scholarly journals Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data. Generalizations

1985 ◽  
Vol 5 (4) ◽  
pp. 584-590 ◽  
Author(s):  
Clifford S. Patlak ◽  
Ronald G. Blasberg
Keyword(s):  
Compartmental Analysis ◽  
Graphical Analysis ◽  
Test Substance ◽  
Multiple Time ◽  
Sequential Data ◽  
Compartmental System ◽  
Blood Concentrations ◽  
Reversible Binding ◽  
Uptake Data ◽  
Actual Configuration

The method of graphical analysis for the evaluation of sequential data (e.g., tissue and blood concentrations over time) in which the test substance is irreversibly trapped in the system has been expanded. A simpler derivation of the original analysis is presented. General equations are derived that can be used to analyze tissue uptake data when the blood–plasma concentration of the test substance cannot be easily measured. In addition, general equations are derived for situations when trapping of the test substance is incomplete and for a combination of these two conditions. These derivations are independent of the actual configuration of the compartmental system being analyzed and show what information can be obtained for the period when the reversible compartments are in effective steady state with the blood. This approach is also shown to result in equations with at least one less nonlinear term than those derived from direct compartmental analysis. Specific applications of these equations are illustrated for a compartmental system with one reversible region (with or without reversible binding) and one irreversible region.

“The Effect of Obstructive Sleep Apnea on Peripheral Blood Amino Acid and Biogenic Amine Metabolome at Multiple Time Points Overnight“

2020 ◽  
Author(s):  
Ott Kiens ◽  
Egon Taalberg ◽  
Viktoria Ivanova ◽  
Ketlin Veeväli ◽  
Triin Laurits ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Amino Acid ◽  
Sleep Apnea ◽  
Biogenic Amines ◽  
Peripheral Blood ◽  
Apnea Hypopnea Index ◽  
Multiple Time ◽  
Blood Concentrations ◽  
Time Points ◽  
Obstructive Sleep

Abstract There are no clinical studies that have investigated the differences in blood serum metabolome between obstructive sleep apnea (OSA) patients and controls. In a single-center prospective observational study, we compared metabolomic profiles in the peripheral blood of OSA patients with apnea-hypopnea index (AHI) > 15/h and control individuals. Blood was obtained at 3 different time points overnight: 21:00 p.m.; 5:00 a.m. and 7:00 a.m. We used a targeted approach for detecting amino acids and biogenic amines and analyzed the data with ranked general linear model for repeated measures. We recruited 31 patients with moderate-to-severe OSA and 32 controls. Significant elevations in median concentrations of alanine, proline and kynurenine in OSA patients compared to controls were detected. Significant changes in the overnight dynamics of peripheral blood concentrations occurred in OSA: glutamine, serine, threonine, tryptophan, kynurenine and glycine levels increased, whereas a fall occurred in the same biomarker levels in controls. Phenylalanine and proline levels decreased slightly, compared to a steeper fall in controls. The study indicates that serum profiles of amino acid and biogenic amines are significantly altered in patients with OSA referring to vast pathophysiologic shifts reflected in the systemic metabolism.

A compartmental analysis of solute transfer and exchange across blood-nerve barrier

1988 ◽  
Vol 255 (2) ◽  
pp. R317-R325 ◽  
Author(s):  
E. Rechthand ◽  
Q. R. Smith ◽  
S. I. Rapoport
Keyword(s):  
Peripheral Nerve ◽  
Compartmental Analysis ◽  
Compartment Model ◽  
Solute Diffusion ◽  
Transfer Constant ◽  
Solute Transfer ◽  
Solute Exchange ◽  
Brain Vasculature ◽  
Graphic Analysis ◽  
Uptake Data

A three-compartment model was derived to analyze solute exchange among plasma, peripheral nerve epineurium, and endoneurium. The model was fit to measured tibial-nerve epineurial and endoneurial contents of [14C]sucrose after intravenous bolus injection of tracer in pentobarbital sodium-anesthetized rats. The transfer constant (K) for tracer at epineurial vessels approximated 1.1 X 10(-3) ml.s-1.g whole-nerve-1. K at the blood-nerve barrier (BNB) equaled 1.36-1.51 X 10(-5) ml.s-1.g endoneurium-1. The endoneurial uptake data were analyzed also by a simplified two-compartment model incorporating solute exchange between plasma and endoneurium. K at the BNB (1.46 X 10(-5) ml.s-1.g endoneurium-1), determined by multiple uptake time graphic analysis, was only threefold greater than K at the blood-brain barrier. The transfer constant at the perineurium alone was determined in situ and equaled (1 X 10(-6) ml.s-1.g endoneurium-1. Calculated permeability coefficients (X 10(-8) cm/s) equaled 3.2 at the perineurium, 23 at the endoneurial capillaries, and 3.2 at the brain vasculature. The results demonstrate that for hydrophilic nonelectrolytes 1) flux across the perineurium contributes significantly to solute uptake from plasma into the endoneurium; 2) although nerve capillaries are more permeable than brain capillaries, the tissues of the BNB function as a unit to markedly restrict solute diffusion into the endoneurium; and 3) a two-compartment analysis accurately describes hydrophilic solute transfer from plasma into peripheral nerve.

scholarly journals Evaluation of Methods for Generating Parametric (R)-[11C]PK11195 Binding Images

2007 ◽  
Vol 27 (9) ◽  
pp. 1603-1615 ◽  
Author(s):  
Alie Schuitemaker ◽  
Bart NM van Berckel ◽  
Marc A Kropholler ◽  
Reina W Kloet ◽  
Cees Jonker ◽  
...  
Keyword(s):  
Basis Function ◽  
Arterial Input Function ◽  
Parametric Method ◽  
Compartmental Analysis ◽  
Accurate Method ◽  
Graphical Analysis ◽  
Binding Potential ◽  
Reference Tissue ◽  
Parametric Images ◽  
Arterial Blood

Activated microglia can be visualised using ( R)-[11C]PK11195 (1-[2-chlorophenyl]- N-methyl- N-[1-methyl-propyl]-3-isoquinoline carboxamide) and positron emission tomography (PET). In previous studies, various methods have been used to quantify ( R)-[11C]PK11195 binding. The purpose of this study was to determine which parametric method would be best suited for quantifying ( R)-[11C]PK11195 binding at the voxel level. Dynamic ( R)-[11C]PK11195 scans with arterial blood sampling were performed in 20 healthy and 9 Alzheimer's disease subjects. Parametric images of both volume of distribution ( Vd) and binding potential ( BP) were obtained using Logan graphical analysis with plasma input. In addition, BP images were generated using two versions of the basis function implementation of the simplified reference tissue model, two versions of Ichise linearisations, and Logan graphical analysis with reference tissue input. Results of the parametric methods were compared with results of full compartmental analysis using nonlinear regression. Simulations were performed to assess accuracy and precision of each method. It was concluded that Logan graphical analysis with arterial input function is an accurate method for generating parametric images of Vd. Basis function methods, one of the Ichise linearisations and Logan graphical analysis with reference tissue input provided reasonably accurate and precise estimates of BP. In pathological conditions with reduced flow rates or large variations in blood volume, the basis function method is preferred because it produces less bias and is more precise.

scholarly journals A Strategy for Removing the Bias in the Graphical Analysis Method

2001 ◽  
Vol 21 (3) ◽  
pp. 307-320 ◽  
Author(s):  
Jean Logan ◽  
Joanna S. Fowler ◽  
Nora D. Volkow ◽  
Yu Shin Ding ◽  
Gene-Jack Wang ◽  
...  
Keyword(s):  
Least Squares ◽  
Graphical Method ◽  
Graphical Analysis ◽  
Distribution Volume ◽  
Noise Model ◽  
Data Sets ◽  
Multiple Time ◽  
Analysis Method ◽  
Reference Tissue ◽  
The One

The graphical analysis method, which transforms multiple time measurements of plasma and tissue uptake data into a linear plot, is a useful tool for rapidly obtaining information about the binding of radioligands used in PET studies. The strength of the method is that it does not require a particular model structure. However, a bias is introduced in the case of noisy data resulting in the underestimation of the distribution volume (DV), the slope obtained from the graphical method. To remove the bias, a modification of the method developed by Feng et al. (1993) , the generalized linear least squares (GLLS) method, which provides unbiased estimates for compartment models was used. The one compartment GLLS method has a relatively simple form, which was used to estimate the DV directly and as a smoothing technique for more general classes of model structures. In the latter case, the GLLS method was applied to the data in two parts, that is, one set of parameters was determined for times 0 to T1 and a second set from T1 to the end time. The curve generated from these two sets of parameters then was used as input to the graphical method. This has been tested using simulations of data similar to that of the PET ligand [11C]- d-threo-methylphenidate (MP, DV = 35 mL/mL) and 11C raclopride (RAC, DV = 1.92 mL/mL) and compared with two examples from image data with the same tracers. The noise model was based on counting statistics through the half-life of the isotope and the scanning time. Five hundred data sets at each noise level were analyzed. Results (DV) for the graphical analysis (DVg), the nonlinear least squares (NLS) method (DVnls), the one-tissue compartment GLLS method (DVf), and the two part GLLS followed by graphical analysis (DVfg) were compared. DVFG was found to increase somewhat with increasing noise and in some data sets at high noise levels no estimate could be obtained. However, at intermediate levels it provided a good estimation of the true DV. This method was extended to use a reference tissue in place of the input function to generate the distribution volume ratio (DVR) to the reference region. A linearized form of the simplified reference tissue method of Lammertsma and Hume (1996) was used. The DVR generated directly from the model (DVRfl) was compared with DVRfg (determined from a “smoothed” uptake curve as for DVfg) using the graphical method.

Decrease in Ionized and Total Magnesium Blood Concentrations in Endurance Athletes Following an Exercise Bout Restores within Hours—Potential Consequences for Monitoring and Supplementation

2017 ◽  
Vol 27 (3) ◽  
pp. 264-270 ◽  
Author(s):  
Rieneke Terink ◽  
Michiel G.J. Balvers ◽  
Maria T. Hopman ◽  
Renger F. Witkamp ◽  
Marco Mensink ◽  
...  
Keyword(s):  
Exercise Bout ◽  
Sport Performance ◽  
Endurance Athletes ◽  
Diurnal Fluctuation ◽  
Time Interval ◽  
Multiple Time ◽  
Blood Concentrations ◽  
Blood Samples ◽  
Time Points ◽  
Magnesium Status

Magnesium is essential for optimal sport performance, generating an interest to monitor its status in athletes. However, before measuring magnesium status in blood could become routine, more insight into its diurnal fluctuations and effects of exercise itself is necessary. Therefore, we measured the effect of an acute bout of exercise on ionized (iMg) and total plasma magnesium (tMg) in blood obtained from 18 healthy well-trained endurance athletes (age, 31.1 ± 8.1 yr.; VO2max, 50.9 ± 7.5 ml/kg/min) at multiple time points, and compared this with a resting situation. At both days, 7 blood samples were taken at set time points (8:30 fasted, 11:00, 12:30, 13:30, 15:00, 16:00, 18:30). The control day was included to correct for a putative diurnal fluctuation of magnesium. During the exercise day, athletes performed a 90 min bicycle ergometer test (70% VO2max) between 11:00 and 12:30. Whole blood samples were analyzed for iMg and plasma for tMg concentrations. Both concentrations decreased significantly after exercise (0.52 ± 0.04–0.45 ± 0.03 mmol/L and 0.81 ± 0.07–0.73 ± 0.06 mmol/L, respectively, p < .001) while no significant decline was observed during that time-interval on control days. Both, iMg and tMg, returned to baseline, on average, 2.5 hr after exercise. These findings suggest that timing of blood sampling to analyze Mg status is important. Additional research is needed to establish the recovery time after different types of exercise to come to a general advice regarding the timing of magnesium status assessment in practice.

scholarly journals First Human Trial of FTY720, a Novel Immunomodulator, in Stable Renal Transplant Patients

2002 ◽  
Vol 13 (4) ◽  
pp. 1073-1083
Author(s):  
Klemens Budde ◽  
Robert L. Schmouder ◽  
Reinhard Brunkhorst ◽  
Bjorn Nashan ◽  
Peter W. Lücker ◽  
...  
Keyword(s):  
Renal Transplant ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Multiple Time ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Blood Concentrations ◽  
Transplant Patients ◽  
Renal Transplant Patients ◽  
Oral Doses

ABSTRACT. FTY720 is a novel immunomodulator to be developed for use in organ transplantation. The primary objective of this study was to measure safety, single-dose pharmacokinetics, and pharmacodynamics in stable renal transplant patients—the first human use of FTY720. This study used a randomized, double-blind, placebo-controlled design that explored single oral doses of FTY720 from 0.25 to 3.5 mg in 20 stable renal transplant patients on a cyclosporine-based regimen. Safety assessments and blood samples were taken predose and at multiple time points during a 96-h period postdose. Standard pharmacokinetic parameters were derived from the FTY720 whole blood concentrations, measured by HPLC/MS/MS. FTY720 was well tolerated, with no serious adverse events. Transient, asymptomatic bradycardia occurred after administration in 10 of 24 doses of FTY720. Pharmacokinetics are characterized by a prolonged absorption phase; the terminal elimination phase started 36 h after the administration, with elimination half-life (t1/2) ranging from 89 to 157 h independent of dose. Maximum plasma concentration and AUC were proportional to dose with low intersubject variability, the apparent volume of distribution (Vd/F) ranged from 1116 to 1737 L. FTY pharmacodynamics were characterized by a reversible transient lymphopenia within 6 h, the nadir being 42% of baseline. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Single oral doses of FTY720 ranging from 0.25 to 3.5 mg were well tolerated and caused a reversible selective lymphopenia. Transient, but asymptomatic bradycardia was the most common adverse event. The long t1/2 suggests less frequent dosing intervals. The size of Vd/F is in excess of blood volume, consistent with widespread tissue distribution

scholarly journals PET Studies of Net Blood—Brain Clearance of FDOPA to Human Brain: Age-Dependent Decline of [18F]Fluorodopamine Storage Capacity

2005 ◽  
Vol 25 (7) ◽  
pp. 807-819 ◽  
Author(s):  
Yoshitaka Kumakura ◽  
Ingo Vernaleken ◽  
Gerhard Gründer ◽  
Peter Bartenstein ◽  
Albert Gjedde ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Storage Capacity ◽  
Compartmental Analysis ◽  
Graphical Analysis ◽  
Negative Bias ◽  
Precursor Pool ◽  
Healthy Elderly ◽  
Age Related ◽  
The Brain

Conventional methods for the graphical analysis of 6-[18F]fluorodopa (FDOPA)/positron emission tomography (PET) recordings ( Kappin) 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 ( Kapp). Comparison of Kappin and Kapp maps revealed a global negative bias in the conventional estimates of FDOPA clearance. The present OMFD subtraction method revealed curvature in plots of Kapp 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 ( kloss). The effective distribution volume (EDV2; K/ kloss) 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.

scholarly journals The Use of Alternative Forms of Graphical Analysis to Balance Bias and Precision in PET Images

2010 ◽  
Vol 31 (2) ◽  
pp. 535-546 ◽  
Author(s):  
Jean Logan ◽  
David Alexoff ◽  
Joanna S Fowler
Keyword(s):  
Volume Ratio ◽  
Image Data ◽  
Compartment Model ◽  
Graphical Analysis ◽  
Distribution Volume ◽  
Good Precision ◽  
Reference Tissue ◽  
Positron Emission ◽  
Distribution Volume Ratio ◽  
Uptake Data

Graphical analysis (GA) is an efficient method for estimating total tissue distribution volume ( VT) from positron emission tomography (PET) uptake data. The original GA produces a negative bias in VT in the presence of noise. Estimates of VT using other GA forms have less bias but less precision. Here, we show how the bias terms are related between the GA methods and how using an instrumental variable (IV) can also reduce bias. Results are based on simulations of a two-compartment model with VT's ranging from 10.5 to 64 mL/cm3 and from PET image data with the tracer [11C]DASB ([11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl) benzonitrile). Four estimates of VT (or distribution volume ratio (DVR) using a reference tissue) can be easily computed from different formulations of GA including the IV. As noise affects the estimates from all four differently, they generally do not provide the same estimates. By taking the median value of the four estimates, we can decrease the bias and reduce the effect of large values contributing to noisy images. The variance of the four estimates can serve as a guide to the reliability of the median estimate. This may provide a general method for the generation of parametric images with little bias and good precision.

Mechanism of L-glucose, raffinose, and inulin transport across intact blood-brain barriers

1990 ◽  
Vol 258 (3) ◽  
pp. H695-H705 ◽  
Author(s):  
K. J. Lucchesi ◽  
R. E. Gosselin
Keyword(s):  
Molecular Size ◽  
Compartment Model ◽  
Graphical Analysis ◽  
Capillary Endothelium ◽  
Multiple Time ◽  
Brain Capillary ◽  
Molecular Weights ◽  
Blood Brain ◽  
Two Compartment Model ◽  
The Brain

Brain capillary permeability-surface area products (PS) of hydrophilic solutes were evaluated in terms of a conventional two-compartment model. In rats whose blood-brain barrier (BBB) was presumed to be intact, metabolically inert carbohydrates with different molecular weights were injected in pairs to elucidate whether their transfer into the brain proceeds by diffusion through water- or lipid-filled channels or by vesicular transport. The distribution volume of 70 kDa dextran 10 min after intravenous injection was used as a measure of the residual volume of plasma in brain tissue after death. The two-compartment model yielded larger PS values for inulin and raffinose than for L-glucose, and the PS values of inulin and L-glucose were found to decrease as the labeling time was lengthened (10, 30, and 60 min). These observations were interpreted to mean that a rapidly equilibrating compartment was present between blood and brain, rendering the two-compartment model inadequate for computing true transfer rate constants. When multiple-time uptake data were reanalyzed using the three-compartment graphical analysis of Patlak, Blasberg, and Fenstermacher (J. Cereb. Blood Flow Metab. 3: 1-7, 1983), solutes of differing molecular size were found to enter the brain at approximately equal rates. This observation suggested that the predominant transport mechanism across an intact BBB is vesicular. Specifically, unidirectional transport is likely to be initiated by solute binding to the glycocalyx on the luminal surface of brain capillary endothelium. Apparently more inulin than L-glucose is absorbed, which may account for its slightly faster transfer across the BBB. We suggest that this adsorptive surface is the location of the rapidly equilibrating compartment on the plasma side of the BBB.

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