases the risk of sudden death syndrome. Long QT syndrome (LQTS) as a cardiac adverse drug reaction is a multifactorial symptomatic disorder, the development of which is influenced by modifying factors (APs’ dose, duration of APs therapy, APs polytherapy, and monotherapy, etc.) and non-modifying factors (genetic predisposition, gender, age, etc.). The genetic predisposition to AP-induced LQTS may be due to several causes, including causal mutations in the genes responsible for monoheme forms of LQTS, single nucleotide variants (SNVs) of the candidate genes encoding voltage-dependent ion channels expressed both in the brain and in the heart, and SNVs of candidate genes encoding key enzymes of APs metabolism. This narrative review summarizes the results of genetic studies on AP-induced LQTS and proposes a new personalized approach to assessing the risk of its development (low, moderate, high). We recommend implementation in protocols of primary diagnosis of AP-induced LQTS and medication dispensary additional observations of the risk category of patients receiving APs, deoxyribonucleic acid profiling, regular electrocardiogram monitoring, and regular therapeutic drug monitoring of the blood APs levels.
Publisher: Wiley
Date: 2016
DOI: 10.1111/JNC.13453
Publisher: Frontiers Media SA
Date: 10-04-2018
Publisher: Elsevier BV
Date: 10-1997
DOI: 10.1016/S0165-0270(97)00094-0
Abstract: The biological accuracy of a nonlinear compartmental model describing the in vivo kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]FDOPA) metabolism was investigated. Tissue activities for [18F]FDOPA and its labeled metabolites 3-O-methyl-[18F]FDOPA ([18F]OMFD), 6-[18F]fluorodopamine ([18F]FDA), L-3,4-dihydroxy-6-[18F]fluorophenylacetic acid ([18F]FDOPAC), and 6-[18F]fluorohomovanillic acid ([18F]FHVA) were calculated using a plasma [18F]FDOPA input function, and kinetic constants estimated previously by chromatographic fractionation of 18F-labeled compounds in plasma and brain extracts from rat. Present data accurately reflected the measured radiochemical composition in rat brain for tracer circulation times past 10 min. We formulated the hypothesis that the discrepancy between calculated and measured fractions of [18F]FDOPA and the deaminated metabolite [18F]FDOPAC at times earlier than 10 min reflected storage of [18F]FDA in vesicles without monoamine oxidase. This hypothesis explained the initially rapid appearance of [18F]FDOPAC in striatum by delayed transfer of [18F]FDA from cytosol into vesicles. We conclude that the simpler model of [18F]FDOPA compartmentation is accurate when the cytosolic and vesicular fractions of [18F]FDA are at steady-state the approach to equilibrium has a time constant of 15-30 min. The present model is valid for positron emission tomography studies of [18F]FDOPA metabolism in living brain.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2009
DOI: 10.1007/S11307-009-0281-5
Abstract: The aim of this study is to evaluate a non-invasive method for measuring myocardial perfusion defect size in mice using a clinical single-photon emission computed tomography system equipped with pinhole collimators (pinhole SPECT). Thirty days after ligation of the left anterior descending coronary artery, 13 mice (C57BL/6J) were imaged following intravenous injection of 370 MBq [99mTc]sestamibi. Eight control mice without myocardial infarction were likewise investigated. Image quality optimization had been achieved by repeated scanning of a multiple point phantom, with varying zoom factors, number of projection angles, and pinhole diameter. Volumetric s ling was used to generate polar maps, in which intensity was normalized to that of a standard septal region of interest (ROI), which was set at 100%. Receiver operating characteristic analyses were performed to define an optimal threshold as compared to histologically measured defect sizes, which were considered as gold standard. A spatial resolution of 1.9 mm was achieved using a pinhole diameter of 0.5 mm, a zoom factor of 2, and 6 degrees projection angles. Histological results were best reproduced by a 60% threshold relative to the septal reference ROI. By applying this threshold, SPECT perfusion defect sizes revealed very high correlation to the histological results (R(2) = 0.867) with excellent intra- and interobserver reproducibility (intraclass correlation coefficients of 0.84 and 0.82). We achieved a spatial resolution of 1.9 mm in myocardial perfusion imaging in mice using a clinical SPECT system mounted with pinhole collimators. Compared to a histological gold standard, the infarct sizes were accurately estimated, indicating that this method shows promise to monitor experimental cardiac interventions in mice.
Publisher: Wiley
Date: 16-12-2019
DOI: 10.1002/MDS.27945
Abstract: Striatal dopamine deficiency and metabolic changes are well‐known phenomena in dementia with Lewy bodies and can be quantified in vivo by 123 I‐Ioflupane brain single‐photon emission computed tomography of dopamine transporter and 18 F‐fluorodesoxyglucose PET. However, the linkage between both biomarkers is ill‐understood. We used the hitherto largest study cohort of combined imaging from the European consortium to elucidate the role of both biomarkers in the pathophysiological course of dementia with Lewy bodies. We compared striatal dopamine deficiency and glucose metabolism of 84 dementia with Lewy body patients and comparable healthy controls. After normalization of data, we tested their correlation by region‐of‐interest–based and voxel‐based methods, controlled for study center, age, sex, education, and current cognitive impairment. Metabolic connectivity was analyzed by inter‐region coefficients stratified by dopamine deficiency and compared to healthy controls. There was an inverse relationship between striatal dopamine availability and relative glucose hypermetabolism, pronounced in the basal ganglia and in limbic regions. With increasing dopamine deficiency, metabolic connectivity showed strong deteriorations in distinct brain regions implicated in disease symptoms, with greatest disruptions in the basal ganglia and limbic system, coincident with the pattern of relative hypermetabolism. Relative glucose hypermetabolism and disturbed metabolic connectivity of limbic and basal ganglia circuits are metabolic correlates of dopamine deficiency in dementia with Lewy bodies. Identification of specific metabolic network alterations in patients with early dopamine deficiency may serve as an additional supporting biomarker for timely diagnosis of dementia with Lewy bodies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Publisher: SAGE Publications
Date: 31-10-2007
Abstract: Deficiency of phenylalanine hydroxylase activity in phenylketonuria (PKU) causes an excess of phenylalanine (Phe) throughout the body, predicting impaired synthesis of catecholamines in the brain. To test this hypothesis, we used positron emission tomography (PET) to measure the utilization of 6-[ 18 F]fluoro-l-dopamine (FDOPA) in the brain of adult patients suffering from PKU and in healthy controls. Dynamic 2-h long FDOPA emission recordings were obtained in seven adult PKU patients (five females, two males age: 21 to 27 years) with elevated serum Phe levels, but lacking neurologic deficits. Seven age-matched, healthy volunteers were imaged under identical conditions. The utilization of FDOPA in striatum was calculated by linear graphical analysis ( k 3 S , min −1 ), with cerebellum serving as a nonbinding reference region. The time to peak activity in all brain time—radioactivity curves was substantially delayed in the PKU patients relative to the control group. The mean magnitude of k 3 S in the striatum of the PKU patients (0.0052±0.0004 min −1 ) was significantly lower than in the control group (0.0088±0.0009 min −1 ) ( P .001). There was no significant correlation between in idual serum Phe levels and k 3 S . The unidirectional clearance of FDOPA to brain was impaired in adult patients suffering from PKU, presumably reflecting the competitive inhibition of the large neutral amino acid carrier by Phe. Assuming this competition to be spatially uniform, the relationship between striatum and cerebellum time—activity curves additionally suggests inhibition of DOPA efflux, possibly also due to competition from Phe. The linear graphical analysis shows reduced k 3 S in striatum, indicating reduced DOPA decarboxylase activity.
Publisher: SAGE Publications
Date: 1993
DOI: 10.1038/JCBFM.1993.8
Abstract: In 11 normal volunteers and six patients with Parkinson's disease, we compared six different analyses of dopaminergic function with l-3,4-dihydroxy-6-[ 18 F]fluorophenylalanine (FDOPA) and positron emission tomography (PET). The caudate nucleus, putamen, and several reference regions were identified in PET images, using magnetic resonance imaging (MRI). The six analyses included two direct determinations of DOPA decarboxylase activity ( k D 3 , k* 3 ), the slope–intercept plot based on plasma concentration ( K), two slope–intercept plots based on tissue content ( k r 3 , k s 3 ), and the striato–occipital ratio [ R( T)]. For all analyses, the difference between two groups of subjects (normal volunteers and patients with Parkinson's disease) was larger in the putamen than in the caudate. For the caudate nucleus, the DOPA decarboxylase activity ( k D 3 , k* 3 ), tissue slope–intercept plots ( k r 3 , k s 3 ), and striato–occipital ratio [ R( T)] analyses significantly discriminated between the normal volunteers and the patients with Parkinson's disease ( p 0.005) [with least significance for k* 3 ( p 0.05)], while the plasma slope–intercept plot ( K) failed to do so. For the putamen, the values for k D 3 , k* 3 , K, k r 3 , k s 3 and R( T) of normal volunteers were significantly higher than those of patients ( p 0.005) [with least significance for K ( p 0.025)]. Linear correlations were significant between k D 3 and k s 3 k D 3 and k r 3 k D 3 and R( T) and k D 3 and k* 3 , in this order of significance. We found no correlation between k D 3 and K values in the caudate nucleus.
Publisher: SAGE Publications
Date: 1993
DOI: 10.1038/JCBFM.1993.7
Abstract: DOPA decarboxylase is the enzyme directly responsible for the synthesis of the neurotransmitters dopamine and serotonin, and indirectly of noradrenaline, in brain. We used the decarboxylation coefficient ( k D 3 ) of 6-[ 18 F]fluoro-DOPA (FDOPA) to denote the relative activity of l-DOPA decarboxylase in vivo in the human brain. To determine the relative enzyme activity with positron emission tomography (PET), we evaluated the model that separates the metabolism into compartments of nondiffusible and diffusible (i.e., transient) tracer metabolites. Error analysis indicated that the least-squares optimization alone was not sufficient to yield accurate estimates of k D 3 in the presence of the inherent error of PET. To improve the accuracy of the k D 3 estimates by optimizing the number of parameters, we introduced biological constraints which included a tracer partition volume ( V e ) common to frontal cortex and striatum, and a fixed ratio ( q) between the blood–brain barrier transport coefficients of O-methyl-[ 18 F]fluoro-DOPA and FDOPA, the two sources of radioactivity in plasma. We found that a two-step analysis yielded sufficiently accurate estimates of k D 3 . The two steps include the initial estimation of the partition volume in frontal cortex and the subsequent use of this value to determine k D 3 in striatum and other structures. We studied twelve healthy controls (age 45 ± 15 years). The average k D 3 value was 0.081 ± 0.024 min −1 (coefficient of variation (COV) 30%) for caudate nucleus, 0.074 ± 0.013 min“ 1 (COV 18%) for putamen, and 0.010 ± 0.005 min −1 (COV 50%) for cerebral cortex.
Publisher: SAGE Publications
Date: 11-1997
DOI: 10.1097/00004647-199711000-00014
Abstract: To test the hypothesis that dopamine (DA) receptors influence cerebral DOPA-decarboxylase (DDC) activity in vivo, we used HPLC to measure the kinetics of the cerebral uptake and metabolism of [ 3 H]DOPA in carbidopa-treated rats, and in rats also treated acutely with a DA receptor antagonist (flupenthixol, 2 mg/kg, intraperitoneally) or a DA receptor agonist (apomorphine, 200 μg/g, subcutaneously). The unidirectional blood-brain clearance of [ 3 H]DOPA (K 1 DOPA , 0.030 mL g −1 min −1 ) increased by 50% after flupenthixol. The magnitudes of the relative DDC activity (k 3 DOPA ) in striatum (0.20 min −1 ), olfactory tubercle (0.11 min −1 ), and hypothalamus (0.15 min −1 ) of carbidopa-treated rats were doubled with flupenthixol, but cortical DDC activity was unaffected (0.02 min −1 ). Apomorphine reduced the magnitude of k 3 DOPA in striatum by 20%. The rate constant for catabolism of [ 3 H]DA formed in brain (k 7 ′, monoamine oxidase [MAO] activity), which ranged from 0.025 min −1 in striatum to 0.08 min −1 in hypothalamus of carbidopa-treated rats, globally increased 2- to 4-fold after flupenthixol, and decreased to 0.003 min −1 in striatum after apomorphine. These in vivo results confirm the claim that acute blockade of DA receptors with flupenthixol stimulates the synthesis of [ 3 H]DA from [ 3 H]DOPA, and that this [ 3 H]DA is subject to accelerated catabolism. Conversely, activation of the DA receptors with apomorphine inhibits DDC activity and DA catabolism.
Publisher: Wiley
Date: 06-1994
Abstract: The blood-brain permeabilities of L-[3H]tyrosine and the tyrosine hydroxylase (TH) inhibitor alpha-[14C]methyl-para-tyrosine ([14C]AMPT) were determined in rat striatum, a brain region rich in TH activity, and in other brain regions containing relatively little TH activity. In striatum, the unidirectional clearance rate (K1) for L-[3H]tyrosine (6.2 ml hg-1 min-1) was significantly greater than the rates for L-[14C]AMPT (2.8 ml hg-1 min-1) and D-[14C]AMPT (0.8 ml hg-1 min-1). The apparent volume of distribution (Vf) for L-[14C]AMPT in striatum (72.5 +/- 4.0 ml hg-1) did not differ from the Vf in other brain regions. The homogeneous distribution of L-[14C]AMPT in rat brain indicates that labeled AMPT is unsuitable for the study of TH in vivo by quantitative autoradiography.
Publisher: Elsevier BV
Date: 07-2003
DOI: 10.1016/S1053-8119(03)00079-X
Abstract: Positive reinforcing properties of nicotine and the psychostimulants have been attributed to elevated dopamine release in the basal ganglia. It is well known that the specific binding of [(11)C]raclopride to dopamine D(2,3) receptors in living striatum is reduced by cocaine and hetamines, revealing increased competition between endogenous dopamine and [(11)C]raclopride for dopamine D(2,3) receptors. However, the sensitivity of [(11)C]raclopride binding to nicotine-induced dopamine release is less well documented. In order to provide the basis for mapping effects of nicotine, we first optimized reference tissue methods for quantifying [(11)C]raclopride binding sites in striatum of living pigs (n = 16). In the same animals, the rate of cerebral blood flow (CBF) was mapped using [(15)O]water. Neither a low dose of nicotine (50 mu kg(-1), iv) nor a high dose of nicotine (500 microg kg(-1), iv) altered CBF in the pig brain, an important condition for calculating the binding of radioligands when using a reference tissue to estimate the free ligand concentration. The methods of Logan and of Lammertsma were compared using the cerebellum or the occipital cortex as reference tissues for calculating the binding potential (pB) of [(11)C]raclolpride in brain. Irrespective of the method used, the mean undrugged baseline pB in striatum (ca. 2.0) was significantly asymmetric, with highest binding in the left caudate and right putamen. Test-retest estimates of pB were stable. Subtraction of Logan pB maps revealed that the low dose of nicotine reduced the pB of [(11)C]raclopride by 10% in a cluster of voxels in the left anteroventral striatum, but this effect did not persist after correction for multiple comparisons. The high dose of nicotine (n = 9) acutely reduced pB by 10% bilaterally in the ventral striatum 3 h after the high nicotine dose, the reductions had shifted dorsally and caudally into the caudate and putamen. Evidently, nicotine challenge enhances the competition between endogenous dopamine for [(11)C]raclopride binding sites with a complex temporal and spacial pattern in pig brain, initially presenting in the left ventral striatum.
Publisher: Society of Nuclear Medicine
Date: 31-05-2013
DOI: 10.2967/JNUMED.112.114660
Abstract: The progression of β-amyloid deposition in the brains of mice overexpressing Swedish mutant β-amyloid precursor protein (APP-Swe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel β-amyloid tracer (18)F-florbetaben. Groups of APP-Swe and age-matched wild-type (WT) mice (age range, 10-20 mo) were investigated. Dynamic emission recordings were acquired with a small-animal PET scanner during 90 min after the administration of (18)F-florbetaben (9 MBq, intravenously). After spatial normalization of in idual PET recordings to common coordinates for mouse brain, binding potentials (BPND) and standardized uptake value ratios (SUVRs) were calculated relative to the cerebellum. Voxelwise analyses were performed using statistical parametric mapping (SPM). Histochemical analyses and ex vivo autoradiography were ultimately performed in a subset of animals as a gold standard assessment of β-amyloid plaque load. SUVRs calculated from static recordings during the interval of 30-60 min after tracer injection correlated highly with estimates of BPND based on the entire dynamic emission recordings. (18)F-florbetaben binding did not significantly differ in APP-Swe mice and WT animals at 10 and 13 mo of age. At 16 mo of age, the APP-Swe mice had a significant 7.9% increase (P < 0.01) in cortical (18)F-florbetaben uptake above baseline and at 20 mo there was a 16.6% increase (P < 0.001), whereas WT mice did not show any temporal changes in tracer uptake during the interval of follow-up. Voxelwise SPM analyses revealed the first signs of increased cortical binding at 13 mo and confirmed progressive binding increases in both the frontal and the temporal cortices (P < 0.001 uncorrected) to 20 mo. The SUVR strongly correlated with percentage plaque load (R = 0.95, P < 0.001). In the first longitudinal PET study in an AD mouse model using the novel β-amyloid tracer (18)F-florbetaben, the temporal and spatial progression of amyloidogenesis in the brain of APP-Swe mice were sensitively monitored. This method should afford the means for preclinical testing of novel therapeutic approaches to the treatment of AD.
Publisher: Informa UK Limited
Date: 04-2018
DOI: 10.2147/NDT.S148557
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.NEUROIMAGE.2009.09.048
Abstract: We used microPET to map the dose-response to the novel P-glycoprotein (P-gp) inhibitor tariquidar (TQD) of the initial influx of the P-gp substrate [(18)F]-MPPF in rat brain, and to test for effects of P-gp inhibition on the subsequent binding of [(18)F]-MPPF to serotonin 5-HT(1A) receptors. Summation maps of [(18)F]-MPPF uptake during the first 100 seconds after intravenous injection were calculated in groups of rats with vehicle (glucose 5%) pretreatment, or following pretreatment with TQD at doses of 5, 15, or 30 mg/kg. The early summation image (K(1)-weighted), were validated as a surrogate marker for the physiological blood-brain clearance (K(1) ml g(-)(1) min(-1)) by linear graphic analysis of the unidirectional blood-brain clearance relative to an image-based arterial input measured in the left ventricle of the heart. In the same animals, parametric maps of the [(18)F]-MPPF binding potential (BP(ND)) were calculated from the entire 60-minute emission recordings using conventional reference tissue methods. All [(18)F]-MPPF recordings were followed by an [(18)F]-FDG emission recording, the summation of which was used for spatial normalization to a rat brain atlas. Test-retest variability of K(1)-weighted uptake and BP(ND) was 25%. TQD treatment evoked a global dose-dependent increase in K(1)-weighted summation, which increased 2.5-fold with TQD (30 mg/kg), suggesting an IC(50) of 5 mg/kg TQD. All TQD doses increased the apparent [(18)F]-MPPF BP(ND) calculated by the Logan method by 30%-40%, a bias likely arising due to increased free [(18)F]-MPPF concentrations in brain. TQD (15 mg/kg) evoked a 45% global increase in [(18)F]-FDG uptake, suggesting perturbation of brain energy metabolism due to P-gp blockade.
No related grants have been discovered for Paul Cumming.