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1.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.
A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.
The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Objective
The objective of this analysis is to assess the effectiveness and safety of positron emission tomography (PET) imaging using F-18-fluorodeoxyglucose (FDG) for the assessment of myocardial viability. To evaluate the effectiveness of FDG PET viability imaging, the following outcomes are examined:
the diagnostic accuracy of FDG PET for predicting functional recovery;
the impact of PET viability imaging on prognosis (mortality and other patient outcomes); and
the contribution of PET viability imaging to treatment decision making and subsequent patient outcomes.
Clinical Need: Condition and Target Population
Left Ventricular Systolic Dysfunction and Heart Failure
Heart failure is a complex syndrome characterized by the heart’s inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality.
In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD)1 is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997.
Treatment Options
In general, there are three options for the treatment of heart failure: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure.
Myocardial Viability
Left ventricular dysfunction may be permanent if a myocardial scar is formed, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically:
dobutamine echocardiography (echo),
stress echo with contrast,
SPECT using either technetium or thallium,
cardiac magnetic resonance imaging (cardiac MRI), and
positron emission tomography (PET).
Dobutamine Echocardiography
Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 – 10 μg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability.
Stress Echocardiography with Contrast
Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium.
SPECT
SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (> 10% increase in tracer uptake) on the re-injection images.
The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (> 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%.
There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery.
Cardiac Positron Emission Tomography
Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG).
During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. This collision results in annihilation where the combined mass of the positron and electron is converted into energy in the form of two 511 keV gamma rays, which are then emitted in opposite directions (180 degrees) and captured by an external array of detector elements in the PET gantry. Computer software is then used to convert the radiation emission into images. The system is set up so that it only detects coincident gamma rays that arrive at the detectors within a predefined temporal window, while single photons arriving without a pair or outside the temporal window do not active the detector. This allows for increased spatial and contrast resolution.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of PET for detecting myocardial viability?
What is the prognostic value of PET viability imaging (mortality and other clinical outcomes)?
What is the contribution of PET viability imaging to treatment decision making?
What is the safety of PET viability imaging?
Literature Search
A literature search was performed on July 17, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 to July 16, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In addition, published systematic reviews and health technology assessments were reviewed for relevant studies published before 2004. Reference lists of included studies were also examined for any additional relevant studies not already identified. The quality of the body of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
English language full-reports
Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies
Patients with chronic, known CAD
PET imaging using FDG for the purpose of detecting viable myocardium
Criteria applying to diagnostic accuracy studies:
Assessment of functional recovery ≥3 months after revascularization
Raw data available to calculate sensitivity and specificity
Gold standard: prediction of global or regional functional recovery
Criteria applying to prognosis studies:
Mortality studies that compare revascularized patients with non-revascularized patients and patients with viable and non-viable myocardium
Exclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
PET perfusion imaging
< 20 patients
< 18 years of age
Patients with non-ischemic heart disease
Animal or phantom studies
Studies focusing on the technical aspects of PET
Studies conducted exclusively in patients with acute myocardial infarction (MI)
Duplicate publications
Criteria applying to diagnostic accuracy studies
Gold standard other than functional recovery (e.g., PET or cardiac MRI)
Assessment of functional recovery occurs before patients are revascularized
Outcomes of Interest
Diagnostic accuracy studies
Sensitivity and specificity
Positive and negative predictive values (PPV and NPV)
Positive and negative likelihood ratios
Diagnostic accuracy
Adverse events
Prognosis studies
Mortality rate
Functional status
Exercise capacity
Quality of Life
Influence on PET viability imaging on physician decision making
Statistical Methods
Pooled estimates of sensitivity and specificity were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance was defined by P values less than 0.05, where “false discovery rate” adjustments were made for multiple hypothesis testing. Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced. The area under the sROC curve was estimated by numerical integration with a cubic spline (default option). Finally, pooled estimates of mortality rates were calculated using weighted means.
Quality of Evidence
The quality of evidence assigned to individual diagnostic studies was determined using the QUADAS tool, a list of 14 questions that address internal and external validity, bias, and generalizibility of diagnostic accuracy studies. Each question is scored as “yes”, “no”, or “unclear”. The quality of the body of evidence was then assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
A total of 40 studies met the inclusion criteria and were included in this review: one health technology assessment, two systematic reviews, 22 observational diagnostic accuracy studies, and 16 prognosis studies. The available PET viability imaging literature addresses two questions: 1) what is the diagnostic accuracy of PET imaging for the assessment; and 2) what is the prognostic value of PET viability imaging. The diagnostic accuracy studies use regional or global functional recovery as the reference standard to determine the sensitivity and specificity of the technology. While regional functional recovery was most commonly used in the studies, global functional recovery is more important clinically. Due to differences in reporting and thresholds, however, it was not possible to pool global functional recovery.
Functional recovery, however, is a surrogate reference standard for viability and consequently, the diagnostic accuracy results may underestimate the specificity of PET viability imaging. For example, regional functional recovery may take up to a year after revascularization depending on whether it is stunned or hibernating tissue, while many of the studies looked at regional functional recovery 3 to 6 months after revascularization. In addition, viable tissue may not recover function after revascularization due to graft patency or re-stenosis. Both issues may lead to false positives and underestimate specificity. Given these limitations, the prognostic value of PET viability imaging provides the most direct and clinically useful information. This body of literature provides evidence on the comparative effectiveness of revascularization and medical therapy in patients with viable myocardium and patients without viable myocardium. In addition, the literature compares the impact of PET-guided treatment decision making with SPECT-guided or standard care treatment decision making on survival and cardiac events (including cardiac mortality, MI, hospital stays, unintended revascularization, etc).
The main findings from the diagnostic accuracy and prognosis evidence are:
Based on the available very low quality evidence, PET is a useful imaging modality for the detection of viable myocardium. The pooled estimates of sensitivity and specificity for the prediction of regional functional recovery as a surrogate for viable myocardium are 91.5% (95% CI, 88.2% – 94.9%) and 67.8% (95% CI, 55.8% – 79.7%), respectively.
Based the available very low quality of evidence, an indirect comparison of pooled estimates of sensitivity and specificity showed no statistically significant difference in the diagnostic accuracy of PET viability imaging for regional functional recovery using perfusion/metabolism mismatch with FDG PET plus either a PET or SPECT perfusion tracer compared with metabolism imaging with FDG PET alone.
FDG PET + PET perfusion metabolism mismatch: sensitivity, 89.9% (83.5% – 96.4%); specificity, 78.3% (66.3% – 90.2%);
FDG PET + SPECT perfusion metabolism mismatch: sensitivity, 87.2% (78.0% – 96.4%); specificity, 67.1% (48.3% – 85.9%);
FDG PET metabolism: sensitivity, 94.5% (91.0% – 98.0%); specificity, 66.8% (53.2% – 80.3%).
Given these findings, further higher quality studies are required to determine the comparative effectiveness and clinical utility of metabolism and perfusion/metabolism mismatch viability imaging with PET.
Based on very low quality of evidence, patients with viable myocardium who are revascularized have a lower mortality rate than those who are treated with medical therapy. Given the quality of evidence, however, this estimate of effect is uncertain so further higher quality studies in this area should be undertaken to determine the presence and magnitude of the effect.
While revascularization may reduce mortality in patients with viable myocardium, current moderate quality RCT evidence suggests that PET-guided treatment decisions do not result in statistically significant reductions in mortality compared with treatment decisions based on SPECT or standard care protocols. The PARR II trial by Beanlands et al. found a significant reduction in cardiac events (a composite outcome that includes cardiac deaths, MI, or hospital stay for cardiac cause) between the adherence to PET recommendations subgroup and the standard care group (hazard ratio, .62; 95% confidence intervals, 0.42 – 0.93; P = .019); however, this post-hoc sub-group analysis is hypothesis generating and higher quality studies are required to substantiate these findings.
The use of FDG PET plus SPECT to determine perfusion/metabolism mismatch to assess myocardial viability increases the radiation exposure compared with FDG PET imaging alone or FDG PET combined with PET perfusion imaging (total-body effective dose: FDG PET, 7 mSv; FDG PET plus PET perfusion tracer, 7.6 – 7.7 mSV; FDG PET plus SPECT perfusion tracer, 16 – 25 mSv). While the precise risk attributed to this increased exposure is unknown, there is increasing concern regarding lifetime multiple exposures to radiation-based imaging modalities, although the incremental lifetime risk for patients who are older or have a poor prognosis may not be as great as for healthy individuals.
PMCID: PMC3377573  PMID: 23074393
2.  Magnetic Resonance Imaging (MRI) for the Assessment of Myocardial Viability 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of noninvasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.
A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.
A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Objective
The objective of this analysis is to assess the effectiveness and cost-effectiveness of cardiovascular magnetic resonance imaging (cardiac MRI) for the assessment of myocardial viability. To evaluate the effectiveness of cardiac MRI viability imaging, the following outcomes were examined: the diagnostic accuracy in predicting functional recovery and the impact of cardiac MRI viability imaging on prognosis (mortality and other patient outcomes).
Clinical Need: Condition and Target Population
Left Ventricular Systolic Dysfunction and Heart Failure
Heart failure is a complex syndrome characterized by the heart’s inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality.
In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD) 1 is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997.
Treatment Options
In general, there are three options for the treatment of heart failure: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or, in some cases, through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure.
Myocardial Viability
Left ventricular dysfunction may be permanent, due to the formation of myocardial scar, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically:
dobutamine echocardiography (echo),
stress echo with contrast,
SPECT using either technetium or thallium,
cardiac magnetic resonance imaging (cardiac MRI), and
positron emission tomography (PET).
Dobutamine Echocardiography
Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 – 10 µg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability.
Stress Echocardiography with Contrast
Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium.
SPECT
SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (> 10% increase in tracer uptake) on the re-injection images.
The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (> 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%.
There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%.
Cardiac Positron Emission Tomography
Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG).
During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. This collision results in annihilation where the combined mass of the positron and electron is converted into energy in the form of two 511 keV gamma rays, which are then emitted in opposite directions (180 degrees) and captured by an external array of detector elements in the PET gantry. Computer software is then used to convert the radiation emission into images. The system is set up so that it only detects coincident gamma rays that arrive at the detectors within a predefined temporal window, while single photons arriving without a pair or outside the temporal window do not active the detector. This allows for increased spatial and contrast resolution.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of cardiac MRI for detecting myocardial viability?
What is the impact of cardiac MRI viability imaging on prognosis (mortality and other clinical outcomes)?
How does cardiac MRI compare with cardiac PET imaging for the assessment of myocardial viability?
What is the contribution of cardiac MRI viability imaging to treatment decision making?
Is cardiac MRI cost-effective compared with other cardiac imaging modalities for the assessment of myocardial viability?
Literature Search
A literature search was performed on October 9, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 until October 9, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. In addition, published systematic reviews and health technology assessments were reviewed for relevant studies published before 2005. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language full-reports
Published between January 1, 2005 and October 9, 2009
Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies
Patients with chronic, known coronary artery disease (CAD)
Used contrast-enhanced MRI
Assessment of functional recovery ≥ 3 months after revascularization
Exclusion Criteria
< 20 patients
< 18 years of age
Patients with non-ischemic heart disease
Studies conducted exclusively in patients with acute myocardial infarction (MI)
Studies where TP, TN, FP, FN cannot be determined
Outcomes of Interest
Sensitivity
Specificity
Positive predictive value (PPV)
Negative Predictive value (NPV)
Positive likelihood ratio
Negative likelihood ratio
Diagnostic accuracy
Mortality rate (for prognostic studies)
Adverse events
Summary of Findings
Based on the available very low quality evidence, MRI is a useful imaging modality for the detection of viable myocardium. The pooled estimates of sensitivity and specificity for the prediction of regional functional recovery as a surrogate for viable myocardium are 84.5% (95% CI: 77.5% – 91.6%) and 71.0% (95% CI: 68.8% – 79.2%), respectively.
Subgroup analysis demonstrated a statistically significant difference in the sensitivity of MRI to assess myocardial viability for studies using ≤25% hyperenhancement as a viability threshold versus studies using ≤50% hyperenhancement as their viability threshold [78.7 (95% CI: 69.1% - 88.2%) and 96.2 (95% CI: 91.8 – 100.6); p=0.0044 respectively]. Marked differences in specificity were observed [73.6 (95% CI: 62.6% - 84.6%) and 47.2 (95% CI: 22.2 – 72.3); p=0.2384 respectively]; however, these findings were not statistically significant.
There were no statistically significant differences between the sensitivities or specificities for any other subgroups including mean preoperative LVEF, imaging method for function recovery assessment, and length of follow-up.
There was no evidence available to determine whether patients with viable myocardium who are revascularized have a lower mortality rate than those who are treated with medical therapy.
PMCID: PMC3426228  PMID: 23074392
3.  Investigation of dynamic SPECT measurements of the arterial input function in human subjects using simulation, phantom and human studies 
Physics in Medicine and Biology  2011;57(2):375-393.
Computer simulations, a phantom study and a human study were performed to determine whether a slowly rotating single-photon computed emission tomography (SPECT) system could provide accurate arterial input functions for quantification of myocardial perfusion imaging using kinetic models. The errors induced by data inconsistency associated with imaging with slow camera rotation during tracer injection were evaluated with an approach called SPECT/P (dynamic SPECT from positron emission tomography (PET)) and SPECT/D (dynamic SPECT from database of SPECT phantom projections). SPECT/P simulated SPECT-like dynamic projections using reprojections of reconstructed dynamic 94Tc-methoxyisobutylisonitrile (94Tc-MIBI) PET images acquired in three human subjects (1 min infusion). This approach was used to evaluate the accuracy of estimating myocardial wash-in rate parameters K1 for rotation speeds providing 180° of projection data every 27 or 54 s. Blood input and myocardium tissue time-activity curves (TACs) were estimated using spatiotemporal splines. These were fit to a one-compartment perfusion model to obtain wash-in rate parameters K1. For the second method (SPECT/D), an anthropomorphic cardiac torso phantom was used to create real SPECT dynamic projection data of a tracer distribution derived from 94Tc-MIBI PET scans in the blood pool, myocardium, liver and background. This method introduced attenuation, collimation and scatter into the modeling of dynamic SPECT projections. Both approaches were used to evaluate the accuracy of estimating myocardial wash-in parameters for rotation speeds providing 180° of projection data every 27 and 54 s. Dynamic cardiac SPECT was also performed in a human subject at rest using a hybrid SPECT/CT scanner. Dynamic measurements of 99mTc-tetrofosmin in the myocardium were obtained using an infusion time of 2 min. Blood input, myocardium tissue and liver TACs were estimated using the same spatiotemporal splines. The spatiotemporal maximum-likelihood expectation-maximization (4D ML-EM) reconstructions gave more accurate reconstructions than did standard frame-by-frame static 3D ML-EM reconstructions. The SPECT/P results showed that 4D ML-EM reconstruction gave higher and more accurate estimates of K1 than did 3D ML-EM, yielding anywhere from a 44% underestimation to 24% overestimation for the three patients. The SPECT/D results showed that 4D ML-EM reconstruction gave an overestimation of 28% and 3D ML-EM gave an underestimation of 1% for K1. For the patient study the 4D ML-EM reconstruction provided continuous images as a function of time of the concentration in both ventricular cavities and myocardium during the 2 min infusion. It is demonstrated that a 2 min infusion with a two-headed SPECT system rotating 180° every 54 s can produce measurements of blood pool and myocardial TACs, though the SPECT simulation studies showed that one must sample at least every 30 s to capture a 1 min infusion input function.
doi:10.1088/0031-9155/57/2/375
PMCID: PMC3325151  PMID: 22170801
4.  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.
doi:10.1007/s11307-005-0014-3
PMCID: PMC3009470  PMID: 16132473
Tracer kinetics; MicroPET; Virtual experimentation; Molecular imaging
5.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
Objective
The objective was to update the 2001 systematic review conducted by the Institute For Clinical Evaluative Sciences (ICES) on the use of positron emission tomography (PET) in assessing myocardial viability. The update consisted of a review and analysis of the research evidence published since the 2001 ICES review to determine the effectiveness and cost-effectiveness of PET in detecting left ventricular (LV) viability and predicting patient outcomes after revascularization in comparison with other noninvasive techniques.
Background
Left Ventricular Viability
Heart failure is a complex syndrome that impairs the contractile ability of the heart to maintain adequate blood circulation, resulting in poor functional capacity and increased risk of morbidity and mortality. It is the leading cause of hospitalization in elderly Canadians. In more than two-thirds of cases, heart failure is secondary to coronary heart disease. It has been shown that dysfunctional myocardium resulting from coronary heart disease (CAD) may recover contractile function (i.e. considered viable). Dysfunctional but viable myocardium may have been stunned by a brief episode of ischemia, followed by restoration of perfusion, and may regain function spontaneously. It is believed that repetitive stunning results in hibernating myocardium that will only regain contractile function upon revascularization.
For people with CAD and severe LV dysfunction (left ventricular ejection fraction [LVEF] <35%) refractory to medical therapy, coronary artery bypass and heart transplantation are the only treatment options. The opportunity for a heart transplant is limited by scarcityof donor hearts. Coronary artery bypass in these patients is associated with high perioperative complications; however, there is evidence that revascularization in the presence of dysfunctional but viable myocardium is associated with survival benefits and lower rates of cardiac events. The assessment of left ventricular (LV) viability is, therefore, critical in deciding whether a patient with coronary artery disease and severe LV dysfunction should undergo revascularization, receive a heart transplant, or remain on medical therapy.
Assessment of Left Ventricular Viability
Techniques for assessing myocardial viability depend on the measurement of a specific characteristic of viable myocytes such as cell membrane integrity, preserved metabolism, mitochondria integrity, and preserved contractile reserve. In Ontario, single photon emission computed tomography (SPECT) using radioactive 201thallium is the most commonly used technique followed by dobutamine echocardiography. Newer techniques include SPECT using technetium tracers, cardiac magnetic resonance imaging, and PET, the subject of this review.
Positron Emission Tomography
PET is a nuclear imaging technique based on the metabolism of radioactive analogs of normal substrates such as glucose and water. The radiopharmaceutical used most frequently in myocardial viability assessment is F18 fluorodeoxyglucose (FDG), a glucose analog. The procedure involves the intravenous administration of FDG under controlled glycemic conditions, and imaging with a PET scanner. The images are reconstructed using computer software and analyzed visually or semi-quantitatively, often in conjunction with perfusion images. Dysfunctional but stunned myocardium is characterized by normal perfusion and normal FDG uptake; hibernating myocardium exhibits reduced perfusion and normal/enhanced FDG uptake (perfusion/metabolism mismatch), whereas scar tissue is characterized by reduction in both perfusion and FDG uptake (perfusion/metabolism match).
Review Strategy
The Medical Advisory Secretariat used a search strategy similar to that used in the 2001 ICES review to identify English language reports of health technology assessments and primary studies in selected databases, published from January 1, 2001 to April 20, 2005. Patients of interest were those with CAD and severe ventricular dysfunction being considered for revascularization that had undergone viability assessment using either PET and/or other noninvasive techniques. The outcomes of interest were diagnostic and predictive accuracy with respect to recovery of regional or global LV function, long-term survival and cardiac events, and quality of life. Other outcomes of interest were impact on treatment decision, adverse events, and cost-effectiveness ratios.
Of 456 citations, 8 systematic reviews/meta-analyses and 37 reports on primary studies met the selection criteria. The reports were categorized using the Medical Advisory Secretariat levels of evidence system, and the quality of the reports was assessed using the criteria of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) developed by the Centre for Dissemination of Research (National Health Service, United Kingdom). Analysis of sensitivity, specificity, predictive values and likelihood ratios were conducted for all data as well as stratified by mean left ventricular ejection fraction (LVEF). There were no randomized controlled trials. The included studies compared PET with one or more other noninvasive viability tests on the same group of patients or examined the long-term outcomes of PET viability assessments. The quality assessment showed that about 50% or more of the studies had selection bias, interpreted tests without blinding, excluded uninterpretable segments in the analysis, or did not have clearly stated selection criteria. Data from the above studies were integrated with data from the 2001 ICES review for analysis and interpretation.
Summary of Findings
The evidence was derived from populations with moderate to severe ischemic LV dysfunction with an overall quality that ranges from moderate to low.
PET appears to be a safe technique for assessing myocardial viability.
CAD patients with moderate to severe ischemic LV dysfunction and residual viable myocardium had significantly lower 2-year mortality rate (3.2%) and higher event-free survival rates (92% at 3 years) when treated with revascularization than those who were not revascularized but were treated medically (16% mortality at 2-years and 48% 3-year event-free survival).
A large meta-analysis and moderate quality studies of diagnostic accuracy consistently showed that compared to other noninvasive diagnostic tests such as thallium SPECT and echocardiography, FDG PET has:
Higher sensitivity (median 90%, range 71%–100%) and better negative likelihood ratio (median 0.16, range 0–0.38; ideal <0.1) for predicting regional myocardial function recovery after revascularization.
Specificity (median 73%, range 33%–91%) that is similar to other radionuclide imaging but lower than that of dobutamine echocardiography
Less useful positive likelihood ratio (median 3.1, range 1.4 –9.2; ideal>10) for predicting segmental function recovery.
Taking positive and negative likelihood ratios together suggests that FDG PET and dobutamine echocardiography may produce small but sometimes important changes in the probability of recovering regional wall motion after revascularization.
Given its higher sensitivity, PET is less likely to produce false positive results in myocardial viability. PET, therefore, has the potential to identify some patients who might benefit from revascularization, but who would not have been identified as suitable candidates for revascularization using thallium SPECT or dobutamine echocardiography.
PET appears to be superior to other nuclear imaging techniques including SPECT with 201thallium or technetium labelled tracers, although recent studies suggest that FDG SPECT may have comparable diagnostic accuracy as FDG PET for predicting regional and global LV function recovery.
No firm conclusion can be reached about the incremental value of PET over other noninvasive techniques for predicting global function improvement or long-term outcomes in the most important target population (patients with severe ischemic LV dysfunction) due to lack of direct comparison.
An Ontario-based economic analysis showed that in people with CAD and severe LV dysfunction and who were found to have no viable myocardium or indeterminate results by thallium SPECT, the use of PET as a follow-up assessment would likely result in lower cost and better 5-year survival compared to the use of thallium SPECT alone. The projected annual budget impact of adding PET under the above scenario was estimated to range from $1.5 million to $2.3 million.
Conclusion
In patients with severe LV dysfunction, that are deemed to have no viable myocardium or indeterminate results in assessments using other noninvasive tests, PET may have a role in further identifying patients who may benefit from revascularization. No firm conclusion can be drawn on the impact of PET viability assessment on long-term clinical outcomes in the most important target population (i.e. patients with severe LV dysfunction).
PMCID: PMC3385418  PMID: 23074467
6.  Determination of in vivo Bmax and Kd for [11C]GR103545, an agonist PET tracer for kappa opioid receptors: A study in nonhuman primates 
The kappa opioid receptors (KOR) are involved in mood disorders and addictive conditions. In vivo imaging studies of this receptor in humans have not been reported due to the lack of a selective ligand. We employed a recently developed selective KOR agonist tracer, [11C]GR103545, and performed a study in rhesus monkeys to estimate the in vivo receptor concentration (Bmax) and dissociation equilibrium constant (Kd).
Methods
Four rhesus monkeys underwent a total of 12 scans with [11C]GR103545 on the Focus 220 scanner under baseline and self-blocking conditions. The injected mass was 0.042±0.014 µg/kg for the baseline scans and ranged from 0.17 to 0.3 µg/kg for the self-blocking scans. The radiotracer was administered in a bolus plus infusion (B+I) protocol, and cerebellum used as reference region in kinetic analysis. Binding potential (BPND) values were computed as [(CROI/CREF)-1], where CROI and CREF are the mean of the radioactivity concentrations from 90 to 120 min post tracer administration in a given region of interest (ROI) and in the cerebellum. In six scans, arterial input functions and free fraction in plasma (fp) were measured, and a 2 -tissue compartment model was used to compute the volume of distribution in the cerebellum (VT_REF), which was then employed to estimate the free to non-displaceable concentration ratio (fND) as fp/VT_REF. A Scatchard plot was used to estimate Bmax, and KdND = Kd/fND, the Kd value with respect to the cerebellar concentration. Individual data were first analyzed separately, then pooled together. When KdND was allowed to vary among ROIs, results were very variable; therefore KdND was constrained to be constant across ROIs whereas Bmax was allowed to be ROI-dependent and animal-dependent.
Results
A global estimate of 1.72 nM was obtained for KdND. Estimated Bmax ranged from 0.3 to 6.1 nM across ROIs and animals. The Kd estimate of 0.048 nM, obtained by correcting KdND by the factor fND, was between the in vitro Kd values of 0.018 nM to 0.4 nM (obtained from functional assays in rabbit vas deferens and radioligand competition assays using cloned human receptors, respectively). Based on these data, a suitable tracer dose of 0.02 µg/kg was selected for use in humans.
Conclusions
The use of a B+I protocol with the KOR agonist tracer [11C]GR103545 permitted the successful estimation of Bmax and KdND in vivo. Based on the estimated Kd value, a tracer dose of 1.4 µg (3.38 nmol) for an average body weight of 70 k g was chosen as the mass dose limit in human studies using this novel agonist radiotracer.
doi:10.2967/jnumed.112.112672
PMCID: PMC3775350  PMID: 23424192
PET; Kappa opioid receptors; Agonist; In vivo affinity
7.  Positron Emission Tomography Imaging of Regional Pulmonary Perfusion and Ventilation 
Positron emission tomography (PET) imaging is a noninvasive, quantitative method to assess pulmonary perfusion and ventilation in vivo. The core of this article focuses on the use of [13N]nitrogen (13N2) and PET to assess regional gas exchange. Regional perfusion and shunt can be measured with the 13N2–saline bolus infusion technique. A bolus of 13N2, dissolved in saline solution, is injected intravenously at the start of a brief apnea, while the tracer kinetics in the lung is measured by a sequence of PET frames. Because of its low solubility in blood, virtually all 13N2 delivered to aerated lung regions diffuses into the alveolar airspace, where it accumulates in proportion to regional perfusion during the apnea. In contrast, lung regions that are perfused but are not aerated and do not exchange gas (i.e., “shunting” units) do not retain 13N2 during apnea and the tracer concentration drops after the initial peak. Accurate estimates of regional perfusion and regional shunt can be derived by applying a mathematical model to the pulmonary kinetics of a 13N2–saline bolus. When breathing is resumed, specific alveolar ventilation can be calculated from the tracer washout rate, because 13N2 is eliminated almost exclusively by ventilation. Because of the rapid elimination of the tracer, 13N2 infusion scans can be followed by 13N2 inhalation scans that allow determination of regional gas fraction. This article describes insights into the pathophysiology of acute lung injury, pulmonary embolism, and asthma that have been gained by PET imaging of regional gas exchange.
doi:10.1513/pats.200508-088DS
PMCID: PMC2713340  PMID: 16352758
adult respiratory distress syndrome; asthma; emission-computed tomography; nitrogen isotopes; pulmonary embolism; pulmonary gas exchange
8.  External quantification of myocardial perfusion by exponential infusion of positron-emitting radionuclides. 
Journal of Clinical Investigation  1980;66(5):918-927.
A technique was developed and evaluated using the exponential infusion of positron-emitting diffusible tracers to quantitate myocardial perfusion. The approach employs a parameter that rapidly reaches a constant value as a function of tracer delivery rate, isotope decay constant, and the monotonically increasing tissue radioactivity. Isolated rabbit hearts with controlled flow were used to evaluate the approach, because tracer kinetics in such preparations mimic those in vivo. Accordingly, exponential infusions of H2 15O and [11C]butanol were administered to 25 isolated rabbit hearts perfused with Krebs-Henseleit solution (KH) alone or KH enriched with erythrocytes (KH-RBC, hematocrit = 40). With flow varied from 1.2 to 5 ml/g per min in eight KH hearts infused with H2 15O, actual and estimated flow correlated closely (r = 0.95, n = 52 determinations). For the KH-RBC hearts, flow was varied from 0.3 to 1.5 ml/g per min. Actual and estimated flow correlated significantly for both the 14 KH-RBC hearts infused with H2 15O (r = 0.90, n = 89 determinations) and the 3 KH-RBC hearts infused with [11C]butanol (r = 0.93, n = 13 determinations). In addition, the required exponentially increasing arterial tracer concentrations were shown to be attainable in vivo in dogs and rhesus monkeys after intravenous exponential administrations of tracer. The results suggest that the approach developed employing exponential tracer infusion permits accurate measurement of myocardial perfusion and that it should prove useful in the noninvasive measurement of regional myocardial perfusion in vivo by positron emission tomography.
PMCID: PMC371526  PMID: 6968756
9.  Assessment of receptor occupancy-over-time of two dopamine transporter inhibitors by [11C]CIT and target controlled infusion 
Upsala Journal of Medical Sciences  2011;116(2):100-106.
Introduction
Occupancy-over-time was determined for two dopamine transporter (DAT) inhibitors through modeling of their ability to displace the PET ligand [11C]CIT. The tracer was held at a pseudo steady state in a reference tissue by target controlled infusion.
Methods
Rhesus monkeys (n = 5) were given [11C]CIT and studied with a PET scanner. Tracer uptake in the reference tissue cerebellum was held at a pseudo steady state by use of target controlled infusion. The pharmacokinetics/pharmacodynamics(PK/PD) of [11C]CIT was assessed through the simplified reference tissue model (SRTM). Bupropion (n = 2) and GBR-12909 (n = 2) receptor occupancies were estimated through modeling of their effects on [11C]CIT displacement.
Results
There was a high uptake of [11C]CIT in striatum, which contains a high DAT density. The reference tissue cerebellum had a comparatively low uptake. The modeling of [11C]CIT PK/PD properties in striatum showed high binding potential (BP = 5.34 ± 0.78). Both DAT inhibitors caused immediate displacement of [11C]CIT after administration. The occupancy-over-time was modeled as a mono-exponential function, describing initial maximal occupancy (Occ0) and rate of ligand–receptor dissociation (koff). GBR-12909 showed irreversible binding (koff = 0) after an initial occupancy of 76.1%. Bupropion had a higher initial occupancy (84.5%) followed by a release half-life of 33 minutes (koff = 0.021).
Conclusions
The proposed model can be used for assessment of in-vivo occupancy-over-time of DAT ligands by use of target controlled infusion of [11C]CIT. The concept of assessing drug–receptor interactions by studying perturbations of a PET tracer from a pseudo steady state can be transferred to other CNS systems.
doi:10.3109/03009734.2011.563878
PMCID: PMC3078538  PMID: 21443419
CCIP; [11C]CIT; DAT inhibitor; SRTM; TCI
10.  Ready for prime time? Dual tracer PET and SPECT imaging 
Dual isotope single photon emission computed tomography (SPECT) and dual tracer positron emission tomography (PET) imaging have great potential in clinical and molecular applications in the pediatric as well as the adult populations in many areas of brain, cardiac, and oncologic imaging as it allows the exploration of different physiological and molecular functions (e.g., perfusion, neurotransmission, metabolism, apoptosis, angiogenesis) under the same physiological and physical conditions. This is crucial when the physiological functions studied depend on each other (e.g., perfusion and metabolism) hence requiring simultaneous assessment under identical conditions, and can reduce greatly the quantitation errors associated with physical factors that can change between acquisitions (e.g., human subject or animal motion, change in the attenuation map as a function of time) as is detailed in this editorial. The clinical potential of simultaneous dual isotope SPECT, dual tracer PET and dual SPECT/PET imaging are explored and summarized. In this issue of AJNMMI (http://www.ajnmmi.us), Chapman et al. explore the feasibility of simultaneous and sequential SPECT/PET imaging and conclude that down-scatter and crosstalk from 511 keV photons preclude obtaining useful SPECT information in the presence of PET radiotracers. They report on an alternative strategy that consists of performing sequential SPECT and PET studies in hybrid microPET/SPECT/CT scanners, now widely available for molecular imaging. They validate their approach in a phantom consisting of a 96-well plate with variable 99mTc and 18F concentrations and illustrate the utility of such approaches in two sequential SPECT-PET/CT studies that include 99mTc-MAA/18F-NaF and 99mTc-Pentetate/18F-NaF. These approaches will need to be proven reproducible, accurate and robust to variations in the experimental conditions before they can be accepted by the molecular imaging community and be implemented in routine molecular microPET and microSPECT explorations. Although currently not accepted as standard procedures in the molecular imaging community, such approaches have the potential to open the way to new SPECT/PET explorations that allow studying molecular mechanisms and pathways in the living animal under similar physiological conditions. Although still premature for the clinical setting, these approaches can be extended to clinical research once proven accurate and precise in vivo in small and large animal models.
PMCID: PMC3484417  PMID: 23145358
Dualisotope; dual tracer; positron emission tomography (PET); single photon emission tomography (SPECT); quantitative imaging
11.  Preclinical evaluation of carbon-11 and fluorine-18 sulfonamide derivatives for in vivo radiolabeling of erythrocytes 
EJNMMI Research  2013;3:4.
Background
To date, few PET tracers for in vivo labeling of red blood cells (RBCs) are available. In this study, we report the radiosynthesis and in vitro and in vivo evaluation of 11C and 18F sulfonamide derivatives targeting carbonic anhydrase II (CA II), a metallo-enzyme expressed in RBCs, as potential blood pool tracers. A proof-of-concept in vivo imaging study was performed to demonstrate the feasibility to assess cardiac function and volumes using electrocardiogram (ECG)-gated positron emission tomography (PET) acquisition in comparison with cine magnetic resonance imaging (cMRI) in rats and a pig model of myocardial infarction.
Methods
The inhibition constants (Ki) of CA II were determined in vitro for the different compounds by assaying CA-catalyzed CO2 hydration activity. Binding to human RBCs was estimated after in vitro incubation of the compounds with whole blood. Biodistribution studies were performed to evaluate tracer kinetics in NMRI mice. ECG-gated PET acquisition was performed in Wistar rats at rest and during pharmacological stress by infusing dobutamine at 10 μg/kg/min and in a pig model of myocardial infarction. Left ventricular ejection fraction (LVEF) and volumes were compared with values from cMRI.
Results
The Ki of the investigated compounds for human CA II was found to be in the range of 8 to 422 nM. The fraction of radioactivity associated with RBCs was found to be ≥90% at 10- and 60-min incubation of tracers with heparinized human blood at room temperature for all tracers studied. Biodistribution studies in mice indicated that 30% to 67% of the injected dose was retained in the blood pool at 60 min post injection. A rapid and sustained tracer uptake in the heart region with an average standardized uptake value of 2.5 was observed from micro-PET images. The LVEF values obtained after pharmacological stress in rats closely matched between the cMRI and micro-PET values, whereas at rest, a larger variation between LVEF values obtained by both techniques was observed. In the pig model, a good agreement was observed between PET and MRI for quantification of left ventricular volumes and ejection fraction.
Conclusions
The 11C and 18F sulfonamide derivatives can be used for efficient in vivo radiolabeling of RBCs, and proof-of-concept in vivo imaging studies have shown the feasibility and potential of these novel tracers to assess cardiac function.
doi:10.1186/2191-219X-3-4
PMCID: PMC3561128  PMID: 23316861
Blood pool imaging; Carbonic anhydrases; PET tracers; Sulfonamides
12.  An In Vivo Comparison of Cis- and Trans- [18F]Mefway in the Nonhuman Primate 
Nuclear medicine and biology  2011;38(7):925-932.
Introduction
[18F]Mefway is a serotonin 5-HT1A PET radiotracer with high specificity and favorable in vivo imaging properties. The chemical structure of 18F]mefway permits 18F labeling in either the cis- or trans- positions at the 4-cyclohexyl site. We have previously reported on the in vivo kinetics of trans-[18F]mefway in the nonhuman primate. In this work we compare in vivo binding of cis-[18F]mefway and trans-[18F]mefway to evaluate the properties of cis-[18F]mefway for 5-HT1A PET imaging.
Methods
The cis- and trans- [18F]mefway tracers were synthesized via nucleophilic substitution with their respective tosylate precursors. Two monkeys (1m, 1f) were given bolus injections of both cis- and trans- labeled [18F]mefway in separate experiments. Dynamic scans were acquired for 90 minutes with a microPET P4 scanner. Time activity curves were extracted in the areas of the mesial temporal cortex (MTC), anterior cingulate gyrus (aCG), insular cortex (IC), raphe nuclei (RN), and cerebellum (CB). The in vivo behavior of the radiotracers were compared based upon the nondisplaceable binding potential (BPND) using the CB as a reference region.
Results
Averaged over the 2 subjects, BPND values were MTC: 7.7, 0.58; aCG: 4.95, 0.32; IC: 3.27, 0.2; and RN: 3.05, 0.13 for trans-[18F]mefway and cis-[18F]mefway, respectively.
Conclusion
The cis- labeled [18F]mefway tracer has low specific binding throughout the 5-HT1A regions of brain compared to trans-[18F]mefway suggesting that the target to background binding of cis-[18F]mefway may limit its use for in vivo assessment of 5-HT1A binding.
doi:10.1016/j.nucmedbio.2011.04.001
PMCID: PMC3190069  PMID: 21741252
5-HT1A; PET; serotonin; mefway
13.  Awake Nonhuman Primate Brain PET Imaging with Minimal Head Restraint: Evaluation of GABAA Benzodiazepine Binding with [11C]Flumazenil in Awake and Anesthetized Animals 
Neuroreceptor imaging in the nonhuman primate (NHP) is valuable for translational research approaches in humans. However, the majority of NHP studies are conducted under anesthesia, which affects the interpretability of receptor binding measures. The aims of this study are to develop awake NHP imaging with minimal head restraint and to compare in vivo binding of GABAA-benzodiazepine radiotracer [11C]flumazenil under anesthetized and awake conditions. We hypothesized that [11C]flumazenil binding potential (BPND) would be higher in isoflurane-anesthetized monkeys.
Methods
The Focus-220 small animal PET scanner was fitted to a mechanical device that raised and tilted the scanner 45° while the awake NHP was tilted back 35° in a custom chair for optimal brain positioning. This required acclimation of the animals to the chair, touch-screen tasks, i.v. catheter insertion, and tilting. For PET studies, the bolus plus constant infusion (B/I) method was used for [11C]flumazenil administration. Two rhesus monkeys were scanned under the awake (n=6 scans) and isoflurane-anesthetized (n=4 scans) conditions. The Vicra infrared camera was used to track head motion during PET scans. Under the awake condition, emission and head motion-tracking data were acquired for 40-75 min post-injection. Anesthetized monkeys were scanned for 90 min. Cortisol measurements were acquired during awake and anesthetized scans. Equilibrium analysis was used for both the anesthetized (n=4) and awake (n=5) datasets to compute mean BPND images in NHP template space, using the pons as a reference region. Percent change per min (%Δ/min) in radioactivity concentration was calculated in high and low binding regions to assess the quality of equilibrium.
Results
The monkeys acclimated to procedures in the NHP chair necessary to perform awake PET imaging. Image quality was comparable between awake and anesthetized conditions. The relationship between awake and anesthetized values was BPND(awake)=0.94BPND(anesthetized)+0.36, r2=0.95. Cortisol levels were significantly higher under the awake condition (p<0.05).
Conclusions
We successfully performed awake NHP imaging with minimal head restraint. There was close agreement in [11C]flumazenil BPND values between awake and anesthetized conditions.
doi:10.2967/jnumed.113.122077
PMCID: PMC3857935  PMID: 24115528
PET; monkey; conscious; flumazenil; isoflurane; GABA shift; cortisol
14.  Tumor hypoxia imaging in orthotopic liver tumors and peritoneal metastasis: a comparative study featuring dynamic 18F-MISO and 124I-IAZG PET in the same study cohort 
Purpose
The purpose of this paper is to compare the uptake of two clinically promising positron emission tomography (PET) hypoxia targeting agents, 124I-iodoazomycin galactopyranoside (124I-IAZG) and 18F-fluoromisonidazole (18F-FMISO), by dynamic microPET imaging, in the same rats bearing liver tumors and peritoneal metastasis.
Methods
Morris hepatoma (RH7777) fragments were surgically implanted into the livers of four nude rats. Tumors formed in the liver and disseminated into the peritoneal cavity. Each rat had a total of two to three liver tumors and peritoneal metastasis measuring 10–15 mm in size. Animals were injected with 18F-FMISO, followed on the next day (upon complete 18F decay) by 124I-IAZG. The animals were imaged in list mode on the microPET system from the time of injection of each tracer for 3 h and then again at 6 h and 24 h for the long-lived 124I-IAZG tracer (4.2-day half-life). Micro computed tomography (CT) scans of each rat were performed for co-registration with the microPET scans acquired with a liver contrast agent, allowing tumor identification. Regions of interest (ROIs) were drawn over the heart, liver, muscle, and the hottest areas of the tumors. Time-activity curves (TACs) were drawn for each tissue ROI.
Results
The 18F-FMISO signal increased in tumors over the 3-h time course of observation. In contrast, after the initial injection, the 124I-IAZG signal slowly and continuously declined in the tumors. Nevertheless, the tumor-to-normal-tissue ratios of 124I-IAZG increased, but more slowly than those of 18F-FMISO and as a result of the differentially faster clearance from the surrounding normal tissues. These pharmacokinetic patterns were seen in all 11 tumors of the four animals.
Conclusions
18F-FMISO localizes in the same intra-tumor regions as 124I-IAZG. The contrast ratios (tumor/background) reach similar values for the two hypoxia tracers, but at later times for 124I-IAZG than for 18F-FMISO and, therefore, with poorer count statistics. As a consequence, the 18F-FMISO images are of superior diagnostic image quality to the 124I-IAZG images in the Morris hepatoma McA-R-7777 tumor model.
doi:10.1007/s00259-007-0522-2
PMCID: PMC2723938  PMID: 17786438
Hypoxia; Fluoromisonidazole; Iodoazomycin galactopyranoside; MicroPET; Dynamic PET
15.  Single-scan dual-tracer FLT+FDG PET tumor characterization 
Physics in medicine and biology  2013;58(3):429-449.
Rapid multi-tracer PET aims to image two or more tracers in a single scan, simultaneously characterizing multiple aspects of physiology and function without the need for repeat imaging visits. Using dynamic imaging with staggered injections, constraints on the kinetic behavior of each tracer are applied to recover individual-tracer measures from the multi-tracer PET signal. The ability to rapidly and reliably image both 18F-fluorodeoxyglucose (FDG) and 18F-fluorothymidine (FLT) would provide complementary measures of tumor metabolism and proliferative activity, with important applications in guiding oncologic treatment decisions and assessing response. However, this tracer combination presents one of the most challenging dual-tracer signal-separation problems—both tracers have the same radioactive half-life, and the injection delay is short relative to the half-life and tracer kinetics. This work investigates techniques for single-scan dual-tracer FLT+FDG PET tumor imaging, characterizing the performance of recovering static and dynamic imaging measures for each tracer from dual-tracer datasets. Simulation studies were performed to characterize dual-tracer signal-separation performance for imaging protocols with both injection orders and injection delays of 10–60 min. Better performance was observed when FLT was administered first, and longer delays before administration of FDG provided more robust signal-separation and recovery of the single-tracer imaging measures. An injection delay of 30 min led to good recovery (R > 0.96) of static image values (e.g. SUV), Knet, and K1 as compared to values from separate, single-tracer time-activity curves. Recovery of higher order rate parameters (k2, k3) was less robust, indicating that information regarding these parameters was harder to recover in the presence of statistical noise and dual-tracer effects. Performance of the dual-tracer FLT(0 min)+FDG(32 min) technique was further evaluated using PET/CT imaging studies in five patients with primary brain tumors where the data from separate scans of each tracer were combined to synthesize dual-tracer scans with known single-tracer components; results demonstrated similar dual-tracer signal recovery performance. We conclude that rapid dual-tracer FLT+FDG tumor imaging is feasible and can provide quantitative tumor imaging measures comparable to those from conventional separate-scan imaging.
doi:10.1088/0031-9155/58/3/429
PMCID: PMC3553659  PMID: 23296314
16.  Methodology for Quantitative Rapid Multi-Tracer PET Tumor Characterizations 
Theranostics  2013;3(10):757-773.
Positron emission tomography (PET) can image a wide variety of functional and physiological parameters in vivo using different radiotracers. As more is learned about the molecular basis for disease and treatment, the potential value of molecular imaging for characterizing and monitoring disease status has increased. Characterizing multiple aspects of tumor physiology by imaging multiple PET tracers in a single patient provides additional complementary information, and there is a significant body of literature supporting the potential value of multi-tracer PET imaging in oncology. However, imaging multiple PET tracers in a single patient presents a number of challenges. A number of techniques are under development for rapidly imaging multiple PET tracers in a single scan, where signal-recovery processing algorithms are employed to recover various imaging endpoints for each tracer. Dynamic imaging is generally used with tracer injections staggered in time, and kinetic constraints are utilized to estimate each tracers' contribution to the multi-tracer imaging signal. This article summarizes past and ongoing work in multi-tracer PET tumor imaging, and then organizes and describes the main algorithmic approaches for achieving multi-tracer PET signal-recovery. While significant advances have been made, the complexity of the approach necessitates protocol design, optimization, and testing for each particular tracer combination and application. Rapid multi-tracer PET techniques have great potential for both research and clinical cancer imaging applications, and continued research in this area is warranted.
doi:10.7150/thno.5201
PMCID: PMC3840410  PMID: 24312149
PET tracers; Tumor Characterizations
17.  Quantitative approaches of dynamic FDG-PET and PET/CT studies (dPET/CT) for the evaluation of oncological patients 
Cancer Imaging  2012;12(1):283-289.
Abstract
Objectives: The use of dynamic positron emission tomography/computed tomography (dPET/CT) studies with [18F]deoxyglucose (FDG) in oncological patients is limited and primarily confined to research protocols. A more widespread application is, however, desirable, and may help to assess small therapeutic effects early after therapy as well as to differentiate borderline differences between tumour and non-tumour lesions, e.g., lipomas versus low-grade liposarcomas. The aim is to present quantification approaches that can be used for the evaluation of dPET/CT series in combination with parametric imaging and to demonstrate the feasibility with regard to tumour diagnostics and therapy management. Methods: A 60-min data acquisition and short acquisition protocols (20-min dynamic series and a static image 60 min post injection) are discussed. A combination of a modified two-tissue compartment model and non-compartmental approaches from the chaos theory (fractal dimension of the time–activity curves) are presented. Fused PET/CT images as well as regression-based parametric images fused with CT or with PET/standardised uptake value images are demonstrated for the exact placement of volumes of interest. Results: The two-tissue compartmental method results in the calculation of 5 kinetic parameters, the fractional blood volume VB (known also as the distribution volume), and the transport rates k1 to k4. Furthermore, the influx according to Patlak can be calculated from the transport rates. The fractal dimension of the time–activity curves describes the heterogeneity of the tracer distribution. The use of the regression-based parametric images of FDG helps to visualise the transport/perfusion and the transport/phosphorylation-dependent FDG uptake, and adds a new dimension to the existing conventional PET or PET/CT images. Conclusions: More sophisticated quantification methods and dedicated software as well as high computational power and faster acquisition protocols can facilitate the assessment of dPET/CT, and may find use in clinical routine, in particular for the assessment of early therapeutic effects or new treatment protocols in combination with the new generation of PET/CT scanners.
doi:10.1102/1470-7330.2012.0033
PMCID: PMC3485644  PMID: 23033440
Dynamic PET; oncology; compartment modelling; non-compartment modelling; parametric imaging; feature extraction
18.  Multi-graphical analysis of dynamic PET 
NeuroImage  2009;49(4):2947-2957.
In quantitative dynamic PET studies, graphical analysis methods including the Gjedde-Patlak plot, the Logan plot, and the relative equilibrium-based graphical plot (RE plot) (Zhou et al., 2009b) are based on the theory of a compartmental model with assumptions on tissue tracer kinetics. If those assumptions are violated, then the resulting estimates may be biased. In this study, a multi-graphical analysis method was developed to characterize the non-relative equilibrium effects on the estimates of total distribution volume (DVT) from the RE plot. A novel bi-graphical analysis method using the RE plot with the Gjedde-Patlak plot (RE-GP plots) was proposed to estimate DVT for the quantification of reversible tracer kinetics that may not be at relative equilibrium states during PET study period. The RE-GP plots, and the Logan plot were evaluated by 19 [11C]WIN35,428 and 10 [11C]MDL100,907 normal human dynamic PET studies with brain tissue tracer kinetics measured at both region of interest (ROI) and pixel levels. A 2-tissue compartment model (2TCM) was used to fit ROI time activity curves (TACs). By applying multi-graphical plots to the 2TCM fitted ROI TACs which were considered as the noise free tracer kinetics, the estimates of DVT from the RE-GP plots, the Logan plot, and the 2TCM fitting were equal to each other. For the measured ROI TACs, there was no significant difference between the estimates of the DVT from the RE-GP plots and those from 2TCM fitting (p = 0.77), but the estimates of the DVT from the Logan plot were significantly (p < 0.001) lower, 2.3% on average, than those from 2TCM fitting. There was a highly linear correlation between the ROI DVT form the parametric images (Y) and those from the ROI kinetics (X) by using the RE-GP plots (Y = 1.01X + 0.23, R2 = 0.99). For the Logan plot, the ROI estimates from the parametric images were 13% to 83% lower than those from ROI kinetics. The computational time for generating parametric images was reduced by 69% on average by the RE-GP plots in contrast to the Logan plot. In conclusion, the bigraphical analysis method using the RE-GP plots was a reliable, robust and computationally efficient kinetic modeling approach to improve the quantification of dynamic PET.
doi:10.1016/j.neuroimage.2009.11.028
PMCID: PMC2824569  PMID: 19931403
Gjedde-Patlak plot; Logan plot; relative equilibrium; RE plot; PET
19.  FDG kinetic modeling in small rodent brain PET: optimization of data acquisition and analysis 
EJNMMI Research  2013;3:61.
Background
Kinetic modeling of brain glucose metabolism in small rodents from positron emission tomography (PET) data using 2-deoxy-2-[18 F]fluoro-d-glucose (FDG) has been highly inconsistent, due to different modeling parameter settings and underestimation of the impact of methodological flaws in experimentation. This article aims to contribute toward improved experimental standards. As solutions for arterial input function (IF) acquisition of satisfactory quality are becoming available for small rodents, reliable two-tissue compartment modeling and the determination of transport and phosphorylation rate constants of FDG in rodent brain are within reach.
Methods
Data from mouse brain FDG PET with IFs determined with a coincidence counter on an arterio-venous shunt were analyzed with the two-tissue compartment model. We assessed the influence of several factors on the modeling results: the value for the fractional blood volume in tissue, precision of timing and calibration, smoothing of data, correction for blood cell uptake of FDG, and protocol for FDG administration. Kinetic modeling with experimental and simulated data was performed under systematic variation of these parameters.
Results
Blood volume fitting was unreliable and affected the estimation of rate constants. Even small sample timing errors of a few seconds lead to significant deviations of the fit parameters. Data smoothing did not increase model fit precision. Accurate correction for the kinetics of blood cell uptake of FDG rather than constant scaling of the blood time-activity curve is mandatory for kinetic modeling. FDG infusion over 4 to 5 min instead of bolus injection revealed well-defined experimental input functions and allowed for longer blood sampling intervals at similar fit precisions in simulations.
Conclusions
FDG infusion over a few minutes instead of bolus injection allows for longer blood sampling intervals in kinetic modeling with the two-tissue compartment model at a similar precision of fit parameters. The fractional blood volume in the tissue of interest should be entered as a fixed value and kinetics of blood cell uptake of FDG should be included in the model. Data smoothing does not improve the results, and timing errors should be avoided by precise temporal matching of blood and tissue time-activity curves and by replacing manual with automated blood sampling.
doi:10.1186/2191-219X-3-61
PMCID: PMC3737082  PMID: 23915734
CMRglc; FDG; Fractional blood volume; Kinetic modeling; Reliability; Positron emission tomography; Infusion
20.  Dynamic Small-Animal PET Imaging of Tumor Proliferation with 3′-Deoxy-3′-18F-Fluorothymidine in a Genetically Engineered Mouse Model of High-Grade Gliomas 
3′-Deoxy-3′-18F-fluorothymidine (18F-FLT), a partially metabolized thymidine analog, has been used in preclinical and clinical settings for the diagnostic evaluation and therapeutic monitoring of tumor proliferation status. We investigated the use of 18F-FLT for detecting and characterizing genetically engineered mouse (GEM) high-grade gliomas and evaluating the pharmacokinetics in GEM gliomas and normal brain tissue. Our goal was to develop a robust and reproducible method of kinetic analysis for the quantitative evaluation of tumor proliferation.
Methods
Dynamic 18F-FLT PET imaging was performed for 60 min in glioma-bearing mice (n = 10) and in non–tumor-bearing control mice (n = 4) by use of a dedicated small-animal PET scanner. A 3-compartment, 4-parameter model was used to characterize 18F-FLT kinetics in vivo. For compartmental analysis, the arterial input was measured by placing a region of interest over the left ventricular blood pool and was corrected for partial-volume averaging. The 18F-FLT “trapping” and tissue flux model parameters were correlated with measured uptake (percentage injected dose per gram [%ID/g]) values at 60 min.
Results
18F-FLT uptake values (%ID/g) at 1 h in brain tumors were significantly greater than those in control brains (mean ± SD: 4.33 ± 0.58 and 0.86 ± 0.22, respectively; P < 0.0004). Kinetic analyses of the measured time–activity curves yielded independent, robust estimates of tracer transport and metabolism, with compartmental model–derived time–activity data closely fitting the measured data. Except for tracer transport, statistically significant differences were found between the applicable model parameters for tumors and normal brains. The tracer retention rate constant strongly correlated with measured 18F-FLT uptake values (r = 0.85, P < 0.0025), whereas a more moderate correlation was found between net 18F-FLT flux and 18F-FLT uptake values (r = 0.61, P < 0.02).
Conclusion
A clinically relevant mouse glioma model was characterized by both static and dynamic small-animal PET imaging of 18F-FLT uptake. Time–activity curves were kinetically modeled to distinguish early transport from a subsequent tracer retention phase. Estimated 18F-FLT rate constants correlated positively with %ID/g measurements. Dynamic evaluation of 18F-FLT uptake offers a promising approach for noninvasively assessing cellular proliferation in vivo and for quantitatively monitoring new antiproliferation therapies.
doi:10.2967/jnumed.107.047092
PMCID: PMC2888473  PMID: 18287265
18F-FLT; proliferation; brain tumors
21.  18F, 64Cu, and 68Ga labeled RGD-bombesin heterodimeric peptides for PET imaging of breast cancer 
Bioconjugate chemistry  2009;20(5):1016-1025.
Radiolabeled RGD and bombesin (BBN) radiotracers that specifically target integrin αvβ3 and gastrin releasing peptide receptor (GRPR) are both promising radiopharmaceuticals for tumor imaging. We recently designed and synthesized a RGD-BBN heterodimeric peptide with both RGD and BBN motifs in one single molecule. The 18F-labeled RGD-BBN heterodimer exhibited dual integrin αvβ3 and GRPR targeting in a PC-3 prostate cancer model. In this study we investigated whether radiolabeled RGD-BBN tracers can be used to detect breast cancer by using microPET. Cell binding assay demonstrated that the high GRPR expressing breast cancer cells typically express low to moderate level of integrin αvβ3, while high integrin αvβ3 expressing breast cancer cells have negligible level of GRPR. We labeled RGD-BBN heterodimer with three positron emitting radionuclides 18F, 64Cu and 68Ga, and investigated the corresponding PET radiotracers in both orthotopic T47D (GRPR+/low integrin αvβ3) and MDA-MB-435 (GRPR−/integrin αvβ3+) breast cancer models. The three radiotracers all possessed in vitro dual integrin αvβ3 and GRPR binding affinity. The advantages of the RGD-BBN radiotracers over the corresponding BBN analogues are obvious for imaging MDA-MB-435 (GRPR−/integrin αvβ3+) tumor. 18F-FB-PEG3-RGD-BBN showed lower tumor uptake than 64Cu-NOTA-RGD-BBN and 68Ga-NOTA-RGD-BBN but was able to visualize breast cancer tumors with high contrast. Synthesis of 64Cu-NOTA-RGD-BBN and 68Ga-NOTA-RGD-BBN is much faster and easier than 18F-FB-PEG3-RGD-BBN. 64Cu-NOTA-RGD-BBN showed prolonged tumor uptake, but also higher liver retention and kidney uptake than 68Ga-NOTA-RGD-BBN and 18F-FB-PEG3-RGD-BBN. 68Ga-NOTA-RGD-BBN possessed high tumor signals, but also relatively high background uptake as compared with the other two radiotracers. In summary, the prosthetic labeling groups, chelators and isotopes all have profound effect on the tumor targeting efficacy and in vivo kinetics of the RGD-BBN tracers for dual integrin and GRPR recognition. Further development of suitably labeled RGD-BBN tracers for PET imaging of cancer is warranted.
doi:10.1021/bc9000245
PMCID: PMC2895820  PMID: 20540537
22.  Nonparametric Residue Analysis of Dynamic PET Data With Application to Cerebral FDG Studies in Normals 
Kinetic analysis is used to extract metabolic information from dynamic positron emission tomography (PET) uptake data. The theory of indicator dilutions, developed in the seminal work of Meier and Zierler (1954), provides a probabilistic framework for representation of PET tracer uptake data in terms of a convolution between an arterial input function and a tissue residue. The residue is a scaled survival function associated with tracer residence in the tissue. Nonparametric inference for the residue, a deconvolution problem, provides a novel approach to kinetic analysis—critically one that is not reliant on specific compartmental modeling assumptions. A practical computational technique based on regularized cubic B-spline approximation of the residence time distribution is proposed. Nonparametric residue analysis allows formal statistical evaluation of specific parametric models to be considered. This analysis needs to properly account for the increased flexibility of the nonparametric estimator. The methodology is illustrated using data from a series of cerebral studies with PET and fluorodeoxyglucose (FDG) in normal subjects. Comparisons are made between key functionals of the residue, tracer flux, flow, etc., resulting from a parametric (the standard two-compartment of Phelps et al. 1979) and a nonparametric analysis. Strong statistical evidence against the compartment model is found. Primarily these differences relate to the representation of the early temporal structure of the tracer residence—largely a function of the vascular supply network. There are convincing physiological arguments against the representations implied by the compartmental approach but this is the first time that a rigorous statistical confirmation using PET data has been reported. The compartmental analysis produces suspect values for flow but, notably, the impact on the metabolic flux, though statistically significant, is limited to deviations on the order of 3%–4%. The general advantage of the nonparametric residue analysis is the ability to provide a valid kinetic quantitation in the context of studies where there may be heterogeneity or other uncertainty about the accuracy of a compartmental model approximation of the tissue residue.
doi:10.1198/jasa.2009.0021
PMCID: PMC2760850  PMID: 19830267
Deconvolution; Functional inference; Kinetic analysis; Regularization
23.  Nonlinear Model for Capillary-Tissue Oxygen Transport and Metabolism 
Annals of biomedical engineering  1997;25(4):604-619.
Oxygen consumption in small tissue regions cannot be measured directly, but assessment of oxygen transport and metabolism at the regional level is possible with imaging techniques using tracer 15O-oxygen for positron emission tomography. On the premise that mathematical modeling of tracer kinetics is the key to the interpretation of regional concentration-time curves, an axially-distributed capillary-tissue model was developed that accounts for oxygen convection in red blood cells and plasma, nonlinear binding to hemoglobin and myoglobin, transmembrane transport among red blood cells, plasma, interstitial fluid and parenchymal cells, axial dispersion, transformation to water in the tissue, and carriage of the reaction product into venous effluent. Computational speed was maximized to make the model useful for routine analysis of experimental data. The steady-state solution of a parent model for nontracer oxygen governs the solutions for parallel-linked models for tracer oxygen and tracer water. The set of models provides estimates of oxygen consumption, extraction, and venous pO2 by fitting model solutions to experimental tracer curves of the regional tissue content or venous outflow. The estimated myocardial oxygen consumption for the whole heart was in good agreement with that measured directly by the Fick method and was relatively insensitive to noise. General features incorporated in the model make it widely applicable to estimating oxygen consumption in other organs from data obtained by external detection methods such as positron emission tomography.
PMCID: PMC3589573  PMID: 9236974
Nonlinear modeling; Convection; Diffusion; Permeation; Binding; Metabolic reaction; Heart; Myocardial blood flow; Heterogeneity; PET
24.  Masked volume wise principal component analysis of small adrenocortical tumours in dynamic [11C]-metomidate positron emission tomography 
Background
In previous clinical Positron Emission Tomography (PET) studies novel approaches for application of Principal Component Analysis (PCA) on dynamic PET images such as Masked Volume Wise PCA (MVW-PCA) have been introduced. MVW-PCA was shown to be a feasible multivariate analysis technique, which, without modeling assumptions, could extract and separate organs and tissues with different kinetic behaviors into different principal components (MVW-PCs) and improve the image quality.
Methods
In this study, MVW-PCA was applied to 14 dynamic 11C-metomidate-PET (MTO-PET) examinations of 7 patients with small adrenocortical tumours. MTO-PET was performed before and 3 days after starting per oral cortisone treatment. The whole dataset, reconstructed by filtered back projection (FBP) 0–45 minutes after the tracer injection, was used to study the tracer pharmacokinetics.
Results
Early, intermediate and late pharmacokinetic phases could be isolated in this manner. The MVW-PC1 images correlated well to the conventionally summed image data (15–45 minutes) but the image noise in the former was considerably lower. PET measurements performed by defining "hot spot" regions of interest (ROIs) comprising 4 contiguous pixels with the highest radioactivity concentration showed a trend towards higher SUVs when the ROIs were outlined in the MVW-PC1 component than in the summed images. Time activity curves derived from "50% cut-off" ROIs based on an isocontour function whereby the pixels with SUVs between 50 to 100% of the highest radioactivity concentration were delineated, showed a significant decrease of the SUVs in normal adrenal glands and in adrenocortical adenomas after cortisone treatment.
Conclusion
In addition to the clear decrease in image noise and the improved contrast between different structures with MVW-PCA, the results indicate that the definition of ROIs may be more accurate and precise in MVW-PC1 images than in conventional summed images. This might improve the precision of PET measurements, for instance in therapy monitoring as well as for delineation of the tumour in radiation therapy planning.
doi:10.1186/1471-2342-9-6
PMCID: PMC2680831  PMID: 19386097
25.  Derivation of a Compartmental Model for Quantifying 64Cu-DOTA-RGD Kinetics in Tumor-Bearing Mice 
Journal of Nuclear Medicine  2009;50(2):250-258.
Radiolabeled arginine-glycine-aspartate (RGD) peptides are increasingly used in preclinical and clinical studies to assess the expression and function of the αvβ3 integrin, a cellular adhesion molecule involved in angiogenesis and tumor metastasis formation. To better understand the PET signal obtained with radiolabeled RGD peptides, we have constructed a compartmental model that can describe the time–activity curves in tumors after an intravenous injection.
Methods
We analyzed 60-min dynamic PET scans obtained with 64Cu-1,4,7,10-tetraazacyclododecane-N,N′,N″,N′′-tetraacetic acid (DOTA)-RGD in 20 tumor-bearing severe combined immunodeficient (SCID) mice after a bolus dose (18,500 kBq [500 μCi]), using variations of the standard 2-compartment (4k) tissue model augmented with a compartment for irreversible tracer internalization. αvβ3 binding sites were blocked in 5 studies with a coinjection of cold peptide. In addition, 20 h after injection, static PET was performed on 9 of 20 mice. We fitted 2k (k3 = k4 = 0), 3k (k4 = 0), 4k, and 4kc (k4 = constant) models to the PET data and used several criteria to determine the best model structure for describing 64Cu-DOTA-RGD kinetics in mice. Akaike information criteria (AIC), calculated from model fits and the ability of each model to predict tumor concentration 20 h after tracer injection, were considered.
Results
The 4kc model has the best profile in terms of AIC values and predictive ability, and a constant k4 is further supported by Logan–Patlak analysis and results from iterative Bayesian parameter estimation. The internalization compartment allows quantification of the putative tracer internalization rate for each study, which is estimated here to be approximately an order of magnitude less than k3 and thus does not confound the apparent specific binding of the tracer to the tumor integrin during the first 60 min of the scan. Analysis of specific (S) and nonspecific or nondisplaceable (ND) binding using fitted parameter values showed that the 4kc model provided expected results when comparing αvβ3 blocked and nonblocked studies. That is, specific volume of distribution, [VS = (K1k3)/(k2k4)], is much higher than is nondisplaceable volume of distribution, [VND = (K1/k2)], in nonblocking studies (2.2 ± 0.6 vs. 0.85 ± 0.14); VS and VND are about the same in the blocking studies (0.46 ± 1.6 vs. 0.56 ± 0.09). Also, the ratio of static tumor and plasma measurements at 60 and 10 min [CT(60)/CP(10)] is highly correlated (RS = 0.92) to tumor VS.
Conclusion
We have developed and tested a compartmental model for use with the 64Cu-DOTA-RGD PET tracer and demonstrated its potential as a tool for analysis and design of preclinical and clinical imaging studies.
doi:10.2967/jnumed.108.054049
PMCID: PMC3319446  PMID: 19164244
compartmental model; pharmacokinetics; small-animal PET; RGD peptide; αvβ3 integrin

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