A system for continuous production and infusion of [15O]H2O for PET activation studies.

A system for continuous production and infusion of [15O]H2O has been designed for Positron Emission Tomography brain activation studies. The infusion system consists of two Horizon Nxt infusion pumps, a four-port-two-position valve and a sterile 50 ml vial. The line and the back check valve between the furnace and the reservoir were heated in order to reduce vapor condensation in the line. The variation of the production of [15O]H2O was < 1%. The activity delivered as measured by scanner counts varied < 2% during the steady state period. The system has been demonstrated to be capable of delivering activity over a wide range of conditions.     

Enhancement of the signal-to-noise ratio in H2(15)O bolus PET activation images: a combined cold-bolus, switched protocol.

To increase the signal-to-noise ratio (S/N) of H2(15)O bolus PET activation images, we designed and tested a data acquisition protocol that alters the relative distribution of tracer in the uptake and washout phases of the input function. This protocol enhances the S/N gains obtained with conventional switched protocols by combining task switching and the use of a large bolus of blood free of tracer (cold bolus). The cold bolus is formed by sequestering blood in the lower limbs with a double cuff before tracer injection. METHODS: The effect of a combined cold-bolus, switched protocol on the signal from activation images was first simulated using a compartmental model of the uptake of H2(15)O into the brain. Then, the effectiveness of the protocol was investigated in 4 healthy volunteers performing a language task. Each volunteer underwent scanning 12 times: 3 activation/ baseline and 3 baseline/activation scans using the conventional switched protocol and 3 activation/baseline and 3 baseline/activation scans using the combined cold-bolus, switched protocol. The S/N changes introduced when using the cold bolus were analyzed by comparing, across protocols, the magnitude and statistical significance of the activation foci associated with the execution of the language task identified in the averaged subtracted images, and by comparing image noise levels. RESULTS: In the simulated datasets, the combined protocol yielded a substantial increase in the activation signals for scan durations greater than 60 s, in comparison with equivalent signals yielded by the switched protocol alone. In the PET experiments, activation foci obtained using the combined protocol had significantly higher t statistic values than did equivalent foci detected using the conventional switched protocol (mean improvement, 36%). Analysis of the S/N in the averaged subtracted images revealed that the improvements in statistical significance of the activation foci were caused by increases in the signal magnitudes and not by decreases in overall image noise. CONCLUSION: We designed a data acquisition protocol for H2(15)O bolus PET activation studies that combines the use of a tracer-free bolus with a switched protocol. Simulated and experimental data suggest that this combined protocol enhances the S/N gains obtained with a conventional switched protocol. Implementation of the combined protocol in H2(15)O bolus activation studies was easy.     

Cortical activation in profoundly deaf patients during cochlear implant stimulation demonstrated by H2(15)O PET

Cochlear implants (CIs) are used to provide sensations of sound to profoundly deaf patients. The performance of the CI is assessed mainly by the subjective reports of patients. The aim of this study was to look for objective cortical responses to the stimulation of the CI. Two postlingually and two prelingually deaf patients were investigated by positron emission tomography (PET) using 15O-labeled water (H2(15)O) to determine the regional cerebral blood flow (rCBF). Instead of quantifying rCBF in absolute terms, it was estimated by referring the regional tissue concentration of H2(15)O to the mean whole brain concentration. CI stimulation encoded from white noise and sequential words led to an increased rCBF in the primary and secondary (Wernicke) auditory cortex. Relative elevations of up to 33% were observed bilaterally, although they were higher contralateral to the CI. These results were obtained not only in the postlingually deaf patients but also in two patients who had never been able to hear. Thus, it could be demonstrated that PET measurements of cerebral H2(15)O distribution yield objective responses of the central auditory system during electrical stimulation by CIs in profoundly deaf patients.     

Analysis of blood flow and glucose metabolism in mammary carcinomas and normal breast: a H2(15)O PET and 18F-FDG PET study

OBJECTIVE: To determine parameters of perfusion, distribution coefficient, and glucose metabolism as part of the tumour-specific micromilieu of breast cancer and compare them with corresponding values in normal breast tissue. METHODS: H2(15)O PET and 18F-FDG PET were performed on 10 patients with advanced invasive ductal carcinomas of the breast. Perfusion, distribution coefficient, and glucose metabolism and standardized uptake were quantified and analysed. RESULTS: Mean values based on the regions of interest were 59.2+/-43.9 ml x min(-1) x 100 g(-1) (perfusion), 0.58+/-0.26 ml x g(-1) (distribution coefficient), 7.76+/-6.10 (standardized uptake), and 5.4+/-2.5 mg x min(-1) x 100 g(-1) (glucose metabolism). The corresponding values for normal breast tissue were 22.1+/-13.2 ml x min x 100 g(-1) (perfusion), 0.16+/-0.05 ml x g(-1) (distribution coefficient), 0.33+/-0.07 (standardized uptake), and 0.18+/-0.08 mg x min x 100 g(-1) (glucose metabolism). For each tumour-normal tissue parameter pair, the mean values were significantly higher in tumours than normal breast tissue. Region-of-interest and pixel-wise correlation analysis revealed a positive association between glucose metabolism and distribution coefficient and glucose metabolism and perfusion for 7/10 tumours investigated. CONCLUSIONS: H2(15)O PET and 18F-FDG PET were able to differentiate breast cancer and normal breast tissue. The pixel-wise analysis revealed information about the heterogeneity of tumour fine structure in perfusion, distribution coefficient, and glucose metabolism, which may provide important guidelines for improving individual treatment.     

A stereotaxic method of anatomical localization by means of H2 15O positron emission tomography applicable to the brain activation study in cats: Registration of images of cerebral blood flow to brain atlas

In the neuronal activation study of normal animals, precise anatomical correlation, preferentially to a detailed brain atlas, is required for the activation foci co-registration. To obtain precise regional correlation between H₂ ¹⁵O-PET images and the brain atlas, a method of stereotaxic image reorientation was applied to an activation study with vibrotactile stimulation. Cats anesthetized with halothane underwent repeated measurements of regional cerebral blood flow (rCBF) in the resting condition and during vibration of the right forepaw. The image set was adjusted three-dimensionally to the atlas. The postmortem brain was sectioned according to the atlas planes. The activated areas were determined by the stimulus-minus-resting subtraction images, and the areas were projected to the atlas. The PET images of the cat brain were compatible both to the postmortem brain slices and to the brain atlas. The activation foci obtained from the subtraction images corresponded to the area around the coronal sulcus, which is electrophysiologically known as the primary sensory area as described in the atlas. There were precise regional correlations between the PET image and anatomy in a PET activation study of the cat by means of stereotaxic image reorientation.     

Simplified quantitative determination of cerebral perfusion reserve with H2 15O PET and acetazolamide

The measurement of regional cerebral blood flow (rCBF) and perfusion reserve (PR) with H₂¹⁵O positron emission tomography (PET) and acetazolamide challenge is of importance in evaluating patients with cerebrovascular disease and is thought to be useful in selecting patients for possible vascular surgery. Full quantitative assessment of rCBF with PET requires arterial blood sampling, which is inconvenient in a clinical setting. In this work, we present a simple non-invasive method with which to quantitatively evaluate PR in one PET session lasting no more than 30 min. In ten patients with cerebrovascular disease, rCBF was measured with H₂¹⁵O PET under the baseline condition and after administration of 1 g acetazolamide using a standard technique involving arterial blood sampling. The activity accumulated over 60 s was normalized to injected activity per kilogram body weight (nAA) and compared with rCBF in eight different brain regions. A high linear correlation was found for PR based on nAA (PR_nAA) and rCBF (PR_rCBF) (PR_nAA=0.843 PR_rCBF + 0.092, r=0.83, Pearson's correlation coefficient). Bland-Altman analyses further confirmed that PR_nAA reflects PR in a quantitative manner. These results demonstrate that the method based on normalized counts allows the quantitative assessment of PR without blood sampling.     

Constant-infusion H(2)15O PET and acetazolamide challenge in the assessment of cerebral perfusion status.

Assessing the baseline perfusion and perfusion reserve after acetazolamide (ACZ) challenge is a common method for the evaluation of patients with cerebrovascular disease. Most previous studies using H(2)(15)O PET applied the bolus injection technique. There is considerable discrepancy regarding the optimal time point of imaging after ACZ injection. The purpose of this study was to continuously monitor cerebral blood flow (CBF) after ACZ using constant-infusion H(2)(15)O PET. METHODS: Four patients with stenoses of an internal carotid artery and 6 with moyamoya disease were studied. H(2)(15)O was continuously infused, and data were recorded in 1-min frames. After equilibration of H(2)(15)O, 5 min of baseline data were acquired, and then 1 g of ACZ was administered intravenously and data collection continued for 10-22 min. Arterial blood was continuously drawn for absolute quantification of CBF. RESULTS: The arterial (15)O concentration remained generally stable during scanning, and the cerebellar blood flow fluctuations of the 5 baseline scans were small. The scan-to-scan difference was 6% (difference of 2 successive scans/mean). In the nonpathologic areas, the increase in CBF started 1-2 min after administration of ACZ. The largest fraction of the increase occurred from 0 to 10 min. The ratio of CBF in pathologic areas to CBF in cerebellum showed an initial decrease that stabilized after 5 min. CONCLUSION: A continuous-infusion protocol is a viable alternative to single bolus injections for the assessment of cerebral perfusion status. Such a protocol is advantageous when the time course of CBF after an intervention is not known. With continuous monitoring, the optimal time point for evaluation of a certain parameter can be chosen post hoc. Furthermore, the time course of CBF itself may allow the definition of new parameters for evaluating perfusion status in cerebrovascular patients, both for assessment before a revascularization procedure and for follow-up. A limitation of the present study is the relatively small number of patients with each type of cerebrovascular disease and the lack of healthy subjects.     

FDG PET in lymphoma: the need for standardization of interpretation. An observer variation study

OBJECTIVE: To measure and describe patterns of interobserver variation in visual interpretation of 18-FDG PET in malignant lymphoma. METHODS: Eleven nuclear medicine physicians with different levels of PET experience independently reviewed 37 18F-FDG PET scans of lymphoma patients (10 obtained at presentation, 27 during or after therapy). They were requested to identify and localize suspicious lymphoma sites and to assign a stage to the baseline scans, and to interpret the remaining scans for the presence of viable lymphoma. Individual (extra-)nodal regions were assessed for the likelihood of malignancy as positive, negative or equivocal. These results were compared to expert readings after dichotomization in conservative and sensitive reading classifications. RESULTS: Sixty-one percent and 56% (using sensitive and conservative reading, respectively) of the baseline scans were scored in accordance with the experts. Fourteen of the 27 scans obtained for therapy evaluation with viable tumour sites were scored in accordance with the experts in 82% and 94% of the patients, using conservative and sensitive reading, respectively. The 13 negative scans were scored in agreement with the experts in only 45% of the cases. False positivity pertained especially to the neck, periclavicular, axilla, mediastinum, lung and bone marrow. More experienced observers tended to have fewer false negative scores. CONCLUSION: There are substantial disparities among nuclear medicine physicians' interpretations of FDG PET scans of lymphoma patients, which may affect patient care and results of multi-institutional clinical trials. A well-defined set of criteria is urgently needed to improve consistency.     

Quantitative cerebral H2(15)O perfusion PET without arterial blood sampling,a method based on washout rate

The quantitative determination of regional cerebral blood flow (rCBF) is important in certain clinical and research applications. The disadvantage of most quantitative methods using H(2)(15)O positron emission tomography (PET) is the need for arterial blood sampling. In this study a new non-invasive method for rCBF quantification was evaluated. The method is based on the washout rate of H(2)(15)O following intravenous injection. All results were obtained with Alpert's method, which yields maps of the washin parameter K(1) (rCBF(K1)) and the washout parameter k(2) (rCBF(k2)). Maps of rCBF(K1) were computed with measured arterial input curves. Maps of rCBF(k2*) were calculated with a standard input curve which was the mean of eight individual input curves. The mean of grey matter rCBF(k2*) (CBF(k2*)) was then compared with the mean of rCBF(K1) (CBF(K1)) in ten healthy volunteer smokers who underwent two PET sessions on day 1 and day 3. Each session consisted of three serial H(2)(15)O scans. Reproducibility was analysed using the rCBF difference scan 3-scan 2 in each session. The perfusion reserve (PR = rCBF(acetazolamide)-rCBF(baseline)) following acetazolamide challenge was calculated with rCBF(k2*) (PR(k2*)) and rCBF(K1) (PR(K1)) in ten patients with cerebrovascular disease. The difference CBF(k2*)-CBF(K1) was 5.90+/-8.12 ml/min/100 ml (mean+/-SD, n=55). The SD of the scan 3-scan 1 difference was 6.1% for rCBF(k2*) and rCBF(K1), demonstrating a high reproducibility. Perfusion reserve values determined with rCBF(K1) and rCBF(k2*) were in high agreement (difference PR(k2*)-PR(K1)=-6.5+/-10.4%, PR expressed in percentage increase from baseline). In conclusion, a new non-invasive method for the quantitative determination of rCBF is presented. The method is in good agreement with Alpert's original method and the reproducibility is high. It does not require arterial blood sampling, yields quantitative voxel-by-voxel maps of rCBF, and is computationally efficient and easy to implement.     

Mapping of local renal blood flow with PET and H(2)(15)O.

We developed a noninvasive method for the mapping of regional renal blood flow in humans using PET and H(2)(15)O. METHODS: Fifteen subjects participated in the study, 5 with normal renal function and 10 with renal disease. The protocol used a whole-body PET scanner, intravenous bolus injection of 1,110-1,850 MBq H(2)(15)O and sequential imaging at 3 s per frame. (131)I-Iodohippuran was used to independently assess effective renal plasma flow in each subject. Hippuran clearance and renal blood flow (RBF) were measured twice, before and after treatment with probenecid, to verify that RBF is not affected. Flow analysis was based on the Kety model, according to the operational equation: C(t) = F integral C(a)(u)du - k integral C(u)du, where F is the RBF, k is the tissue-to-blood clearance rate, C is the PET concentration, and C(a) is the tracer concentration in the abdominal aorta. F and k were estimated by linear least squares on a pixel-by-pixel basis to produce quantitative maps (parametric images) of RBF. The flow maps were analyzed by regions of interest (largely excluding the medulla and collecting system) for each kidney on each slice and pooled to yield mean RBF. RESULTS: In the 5 healthy subjects, mean RBF was 3.4 +/- 0.4 mL/min/g. There was no difference in flow between kidneys (t = -0.59; n = 11; P > 0.95). Before treatment with probenecid, RBF was linearly related to hippuran clearance (r(2) = 0.92). Probenecid treatment significantly reduced hippuran clearance (P < 0.003), but RBF was unchanged (P > 0.17). Compared with healthy control subjects, RBF was significantly decreased in patients with renal disease (P < 0.002). Flow maps were of good quality in all subjects, exhibiting characteristic patterns, with higher values in regions composed largely of renal cortex. CONCLUSION: Parametric mapping of RBF with PET and H(2)(15)O provides a straightforward, noninvasive method for quantitative mapping of RBF, which may prove useful in research applications and in the management of patients whose therapy alters renal tubular transport.     

Simplified quantitative determination of cerebral perfusion reserve with H2(15)O PET and acetazolamide

The measurement of regional cerebral blood flow (rCBF) and perfusion reserve (PR) with H2(15)O positron emission tomography (PET) and acetazolamide challenge is of importance in evaluating patients with cerebrovascular disease and is thought to be useful in selecting patients for possible vascular surgery. Full quantitative assessment of rCBF with PET requires arterial blood sampling, which is inconvenient in a clinical setting. In this work, we present a simple non-invasive method with which to quantitatively evaluate PR in one PET session lasting no more than 30 min. In ten patients with cerebrovascular disease, rCBF was measured with H2(15)O PET under the baseline condition and after administration of 1 g acetazolamide using a standard technique involving arterial blood sampling. The activity accumulated over 60 s was normalized to injected activity per kilogram body weight (nAA) and compared with rCBF in eight different brain regions. A high linear correlation was found for PR based on nAA (PRnAA) and rCBF (PRrCBF) (PRnAA=0.843 PRrCBF + 0.092, r=-0.83, Pearson's correlation coefficient). Bland-Altman analyses further confirmed that PRnAA reflects PR in a quantitative manner. These results demonstrate that the method based on normalized counts allows the quantitative assessment of PR without blood sampling.     

Optimal dose of injection in activation study with O-15 water and PET

In activation studies with the bolus method for O-15 water and PET, the radiotracer concentration may reach the limits of the system in terms of dead time correction and accidental coincidence. To obtain the optimal injection dose of O-15 water, we performed a normal volunteer study to evaluate the relationship between the injected dose and the radioactivity concentration in the brain and a phantom study to evaluate the performance of the PET scanner (PCT3600W) under high count rate conditions and the effect of averaging on the signal to noise ratio for the PET images. A linear relationship was noted between the injected dose (normalized for each body weight: x) and the mean radiotracer concentration in the brain measured by PET (y) (y = 2.52 + 30.1x, n = 64, r = 0.87, p < 0.001). The percent error in the measurement of radioactivity with PET was within ± 5% in the 100 to 2000 nCi/m/ (3.7–74 KBq/mZ) range. Below 100 nCi/mZ (3.7 KBq/mZ), the percent error increased due to the rapid increase in noise in the reconstructed images. Over 1000 nCi/ mZ (37 KBq/mZ), on the other hand, the noise was almost unchanged. With our PET scanner, the optimal range of the radiotracer concentration in the brain is below 1000 nCi/mZ (37 KBq/mZ), corresponding to an injection dose of 33 mCi (1.22 GBq)/60 kg body weight. With the same total dose, the increment of number of repeated measurements for averaging provided the better signal to noise ratio. In designing a paradigm for an activation PET study, the injection dose and the number of repeated measurements for averaging should be considered.     

Sequential H(2)(15)O PET studies in baboons: before and after amphetamine.

PET and (11)C-raclopride have been used to assess dopamine activity in vivo using a paradigm that involved d-amphetamine (AMPH)-induced endogenous dopamine release that led to reductions (relative to baseline) in the (11)C-raclopride-specific binding parameter (binding potential). A common assumption in bolus injection PET studies of this type is that cerebral blood flow (CBF) does not vary during the scan. The goal of this work was to examine the effect of AMPH administration on sequential PET measures of CBF. METHODS: Eight dynamic H(2)(15)O PET scans were acquired with arterial blood sampling in 6 baboons: 4 scans before AMPH (over 60 min) and 4 scans after AMPH (over 60 min) (0.6 mg/kg AMPH). Magnetic resonance images (coregistered to PET) were used to define regions of interest that included cortex, striatum (including subregions), and cerebellum. Data were analyzed using a 1-tissue compartment model. CBF was assessed through K(1) (mL/mL/min). RESULTS: Temporal patterns of the CBF alterations were similar across regions for each baboon. For 5 of 6 baboons, a general pattern of an initial increase in K(1) was observed after AMPH that gradually declined toward baseline, after minimizing anesthesia-induced variability in the in vivo measures. Although these alterations after AMPH were statistically significant in particular subcortical regions and cerebellum, such changes would not likely influence measures of (11)C-raclopride binding potential to a significant extent. CONCLUSION: These data support previous PET studies for which constant blood flow was assumed during the bolus PET (11)C-raclopride/AMPH experiment across striatal subregions, while underscoring the importance of considering effects of anesthesia when interpreting in vivo imaging parameters.     

Repeatability of cold pressor test-induced flow increase assessed with H(2)(15)O and PET.

The aim of this study was to evaluate the repeatability of endothelium-related myocardial blood flow (MBF) responses to cold pressor testing (CPT) as assessed by PET. METHODS: In 10 age-matched control subjects (26.6 +/- 3.4 y) and 10 tobacco smokers (24.9 +/- 3.3 y) MBF was assessed at rest and after repeated CPT (CPT1 and CPT2, 40 min apart) using PET with H(2)(15)O. CPT was performed by a 2-min immersion of the subject's foot in ice water. MBF values were corrected for cardiac workload (rate.pressure product), and the repeatability of CPT-related MBF values was assessed according to Bland and Altman. RESULTS: Corrected MBF at CPT1 and CPT2 were comparable in control subjects (1.79 +/- 0.37 vs. 1.70 +/- 0.35 mL/min/g; P = not significant [NS]) and in smokers (1.97 +/- 0.42 vs. 1.80 +/- 0.41 mL/min/g; P = NS). Repeatability coefficients in control subjects and smokers were 0.46 mL/min/g (27% of the mean MBF) and 0.51 mL/min/g (27%), respectively. MBF increased significantly after CPT in both groups but tended to be lower in smokers (P = 0.08). CONCLUSION: PET measured MBF combined with CPT is a feasible and repeatable method for the evaluation of endothelium-related changes of MBF.     

Quantification of regional myocardial blood flow using dynamic H2(15)O PET and factor analysis.

Because the use of factor analysis has been proposed for extracting pure physiologic temporal or spatial information from dynamic nuclear medicine images, factor analysis should be capable of robustly estimating regional myocardial blood flow (rMBF) using H2(15)O PET without additional C15O PET, which is a cumbersome procedure for patients. Therefore, we measured rMBF using time-activity curves (TACs) obtained from factor analysis of dynamic myocardial H2(15)O PET images without the aid of C15O PET. METHODS: H2(15)O PET of six healthy dogs at rest and during stress was performed simultaneously with microsphere studies using 85Sr, 46Sc, and 113SN: We performed factor analysis in two steps after reorienting and masking the images to include only the cardiac region. The first step discriminated each factor in the spatial distribution and acquired the input functions, and the second step extracted regional-tissue TACS: Image-derived input functions obtained by factor analysis were compared with those obtained by the sampling method. rMBF calculated using a compartmental model with tissue TACs from the second step of the factor analysis was compared with rMBF measured by microsphere studies. RESULTS: Factor analysis was successful for all the dynamic H2(15)O PET images. The input functions obtained by factor analysis were nearly equal to those obtained by arterial blood sampling, except for the expected delay. The correlation between rMBF obtained by factor analysis and rMBF obtained by microsphere studies was good (r = 0.95). The correlation between rMBF obtained by the region-of-interest method and rMBF obtained by microsphere studies was also good (r = 0.93). CONCLUSION: rMBF can be measured robustly by factor analysis using dynamic myocardial H2(15)O PET images without additional C15O blood-pool PET.     

Calf flow reserve with H(2)(15)O PET as a quantifiable index of lower extremity flow.

Objective measures of recruitable blood flow are of importance in angiogenesis trials. We validated a new PET-derived flow reserve (FR) measurement in healthy subjects and subjects with peripheral artery disease (PAD). METHODS: Five healthy volunteers and 5 subjects with PAD underwent cannulation of the femoral artery and vein. Basal and maximal flow (100 micro g/kg/min of adenosine infused intraarterially) in the lower extremity was determined using thermodilution (TD) techniques. Subjects then underwent plethysmography (PL) followed by PET measurements of blood flow at the calf level. For the PET studies, a transmission scan followed by injection of 1.85 GBq (50 mCi) H(2)(15)O and dynamic scanning for 5 min were acquired in five 1-min frames. Regions of interest were drawn on successive PET image slices, and radioactivity was quantified from the first-minute scan after injection. FR for each of the 3 modalities was expressed as the ratio of adenosine to basal flow. RESULTS: PET-derived FR correlated strongly with TD (r = 0.82; P = 0.004) but not with PL (r = 0.17; P = 0.85). The mean average difference in FR between healthy volunteers and PAD subjects was 13.0 with PET and 4.5 with TD. The intra- and intersubject variability for PET expressed as the coefficient of variation was 10.5% and 29.0% for healthy subjects and 7.0% and 52.9% in PAD, respectively. CONCLUSION: As expected, FR was significantly lower in PAD subjects compared with healthy subjects as assessed with TD and PET but not with PL. PET-derived FR appears to be reproducible and generates sharper and higher indices of recruitable flow in healthy subjects and PAD. These findings have implications for the use of PET-derived FR as a sensitive index of recruitable flow in angiogenesis trials.