David E. Kuhl

The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man.

A method has been developed to measure local glucose consumption in the various structures of the brain in man with three-dimensional resolution. [18F]-2-deoxy-2-fluoro-D-glucose is used as a tracer for the exchange of glucose between plasma and brain and its phosphorylatdon by hexokinase in the tissue. A mathematical model and derived operational equation are used which enable local cerebral glucose consumption to be calculated in terms of the following measurable variables. An intravenous bolus of [18F]-2-deoxy-2-fluoro-D-glucose is given and the arterial specific activity monitored for a predetermined period of from 30 to 120 minutes. Starting at 30 minutes, the activity in a series of sections through the brain is determined with three-dimensional resolution by an emission tomographic scanner. The method was used to measure local cerebral glucose consumption in two normal volunteers. The values in gray matter structures range from 5.79 mg/100 g per minute in the cerebellar cortex to 10.27 in the visual cortex, whereas, in white matter structures, the values range from 3.64 mg/100 g per minute in the corpus callosum to 4.22 in the occipital lobe. Average values for gray matter, white matter, and whole brain metabolic rates, calculated as a weighted average based on the approximate volume of each structure, are 8.05, 3.80, and 5.90 mg/100 g per minute, respectively. The value of 5.9 mg/100 g per minute compares favorably with values previously reported. Ore Res 44: 127-137, 1979

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.

Alzheimer's disease versus dementia with Lewy bodies: Cerebral metabolic distinction with autopsy confirmation

Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimers disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy‐confirmed pure AD patients. In addition, 53 patients with clinically‐diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy‐confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD −23% and DLBD −29% vs AD −8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically‐diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later clinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.

N-13 ammonia as an indicator of myocardial blood flow.

We have characterized N-13 ammonia as a myocardial blood flow imaging agent suitable for positron-emission computed tomography. However, the mechanisms of uptake and retention of this agent in myocardium are not known, and effects of altered metabolism were not considered. Therefore, we studied the uptake and retention of N-13 ammonia in myocardium under various hemodynamic and metabolic conditions in open-chest dogs. N-13 ammonia was extracted nearly 100% during its initial capillary transit, followed by metabolic trapping that competed with flow-dependent back diffusion. At control flows, the first capillary transit extraction fraction (E) of N-13 ammonia averaged 0.82 ± 0.06. It fell with higher flows by E = 1 − 0.607 exp − 125/F. Myocardial N-13 tissue clearance half-times were similarly inversely related to blood flow, and ranged from 110–642 minutes. Cardiac work and changes in the myocardial inotropic state induced by isoproterenol and propranolol did not affect E or the tissue clearance half-times. Low plasma pH reduced E by an average of 20%, while elevated plasma pH had no effect. Decreases in flow below control also were associated with a fall in E. Inhibition of glutamine synthetase with L-methionine sulfoximine impaired metabolic trapping of N-13 ammonia and implicates the glutamic acid-glutamine reaction as the primary mechanism for ammonia fixation. The product of E times flow predicts the myocardial N-13 tissue concentrations, which increased by 70% when flow was doubled. Thus, blood flow and metabolic trapping are the primary determinants of myocardial uptake and retention of N-13 ammonia. The relative constancy of metabolic trapping over a wide range of hemodynamic and metabolic conditions demonstrates the value of N-13 ammonia as a myocardial blood flow imaging agent.

Tomographic mapping of human cerebral metabolism: Auditory stimulation

Cerebral metabolic responses to verbal and nonverbal auditory stimuli were examined, using 18F-fluorodeoxyglucose and positron CT. Twenty right-handed subjects were studied in both control and stimulated states. Monaural verbal stimuli produced diffuse metabolic changes in the left hemisphere and bilateral activation of the transverse and posterior temporal lobes. Monaural nonverbal stimulation with chords demonstrated bilateral parietotemporal activations and diffuse right greater than left frontotemporal asymmetries. Tone sequence pairs presented monaurally produced asymmetries that differed by the subjects analysis strategy. Nonanalytical, musically naive subjects had right greater than left frontotemporal asymmetries, whereas analytic or musically sophisticated subjects had an absence of right greater than left relative hypermetabolism and demonstrated left greater than right temporal asymmetries. Binaural presentation of a factual story and music produced diffuse bilateral activations of the temporal and frontal cortex. Known anatomic asymmetries of the perisylvian cortex were revealed by high-resolution tomography. These results demonstrate that metabolic responses to auditory stimuli are determined by the content of the stimulus and the analysis strategy of the subject rather than the side of stimulation. The results also demonstrate the capacity of functional imaging techniques to study the physiologic cerebral mechanisms underlying auditory processing.

Compartmental Analysis of [11C]Flumazenil Kinetics for the Estimation of Ligand Transport Rate and Receptor Distribution Using Positron Emission Tomography

The in vivo kinetic behavior of [11C]flumazenil ([11C]FMZ), a non-subtype-specific central benzodiazepine antagonist, is characterized using compartmental analysis with the aim of producing an optimized data acquisition protocol and tracer kinetic model configuration for the assessment of [11C]FMZ binding to benzodiazepine receptors (BZRs) in human brain. The approach presented is simple, requiring only a single radioligand injection. Dynamic positron emission tomography data were acquired on 18 normal volunteers using a 60- to 90-min sequence of scans and were analyzed with model configurations that included a three-compartment, four-parameter model, a three-compartment, three-parameter model, with a fixed value for free plus nonspecific binding; and a two-compartment, two-parameter model. Statistical analysis indicated that a four-parameter model did not yield significantly better fits than a three-parameter model. Goodness of fit was improved for three- versus two-parameter configurations in regions with low receptor density, but not in regions with moderate to high receptor density. Thus, a two-compartment, two-parameter configuration was found to adequately describe the kinetic behavior of [11C]FMZ in human brain, with stable estimates of the model parameters obtainable from as little as 20–30 min of data. Pixel-by-pixel analysis yields functional images of transport rate (K1) and ligand distribution volume (DV“), and thus provides independent estimates of ligand delivery and BZR binding.

Quantitation in Positron Emission Computed Tomography: 5. Physical–anatomical Effects

The effect of neuroanatomical structure size, shape, and position versus spatial tomographic resolution on quantitation in positron computed tomography was investigated. For neuroanatomical structures, voxel sizes in excess of 3 ml exceeded the volume of most structures examined. When the voxel size exceeded structure volume, calculated recovery coefficient (fraction of the true isotope concentration measured in the image) fell to ≤ 42%. Partial volume effects in the plane of section analyzed by computer simulation produced errors that were largest for small, thin, irregularly shaped structures whose averaged pixel values were most different from neighboring structures. Smallest errors occurred in large, circular structures surrounded by regions of similar pixel values. Computer simulation of regional cerebral asymmetries of pixel values demonstrated that the measurement of these asymmetries was often predominated (enhanced or obliterated) by partial volume effects related to structure size and shape. Large, circular, and widely separated regional asymmetries were more easily detected at a given spatial resolution than small, thin, adjacent regions. Recommendations for error reduction and possible correction factors are provided and discussed.

Effects of Human Aging on Patterns of Local Cerebral Glucose Utilization Determined by the [18F] Fluorodeoxyglucose Method

The [18F]fluorodeoxyglucose (FDG) scan method with positron emission computed tomography was used to determine patterns of local cerebral glucose utilization (LCMRglu) in 40 normal volunteer subjects aged 18 to 78 years. Throughout all the studies, each subject was quiet, without movement, with eyes open and ears unplugged, exposed only to ambient room light and sound. For the entire group, whole brain mean CMRglu was 26.1 ± 6.1 μmol 100 g−1 min−1 (mean ± SD, n = 40). At age 78, mean CMRglu was, on the average, 26% less than at age 18, an alteration of the same order as the variance among subjects at any age. The gradual decline of mean CMRglu with advancing age occurred at a faster rate than was reported for mean cerebral oxygen utilization, possibly due to increasingly altered pathways for glucose utilization, or to increasing oxidation of ketone bodies or other alternative substrates. Glucose utilization in the hemispheres was symmetrical and mean CMRglu of overall cortex, caudate, and thalamus was equal in individuals at all ages. The slopes of decline with age were similar when LCMRglu was averaged over zones corresponding to centrum semiovale, caudate, putamen, and frontal, temporal, parietal, occipital, and primary visual cortex. However, the metabolic ratio of superior frontal cortex to superior parietal cortex declined with age, possibly due to selective degeneration of superior frontal cortex or to differences between age groups in the sensory and cognitive response to the study. These results should be useful in distinguishing age from disease effects when the FDG scan method is used.

In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease

Objective: To validate an in vivo method for mapping acetylcholinesterase (AChE) activity in human brain, preparatory to monitoring inhibitor therapy in AD. Background: AChE activity is decreased in postmortem AD brain. Lacking a reliable in vivo measure, little is known about central activity in early AD, when the disease is commonly targeted by AChE inhibitor drug therapy. Methods: Intravenous N-[11C]methylpiperidin-4-yl propionate ([11C]PMP) served as an in vivo AChE substrate. AChE activity was defined using cerebral PET for tracer kinetic estimates of the local rate of [11C]PMP hydrolysis in 26 normal controls and 14 patients with AD. Eleven AD patients also had concomitant in vivo cerebral measures of vesicular acetylcholine transporter (cholinergic terminal) density and glucose metabolism. Results: Cerebral AChE activity measures 1) were independent of changes in tracer delivery to cerebral cortex; 2) agreed with reported postmortem data concerning normal relative cerebral distributions, absence of large age-effect in normal aging, and deficits in AD; 3) correlated in AD cerebral cortex with concomitant in vivo measures of cholinergic terminal deficits, but not with metabolic deficits; and 4) agreed quantitatively with predicted level of cerebral AChE inhibition induced by physostimine. Conclusions: This in vivo PET method provided valid measures of central AChE activity in normal subjects and AD patients. Applied in early AD, it should facilitate inhibitor treatment by confirming central inhibition, optimizing drug dosage, identifying likely responders, and testing surrogate markers of therapeutic response.

Reduced Cerebral Glucose Metabolism in Asymptomatic Subjects at Risk for Huntington's Disease

Symptomatic patients with Huntingtons disease may have reduced glucose metabolism in the caudate nuclei. We used positron emission tomography and [18F]fluorodeoxyglucose to study cerebral glucose metabolism in 95 subjects: 58 clinically asymptomatic (chorea-free) subjects at risk for Huntingtons disease, 10 symptomatic patients with the disease, and 27 controls. All the symptomatic patients had marked reductions in caudate glucose metabolism. Despite a normal structural appearance on computed tomography, caudate glucose metabolism was bilaterally reduced in 31 percent of the subjects at risk (18 of 58). Using each at-risk subjects age and the sex of the affected parent, we averaged individual risk estimates for the development of Huntingtons disease for this group and predicted that the probability of having the clinically unexpressed Huntingtons disease gene should be 33.9 +/- 6.0 percent for the group. Thus, there was excellent agreement between the predicted percentage of carriers of the Huntingtons disease gene (33.9 +/- 6.0 percent) and the percentage with metabolic abnormalities of the caudate nuclei (31 percent). These results indicate that the measurement of glucose metabolism may allow the observation of the pathophysiologic effects of the Huntingtons disease gene during the natural development of the disease. It may also provide a direct means to monitor the response to experimental treatments during both the clinically asymptomatic and the symptomatic phases of the disorder.