Alan H. Lockwood

A Simplified in vivo Autoradiographic Strategy for the Determination of Regional Cerebral Blood Flow by Positron Emission Tomography: Theoretical Considerations and Validation Studies in the Rat

A simplified mathematical model is described for the measurement of regional cerebral blood flow by positron emission tomography in man, based on a modification of the autoradiographic strategy originally developed for experimental animal studies. A modified ramp intravenous infusion of radiolabeled tracer is used; this results in a monotonically increasing curvilinear arterial activity curve that may be accurately described by a polynomial of low degree (= z). Integrated cranial activity C̄ B is measured in regions of interest during the latter portion of the tracer infusion period (times T1 to T2). It is shown that C ̄ R = ∑ x = 0 z A x , where each of the terms A x is a readily evaluated function of the blood flow rate constant k, the brain:blood partition coefficient for the tracer, the cranial activity integration limits T1 and T2, the coefficients of the polynomial describing the arterial curve, and an iteration factor n that is chosen to yield the desired degree of precision. This relationship permits generation of a table of C̄ B vs. k, thus facilitating on-line computer solution for blood flow. This in vivo autoradiographic paradigm was validated in a series of rats by comparing it to the classical autoradiographic strategy developed by Kety and associates. Excellent agreement was demonstrated between blood flow values obtained by the two methods: CBF in vivo = CBFclassical X 0.99 − 0.02 (units in ml g−1 min−1; correlation coefficient r = 0.966).

Factors that affect the uptake of ammonia by the brain: the blood-brain pH gradient

The brain uptake index (BUI) for [13N]ammonia was measured in 7 areas of the rat brain at 8 different pH values ranging from 6.58 to 7.73. When the regional BUI was plotted as a function of the pH of the test bolus, a significant linear correlation was found for each region (P less than 0.001). The highest slope was observed in the thalamus-basal ganglia complex (0.392 +/- 0.018) (S.D.), and the lowest in the ventral pons (0.143 +/- 0.011). These studies indicate that the brain-blood pH gradient plays a major role in determining the forward flux of ammonia from the blood into the brain in the physiological pH range. Regional differences in the slope may be due to metabolic factors. This pH effect may be important in clinical conditions characterized by hyperammonemia such as hepatic encephalopathy, and in the interpretation of [13N]ammonia emission tomographic images of the brain.

On the uniqueness of cerebral blood flow measured by the in vivo autoradiographic strategy and positron emission tomography

Factors are examined in this report which govern the uniqueness and sensitivity of regional cerebral blood flow (rCBF), as determined by an in vivo autoradiographic strategy and positron emission tomography (PET), and a series of theorems is derived which specify conditions under which a unique relationship between cumulative cranial activity of the tracer (C) and regional blood flow (f) may be assured. It is demonstrated that, independent of the specific form of the arterial tracer input function, flow is a unique function of C whenever the start time (T1) of the PET scan is coincident with the start of tracer infusion. Other theorems state that, even for nonzero T1s, a unique solution for flow may be expected, as long as the duration of the scan is sufficiently short. The implementation of this theory is illustrated using arterial tracer activity curves obtained in three normal subjects by a multiple arterial sampling procedure following the bolus i. v. infusion of 20–30 μCi of [15O]water. Based on these arterial curves, it is confirmed that the C vs. f relationship resulting from scan parameters T1 = 0 and T2 = 1.5 min (i.e., a PET scan of 90 s commencing with tracer infusion) has an excellent separation of flow values within the range of physiological interest, whereas a 90-s scan beginning at time T1 = 1.7 min results in poorer separation of flow values and loss of the monotonic relationship between C and f at higher flows. The results of this study serve to clarify the in vivo autoradiographic method for measuring rCBF in humans and help to define favorable study parameters for assuring uniqueness and sensitivity of the flow measurement.

Blood—Brain Barrier to Ammonia in Humans:

We have developed a method to evaluate the diffusion of ammonia across the blood–brain barrier (BBB) in normal humans, based on measures of CBF and the regional cerebral metabolic rate for ammonia, obtained by positron emission tomography. The extraction fraction for ammonia passing through the cerebral capillary bed was a reciprocal function of CBF. The product of the BBB surface area and ammonia permeability, calculated from the Renkin-Crone model, was 0.32 ± 0.19 cm3 g−1 min−1 (±SD) in gray matter and 0.24 ± 0.16 cm3 g−1 min−1 in white matter. From literature values of the expected capillary surface area ratio, a gray-to-white matter ammonia permeability ratio of 0.37:1.0 was calculated. We speculate that astrocytes may mediate this unexpected difference in permeability, and that the permeability of the BBB to ammonia may be important in the pathogenesis of hyperammonemic brain dysfunction.

11C‐carbon dioxide fixation and equilibration in rat brain Effects on acid‐base measurements

The positron-emitting isotope 11C was used to label CO2 for studies of metabolic fixation and equilibration after a single-breath inhalation by rats. Metabolic fixation and loss of the label via exhalation caused the metabolized fraction of the label in the brain to rise to 30.1 ± 0.7% within 30 minutes. The T12 for equilibration of the label between blood and brain was 1.95 minutes. When the label was 95% equilibrated, 12% was metabolically trapped by brain, and when only 5% was trapped, the blood-brain equilibration process was only 50% complete. Labeled CO2 thus has limited usefulness as an acid-base or metabolic tracer for positron-emission tomography.

Effects of acetazolamide and electrical stimulation on cerebral oxidative metabolism as indicated by the cytochrome oxidase redox state

The intravenous administration of acetazolamide to rats caused a prompt oxidation of cytochrome a,a3 that was associated with an increase in the rate at which this cytochrome underwent additional oxidation and reductive recovery after electrical stimulation of the cerebral cortex. These effects were not observed in animals made hypercapnic after ventilation with 5% CO2. The speed with which these and other metabolic and physiological events occur, after administering the drug, suggests that acetazolamide exerts its effects by complex mechanisms and that the site of action may be in the region of the blood-brain barrier, an area rich in carbonic anhydrase, and noradrenergic innervation.

11C-Iodoantipyrine for the measurement of regional cerebral blood flow by positron emission tomography. Validation studies.

Positron emission tomography (PET) makes it possible to employ an in vivo autoradiographic paradigm to measure regional cerebral blood flow (rCBF) in man. In this study, we synthesized the positron-emitting radiopharmaceutical 11C-iodoantipyrine (11C-IAP) and validated its suitability as a CBF tracer. 11C ( T and one-half 20.4 min) was produced by the (p,alpha) nuclear reaction on 14N. 11C-methyl iodide was used to methylate 3-methyl-1-phenyl-2-pyrazolin-5-one to form 11C-antipyrine, which was iodinated. Radiochemical purity of the 11C-IAP product was 93-98% except as described below. rCBF was measured with 11C-IAP in nitrous oxide-anesthetized Wistar rats by the method of indicator fractionation, and values were compared with rCBF values measured with simultaneously administered commercially produced 14C-IAP. rCBF was studied over a range of arterial Pco2 values (31-58 mm Hg, mean 43.0 +/- 3.5). Mean rCBF data for the 2 tracers agreed to within 4.8% for cerebral hemispheral samples, 3.8% for cerebellum, and 5.3% for brainstem. Mean values (+/- SEM) for rCBF using 11C-IAP were 1.67 +/- 0.20 ml gm-1 min-1 for cerebral hemispheres; 1.32 +/- 0.17 for cerebellum; and 1.50 +/- 0.21 for brainstem. When chromatographic analysis revealed tracer impurity, rCBF, as measured with 11C-IAP, fell consistently below values obtained with 14C-IAP. The data indicate that 11C-IAP, when properly synthesized and submitted to batch-by-batch quality control, may be suitable for measuring rCBF in man by emission tomography.

Adaptation to hyperosmolality in the rat

Hyperosmolality induced in rats results in a progressive increase in brain glutamine levels with out a change in ammonia. This suggests an adaptation in the compartmental nature of the glutamate-ammonia-glutamine metabolic system to provide more brain osmoles without excess ammonia. The brain: blood glucose ratio rose suggesting brain energy use rate reductions previously reported may be due to altered glucose transport or phosphorylation.

Metabolic Encephalopathy: A Mechanistic Approach

Publisher Summary This chapter presents a mechanistic approach to metabolic encephalopathy. The metabolic encephalopathies are a group of disorders that are characterized by an abnormal mental status. Usually, this is the result of a specific disease or organ dysfunction, but intoxications and substrate deficiencies are included as well. Nervous system dysfunction because of metabolic rather than structural disturbances in the brain accounts for about 70% of all examples of coma of unknown etiology. A disturbance of consciousness is the hallmark of all metabolic encephalopathies. Consciousness can be regarded as having two components: (1) an on-off or quantitative component—alertness versus deep coma—and (2) a qualitative component—normal cognitive function versus confusion and inability to perform learned mental tasks. Lesions in the reticular activating system produce coma by affecting the quantitative component, and bilateral lesions of the complete cerebral cortex affect the qualitative aspects of consciousness.

ABSORBED DOSES OF RADIAIION AFIER AN INTRAVENOUS INJECTION OF N - 13 AMMONIA IN MAN: CONCISE COMMUNICATION

Using body distribution data with the MIRD tables and equations, the radiation dose delivered by an i.v. injection of N-13 ammonia has been calculated for several human organs. The liver and the urinary bladder wall receive 0.017 and 0.051 rad/mCi injected respectively; the latter can be reduced by early post-injection voiding. The brain-to-brain absorbed dose is 0.016 rad/mCi injected. The absorbed doses for the whole body, the red marrow, the ovaries, and the testes are, respectively, 0.0055, 0.0054, 0.0098, and 0.0010 rad/mCi injected. Severe liver disease is associated with a reduction in the fraction of the injected N-13 that is excreted in the urine, and thus causes a reduction in the absorbed dose to the urinary bladder wall from the bladder contents. Hepatomegaly increases the fraction of the N-13 ammonia trapped by the liver, and complicates calculation of the absorbed dose of radiation. These data should facilitate the evaluation of the risk from radiation absorption following i.v. injections of N-13 ammonia in humans.