Development, diagnostic performance, and interobserver agreement of a 18F-flurpiridaz PET automated perfusion quantitation system.

BACKGROUND: Computerized methodologies standardize the myocardial perfusion imaging (MPI) interpretation process. METHODS: To develop an automated relative perfusion quantitation approach for 18F-flurpiridaz, PET MPI studies from all phase III trial participants of 18F-flurpiridaz were divided into 3 groups. Count distributions were obtained in N = 40 normal patients undergoing pharmacological or exercise stress. Then, N = 90 additional studies were selected in a derivation group. Following receiver operating characteristic curve analysis, various standard deviations below the mean normal were used as cutoffs for significant CAD, and interobserver variability determined. Finally, diagnostic performance was compared between blinded visual readers and blinded derivations of automated relative quantitation in the remaining N = 548 validation patients. RESULTS: Both approaches yielded comparable accuracies for the detection of global CAD, reaching 71% and 72% by visual reads, and 72% and 68% by automated relative quantitation, when using CAD ≥ 70% or ≥ 50% stenosis for significance, respectively. Similar results were observed when analyzing individual coronary territories. In both pharmacological and exercise stress, automated relative quantitation demonstrated significantly more interobserver agreement than visual reads. CONCLUSIONS: Our automated method of 18F-flurpiridaz relative perfusion analysis provides a quantitative, objective, and highly reproducible assessment of PET MPI in normal and CAD subjects undergoing either pharmacological or exercise stress.

Clinical implications of compromised 82Rb PET data acquisition.

BACKGROUND: We wished to document the prevalence and quantitative effects of compromised 82Rb PET data acquisitions on myocardial flow reserve (MFR). METHODS AND RESULTS: Data were analyzed retrospectively for 246 rest and regadenoson-stress studies of 123 patients evaluated for known or suspected CAD. An automated injector delivered pre-determined activities of 82Rb. Automated quality assurance algorithms identified technical problems for 7% (9/123) of patients. Stress data exhibited 2 instances of scanner saturation, 1 blood peak detection, 1 blood peak width, 1 gradual patient motion, and 2 abrupt patient motion problems. Rest data showed 1 instance of blood peak width and 2 abrupt patient motion problems. MFR was lower for patients with technical problems flagged by the quality assurance algorithms than those without technical problems (1.5 ± 0.5 versus 2.1 ± 0.7, P = 0.01), even though rest and stress ejection fraction, asynchrony and relative myocardial perfusion measures were similar for these two groups (P > 0.05), suggesting that MFR accuracy was adversely affected by technical errors. CONCLUSION: It is important to verify integrity of 82Rb data to ensure MFR computation quality.

18F-flurpiridaz positron emission tomography segmental and territory myocardial blood flow metrics: incremental value beyond perfusion for coronary artery disease categorization.

AIMS: We determined the feasibility and diagnostic performance of segmental 18F-flurpiridaz myocardial blood flow (MBF) measurement by positron emission tomography (PET) compared with the standard territory method, and assessed whether flow metrics provide incremental diagnostic value beyond relative perfusion quantitation (PQ). METHODS AND RESULTS: All evaluable pharmacological stress patients from the Phase III trial of 18F-flurpiridaz were included (n = 245) and blinded flow metrics obtained. For each coronary territory, the segmental flow metric was defined as the lowest 17-segment stress MBF (SMBF), myocardial flow reserve (MFR), or relative flow reserve (RFR) value. Diagnostic performances of segmental and territory MBF metrics were compared by receiver operating characteristic (ROC) areas under the curve (AUC). A multiple logistic model was used to evaluate whether flow metrics provided incremental diagnostic value beyond PQ alone. The diagnostic performances of segmental flow metrics were higher than their territory counterparts; SMBF AUC = 0.761 vs. 0.737; MFR AUC = 0.699 vs. 0.676; and RFR AUC = 0.716 vs. 0.635, respectively (P < 0.001 for all). Similar results were obtained for per-vessel coronary artery disease (CAD) ≥70% stenosis categorization and per-patient analyses. Combinatorial analyses revealed that only SMBF significantly improved the diagnostic performance of PQ in CAD ≥50% stenoses, with PQ AUC = 0.730, PQ + segmental SMBF AUC = 0.782 (P < 0.01), and PQ + territory SMBF AUC = 0.771 (P < 0.05). No flow metric improved diagnostic performance when combined with PQ in CAD ≥70% stenoses. CONCLUSION: Assessment of segmental MBF metrics with 18F-flurpiridaz is feasible and improves flow-based epicardial CAD detection. When combined with PQ, only SMBF provides additive diagnostic performance in moderate CAD.

Early onset of left ventricular regional asynchrony in arteries with sub-clinical stenosis.

BACKGROUND: Asynchrony has been reported to be a marker of ischemic-induced left ventricular dysfunction, the magnitude of which correlates with extent of epicardial coronary disease. We wished to determine whether normal-appearing arterial territories with mild degrees of asynchrony have lower 82Rb PET absolute myocardial blood flow (MBF) and/or lower myocardial flow reserve (MFR). METHODS AND RESULTS: Data were examined retrospectively for 105 patients evaluated for known/suspected CAD who underwent rest/regadenoson-stress 82Rb PET/CT and quantitative coronary angiography. Rest and stress absolute MBF and MFR were quantified from first-pass 82Rb PET curves. Regional relative myocardial perfusion summed stress score (SSS), summed rest score (SRS), regional phase bandwidth (BW), and regional semi-quantitative asynchrony visual scores of (Asynch) were assessed. We found that in apparently normal arteries (SSS < 4, SRS < 4 and stenosis < 70%), those with abnormally low MFR < 2.0 compared to those with MFR ≥ 2.0 had larger phase BW (186 ± 79° vs 158 ± 67°, P = .02), and more visually apparent Asynch (5.7 ± 4.2 vs 3.9 ± 3.6, P = .02), which was associated with increasing stenosis values (ρ = 0.44, P < .0001). CONCLUSION: A subgroup of coronary territories with normal relative perfusion and normal or non-obstructive coronary disease may have reduced MFR, which is signaled physiologically by a mild degree of left ventricular asynchrony.

Relationship of 82Rb PET territorial myocardial asynchrony to arterial stenosis.

OBJECTIVE: 82Rb PET/CT rest/regadenoson-stress data enable quantification of left ventricular rest and stress function, perfusion, and asynchrony. Our study was conducted to determine which parameters best identify patients with multi-vessel disease (MVD) and individual stenosed arteries. METHODS: PET/CT data were reviewed retrospectively for 105 patients referred for evaluation of CAD, who also underwent angiography. % arterial stenosis was determined quantitatively at a core laboratory. Severe stenosis was defined as ≥ 70%, and MVD as 2 or more stenosed arteries. Segmental MBF was calculated from first-pass data for arterial territories. Regional rest and stress systolic and diastolic asynchrony (Asynch) scores were determined from visual examination of phase polar maps. RESULTS: 65 vessels had stenoses ≥ 70%. 15 patients had MVD. ROC area under curve (ROC AUC) for identifying patients with MVD was 83% for Asynch and 73% for MFR. ROC AUC for identifying individual arterial territories with stenoses ≥ 70% was 81% and 72% for Asynch and MFR. CONCLUSION: 82Rb PET/CT accurately identified patients with MVD and individual stenosed territories, with regional asynchrony measurements contributing significantly to identify patients with CAD.

Motion Correction and Its Impact on Absolute Myocardial Blood Flow Measures with PET.

PURPOSE OF REVIEW: Motion artifacts, due to cardiac and respiratory cycles, myocardial cardiac creep, or gross patient movements, have been extensively investigated in the context of relative myocardial perfusion imaging with SPECT and PET. These movements have been identified as a major source of errors in image quantification and diagnosis. Recently, as dynamic PET quantification for myocardial blood flow assessment has entered clinical practice, similar questions have arisen on the impact of motion on final blood flow values. RECENT FINDINGS: While preliminary investigations have underlined the potential impact of these motions on MBF quantification, their correction on dynamic acquisition remains challenging and limited to research studies. Gross patient's body movements occur in a consistent number of cases, particularly during stress acquisition, typically involving a limited number of image frames. If undetected, these movements can lead to great differences in flow values and consequently misdiagnosis. Quality control routines can be applied to automatically inspect the shape of time activity curves and to help identify motion artifacts. Cyclic cardiac and respiratory motion may have a considerable impact on final flow values. Correction of gross body motion represents a priority in the context of optimizing absolute flow clinical routine utilization and protocol standardization.

Technical aspects of acquiring and measuring myocardial blood flow: Method, technique, and QA.

Measuring absolute myocardial blood flow (MBF) is becoming a common aid for diagnosing patients suspected to have coronary artery disease. An MBF study, however, requires a scanner with high count rate capability, is more susceptible to artifacts, and is much more technically involved than static imaging, which leads to a greater risk of artifactual results contaminating the final result. This technical note gives the reader an introductory understanding of the method for calculating MBF. It then describes the scanning protocol, potential pitfalls and how to recognize them, and quality control steps that should be taken to avoid basing a clinical decision on possibly inaccurate flow information.

Relationships between left ventricular asynchrony and myocardial blood flow.

OBJECTIVE: 82Rb PET protocols enable determination of left ventricular asynchrony (LVAS) at rest and stress, along with myocardial blood flow (MBF). We hypothesized that in patients with resting LVAS, MBF differs between those with stress-induced LVAS improvement and those with stress-induced LVAS deterioration. METHODS: We retrospectively analyzed 82Rb rest/regadenoson stress PET studies of 195 patients evaluated for known or suspected coronary artery disease. MBF was computed from first-pass data; function and relative perfusion were computed from myocardial equilibrium data. LVAS was defined as phase contraction bandwidth (BW) above 82Rb gender-specific normal limits, with changes defined as BW moving into or out of normal ranges. RESULTS: Among the 195 patients, 64 had LVAS at rest, of whom 13 reverted to normal and 51 continued to have LVAS with stress. Patients who did not improve had lower stress MBF (1.04 ± 0.69 vs 1.58 ± 0.67, p = .02) and coronary flow reserve (1.94 ± 1.16 vs 3.04 ± 1.22, p = .01) than those who did improve. ROC analysis indicated that the parameter most strongly associated with improvement in asynchrony for patients with resting LVAS was reduction in MBF heterogeneity (ROC area (accuracy) = 84%, sensitivity = 92%, and specificity = 67%). CONCLUSION: LVAS is highly correlated with MBF and CVR, with stress-induced improvement in synchronicity most strongly associated with improved MBF homogeneity.

Compartmental modeling of [(11)C]MENET binding to the norepinephrine transporter in the healthy human brain.

INTRODUCTION: Dysregulation of the noradrenergic system has been implicated in a number of neurological conditions such as Parkinson's and Alzheimer's. [(11)C]MENET is a novel PET radiotracer with high affinity and selectivity for the norepinephrine transporter. The applicability of different kinetic models on [(11)C]MENET PET image quantification in healthy population is evaluated. METHODS: Six healthy volunteers (mean age: 54years) were recruited for the study, five of whom underwent arterial sampling for measurement of the input function. Ninety minute dynamic PET scans were obtained on a high resolution research tomograph with 15mCi of [(11)C]MENET injected at the scan start time. Regions of interest were delineated on the PET scan aided by the corresponding MRI image for anatomical guidance. Distribution volumes and their ratios (DVRs) with respect to the occipital reference tissue were calculated using the full arterial model (FAM), the simplified reference tissue model (SRTM) and the multilinear reference tissue model (MRTM2). RESULTS: Among the FAMs, the single-tissue model was found to be statistically superior to the two-tissue model. [(11)C]MENET focal uptake was observed in the NET-rich regions of the brainstem and subcortical regions including the thalamus, locus cereleus and the raphe nuclei. Highest DVRs were observed in the locus cereleus (mean±standard deviation: 1.39±0.25) and red nucleus (1.35±0.25). DVRs of the thalamus were in good agreement between FAM (1.26±0.13), SRTM (1.23±0.15) and MRTM2 (1.21±0.14). Comparing the FAM to the SRTM and MRTM2, DVRs were underestimated in the thalamus by 3 and 4% on average, respectively. CONCLUSION: The single-tissue compartmental model was sufficient in describing the [(11)C]MENET kinetics in the healthy human brain. SRTM and MRTM2 present themselves as attractive options for estimating NET DVR using an occipital reference region.

Quantitative outcome of registration methods for correcting cardiac drift in cardiac PET/CT imaging.

Myocardial perfusion studies suffer from artifacts caused by misalignment of the transmission and emission data due to the influences of voluntary and involuntary patient motion. Regardless of 68Ge or respiratory-averaged CT based attenuation correction and good patient cooperation, approximately 21% of perfusion studies exhibit artifacts arising from misalignment that cannot be corrected by manipulating the attenuation acquisition protocol. This misalignment, termed cardiac drift, is caused by slow-moving abdominal cavity contents that reposition the heart in the thorax and appear as myocardial uptake overlying the left CT lung in fused PET/CT images. This study evaluates three postimaging registration techniques to correct PET/CT misalignment by altering the transmission map to match myo-cardial uptake. Simulated misalignment studies were performed with a cardiac torso phantom filled with [18F]FDG at 10:1 myocardium/background. An air-filled saline bag affixed to the medial left lung surface served as a distensible lung. An initial CT acquisition was followed by successive PET acquisitions consisting of small displacements of the cardiac insert into the left lung. Phantom transmission scans were aligned to the myocardial uptake in the emission scans by applying 1) full rigid-body translations and rotations, 2) rigid-body restricted to medial / lateral and superior / inferior translation, or 3) an emission-driven method that adds myocardial tissue to the transmission scan. These methods were also applied to 10 low-likelihood coronary artery disease (CAD) patients showing signs of cardiac drift. Full rigid-body registration showed significant over-correction (p < 0.004) of activity concentrations in the artifact areas of the phantom data due the relocation of highly attenuating structures (i.e., spine). Inaccurate regional activity distributions were also observed as streaks extending from the spine and these results were replicated in the patient population. There was no significant difference between the true phantom activity concentration after correction with the emission-driven method. Misalignment corrected with the rigid-body registration results in an increase in activity concentration but fails to accurately recover the true concentration. These data suggest that a nonlinear image registration approach such as an emission-driven method results in a more uniform activity distribution throughout the myocardium, and is more appropriate for addressing the cardiac drift misalignment problem.

Patient Preferences Regarding Colorectal Cancer Screening: Test Features and Cost Willing to Pay Out of Pocket.

The purpose of this investigation was to evaluate whether test features would make an individual more or less likely to undergo colorectal cancer screening and how much an individual would be willing to pay out of pocket for a screening test. The methods include an administration of a survey to consecutive adult patients of a general medicine clinic. The survey consisted of Likert-scale questions assessing the patients' likelihood of choosing a screening test based on various test characteristics. Additional questions measured the patients' age, race, gender, and maximum out-of-pocket cost they would be willing to pay. Chi-square tests were used to assess the associations between the likelihood questions and the various demographic characteristics. In results, survey response rate was 88.8% (213 of 240). Respondents were 48.4% female (103 of 213), 51.6% male (110 of 213), 82.6% White (176 of 213), 11.3% African-American (24 of 213), and 6.1% other (13 of 213). Risk of internal injury and light exposure to radiation were the least desirable test features. Light sedation was the only test feature that most respondents (54.8%) indicated would make them likely or very likely to undergo a colorectal cancer screening test. The vast majority of respondents (86.8%) were willing to pay less than $200 out of pocket for a colorectal cancer screening test. There was no statistically significant difference in the responses of males and females, or in the responses of individuals of different races or different ages regarding test features, or the amount individuals were willing to pay for a screening test. To conclude, survey results suggest that patient education emphasizing the low complication rate of computed tomographic colonography (CTC), the minimal risks associated with the low-level radiation exposure resulting from CTC, and the benefits of a sedation-free test (eg, no risk of sedation-related complication and no need for a driver) may increase patient acceptance of CTC. Additionally, an out-of-pocket cost of <$200 would be preferable from the patient perspective.

Colorectal Cancer Initial Diagnosis: Screening Colonoscopy, Diagnostic Colonoscopy, or Emergent Surgery, and Tumor Stage and Size at Initial Presentation.

INTRODUCTION/BACKGROUND: Rates of colorectal cancer screening are improving but remain suboptimal. Limited information is available regarding how patients are diagnosed with colorectal cancer (for example, asymptomatic screened patients or diagnostic workup because of the presence of symptoms). The purpose of this investigation was to determine how patients were diagnosed with colorectal cancer (screening colonoscopy, diagnostic colonoscopy, or emergent surgery) and tumor stage and size at diagnosis. PATIENTS AND METHODS: Adults evaluated between 2011 and 2014 with a diagnosis of colorectal cancer were identified. Clinical notes, endoscopy reports, surgical reports, radiology reports, and pathology reports were reviewed. Sex, race, ethnicity, age at the time of initial diagnosis, method of diagnosis, presenting symptom(s), and primary tumor size and stage at diagnosis were recorded. Colorectal cancer screening history was also recorded. RESULTS: The study population was 54% male (265 of 492) with a mean age of 58.9 years (range, 25-93 years). Initial tissue diagnosis was established at the time of screening colonoscopy in 10.7%, diagnostic colonoscopy in 79.2%, and during emergent surgery in 7.1%. Cancers diagnosed at the time of screening colonoscopy were more likely to be stage 1 than cancers diagnosed at the time of diagnostic colonoscopy or emergent surgery (38.5%, 7.2%, and 0%, respectively). Median tumor size was 3.0 cm for the screening colonoscopy group, 4.6 cm for the diagnostic colonoscopy group, and 5.0 cm for the emergent surgery group. At least 31% of patients diagnosed at the time of screening colonoscopy, 19% of patients diagnosed at the time of diagnostic colonoscopy, and 26% of patients diagnosed at the time of emergent surgery had never undergone a screening colonoscopy. CONCLUSION: Nearly 90% of colorectal cancer patients were diagnosed after development of symptoms and had more advanced disease than asymptomatic screening patients. Colorectal cancer outcomes will be improved by improving rates of colorectal cancer screening.

Research Resources Survey: Radiology Junior Faculty Development.

RATIONALE AND OBJECTIVES: To assess resources available to junior faculty in US academic radiology departments for research mentorship and funding opportunities and to determine if certain resources are more common in successful programs. MATERIALS AND METHODS: An anonymous survey covering scientific environment and research mentorship and was sent to vice-chairs of research of radiology departments. Results were evaluated to identify practices of research programs with respect to mentorship, resources, and opportunities. Academy of Radiology Research's 2012 National Institutes of Health (NIH) grants and awards list was used to determine if environment and practices correlate with funding. RESULTS: There was a 51% response rate. A greater fraction of clinical faculty gets promoted from assistant to associate professor than research faculty. Research faculty overall submits more funding applications. Most programs support start-up costs and K-awards. Over half of the departments have a vice-chair for faculty development, and most have formal mentorship programs. Faculty members are expected to teach, engage in service, publish, and apply for and get research funding within 3 years of hire. Top-tier programs as judged by NIH awards have a combination of MDs who devote >50% effort to research and PhD faculty. Key factors holding back both clinical and research junior faculty development were motivation, resources, and time, although programs reported high availability of resources and support at the department level. CONCLUSIONS: Better marketing of resources for junior faculty, effort devoted to mentoring clinical faculty in research, and explicit milestones/expectations for achievement could enhance junior faculty success, promote interest in the clinician­scientist career path for radiologists, and lead to greater research success.

Magnetic resonance imaging of rectal cancer: staging and restaging evaluation.

Magnetic resonance imaging is used to non-invasively stage and restage rectal adenocarcinomas. Accurate staging is important as the depth of tumor extension and the presence or absence of lymph node metastases determines if an individual will undergo preoperative neoadjuvant chemoradiation. Accurate description of tumor location is important for presurgical planning. The relationship of the tumor to the anal sphincter in addition to the depth of local invasion determines the surgical approach used for resection. High-resolution T2-weighted imaging is the primary sequence used for initial staging. The addition of diffusion-weighted imaging improves accuracy in the assessment of treatment response on restaging scans. Approximately 10%-30% of individuals will experience a complete pathologic response following chemoradiation with no residual viable tumor found in the resected specimen at histopathologic assessment. In some centers, individuals with no residual tumor visible on restaging MR who are thought to be at high operative risk are monitored with serial imaging and a "watch and wait" approach in lieu of resection. Normal rectal anatomy, MR technique utilized for staging and restaging scans, and TMN staging are reviewed. An overview of surgical techniques used for resection including newer, minimally invasive endoluminal techniques is included.

Optimal section thickness for detection of polyps at MR: resolution phantom study.

PURPOSE: To determine (1) the sensitivity for detection of small polyps with varying MR slice thicknesses using a resolution phantom; (2) reader confidence in polyp detection; and (3) image acquisition time. METHODS: A resolution phantom was created using a 3D printer. Polyp morphologies were sessile (height = diameter), flat (height = 1/2 diameter of the base), and pedunculated (stalk length = polyp diameter). Polyp diameters were 5, 7, 10, and 12 mm. Images were acquired with section thicknesses of 5, 3, and 1 mm. Images were independently reviewed by 4 board-certified radiologists who were blinded to phantom design and sequences parameters. Readers recorded maximal polyp diameter and confidence level that a polyp was present on a 1-100 point scale. Image acquisition time was also recorded. RESULTS: All polyps were detected by all 4 readers in the 5-mm-section thickness series. All polyps were detected by 3 readers in the 3- and 1-mm-section thickness series. The fourth reader identified 11/12 polyps in the 3- and 1-mm-section thickness series. Confidence levels were not statistically significantly different for the different section thicknesses (p = 0.28). Increasing the section thickness from 1 to 5 mm decreased image acquisition time from 3 min 54 s to 41 s. CONCLUSIONS: Five-millimeter-section thickness was adequate for identification of 5-12 mm polyps regardless of shape. Pending further reduction in acquisition time, this prototype sequence holds promise for segmental imaging of the colon with MR colonography.

Quantification of dopamine transporter density with [18F]FECNT PET in healthy humans.

INTRODUCTION: Fluorine-18 labeled 2ß-carbomethoxy-3ß-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane ([(18)F]FECNT) binds reversibly to the dopamine transporter (DAT) with high selectivity. [(18)F]FECNT has been used extensively in the quantification of DAT occupancy in non-human primate brain and can distinguish between Parkinson's and healthy controls in humans. The purpose of this work was to develop a compartment model to characterize the kinetics of [(18)F]FECNT for quantification of DAT density in healthy human brain. METHODS: Twelve healthy volunteers underwent 180 min dynamic [(18)F]FECNT PET imaging including sampling of arterial blood. Regional time-activity curves were extracted from the caudate, putamen and midbrain including a reference region placed in the cerebellum. Binding potential, BPND, was calculated for all regions using kinetic parameters estimated from compartmental and Logan graphical model fits to the time-activity data. Simulations were performed to determine whether the compartment model could reliably fit time-activity data over a range of BPND values. RESULTS: The kinetics of [(18)F]FECNT were well-described by the reversible 2-tissue arterial input and full reference tissue compartment models. Calculated binding potentials in the caudate, putamen and midbrain were in good agreement between the arterial input model, reference tissue model and the Logan graphical model. The distribution volume in the cerebellum did not reach a plateau over the duration of the study, which may be a result of non-specific binding in the cerebellum. Simulations that included non-specific binding show that the reference and arterial input models are able to estimate BPND for DAT densities well below that observed in normal volunteers. CONCLUSION: The kinetics of [(18)F]FECNT in human brain are well-described by arterial input and reference tissue compartment models. Measured and simulated data show that BPND calculated with reference tissue model is proportional to BPND calculated from the arterial input model.

The relationship between ischemia-induced left ventricular dysfunction, coronary flow reserve, and coronary steal on regadenoson stress-gated (82)Rb PET myocardial perfusion imaging.

BACKGROUND: Gated rubidium-82 ((82)Rb) positron emission tomography (PET) imaging studies are acquired both at rest and during pharmacologic stress. Stress-induced ischemic left ventricular dysfunction (LVD) can produce a significant decrease in left ventricular ejection fraction (LVEF) from rest to stress. We determined the prevalence on PET of stress LVD with reduced ejection fraction (EF) and its association with absolute global and regional coronary flow reserve (CFR), and with relative perfusion defect summed difference score (SDS). METHODS AND RESULTS: We studied 205 patients with known or suspected coronary disease (120 M, 75 F, age 69 ± 13 years) who had clinically indicated rest/regadenoson stress (82)Rb PET/CT studies. Data were acquired in dynamic gated list mode. Global and 17-segment regional CFR values were computed from first-pass flow data using a 2-compartment model and factor analysis applied to auto-generated time-activity curves. Rest and stress LVEF and SDS were quantified from gated equilibrium myocardial perfusion tomograms using Emory Cardiac Toolbox software. LVD was defined as a change in LVEF of ≤-5% from rest to stress. A subgroup of 109 patients also had coronary angiography. Stress LVD developed in 32 patients (16%), with mean EF change of -10 ± 5%, vs +6 ± 7% for patients without LVD (P < .0001). EF was similar at rest in patients with and without stress LVD (57 ± 18% vs 56 ± 16%, P = .63), but lower during stress for patients with LVD (47 ± 20% vs 61 ± 16%, P = .0001). CFR was significantly lower in patients with LVD (1.61 ± 0.67 vs 2.21 ± 1.03, Wilcoxon P = .002), and correlated significantly with change in EF (r = 0.35, P < .0001), but not with SDS (r = -0.13, P = .07). The single variable most strongly associated with high risk of CAD (i.e., left main stenosis ≥50%, LAD % stenosis ≥70%, and/or 3-vessel disease) was stress EF (χ(2) = 17.3, P < .0001). There was a higher prevalence of patients with territorial CFR values ≤1.0, consistent with coronary steal, in the LVD group than in the non-LVD group (39% vs 12%, P = .001). CONCLUSIONS: LVD developed in 16% of patients undergoing (82)Rb PET myocardial perfusion imaging, and was associated with multivessel coronary artery disease. There was a significant relationship between LVD and coronary blood flow during stress, with LVD corresponding to a low CFR. Territorial CFR ≤1.0 was more common in patients with LVD than those without, suggesting that coronary steal is an important pathophysiologic mechanism contributing to pharmacologic stress-induced LVD.

Differences in neural activation for object-directed grasping in chimpanzees and humans.

The human faculty for object-mediated action, including tool use and imitation, exceeds that of even our closest primate relatives and is a key foundation of human cognitive and cultural uniqueness. In humans and macaques, observing object-directed grasping actions activates a network of frontal, parietal, and occipitotemporal brain regions, but differences in human and macaque activation suggest that this system has been a focus of selection in the primate lineage. To study the evolution of this system, we performed functional neuroimaging in humans' closest living relatives, chimpanzees. We compare activations during performance of an object-directed manual grasping action, observation of the same action, and observation of a mimed version of the action that consisted of only movements without results. Performance and observation of the same action activated a distributed frontoparietal network similar to that reported in macaques and humans. Like humans and unlike macaques, these regions were also activated by observing movements without results. However, in a direct chimpanzee/human comparison, we also identified unique aspects of human neural responses to observed grasping. Chimpanzee activation showed a prefrontal bias, including significantly more activity in ventrolateral prefrontal cortex, whereas human activation was more evenly distributed across more posterior regions, including significantly more activation in ventral premotor cortex, inferior parietal cortex, and inferotemporal cortex. This indicates a more "bottom-up" representation of observed action in the human brain and suggests that the evolution of tool use, social learning, and cumulative culture may have involved modifications of frontoparietal interactions.

Tissue-type plasminogen activator mediates neuronal detection and adaptation to metabolic stress.

Adenosine monophosphate-activated protein kinase (AMPK) is an energy sensor that regulates cellular adaptation to metabolic stress. Tissue-type plasminogen activator (tPA) is a serine proteinase found in the intravascular space, where its main role is as thrombolytic enzyme, and in neurons, where its function is less well understood. Here, we report that glucose deprivation induces the mobilization and package of neuronal tPA into presynaptic vesicles. Mass spectrometry and immunohistochemical studies show that the release of this tPA in the synaptic space induces AMPK activation in the postsynaptic terminal, and an AMPK-mediated increase in neuronal uptake of glucose and neuronal adenosine 5'(tetrahydrogen triphosphate; ATP) synthesis. This effect is independent of tPA's proteolytic properties, and instead requires the presence of functional N-methyl-D-aspartate receptors (NMDARs). In agreement with these observations, positron emission tomography (PET) studies and biochemical analysis with synaptoneurosomes indicate that the intravenous administration of recombinant tPA (rtPA) after transient middle cerebral artery occlusion (tMCAO) induces AMPK activation in the synaptic space and NMDAR-mediated glucose uptake in the ischemic brain. These data indicate that the release of neuronal tPA or treatment with rtPA activate a cell signaling pathway in the synaptic space that promotes the detection and adaptation to metabolic stress.