Performing Repeated Quantitative Small-Animal PET with an Arterial Input Function Is Routinely Feasible in Rats.

Performing quantitative small-animal PET with an arterial input function has been considered technically challenging. Here, we introduce a catheterization procedure that keeps a rat physiologically stable for 1.5 mo. We demonstrated the feasibility of quantitative small-animal 18F-FDG PET in rats by performing it repeatedly to monitor the time course of variations in the cerebral metabolic rate of glucose (CMRglc). Methods: Aseptic surgery was performed on 2 rats. Each rat underwent catheterization of the right femoral artery and left femoral vein. The catheters were sealed with microinjection ports and then implanted subcutaneously. Over the next 3 wk, each rat underwent 18F-FDG quantitative small-animal PET 6 times. The CMRglc of each brain region was calculated using a 3-compartment model and an operational equation that included a k*4Results: On 6 mornings, we completed 12 18F-FDG quantitative small-animal PET studies on 2 rats. The rats grew steadily before and after the 6 quantitative small-animal PET studies. The CMRglc of the conscious brain (e.g., right parietal region, 99.6 ± 10.2 µmol/100 g/min; n = 6) was comparable to that for 14C-deoxyglucose autoradiographic methods. Conclusion: Maintaining good blood patency in catheterized rats is not difficult. Longitudinal quantitative small-animal PET imaging with an arterial input function can be performed routinely.

Redefining the pericontusional penumbra following traumatic brain injury: evidence of deteriorating metabolic derangements based on positron emission tomography.

Abstract The pathophysiological changes in the pericontusional region after traumatic brain injury (TBI) have classically been considered to be ischemic. Using [F-18]fluorodeoxyglucose (FDG) and triple-oxygen PET studies, we examined the pericontusional "penumbra" to assess for increased oxygen extraction fraction (OEF), anaerobic metabolism, and tissue viability. Acute (≤4 days) CT, MRI, and PET studies were performed in eight patients with TBI who had contusions. Four regions-of-interest (ROI) containing the contusion core, pericontusional hypodense gray matter (GM), pericontusional normal-appearing GM, and remote normal-appearing GM, were defined using a semi-automatic method. The correlations of cerebral blood flow (CBF) with OEF, cerebral metabolic rate of oxygen (CMRO2), and cerebral metabolic rate of glucose (CMRglc) were examined. The oxygen-glucose ratio (OGR) in each brain region was evaluated for anaerobic metabolism. The results show that pericontusional tissue had progressively diminishing OEF, CBF, CMRO2, or CMRglc approaching the contusion core. In general, there was a preserved ratio of CBF to CMRO2 in pericontusional hypodense GM. The OGR of the pericontusional hypodense GM was low (<4.0) and was inversely correlated (r=-0.68) with time after injury. A large proportion (%area: 22-76%) of pericontusional hypodense GM tissue had CMRO2 values less than 35 µmol/100 g/min, with this percentage increased with time after injury.

Influence of dietary state and insulin on myocardial, skeletal muscle and brain [F]-fluorodeoxyglucose kinetics in mice.

BACKGROUND: We evaluated the effect of insulin stimulation and dietary changes on myocardial, skeletal muscle and brain [(18)F]-fluorodeoxyglucose (FDG) kinetics and uptake in vivo in intact mice. METHODS: Mice were anesthetized with isoflurane and imaged under different conditions: non-fasted (n = 7; "controls"), non-fasted with insulin (2 IU/kg body weight) injected subcutaneously immediately prior to FDG (n = 6), fasted (n = 5), and fasted with insulin injection (n = 5). A 60-min small-animal PET with serial blood sampling and kinetic modeling was performed. RESULTS: We found comparable FDG standardized uptake values (SUVs) in myocardium in the non-fasted controls and non-fasted-insulin injected group (SUV 45-60 min, 9.58 ± 1.62 vs. 9.98 ± 2.44; p = 0.74), a lower myocardial SUV was noted in the fasted group (3.48 ± 1.73; p < 0.001). In contrast, the FDG uptake rate constant (K(i)) for myocardium increased significantly by 47% in non-fasted mice by insulin (13.4 ± 3.9 ml/min/100 g vs. 19.8 ± 3.3 ml/min/100 g; p = 0.030); in fasted mice, a lower myocardial K(i) as compared to controls was observed (3.3 ± 1.9 ml/min/100 g; p < 0.001). Skeletal muscle SUVs and K(i) values were increased by insulin independent of dietary state, whereas in the brain, those parameters were not influenced by fasting or administration of insulin. Fasting led to a reduction in glucose metabolic rate in the myocardium (19.41 ± 5.39 vs. 3.26 ± 1.97 mg/min/100 g; p < 0.001), the skeletal muscle (1.06 ± 0.34 vs. 0.34 ± 0.08 mg/min/100 g; p = 0.001) but not the brain (3.21 ± 0.53 vs. 2.85 ±0.25 mg/min/100 g; p = 0.19). CONCLUSIONS: Changes in organ SUVs, uptake rate constants and metabolic rates induced by fasting and insulin administration as observed in intact mice by small-animal PET imaging are consistent with those observed in isolated heart/muscle preparations and, more importantly, in vivo studies in larger animals and in humans. When assessing the effect of insulin on the myocardial glucose metabolism of non-fasted mice, it is not sufficient to just calculate the SUV - dynamic imaging with kinetic modeling is necessary.

Quantification of cerebral glucose metabolic rate in mice using 18F-FDG and small-animal PET.

UNLABELLED: The aim of this study was to evaluate various methods for estimating the metabolic rate of glucose utilization in the mouse brain (cMR(glc)) using small-animal PET and reliable blood curves derived by a microfluidic blood sampler. Typical values of (18)F-FDG rate constants of normal mouse cerebral cortex were estimated and used for cMR(glc) calculations. The feasibility of using the image-derived liver time-activity curve as a surrogate input function in various quantification methods was also evaluated. METHODS: Thirteen normoglycemic C57BL/6 mice were studied. Eighteen blood samples were taken from the femoral artery by the microfluidic blood sampler. Tissue time-activity curves were derived from PET images. cMR(glc) values were calculated using 2 different input functions (one derived from the blood samples [IF(blood)] and the other from the liver time-activity curve [IF(liver)]) in various quantification methods, which included the 3-compartment (18)F-FDG model (from which the (18)F-FDG rate constants were derived), the Patlak analysis, and operational equations. The estimated cMR(glc) value based on IF(blood) and the 3-compartment model served as a standard for comparisons with the cMR(glc) values calculated by the other methods. RESULTS: The values of K(1), k(2), k(3), k(4), and K(FDG) estimated by IF(blood) and the 3-compartment model were 0.22 +/- 0.05 mL/min/g, 0.48 +/- 0.09 min(-1), 0.06 +/- 0.02 min(-1), 0.025 +/- 0.010 min(-1), and 0.024 +/- 0.007 mL/min/g, respectively. The standard cMR(glc) value was, therefore, 40.6 +/- 13.3 micromol/100 g/min (lumped constant = 0.6). No significant difference between the standard cMR(glc) and the cMR(glc) estimated by the operational equation that includes k(4) was observed. The standard cMR(glc) was also found to have strong correlations (r > 0.8) with the cMR(glc) value estimated by the use of IF(liver) in the 3-compartment model and with those estimated by the Patlak analysis (using either IF(blood) or IF(liver)). CONCLUSION: The (18)F-FDG rate constants of normal mouse cerebral cortex were determined. These values can be used in the k(4)-included operational equation to calculate cMR(glc). IF(liver) can be used to estimate cMR(glc) in most methods included in this study, with proper linear corrections applied. The validity of using the Patlak analysis for estimating cMR(glc) in mouse PET studies was also confirmed.

Titration of variant HSV1-tk gene expression to determine the sensitivity of 18F-FHBG PET imaging in a prostate tumor.

UNLABELLED: Because of its high selectivity and specificity for the imaging reporter probe 9-(4-(18)F-fluoro-3-[hydroxymethyl]butyl)guanine ((18)F-FHBG), the herpes simplex virus type 1 thymidine kinase (HSV1-tk) variant sr39tk is actively being studied as a PET reporter gene. We recently demonstrated the capability of using a prostate-specific transcriptional amplification PET reporter vector, AdTSTA-sr39tk, to target prostate cancer lymph node metastasis. However, one area that warrants further study is the examination of the sensitivity of PET by determining the minimum percentage of cells expressing the sr39tk transgene needed for detection. Addressing this question could determine the sensitivity of vector-mediated sr39tk PET in cancer-targeting strategies. METHODS: DU-145, PC-3, and CWR22Rv.1 prostate cancer cell lines (a total of 1 x 10(6) cells) were studied, of which 7%, 10%, 25%, 50%, or 70% were transduced with the lentiviral vector constitutively expressing HSV1-sr39tk-IRES-enhanced green fluorescent protein (EGFP). Cells were subcutaneously implanted into the left shoulder of severe combined immunodeficient mice and evaluated. Tumor cells comparably transduced with an EGFP control vector were implanted on the right shoulder. Mice were imaged using PET with (18)F-FHBG at 8, 15, and 22 d after tumor implant. On day 23, tumors were isolated and analyzed for sr39tk transgene expression by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), Western blotting, immunohistochemistry, and flow cytometry for EGFP expression. RESULTS: Results showed a linear relationship between the level of sr39tk expression and the quantity of tracer accrual in DU-145, with the minimal value for PET detection at 10%. The magnitude of tracer retention in sr39tk-expressing cells was amplified over time as the tumor grew. Protein levels in the stepwise titration increased with the percentage of sr39tk-transduced cells. CONCLUSION: The stepwise titration of prostate cancer cells transduced with the lenti-CMV-sr39tk-IRES-EGFP determined the minimum number of sr39tk-expressing tumor cells necessary to be detected by PET using the (18)F-FHBG reporter probe. Furthermore, PET signal correlated well with traditional methods of protein evaluation such as flow cytometry, quantitative RT-PCR, Western blotting, and immunohistochemistry. Unlike the traditional methods, however, the use of PET is noninvasive and will be more advantageous in clinical situations.

Estimation of the 18F-FDG input function in mice by use of dynamic small-animal PET and minimal blood sample data.

UNLABELLED: Derivation of the plasma time-activity curve in murine small-animal PET studies is a challenging task when tracers that are sequestered by the myocardium are used, because plasma time-activity curve estimation usually involves drawing a region of interest within the area of the reconstructed image that corresponds to the left ventricle (LV) of the heart. The small size of the LV relative to the resolution of the small-animal PET system, coupled with spillover effects from adjacent myocardial pixels, makes this method reliable only for the earliest frames of the scan. We sought to develop a method for plasma time-activity curve estimation based on a model of tracer kinetics in blood, muscle, and liver. METHODS: Sixteen C57BL/6 mice were injected with (18)F-FDG, and approximately 15 serial blood samples were taken from the femoral artery via a surgically inserted catheter during 60-min small-animal PET scans. Image data were reconstructed by use of filtered backprojection with CT-based attenuation correction. We constructed a 5-compartment model designed to predict the plasma time-activity curve of (18)F-FDG by use of data from a minimum of 2 blood samples and the dynamic small-animal PET scan. The plasma time-activity curve (TACp) was assumed to have 4 exponential components (TAC(P)=A(1)e(lambda(1)t)+A(2)e(lambda(2)t)+A(3)e(lambda(3)t)-(A(1)+A(2)+A(3))e(lambda(4)t)) based on the serial blood samples. Using Bayesian constraints, we fitted 2-compartment submodels of muscle and liver to small-animal PET data for these organs and simultaneously fitted the input (forcing) function to early small-animal PET LV data and 2 blood samples (approximately 10 min and approximately 1 h). RESULTS: The area under the estimated plasma time-activity curve had an overall Spearman correlation of 0.99 when compared with the area under the gold standard plasma time-activity curve calculated from multiple blood samples. Calculated organ uptake rates (Patlak K(i)) based on the predicted plasma time-activity curve had a correlation of approximately 0.99 for liver, muscle, myocardium, and brain when compared with those based on the gold standard plasma time-activity curve. The model was also able to accurately predict the plasma time-activity curve under experimental conditions that resulted in different rates of clearance of the tracer from blood. CONCLUSION: We have developed a robust method for accurately estimating the plasma time-activity curve of (18)F-FDG by use of dynamic small-animal PET data and 2 blood samples.

In vivo quantitation of glucose metabolism in mice using small-animal PET and a microfluidic device.

UNLABELLED: The challenge of sampling blood from small animals has hampered the realization of quantitative small-animal PET. Difficulties associated with the conventional blood-sampling procedure need to be overcome to facilitate the full use of this technique in mice. METHODS: We developed an automated blood-sampling device on an integrated microfluidic platform to withdraw small blood samples from mice. We demonstrate the feasibility of performing quantitative small-animal PET studies using (18)F-FDG and input functions derived from the blood samples taken by the new device. (18)F-FDG kinetics in the mouse brain and myocardial tissues were analyzed. RESULTS: The studies showed that small ( approximately 220 nL) blood samples can be taken accurately in volume and precisely in time from the mouse without direct user intervention. The total blood loss in the animal was <0.5% of the body weight, and radiation exposure to the investigators was minimized. Good model fittings to the brain and the myocardial tissue time-activity curves were obtained when the input functions were derived from the 18 serial blood samples. The R(2) values of the curve fittings are >0.90 using a (18)F-FDG 3-compartment model and >0.99 for Patlak analysis. The (18)F-FDG rate constants K(1)(*), k(2)(*), k(3)(*), and k(4)(*), obtained for the 4 mouse brains, were comparable. The cerebral glucose metabolic rates obtained from 4 normoglycemic mice were 21.5 +/- 4.3 mumol/min/100 g (mean +/- SD) under the influence of 1.5% isoflurane. By generating the whole-body parametric images of K(FDG)(*) (mL/min/g), the uptake constant of (18)F-FDG, we obtained similar pixel values as those obtained from the conventional regional analysis using tissue time-activity curves. CONCLUSION: With an automated microfluidic blood-sampling device, our studies showed that quantitative small-animal PET can be performed in mice routinely, reliably, and safely in a small-animal PET facility.

Semiautomated analysis of small-animal PET data.

UNLABELLED: The objective of the work reported here was to develop and test automated methods to calculate biodistribution of PET tracers using small-animal PET images. METHODS: After developing software that uses visually distinguishable organs and other landmarks on a scan to semiautomatically coregister a digital mouse phantom with a small-animal PET scan, we elastically transformed the phantom to conform to those landmarks in 9 simulated scans and in 18 actual PET scans acquired of 9 mice. Tracer concentrations were automatically calculated in 22 regions of interest (ROIs) reflecting the whole body and 21 individual organs. To assess the accuracy of this approach, we compared the software-measured activities in the ROIs of simulated PET scans with the known activities, and we compared the software-measured activities in the ROIs of real PET scans both with manually established ROI activities in original scan data and with actual radioactivity content in immediately harvested tissues of imaged animals. RESULTS: PET/atlas coregistrations were successfully generated with minimal end-user input, allowing rapid quantification of 22 separate tissue ROIs. The simulated scan analysis found the method to be robust with respect to the overall size and shape of individual animal scans, with average activity values for all organs tested falling within the range of 98% +/- 3% of the organ activity measured in the unstretched phantom scan. Standardized uptake values (SUVs) measured from actual PET scans using this semiautomated method correlated reasonably well with radioactivity content measured in harvested organs (median r = 0.94) and compared favorably with conventional SUV correlations with harvested organ data (median r = 0.825). CONCLUSION: A semiautomated analytic approach involving coregistration of scan-derived images with atlas-type images can be used in small-animal whole-body radiotracer studies to estimate radioactivity concentrations in organs. This approach is rapid and less labor intensive than are traditional methods, without diminishing overall accuracy. Such techniques have the possibility of saving time, effort, and the number of animals needed for such assessments.

Noninvasive measurement of cardiovascular function in mice with high-temporal-resolution small-animal PET.

UNLABELLED: The aim of this study was to explore the feasibility of determining parameters of cardiovascular function in mice noninvasively by high-temporal-resolution imaging with a dedicated small-animal PET system. METHODS: Twenty-five anesthetized mice (28.8 +/- 4.6 g) were injected via an intravenous catheter with a 30-microL bolus of (18)F-FDG (8-44 MBq). The first 9 s of data were reconstructed into 30 frames of 0.3 s using filtered backprojection. The time-activity curve derived from a left ventricle volume of interest was corrected for tracer recirculation and partial volume. Cardiac output was calculated by the Stewart-Hamilton method, in which cardiac output is total injected activity divided by the area under the left ventricle time-activity curve. Cardiac output divided by body weight was defined as cardiac index; cardiac output divided by heart rate yielded the stroke volume. In 5 mice, measurements were repeated 2-4 times to assess reproducibility. In 4 mice, the hemodynamic response to dobutamine was examined by measuring heart rate, cardiac output, and stroke volume. RESULTS: The cardiac output averaged 20.4 +/- 3.4 mL/min; in the repeated measurements, the parameter displayed a mean percentage SD per mouse of 10% +/- 6%. The cardiac index averaged 0.73 +/- 0.19 mL/min/g and the stroke volume 45.0 +/- 6.9 microL, and both correlated with heart rate (r = 0.53, P = 0.007, and r = 0.49, P = 0.01, respectively). During dobutamine stress, heart rate increased from 423 +/- 50 to 603 +/- 30 beats/min (P = 0.002) and cardiac output increased from 18.5 +/- 1.9 to 32.0 +/- 4.2 mL/min (P = 0.008). CONCLUSION: Parameters of cardiovascular function can be measured in mice noninvasively by radionuclide angiography using high-temporal-resolution small-animal PET. Measured values of cardiac output and stroke volume are reproducible and comparable to those obtained with MRI. The approach permits the monitoring of changes in cardiovascular function in response to pharmacologic intervention.

An internet-based "kinetic imaging system" (KIS) for MicroPET.

Many considerations, involving understanding and selection of multiple experimental parameters, are required to perform MicroPET studies properly. The large number of these parameters/variables and their complicated interdependence make their optimal choice nontrivial. We have a developed kinetic imaging system (KIS), an integrated software system, to assist the planning, design, and data analysis of MicroPET studies. The system serves multiple functions-education, virtual experimentation, experimental design, and image analysis of simulated/experimental data-and consists of four main functional modules--"Dictionary," "Virtual Experimentation," "Image Analysis," and "Model Fitting." The "Dictionary" module provides didactic information on tracer kinetics, pharmacokinetic, MicroPET imaging, and relevant biological/pharmacological information. The "Virtual Experimentation" module allows users to examine via computer simulations the effect of biochemical/pharmacokinetic parameters on tissue tracer kinetics. It generates dynamic MicroPET images based on the user's assignment of kinetics or kinetic parameters to different tissue organs in a 3-D digital mouse phantom. Experimental parameters can be adjusted to investigate the design options of a MicroPET experiment. The "Image Analysis" module is a full-fledged image display/manipulation program. The "Model Fitting" module provides model-fitting capability for measured/simulated tissue kinetics. The system can be run either through the Web or as a stand-alone process. With KIS, radiotracer characteristics, administration method, dose level, imaging sequence, and image resolution-to-noise tradeoff can be evaluated using virtual experimentation. KIS is designed for biology/pharmaceutical scientists to make learning and applying tracer kinetics fun and easy.

Imaging beta-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization.

The polymerization of beta-amyloid (A beta) peptides into fibrillary plaques is implicated, in part, in the pathogenesis of Alzheimer's disease. A beta molecular imaging probes (A beta-MIPs) have been introduced in an effort to quantify amyloid burden or load, in subjects afflicted with AD by invoking the classic PET receptor model for the quantitation of neuronal receptor density. In this communication, we explore conceptual differences between imaging the density of amyloid fibril polymers and neuronal receptors. We formulate a mathematical model for the polymerization of A beta with parameters that are mapped to biological modulators of fibrillogenesis and introduce a universal measure for amyloid load to accommodate various interactions of A beta-MIPs with fibrils. Subsequently, we hypothesize four A beta-MIPs and utilize the fibrillogenesis model to simulate PET tissue time activity curves (TACs). Given the unique nature of polymer growth and resulting PET TAC, the four probes report differing amyloid burdens for a given brain pathology, thus complicating the interpretation of PET images. In addition, we introduce the notion of an MIP's resolution, apparent maximal binding site concentration, optimal kinetic topology and its resolving power in characterizing the pathological progression of AD and the effectiveness of drug therapy. The concepts introduced in this work call for a new paradigm that goes beyond the classic parameters B(max) and K(D) to include binding characteristics to polymeric peptide aggregates such as amyloid fibrils, neurofibrillary tangles and prions.

Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study.

Brain trauma is accompanied by regional alterations of brain metabolism, reduction in metabolic rates and possible energy crisis. We hypothesize that microdialysis markers of energy crisis are present during the critical period of intensive care despite the absence of brain ischemia. In all, 19 brain injury patients (mean GCS 6) underwent combined positron emission tomography (PET) for metabolism of glucose (CMRglu) and oxygen (CMRO(2)) and cerebral microdialysis (MD) at a mean time of 36 h after injury. Microdialysis values were compared with the regional mean PET values adjacent to the probe. Longitudinal MD data revealed a 25% incidence rate of metabolic crisis (elevated lactate/pyruvate ratio (LPR) > 40) but only a 2.4% incidence rate of ischemia. Positron emission tomography imaging revealed a 1% incidence of ischemia across all voxels as measured by oxygen extraction fraction (OEF) and cerebral venous oxygen content (CvO(2)). In the region of the MD probe, PET imaging revealed ischemia in a single patient despite increased LPR in other patients. Lactate/pyruvate ratio correlated negatively with CMRO(2) (P < 0.001), but not with OEF or CvO(2). Traumatic brain injury leads to a state of persistent metabolic crisis as reflected by abnormal cerebral microdialysis LPR that is not related to ischemia.

First-Pass Angiography in Mice Using FDG-PET: A Simple Method of Deriving the Cardiovascular Transit Time Without the Need of Region-of-Interest Drawing.

In this study, we developed a simple and robust semi-automatic method to measure the right ventricle to left ventricle (RV-to-LV) transit time (TT) in mice using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). The accuracy of the method was first evaluated using a 4-D digital dynamic mouse phantom. The RV-to-LV TTs of twenty-nine mouse studies were measured using the new method and compared to those obtained from the conventional ROI-drawing method. The results showed that the new method correctly separated different structures (e.g., RV, lung, and LV) in the PET images and generated corresponding time activity curve (TAC) of each structure. The RV-to-LV TTs obtained from the new method and ROI method were not statistically different (P = 0.20; r = 0.76). We expect that this fast and robust method is applicable to the pathophysiology of cardiovascular diseases using small animal models such as rats and mice.

Subcortical white matter metabolic changes remote from focal hemorrhagic lesions suggest diffuse injury after human traumatic brain injury.

OBJECTIVE: We used positron emission tomographic studies to prospectively examine the relationship between glucose and oxidative metabolism in the subcortical white matter (WM) acutely after traumatic brain injury (TBI). The objective was to determine the nature, extent, and degree of metabolic abnormalities in subcortical brain regions remote from hemorrhagic lesions. METHODS: Sixteen normal volunteers and 10 TBI patients (Glasgow Coma Scale score, 4-10; age, 17-64 yr; 6 with focal and 4 with diffuse injury) were studied. Each subject underwent dynamic positron emission tomographic studies using [(15)O]CO, (15)O(2), [(15)O]H(2)O, and fluorodeoxyglucose plus a magnetic resonance imaging scan acutely after TBI. Parametric images of the metabolic rate of oxygen and metabolic rate of glucose were generated, and a molar oxygen-to-glucose utilization ratio was calculated. Data from gray matter and WM remote from hemorrhagic lesions, plus whole brain, were analyzed. RESULTS: There was a significant reduction in the subcortical WM oxygen-to-glucose utilization ratio after TBI compared with normal values (3.99 +/- 0.77 versus 5.37 +/- 1.00; P < 0.01), whereas the mean cortical gray matter and whole-brain values remained unchanged. WM metabolic changes, which were diffuse throughout the hemispheres, were characterized by a reduction in the metabolic rate of oxygen without a concomitant drop in the metabolic rate of glucose. CONCLUSION: The extent and degree of subcortical WM metabolic abnormalities after moderate and severe TBI suggest that diffuse WM injury is a general phenomenon after such injuries. This pervasive finding may indicate that the concept of focal traumatic injury, although valid from a computed tomographic imaging standpoint, may be misleading when considering metabolic derangements associated with TBI.

Accuracy of a method using short inhalation of (15)O-O(2) for measuring cerebral oxygen extraction fraction with PET in healthy humans.

UNLABELLED: PET with short inhalation of (15)O-O(2) provides regional oxygen extraction fraction (OEF) in a shorter acquisition time and with less radiation exposure than does the steady-state method. The purpose of this study was to test the accuracy of the short-inhalation technique for estimating OEF in healthy human volunteers. METHODS: The final study population included 16 healthy volunteers, who underwent a series of dynamic PET scans consisting of short inhalation of (15)O-CO, short inhalation of (15)O-O(2), and a bolus infusion of (15)O-H(2)O to generate parametric images for cerebral blood volume (CBV), cerebral blood flow (CBF), OEF, and metabolic rate of oxygen (CMRO(2)). About 45 min before PET emission scanning, arterial and jugular blood was sampled through a catheter inserted in a radial artery and the right jugular bulb, respectively. PET-derived OEF (OEFpet) of the whole brain was compared with OEF calculated from the arteriovenous blood-sampling technique (OEFav). RESULTS: Whole-brain-averaged CBF (mean +/- SD) measured with PET was 0.40 +/- 0.06 (range, 0.30-0.55) mL/g/min, CBV was 0.05 +/- 0.01 (range, 0.04-0.09) mL/g, CMRO(2) was 2.85 +/- 0.39 (range, 2.35-3.84) mL/100 g/min, and OEFpet was 0.39 +/- 0.06 (range, 0.30-0.51). OEFpet showed a slightly higher value than did OEFav (0.36 +/- 0.05 [range, 0.29-0.46]), but the difference was not significant. The difference in the 2 measurements (OEFpet - OEFav) did not correlate with CBF (r = -0.16; P = not statistically significant [NS]), CBV (r = -0.20; P = NS), CMRO(2) (r = -0.16; P = NS), partial arterial oxygen pressure (r = 0.29; P = NS) or partial arterial carbon dioxide pressure (r = -0.17; P = NS). CONCLUSION: Compared with the arteriovenous blood-sampling technique, a technique using short inhalation of (15)O-O(2) did not significantly over- or underestimate global OEF in healthy human volunteers. The PET technique reasonably estimated the cerebral OEF in local brain tissues of healthy human volunteers.

Acute changes in regional cerebral (18)F-FDG kinetics in patients with traumatic brain injury.

UNLABELLED: During the acute phase after traumatic brain injury (TBI), the metabolic state is regionally heterogeneous. The purpose of this study was to characterize contusional, pericontusional, and remote regions of TBI by estimating glucose transporter and hexokinase activities on the basis of (18)F-FDG kinetic modeling. METHODS: A standard 2-compartment model was used to measure (18)F-FDG kinetic parameters in 21 TBI patients with cerebral contusions studied during the acute phase (3.1 +/- 2.1 [mean +/- SD] d after injury). Nineteen patients also underwent (15)O-water PET to measure regional cerebral blood flow (CBF). A control study ((18)F-FDG and (15)O-water) was done with 18 healthy volunteers. The rate constants K(i), K(1), and k(3) were assumed to represent the uptake, transport, and hexokinase activity of (18)F-FDG, respectively; K(i) was calculated as K(1) x [k(3)/(k(2) + k(3))]. RESULTS: The areas of contusional and pericontusional tissues located 4.5, 13.5, and 22.5 mm away from the contusion (PC(4.5), PC(13.5), and PC(22.5), respectively) demonstrated significantly reduced K(1) values, whereas the K(1) values for remote areas remained normal. The k(3) values were significantly reduced regardless of the distance from the contusion. Pericontusional areas with CT- or MRI-evidenced tissue damage showed significantly lower K(i) (P < 0.001), CBF (P < 0.01), and K(1) (P < 0.0001) values than did areas without such damage, whereas the k(3) values did not differ significantly. Seven patients showed regionally increased (18)F-FDG uptake (hot spots) in pericontusional areas. The k(3) value for the hot spots (0.086 +/- 0.024/min) was significantly higher than that for the remote cortex (P < 0.01), whereas the K(i), CBF, and K(1) values did not show significant differences. Patients with hot spots showed significantly higher K(i) and k(3) values in PC(4.5) (P < 0.05) and higher k(3) values in PC(22.5) (P < 0.05) than did patients without hot spots, whereas the K(1) and CBF values did not differ significantly. CONCLUSION: Brain tissue (18)F-FDG kinetics in TBI patients were consistent with reduced hexokinase activity in the whole brain (including apparently uninjured cortex), whereas glucose transport was impaired only in the area immediately around the contusion. Pericontusional high levels of (18)F-FDG uptake observed in a subgroup of patients could have been the result of regionally increased hexokinase activity.

Selective metabolic reduction in gray matter acutely following human traumatic brain injury.

The aim of this study was to determine whether the apparent loss of overall gray-white matter contrast (GM/WM) seen on FDG-PET imaging reflects the differential changes of glucose metabolic rate (CMRglc) in cortical gray mater (GM) and subcortical white mater (WM) following TBI. The clinical significance of the CMRglc GM-to-WM ratio was also evaluated. Nineteen normal volunteers and 14 TBI patients were studied. Each subject had a quantitative FDG-PET, a quantitative H215O-PET and a MR scan acutely following TBI. Stabilities of the global and regional FDG lumped constants (LC) were studied. Parametric images (pixel unit: mg/min/100g) of FDG uptake rate (CURFDG) and CMRglc were generated. The changes of CMR(glc) in whole brain, GM and WM were studied separately by using a MRI-segmentation-based technique. The GM-to-WM ratios of both CURFDG and CMRglc images were significantly (p < 0.001) decreased (>31%) in TBI patients. The global LC value reduced significantly (p < 0.01) in TBI patients. The CMRglc decreased significantly (p < 0.001) in GM but not in WM (p > 0.1). Kinetic analysis revealed significant (p < 0.001) decrease of GM hexokinase activity in TBI patients. The GM-to-WM ratios of CMRglc correlated (r = 0.64) with the initial Glasgow Coma Score (GCS) of TBI patients. The patients with higher CMRglc GM-to-WM ratios (>1.54) showed good recovery 12 months after TBI. There was a selective CMRglc reduction in cortical GM following TBI. The pathophysiological basis for the reduction in GM-to-WM CMRglc ratio seen on FDG-PET imaging following TBI remains to be determined.

Investigation of a new input function validation approach for dynamic mouse microPET studies.

PURPOSE: Image-derived input functions are desirable for quantifying biological functions in dynamic mouse micro positron emission tomography (PET) studies, but the input function so derived needs to be validated. Conventional validation using serial blood samples is difficult in mice. We introduced the theoretical basis and used computer simulations to show the capability of a new approach that requires only a small number of blood samples per mouse but uses multiple animals. PROCEDURES: 2-Deoxy-2-[(18)F]fluoro-D-glucose (FDG) kinetics (60 minutes) were simulated for 10 to 20 animals with three to six blood samples available per animal. Various amounts/types of noise/errors in the blood measurements were assumed, and different amounts/types of errors were added to the true input function to simulate image-derived input function. Deviations between blood samples and the derived input function were examined by statistical techniques to evaluate the capability of the approach for detecting the simulated errors in the derived input function. RESULTS: For a total of 60 blood samples and a 10% measurement noise, a 5% contaminating error in image-derived input function can be detected with a statistical power of approximately 0.9 and with a 95% confidence. The power of the approach is directly related to the error magnitude in the image-derived input function, and is related to the total number of blood samples taken, but is inversely related to the measurement noise of the blood samples. CONCLUSION: The new validation approach is expected to be useful for validating input functions derived with image-based methods in dynamic mouse microPET studies.

Correlation of regional metabolic rates of glucose with glasgow coma scale after traumatic brain injury.

UNLABELLED: After traumatic brain injury (TBI), subcortical white matter damage may induce a functional disconnection leading to a dissociation of regional cerebral metabolic rate of glucose (CMRglc) between the cerebral cortex and deeper brain regions. Therefore, thalamic and brain stem CMRglc may have a closer correlation than does the cerebral cortex with depth of coma after TBI. METHODS: Eleven adult healthy volunteers and 23 adult patients with TBI (median initial Glasgow Coma Scale score [GCSini], 8) underwent (18)F-FDG PET within 5 d after injury. The CMRglc of cortical areas (remote from hemorrhagic lesions), striatum, thalamus, brain stem, cerebellar cortex, and whole brain was compared with severity of injury and the level of consciousness evaluated using GCSini and the Glasgow Coma Scale score at the time of PET (GCSpet). RESULTS: The regional CMRglc of the brain stem is relatively unaffected by the TBI. Compared with healthy volunteers, TBI patients exhibited significantly depressed CMRglc in the striatum (3.9 +/- 1.3 vs. 5.1 +/- 0.9 mg/100 g/min, P < 0.05) and thalamus (3.1 +/- 1.0 vs. 4.3 +/- 0.9 mg/100 g/min, P < 0.05). CMRglc levels were not statistically lower in the cerebellum (2.9 +/- 0.8 vs. 3.5 +/- 0.8 mg/100 g/min, P = NS) and brain stem (2.5 +/- 0.5 vs. 2.6 +/- 0.5 mg/100 g/min, P = NS). However, compared between comatose and noncomatose patients, CMRglc values in the thalamus (2.7 +/- 0.7 vs. 3.6 +/- 1.2 mg/100 g/min, P < 0.05), brain stem (2.2 +/- 0.4 vs. 2.8 +/- 0.5 mg/100 g/min, P < 0.01), and cerebellar cortex (2.6 +/- 0.5 vs. 3.4 +/- 1.0 mg/100 g/min, P < 0.05) were significantly lower in comatose patients. When individual values of regional CMRglc were plotted against posttraumatic level of consciousness, CMRglc values for the thalamus, brain stem, and cerebellum significantly correlated with the level of consciousness at the time of PET (r = 0.58, P < 0.01; r = 0.66, P < 0.01; r = 0.64, P < 0.01, respectively). CT or MRI findings were normal for the analyzed structures except for 3 patients with diffuse axonal injury of the brain stem. The presence of shear injury was associated with poor GCSini (P < 0.05.) but was not related to GCSpet and brain stem CMRglc. CONCLUSION: A PET investigation using (18)F FDG demonstrated a significant difference in glucose metabolism in the thalamus, brain stem, and cerebellum between comatose and noncomatose patients acutely after TBI. The metabolic rate of glucose in these regions significantly correlated with the level of consciousness at the time of PET.

Measurement of the global lumped constant for 2-deoxy-2-[18F]fluoro-D-glucose in normal human brain using [15O]water and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography imaging. A method with validation based on multiple methodologies.

PURPOSE: This study aims to determine a lumped constant (LC) value that can be applied to the 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography (FDG-PET) study to yield a physiological value of cerebral metabolic rate of glucose (CMR(glc)) in normal brain. PROCEDURES: We developed a more robust method for determining the global FDG LC. Dynamic FDG and H(2)(15)O PET studied were acquired in 18 normal subjects. Arterial-venous difference of blood glucose level was measured. RESULTS: A global LC of 0.65 +/- 0.15 was obtained if a 3-microparameter FDG model (k*(4)=0)was assumed. Assumption of a 4-microparameter FDG model (k*(4) not equal 0) in analyzing the FDG data resulted in a higher LC value of 0.81 +/- 0.18. CONCLUSION: The value of LC used for quantitating CMR(glc) should match the assumption inherent to the method of data analysis. The LC results in this study agree well with recent findings in the literature.