scholarly journals Quantification of PET infusion studies without true equilibrium: A tissue clearance correction

2019 ◽  
Vol 40 (4) ◽  
pp. 860-874
Author(s):  
Ansel T Hillmer ◽  
Richard E Carson

In some positron emission tomography (PET) studies, a reversibly binding radioligand is administered as a constant infusion to establish true equilibrium for quantification. This approach reduces scanning time and simplifies data analysis, but assumes similar behavior of the radioligand in plasma across the study population to establish true equilibrium in all subjects. Bias in outcome measurements can result if this assumption is not met. This work developed and validated a correction that reduces bias in total distribution volume ( VT) estimates when true equilibrium is not present. This correction, termed tissue clearance correction (TCC), took the form [Formula: see text], where β is the radioligand clearance rate in tissue, γ is a radiotracer-specific constant, and VT(A) is the apparent VT. Simulations characterized the robustness of TCC across imperfect values of γ and β and demonstrated reduction to false positive rates. This approach was validated with human infusion data for three radiotracers: [18F]FPEB, (−)-[18F]flubatine, and [11C]UCB-J. TCC reduced bias in VT estimates for all radiotracers and significantly reduced intersubject variance in VT for [18F]FPEB data in some brain regions. Thus, TCC improves quantification of data acquired from PET infusion studies.

2004 ◽  
Vol 24 (9) ◽  
pp. 1037-1045 ◽  
Author(s):  
Lars H. Pinborg ◽  
Karen H. Adams ◽  
Stig Yndgaard ◽  
Steen G. Hasselbalch ◽  
Søren Holm ◽  
...  

The aim of the present study was to develop an experimental paradigm for the study of serotonergic neurotransmission in humans using positron emission tomography and the 5-HT2A selective radioligand [18F]altanserin. [18F]altanserin studies were conducted in seven subjects using the bolus/infusion approach designed for attaining steady state in blood and brain 2 hours after the initial [18F]altanserin administration. Three hours after commencement of radiotracer administration, 0.25 mg/kg of the selective serotonin reuptake inhibitor, citalopram (Lundbeck, Valby, Denmark), was administered to all subjects as a constant infusion for 20 minutes. To reduce 5-HT1A–mediated autoinhibition of cortical 5-HT release, four of the seven subjects were pretreated with the partial 5-HT1A agonist pindolol for 3 days at an increasing oral dose (25 mg on the day of scanning). In each subject, the baseline condition (120 to 180 minutes) was compared with the stimulated condition (195 to 300 minutes). Despite a pronounced increase in plasma prolactin and two subjects reporting hot flushes compatible with an 5-HT–induced adverse effect, cortical [18F]altanserin binding was insensitive to the citalopram challenge, even after pindolol pretreatment. The biochemical and cellular events possibly affecting the unsuccessful translation of the citalopram/pindolol challenge into a change in 5-HT2A receptor binding of [18F]altanserin are discussed.


2015 ◽  
Vol 35 (5) ◽  
pp. 743-746 ◽  
Author(s):  
Martin Bauer ◽  
Rudolf Karch ◽  
Markus Zeitlinger ◽  
Cécile Philippe ◽  
Kerstin Römermann ◽  
...  

As P-glycoprotein (Pgp) inhibition at the blood–brain barrier (BBB) after administration of a single dose of tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate ( R)-[11C]verapamil in five healthy volunteers during continuous intravenous tariquidar infusion. Total distribution volume ( VT) of ( R)-[11C]verapamil in whole-brain gray matter increased by 273 ± 78% relative to baseline scans without tariquidar, which was higher than previously reported VT increases. During tariquidar infusion whole-brain VT was comparable to VT in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB.


2017 ◽  
Vol 29 (1) ◽  
pp. 122
Author(s):  
H. J. Oh ◽  
J. Moon ◽  
G. A. Kim ◽  
S. Lee ◽  
S. H. Paek ◽  
...  

Due to similarities between human and porcine, pigs have been proposed as an excellent experimental animal for human medical research. Especially in paediatric brain research, piglets share similarities with human infants in the extent of peak brain growth at the time of birth and the growth pattern of brain. Thus, these findings have supported the wider use of pigs rather than rodents in neuroscience research. Previously, we reported the production of porcine model of Parkinson's disease (PD) by nuclear transfer using donor cell that had been stably infected with lentivirus containing the human α-synuclein gene. The purpose of this study was to determine the alternation of brain metabolism and dopaminergic neuron destruction using noninvasive method in a 2-yr-old PD model and a control pig. The positron emission tomography (PET) scan was done using Biograph TruePoint40 with a TrueV (Siemens, Munich, Germany). The [18F]N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) was administrated via the ear vein. Static images of the brain for 15 min were acquired from 2 h after injection. The 18F-fluorodeoxy-D-glucose PET (18F-FDG PET) images of the brain were obtained for 15 min at 45 min post-injection. Computed tomography (CT) scan and magnetic resonance imaging (MRI) were performed at the same location of the brain. In both MRI and CT images, there was no difference in brain regions between PD model and control pigs. However, administration of [18F]FP-CIT was markedly decreased in the bilateral putamen of the PD model pig compared with the control pigs. Moreover, [18F]FP-CIT administration was asymmetrical in the PD model pig but it was symmetrical in control pigs. Regional brain metabolism was also assessed and there was no significant difference in cortical metabolism of PD model and control pigs. We demonstrated that PET imaging could provide a foundation for translational Parkinson neuroimaging in transgenic pigs. In the present study, a 2-yr-old PD model pig showed dopaminergic neuron destruction in brain regions. Therefore, PD model pig expressing human α-synuclein gene would be an efficient model for human PD patients. This study was supported by Korea IPET (#311011–05–5-SB010), Research Institute for Veterinary Science, TS Corporation and the BK21 plus program.


2011 ◽  
Vol 31 (8) ◽  
pp. 1807-1816 ◽  
Author(s):  
Pablo M Rusjan ◽  
Alan A Wilson ◽  
Peter M Bloomfield ◽  
Irina Vitcu ◽  
Jeffrey H Meyer ◽  
...  

This article describes the kinetic modeling of [18F]-FEPPA binding to translocator protein 18 kDa in the human brain using high-resolution research tomograph (HRRT) positron emission tomography. Positron emission tomography scans were performed in 12 healthy volunteers for 180 minutes. A two-tissue compartment model (2-CM) provided, with no exception, better fits to the data than a one-tissue model. Estimates of total distribution volume ( VT), specific distribution volume ( VS), and binding potential ( BPND) demonstrated very good identifiability (based on coefficient of variation ( COV)) for all the regions of interest (ROIs) in the gray matter ( COV VT < 7%, COV VS < 8%, COV BPND < 11%). Reduction of the length of the scan to 2 hours is feasible as VS and VT showed only a small bias (6% and 7.5%, respectively). Monte Carlo simulations showed that, even under conditions of a 500% increase in specific binding, the identifiability of VT and VS was still very good with COV<10%, across high-uptake ROIs. The excellent identifiability of VT values obtained from an unconstrained 2-CM with data from a 2-hour scan support the use of VT as an appropriate and feasible outcome measure for [18F]-FEPPA.


2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Seiki Tajima ◽  
Shigeyuki Yamamoto ◽  
Masaaki Tanaka ◽  
Yosky Kataoka ◽  
Masao Iwase ◽  
...  

Fatigue is an indispensable bioalarm to avoid exhaustive state caused by overwork or stresses. It is necessary to elucidate the neural mechanism of fatigue sensation for managing fatigue properly. We performedH2O  15positron emission tomography scans to indicate neural activations while subjects were performing 35-min fatigue-inducing task trials twice. During the positron emission tomography experiment, subjects performed advanced trail-making tests, touching the target circles in sequence located on the display of a touch-panel screen. In order to identify the brain regions associated with fatigue sensation, correlation analysis was performed using statistical parametric mapping method. The brain region exhibiting a positive correlation in activity with subjective sensation of fatigue, measured immediately after each positron emission tomography scan, was located in medial orbitofrontal cortex (Brodmann's area 10/11). Hence, the medial orbitofrontal cortex is a brain region associated with mental fatigue sensation. Our findings provide a new perspective on the neural basis of fatigue.


1997 ◽  
Vol 17 (9) ◽  
pp. 919-931 ◽  
Author(s):  
Robert A. Koeppe ◽  
Kirk A. Frey ◽  
Akito Kume ◽  
Roger Albin ◽  
Michael R. Kilbourn ◽  
...  

This work compares equilibrium to kinetic analysis of positron emission tomography data for the assessment of vesicular monoamine transporter (VMAT2) binding density using (+)-α-[11C]dihydrotetrabenazine ((+)-α-[11C]DTBZ). Studies were performed for 80 minutes after intravenous administration of 18 ± 1 mCi (+)-α-[11C]DTBZ on 9 young control subjects, 20 to 45 years of age. A 9-mCi bolus was injected over the first minute of the study, whereas the remaining 9 mCi were infused at a constant rate over the following 79 minutes. Steady-state was reached in both blood and brain by approximately 30 minutes after initiation of the study. Nonlinear least-squares analysis using two- and three-compartment models, weighted integral analysis using a two-compartment configuration, and Logan plot analysis all yielded kinetic estimates of the total tissue distribution volume, DVtot(kin). These results were compared with equilibrium distribution volume estimates, DVtot(eq), calculated from the tissue to metabolite corrected arterial plasma concentration ratio after 30 minutes. Kinetic modeling results from this study were in close agreement with prior bolus-injection (+)-α-[11C]DTBZ studies. In the current study, coefficients of variation in DVtot(kin) (19% to 23% across regions) and DVtot(eq) (18% to 22%) were nearly identical. Equilibrium estimates of DVtot were slightly lower than kinetic estimates, averaging 5% ± 9% lower ( P = 0.04, paired t test) in regions of high binding density (caudate and putamen), but only 2% ± 6% ( P = 0.09) in lower binding density regions (cortex, thalamus, cerebellum). DVtot(eq) estimates, however, still correlated highly with DVtot(kin) estimates ( r = 0.977−0.989). Steady-state conditions can be achieved in both tissue and blood by 30 minutes, and the tissue-to-blood ratios of (+)-α-[11C]DTBZ at equilibrium yield DVtot(eq) measures that are in close agreement with DVtot(kin) estimates. Thus, a simple, easily tolerated protocol using a loading bolus followed by continuous infusion can provide excellent measures of VMAT2 binding.


2020 ◽  
Vol 14 ◽  
Author(s):  
Amelie Schäfer ◽  
Elizabeth C. Mormino ◽  
Ellen Kuhl

Alzheimer's disease is associated with the cerebral accumulation of neurofibrillary tangles of hyperphosphorylated tau protein. The progressive occurrence of tau aggregates in different brain regions is closely related to neurodegeneration and cognitive impairment. However, our current understanding of tau propagation relies almost exclusively on postmortem histopathology, and the precise propagation dynamics of misfolded tau in the living brain remain poorly understood. Here we combine longitudinal positron emission tomography and dynamic network modeling to test the hypothesis that misfolded tau propagates preferably along neuronal connections. We follow 46 subjects for three or four annual positron emission tomography scans and compare their pathological tau profiles against brain network models of intracellular and extracellular spreading. For each subject, we identify a personalized set of model parameters that characterizes the individual progression of pathological tau. Across all subjects, the mean protein production rate was 0.21 ± 0.15 and the intracellular diffusion coefficient was 0.34 ± 0.43. Our network diffusion model can serve as a tool to detect non-clinical symptoms at an earlier stage and make informed predictions about the timeline of neurodegeneration on an individual personalized basis.


1993 ◽  
Vol 13 (4) ◽  
pp. 656-667 ◽  
Author(s):  
Julie C. Price ◽  
Helen S. Mayberg ◽  
Robert F. Dannals ◽  
Alan A. Wilson ◽  
Hayden T. Ravert ◽  
...  

Kinetic methods were used to obtain regional estimates of benzodiazepine receptor concentration ( Bmax) and equilibrium dissociation constant ( Kd) from high and low specific activity (SA) [11C]flumazenil ([11C] Ro 15-1788) positron emission tomography studies of five normal volunteers. The high and low SA data were simultaneously fit to linear and nonlinear three-compartment models, respectively. An additional inhibition study (pretreatment with 0.15 mg/kg of flumazenil) was performed on one of the volunteers, which resulted in an average gray matter K1/ k2 estimate of 0.68 ± 0.08 ml/ml (linear three-compartment model, nine brain regions). The free fraction of flumazenil in plasma ( f1) was determined for each study (high SA f1: 0.50 ± 0.03; low SA f1: 0.48 ± 0.05). The free fraction in brain ( f2) was calculated using the inhibition K1/ k2 ratio and each volunteer's mean f1 value ( f2 across volunteers = 0.72 ± 0.03 ml/ml). Three methods (Methods I–III) were examined. Method I determined five kinetic parameters simultaneously [ K1, k2, k3 (= kon f2 Bmax), k4, and kon f2/SA] with no a priori constraints. An average kon value of 0.030 ± 0.003 n M−1 min−1 was estimated for receptor-rich regions using Method I. In Methods II and III, the kon f2/SA parameter was specifically constrained using the Method I value of kon and the volunteer's values of f2 and low SA (Ci/μmol). Four parameters were determined simultaneously using Method II. In Method III, K1/ k2 was fixed to the inhibition value and only three parameters were estimated. Method I provided the most variable results and convergence problems for regions with low receptor binding. Method II provided results that were less variable but very similar to the Method I results, without convergence problems. However, the K1/ k2 ratios obtained by Method II ranged from 1.07 in the occipital cortex to 0.61 in the thalamus. Fixing the K1/ k2 ratio in Method III provided a method that was physiologically consistent with the fixed value of f2 and resulted in parameters with considerably lower variability. The average Bmax values obtained using Method III were 100 ± 25 n M in the occipital cortex, 64 ±18 n M in the cerebellum, and 38 ± 5.5 n M in the thalamus; the average Kd was 8.9 ± 1.0 n M (five brain regions).


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