Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer.

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[(18)F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([(11)C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m(-2)·min(-1)) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.

Evidence for regional catecholamine uptake and storage sites in the transplanted human heart by positron emission tomography.

Positron emission tomography in combination with the newly introduced catecholamine analogue [11C]hydroxyephedrine ([11C]HED) enables the noninvasive delineation of sympathetic nerve terminals of the heart. To address the ongoing controversy over possible reinnervation of the human transplant, 5 healthy control subjects and 11 patients were studied after cardiac transplant by this imaging approach. Regional [11C]HED retention was compared to regional blood flow as assessed by rubidium-82. Transplant patients were divided into two groups. Group I had recent (less than 1 yr, 4.4 +/- 2.3 mo) surgery, while group II patients underwent cardiac transplantation more than 2 yr before imaging (3.5 +/- 1.3 yr). [11C]HED retention paralleled blood flow in normals, but was homogeneously reduced in group I. In contrast, group II patients revealed heterogeneous [11C]HED retention, with increased uptake in the proximal anterior and septal wall. Quantitative evaluation of [11C]HED retention revealed a 70% reduction in group I and 59% reduction in group II patients (P less than 0.001). In group II patients, [11C]HED retention reached 60% of normal in the proximal anterior wall. These data suggest the presence of neuronal tissue in the transplanted human heart, which may reflect regional sympathetic reinnervation.

Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation.

BACKGROUND: Structural and electrophysiological changes of the atria occur with prolonged rapid rates; however, the effects of sustained atrial fibrillation (AF) on autonomic innervation of the atria are unknown. We hypothesized that electrophysiological remodeling from rapid atrial rates is accompanied by altered atrial autonomic innervation. METHODS AND RESULTS: Six dogs (paced group) underwent atrial pacing at 600 bpm; 9 dogs (control animals) were not paced. All paced dogs developed sustained AF by week 4 of pacing. All 15 animals underwent positron emission tomography imaging of the atria with [C-11] hydroxyephedrine (HED) to label sympathetic nerve terminals. HED retention in the atria was significantly greater in paced dogs compared with control animals (P=0.03). Tissue samples from the atrial appendages had a greater concentration of norepinephrine in paced animals than in control animals (P=0.01). The coefficient of variation of HED retention was also greater in paced animals (P=0.05) and was greater in the right atrium than in the left atrium (P=0.004). Epicardial activation maps of AF were obtained in the paced animals at baseline and with autonomic manipulation. Mean AF cycle length was longer in the right atrium (109.2+/-5 ms) than in the left atrium (85.8+/-5.5 ms) at baseline (P=0.005). AF cycle length did not vary significantly from baseline (97.6+/-13.4 ms) with stellate stimulation (100.5+/-6 ms) but lengthened with propranolol (107.5+/-6.1 ms, P=0.03). CONCLUSIONS: Rapid rates of AF produce a heterogeneous increase in atrial sympathetic innervation. These changes parallel disparate effects of rapid pacing-induced AF on atrial electrophysiology.

Cardiac sympathetic denervation after transmyocardial laser revascularization.

BACKGROUND: Transmyocardial laser revascularization (TMR) has been shown to improve refractory angina not amenable to conventional coronary interventions. However, the mechanism of action remains controversial, because improved myocardial perfusion has not been consistently demonstrated. We hypothesized that TMR relieves angina by causing myocardial sympathetic denervation. METHODS AND RESULTS: PET imaging of resting and stress myocardial perfusion with [13N]ammonia (NH3) and of sympathetic innervation with [11C]hydroxyephedrine (HED) was performed before and after TMR in 8 patients with class IV angina ineligible for CABG or PTCA. A mean of 50+/-11 channels were created in the left ventricle (LV) with a holmium:YAG laser. A semiautomated program was used to determine NH3 uptake and HED retention in the LV. Perfusion and innervation defects were defined as the percentage of LV with tracer uptake or retention >2 SD below normal mean values. All patients experienced improvement in their angina by 2.4+/-0.5 angina classes after surgery, P=0.008. Sympathetic innervation defects exceeded resting perfusion defects in all patients before TMR (34.6+/-27.3% for HED versus 9.4+/-10.8% for NH3, P=0.008). TMR did not significantly affect resting or stress myocardial perfusion but increased the extent of sympathetic denervation in 6 of 8 patients by 27.5+/-15.9%, P=0.03. In the remaining 2 patients, both sympathetic denervation and stress perfusion defects decreased after surgery. CONCLUSIONS: TMR causes decreased myocardial HED uptake in most patients without significant change in resting or stress myocardial perfusion, suggesting that the improvement in angina may be at least in part due to sympathetic denervation.

Liquid-filled balloon brachytherapy using (68)Ga is effective and safe because of the short 68-minute half-life: results of a feasibility study in the porcine coronary overstretch model.

BACKGROUND: Liquid-filled balloons for coronary brachytherapy provide significant advantages over solid sources in dose homogeneity but carry the risk of life-threatening radiointoxication after balloon rupture and laboratory contamination in case of a spill. We hypothesized that the positron emitter (68)Ga, with a half-life of only 68 minutes, was well suited to overcome these safety obstacles while providing full therapeutic efficacy. METHODS AND RESULTS: The feasibility, efficacy, and safety of (68)Ga liquid-filled balloon brachytherapy were investigated in the porcine coronary overstretch model. Four groups of 5 balloon-induced coronary lesions were irradiated with 8, 12, 16, and 24 Gy targeted to the adventitia. Ten unirradiated lesions served as controls. Segments treated with 16 or 24 Gy exhibited marked suppression of neointimal proliferation at 28-day follow-up, with quantitative parameters of intraluminal proliferation reduced to <20%. This beneficial effect was not compromised by untoward edge effects. Uninjured but irradiated vessels did not show histological signs of radiation damage. The (68)Ga whole-body dose due to balloon rupture was estimated to be 5 rem/50 mCi treatment activity and compared favorably with that of (188)Re (78 rem/50 mCi). CONCLUSIONS: (68)Ga positron radiation suppresses neointimal proliferation at doses of 16 and 24 Gy. This biological efficacy, coupled with the attractive safety profile, suggests the selection of (68)Ga as an attractive isotope for liquid-filled balloon brachytherapy.

Positron emission tomography evaluation of residual radiographic abnormalities in postchemotherapy germ cell tumor patients.

PURPOSE: This study was performed to assess the ability of positron emission tomography (PET) to differentiate residual radiographic abnormalities in postchemotherapy nonseminomatous germ cell tumor (GCT) patients. MATERIALS AND METHODS: Thirty patients with nonseminomatous GCT were evaluated with PET scans before surgical resection of a residual mass or masses. Standardized uptake values (SUV) were calculated for the region of maximal 2-fluoro-2-deoxyglucose (FDG) uptake and compared with histologic findings. RESULTS: Eleven patients had necrosis/fibrosis in the resected specimen, 15 had teratoma, and four viable GCT. The median SUV for the necrosis/fibrosis group was 2.86, teratoma 3.07, and viable GCT 8.81. A significant association between SUV and histology was found when comparing viable GCT versus necrosis/fibrosis plus teratoma (P = .004). Patients with an SUV greater than 5 were 75 times more likely to have viable cancer than teratoma or necrosis/fibrosis (odds ratio; 95% confidence interval, 3.66 to 1,536). PET did not differentiate necrosis/fibrosis from teratoma. However, PET was able to differentiate viable GCT from residual necrosis/fibrosis or teratoma. CONCLUSION: PET-FDG imaging can be useful for detection of residual viable carcinoma following chemotherapy in nonseminomatous GCT patients with residual masses. It may be a valuable adjunct in the determination of which patients should undergo postchemotherapy resection.

Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation.

PURPOSE: We assessed the feasibility of noninvasive metabolic monitoring of cancer chemohormonotherapy using sequential quantitative positron emission tomographic (PET) scans of tumor glucose metabolism with the glucose analog 2-[18F]-fluoro-2-deoxy-D-glucose (FDG). PATIENTS AND METHODS: Eleven women with newly diagnosed primary breast cancers larger than 3 cm in diameter beginning a chemohormonotherapy program underwent a baseline and four follow-up quantitative PET scans during the first three cycles of treatment (days 0 to 63). Tumor response was sequentially determined clinically, radiographically, and then pathologically after nine treatment cycles. RESULTS: Eight patients had partial or complete pathologic responses. Their maximal tumor uptake of FDG assessed by PET decreased promptly with treatment to the following: day 8, 78 +/- 9.2% (P < .03); day 21, 68.1 +/- 7.5% (P < .025); day 42, 60 +/- 5.1% (P < .001); day 63, 52.4 +/- 4.4% (P < .0001) of the basal values. Tumor diameter did not decrease significantly during this period through 63 days. Prompt decreases in the FDG influx rate (K) from basal levels (from .019 to .014 mL/cm3/min) after 8 days of treatment (P < .02) and in the estimated rate of FDG phosphorylation to FDG-6-phosphate (k3) from .055 to .038 min-1 after 8 days of treatment (P < .02) to .029 +/- .004 min-1 at 21 days) (P < .02) were observed. Three nonresponding patients had no significant decrease in tumor uptake of FDG (81 +/- 18% of basal value), influx rate (.015 to .012 mL/cm3/min), or tumor size (81 +/- 12% of basal diameter) comparing basal versus 63-day posttreatment values. CONCLUSION: Quantitative FDG PET scans of primary breast cancers showed a rapid and significant decrease in tumor glucose metabolism after effective treatment was initiated, with the reduction in metabolism antedating any decrement in tumor size. No significant decrease in FDG uptake (SUV) after three cycles of treatment was observed in the nonresponding patients. FDG PET scanning has substantial promise as an early noninvasive metabolic marker of the efficacy of cancer treatment.

Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging.

Evaluation of regional myocardial blood flow by conventional scintigraphic techniques is limited to the qualitative assessment of regional tracer distribution. Dynamic imaging with positron emission tomography allows the quantitative delineation of myocardial tracer kinetics and, hence, the measurement of physiologic processes such as myocardial blood flow. To test this hypothesis, positron emission tomographic imaging in combination with N-13 ammonia was performed at rest and after pharmacologically induced vasodilation in seven healthy volunteers. Myocardial and blood time-activity curves derived from regions of interest over the heart and ventricular chamber were fitted using a three compartment model for N-13 ammonia, yielding rate constants for tracer uptake and retention. Myocardial blood flow (K1) averaged 88 +/- 17 ml/min per 100 g at rest and increased to 417 +/- 112 ml/min per 100 g after dipyridamole infusion (0.56 mg/kg) and handgrip exercise. The coronary reserve averaged 4.8 +/- 1.3 and was not significantly different in the septal, anterior and lateral walls of the left ventricle. Blood flow values showed only a minor dependence on the correction for blood metabolites of N-13 ammonia. These data demonstrate that quantification of regional myocardial blood flow is feasible by dynamic positron emission tomographic imaging. The observed coronary flow reserve after dipyridamole is in close agreement with the results obtained by invasive techniques, indicating accurate flow estimates over a wide range. Thus, positron emission tomography may provide accurate and noninvasive definition of the functional significance of coronary artery disease and may allow the improved selection of patients for revascularization.

Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography.

OBJECTIVES: The purpose of this investigation was to evaluate the sympathetic nervous system of the heart by positron emission tomographic (PET) imaging in patients with diabetes mellitus with and without diabetic autonomic neuropathy. BACKGROUND: The clinical assessment of cardiac involvement in diabetic autonomic neuropathy has been limited to cardiovascular reflex testing. With the recent introduction of radiolabeled catecholamines such as carbon (C)-11 hydroxyephedrine, the sympathetic innervation of the heart can be specifically visualized with PET imaging. METHODS: Positron emission tomographic imaging was performed with C-11 hydroxyephedrine and rest myocardial blood flow imaging with nitrogen-13 ammonia. Three patient groups were studied, including healthy volunteers as control subjects, diabetic patients with normal autonomic function testing and diabetic patients with varying severity of autonomic neuropathy. Homogeneity of cardiac tracer retention as well as absolute tracer retention was determined by relating myocardial tracer retention to an arterial C-11 activity input function. RESULTS: Abnormal regional C-11 hydroxyephedrine retention was seen in seven of eight patients with autonomic neuropathy. Relative tracer retention was significantly reduced in apical, inferior and lateral segments. The extent of the abnormality correlated with the severity of conventional markers of autonomic dysfunction. Absolute myocardial tracer retention index measurements showed a 45 +/- 21% decrease in distal compared with proximal myocardial segments in autonomic neuropathy (0.069 +/- 0.037 min-1 vs. 0.13 +/- 0.052 min-1, p = 0.02). CONCLUSIONS: This study demonstrates a heterogeneous pattern of neuronal abnormalities in patients with diabetic cardiac neuropathy. The extent of this abnormality correlated with the severity of neuropathy assessed by conventional tests. Future studies in larger groups of patients are required to define the relative sensitivity of this imaging approach in detecting cardiac neuropathy and to determine the clinical significance of these scintigraphic findings in comparison with conventional markers of autonomic innervation.

Noninvasive quantification of regional myocardial flow reserve in patients with coronary atherosclerosis using nitrogen-13 ammonia positron emission tomography. Determination of extent of altered vascular reactivity.

OBJECTIVES: The aim of this study was to evaluate patients with coronary artery disease to 1) determine the relation between flow reserve measured by nitrogen-13 (N-13) ammonia kinetic modeling and stenosis severity assessed by quantitative angiography, and 2) examine whether flow reserve is impaired in regions supplied by vessels without significant angiographic disease. BACKGROUND: With the advent of new therapeutic approaches for coronary disease, an accurate noninvasive approach for absolute quantification of flow and flow reserve is needed to evaluate functional severity and extent of atherosclerosis. Nitrogen-13 ammonia kinetic modeling may permit such evaluation. METHODS: Twenty-seven subjects were classified into three groups: group 1 = 5 young volunteers: group 2 = 7 middle-aged volunteers; and group 3 = 15 patients with coronary artery disease. Dynamic N-13 ammonia positron emission tomographic imaging was performed at rest and during adenosine infusion. A three-compartment model was fit to regional N-13 ammonia kinetic data to determine myocardial flow. Group 3 patients underwent quantitative coronary angiography. RESULTS: The regional blood flow results in patients with coronary disease were classified into four subgroups: no significant detectable disease and mild (50% to 69.9% area stenosis), moderate (70% to 94.9% area stenosis) or severe (95% to 100% area stenosis) coronary disease. Flow reserve was 2.95 +/- 0.65; 2.09 +/- 0.47; 2.02 +/- 0.51; 1.3 +/- 0.32, respectively (p < or = 0.01 except mild vs. moderate). Flow reserve was correlated with percent area stenosis (r = -0.56) and minimal lumen diameter (r = 0.75). In volunteers (groups 1 and 2), flow reserves were greater than in segments without detectable disease in group 3 patients (4.10 +/- 0.71 and 3.79 +/- 0.42, respectively, vs. 2.88 +/- 0.56, p < or = 0.02). CONCLUSIONS: The functional severity of coronary disease measured by N-13 ammonia positron emission tomography varied for a given stenosis but was significantly related to angiographic severity. Among patients with coronary disease, myocardial regions without significant angiographic stenoses displayed reduced flow reserve than did regions in control subjects, indicating that vascular reactivity was more diffusely impaired in group 3 than was suggested by angiography. Noninvasive quantification of myocardial flow reserve using dynamic N-13 ammonia positron emission tomography yields important functional data that permit definition of the extent of disease even when disease is not apparent by angiography.

Evaluation of patterns of perfusion and metabolism in dobutamine-responsive myocardium.

OBJECTIVES: We investigated the patterns of perfusion and metabolism in dysfunctional myocardium whose contractility improved with dobutamine. BACKGROUND: Clinical studies have suggested that dobutamine echocardiography can identify hibernating myocardium, but laboratory studies suggest that reduced perfusion limits the response to dobutamine. METHODS: Twenty-five patients with coronary disease and ventricular dysfunction underwent low (5 and 10 micrograms/kg body weight per min) and high dose (maximum of 50 micrograms/kg per min) dobutamine echocardiography and positron emission tomography (PET) using nitrogen-13 (N-13) ammonia and fluorine-18 fluorodeoxyglucose (FDG) for imaging of perfusion and metabolism. Wall motion and tracer uptake were scored in 16 left ventricular segments. RESULTS: Perfusion and metabolism were normal in 56.4%, mildly reduced in 29.1% and mismatched (reduced perfusion, preserved FDG uptake) in 14.5% of dysfunctional segments viable on PET. Wall motion improved with dobutamine in 89 dysfunctional segments (62 at low dose, 27 only at peak dose), and 86 of these (97%) were viable on PET. Improvement in wall motion with dobutamine was more common in segments with normal perfusion and metabolism (56.5%) than in those with mildly reduced tracer uptake (28.5%, p < 0.001) and those with mismatch (32%, p = 0.03). All the segments with a biphasic response were supplied by vessels with > or = 70% stenosis, and 88% had normal perfusion and metabolism. CONCLUSIONS: The majority of viable segments with rest dysfunction had normal perfusion and metabolism, suggesting that myocardial stunning was common. Improvement of wall motion at low and high doses of dobutamine was highly correlated with myocardial viability on PET and was more common in myocardium with normal perfusion. A biphasic response to dobutamine identified segments with normal perfusion and metabolism supplied by severely diseased vessels.

Quantitative comparison of functional contrast from BOLD-weighted spin-echo and gradient-echo echoplanar imaging at 1.5 Tesla and H2 15O PET in the whole brain.

Spin-echo and gradient-echo echoplanar functional magnetic resonance imaging (fMRI) studies at 1.5 Tesla (T) were used to obtain blood oxygenation level-dependent (BOLD) contrast images of the whole brain in seven strongly right-handed women during execution of a complex motor task. Five subjects underwent subsequent H215O positron emission tomography (PET) studies while performing the same task. Group-averaged results for changes in the MRI relaxation rates R2* and R2 at 1.5T in response to neuronal activation in nine cortical, subcortical, and cerebellar motor regions are reported. Results for each method are grouped according to tissue type-cerebral cortex (precentral gyrus and supplementary motor area), subcortical regions (thalamus and putamen), and cerebellar cortex (superior lobule). The observed changes in R2* from activation-induced oxygenation changes were more variable across brain regions with different tissue characteristics than observed changes in R2. The ratio of deltaR2* to deltaR2 was 3.3 +/- 0.9 for cerebral cortex and 2.0 +/- 0.6 for subcortical tissue. deltaR2*, deltaR2, and relative blood flow changes were deltaR2* = -0.201 +/- 0.040 (s-1), deltaR2 = -0.064 +/- 0.011 s(-1), and deltaf/f = 16.7 +/- 0.8% in the cerebral cortex; deltaR2* = -0.100 +/- 0.026 s(-1), deltaR2 = -0.049 +/- 0.009 s(-1), and deltaf/f = 9.4 +/- 0.7% in the subcortical regions; and deltaR2* = -0.215 +/- 0.093 s(-1), deltaR2 = -0.069 +/- 0.012 s(-1), and deltaf/f = 16.2 +/- 1.2% in the cerebellar cortex.

Alternative approach to single-scan estimation of cerebral glucose metabolic rate using glucose analogs, with particular application to ischemia.

In the glucose analog method for determining local glucose utilization rates, time courses of tissue and plasma radioactivity are measured and then analyzed in terms of first-order exchange of label between tissue compartments. The rate of glucose utilization is assumed to have a fixed, linear relationship to the analog phosphorylation rate calculated from the fitted rate constants. Accurate estimation of the rate constants requires many hours of dynamic data acquisition. Therefore, techniques assuming a linear relationship between analog phosphorylation rate and total tissue concentration of label were developed to predict glucose utilization rates from a single scan. Previously reported linearizations differ in their sensitivity to differences between current and average kinetic rate constants, and thus in their accuracy. We have developed a method that is insensitive to the presumed value of the blood flow-capillary wall transport parameter k1. This new single-scan approach has been validated by comparison of the single-scan metabolic rate values with the values calculated from the dynamic measurements.

Quantitation of local cerebral blood flow and partition coefficient without arterial sampling: theory and validation.

A new technique that requires neither arterial blood sampling nor prior knowledge of the indicator's tissue-blood partition coefficient has been developed for quantitation of local CBF. This technique arises from an existing method that uses the inert, freely diffusible gaseous tracer [18F]methyl fluoride (CH3(18)F) and positron computed tomography. The shape of the arterial blood curve is derived from continuous sampling of expired air. The concentration of CH3(18)F in the arterial blood is assumed to be proportional to the expired gas curve interpolated between end-tidal values. The absolute scale of the blood curve is determined by fitting a series of venous blood samples to a multicompartment model. Four validation studies were performed to compare values derived using the venous scaled expired breath input function with those derived using direct arterial samples. The proposed method gave higher flow values than the standard arterial sampling method by an average of 4.4%. These validation studies and data from both normal and patient scans suggest that the method provides the quantitation necessary for interstudy comparisons yet avoids the trauma of an arterial puncture.

Functional brain imaging in apraxia.

BACKGROUND: An extensive literature describes structural lesions in apraxia, but few studies have used functional neuroimaging. We used positron emission tomography (PET) to characterize relative cerebral glucose metabolism in a 65-year-old, right-handed woman with progressive decline in ability to manipulate objects, write, and articulate speech. OBJECTIVE: To characterize functional brain organization in apraxia. DESIGN AND METHODS: The patient underwent a neurological examination, neuropsychological testing, magnetic resonance imaging, and fludeoxyglucose F 18 PET. The patient's magnetic resonance image was coregistered to her PET image, which was compared with the PET images of 7 right-handed, healthy controls. Hemispheric regions of interest were normalized by calcrine cortex. RESULTS: Except for apraxia and mild grip weakness, results of the neurological examination were normal. There was ideomotor apraxia of both hands (command, imitation, and object) and buccofacial apraxia. The patient could recognize meaningful gestures performed by the examiner and discriminate between his accurate and awkward pantomime. The magnetic resonance image showed moderate generalized atrophy and mild ischemic changes. Positron emission tomographic scans showed abnormal fludeoxyglucose F 18 uptake in the posterior frontal, supplementary motor, and parietal regions, the left affected more than the right. Focal metabolic deficit was present in the angular gyrus, an area hypothesized to store conceptual knowledge of skilled movement. CONCLUSIONS: Greater parietal than frontal physiological dysfunction and preserved gesture recognition are not consistent with the theory that knowledge of limb praxis is stored in the dominant parietal cortex. Gesture comprehension may be more diffusely distributed.

Differences between lateral and mesial temporal metabolism interictally in epilepsy of mesial temporal origin.

We performed interictal [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in 17 patients with well-defined unilateral anterior mesial temporal epileptogenic foci as determined by EEG procedures. Sixteen of these patients subsequently underwent surgical resection of the epileptogenic focus. We measured local cerebral metabolic rates for glucose in mesial and lateral temporal structures and compared them with metabolic rates for analogous regions in 16 healthy normal volunteers and the contralateral hemisphere of the epileptic patients. We found relative hypometabolism ipsilateral to the seizure focus more frequently and to a greater degree in the lateral than in the mesial temporal cortex. Since the physiologic abnormalities involved mesial temporal structures, this observation suggests that functional pathways exist between mesial and lateral temporal cortex normally and that these pathways are altered in epilepsy of mesial temporal origin. Hypometabolism did not correlate well with histologic abnormalities in the surgical specimens.

Neuronal mapping of the heart with 6-[18F]fluorometaraminol.

The false neurotransmitter metaraminol labeled with fluorine-18 has been used to noninvasively assess regional adrenergic nerve density in the canine heart. Intravenous administration of 6-[18F]fluorometaraminol (FMR) results in high, selective accumulation of radioactivity in the heart; drug blocking studies with desipramine and reserpine confirm the neuronal locus of FMR. Iodine-125 labeled metaraminol, however, shows no selective accumulation in the canine heart. Positron emission tomography (PET) analyses with FMR of closed-chest dogs bearing left ventricular neuronal defects clearly delineate the region of neuronal impairment; blood perfusion in the left ventricle wall was homogeneous as determined by [13N]NH3 tomograms. The accumulation of FMR in regionally denervated dog heart correlates closely (r = 0.88) with endogenous norepinephrine concentrations. PET-generated 18F time-activity curves demonstrate marked kinetic differences between normal and denervated myocardium. FMR/PET analysis could be used to assess the heterogeneity of sympathetic innervation in human heart disease contingent on the development of FMR with sufficiently high specific activity to clearly avoid pressor activity.

Automated PET attenuation correction model for functional brain imaging.

UNLABELLED: The failure to compensate for subject motion between attenuation correction scans and emission scans precludes the optimization of functional brain imaging techniques. We have developed an automated method for attenuation correction that compensates for subject motion by deriving each set of correction factors from the corresponding emission study. METHODS: The technique consists of generation of an estimated skull image by filtered backprojection of the reciprocal of an emission sinogram; estimation of the thickness and radius of the skull on profiles extracted from the image; scaling the radius and thickness values to generate a model of the brain, skull, and scalp; and assignment of attenuation coefficients to the head model for generation of attenuation correction factors. Values for scale factors and tissue attenuation coefficients were determined empirically by fitting the emission-derived head model to measured transmission data in five subjects using nonlinear regression (group A). The average model parameters, across five datasets (group A), were then used to generate attenuation maps for five independent emission studies (group B). Mean-squared-error values were calculated between the measured transmission data and the two model groups. For comparison, mean squared error values were calculated between the measured transmission data and homogeneous ellipses that were manually fitted to emission images. RESULTS: The difference between the mean squared error for groups A and B was not significant (P>0.8), indicating that model parameters from a small group can be used for other subjects without further fitting. The mean squared error for the automated method was significantly lower than that of the ellipse method (P<0.001). The method reduced emission image variance, resulting in a higher peak Z value in activation images. The elimination of measured transmission scans resulted in a reduction in scan time ( approximately 15 min) and radiation exposure ( approximately 0.5-1.6 mrem). CONCLUSION: We have developed an automated attenuation correction method that compensates for subject motion between scans, accurately reproduces the characteristics of the head, and eliminates the use of measured transmission data to reduce scan duration, statistical noise propagation, and radiation dose.

Modeling of carbon-11-acetate kinetics by simultaneously fitting data from multiple ROIs coupled by common parameters.

UNLABELLED: One of the unique aspects of PET is its ability to noninvasively quantify metabolic processes. Metabolic rate parameters are estimated by fitting the time-activity curves from regions of interest (ROIs) placed on dynamic PET images with a kinetic model. In many cases it is possible to couple these datasets with common parameters, such as the time delay between arrival of tracer in the ROIs and the sampling site. METHODS: Data from eight ROIs placed about images of the myocardium were coupled by the parameters describing the metabolite concentration in the blood. The method was evaluated by comparing estimates of k2 made using the coupled region method and the standard process of fitting data from each region separately. In addition, comparisons were made between estimates of k2 and measured myocardial oxygen consumption. RESULTS: Very little change in mean values of k2 was obtained. The variances, however, were reduced by an average of 37%, compared to the standard method, when the common parameters were not constrained. When the values of the common metabolite parameters were constrained to values previously measured, the average variance in estimates of k2 was reduced by 30%. CONCLUSION: We have demonstrated that the use of this technique can significantly increase the precision of estimates of myocardial oxygen consumption utilizing 11C-acetate PET images. More precise estimates of such quantities can facilitate detection of small regional and/or temporal physiological changes measured with PET. Furthermore, this method can be utilized whenever it is known a priori that one or more kinetic model parameters has the same value for every set of ROI data.

Sampling requirements for dynamic cardiac PET studies using image-derived input functions.

The utilization of image-derived input functions is becoming common in quantitative PET studies of the heart. Consequently, imaging protocols must be designed to sample both blood and tissue concentrations adequately. Most clinical imaging protocols consist of a series of short initial scans to measure the rapid change in blood and tissue tracer concentration levels, followed by scans of gradually increasing length. The number of initial short scans must be matched to the shape of the input function. In this paper, noise-free simulation studies were performed to evaluate the effect of temporal sampling on estimates of the parameters of a two-compartment kinetic model. In addition, the consequences of varying tracer infusion length and timing were studied. The kinetic model parameters' bias decreased when infusion times were lengthened or sampling rates increased. Our results indicated that tracer infusions of 30 sec were best suited for these studies. Two currently employed clinical imaging protocols were then optimized for use with this infusion scheme. Ten initial scans with durations of 10 sec, or twenty of 5 sec length produced unbiased estimates of kinetic model parameters that describe myocardial physiology. Noisy simulations with the equivalent of one million events confirmed these results.