Norman S. MacDonald

Quantitative Measurement of Local Cerebral Blood Flow in Humans by Positron Computed Tomography and 15O-Water

A noninvasive method that employs 15O-water and positron-computed tomography (PCT) was used to measure quantitative local cerebral blood flow (lCBF) in man. 15O-Water (about 30–50 mCi) was introduced through a single-breath inhalation of 15O-carbon dioxide or through an intravenous bolus injection of 15O-water. A sequence of five 2-min PCT scans was initiated at the time of tracer administration. A series of 15–20 blood samples (1 ml each) was withdrawn from the radial artery of the subject over a period of 10 min. Oxygen-15 radioactivities in the blood samples were immediately counted in a well counter to give an input function, which together with the projection data collected by PCT were processed to provide images of lCBF and local water distribution volume. The method was found to be convenient to use and gave good-quality images of lCBF. Quantitative values of lCBF in images were 59 ± 11 and 20 ± 4 ml/min/100 g for gray and white matter, respectively, with a gray-to-white matter ratio of 2.93 and a global flow value of 42 ± 8 ml/min/100 g. Distribution volume of water was 0.85 ± 0.03, 0.76 ± 0.03, and 0.81 ± 0.02 ml/g respectively, for gray matter, white matter, and whole brain.

A noninvasive positron computed tomography technique using oxygen-15--labeled water for the evaluation of neurobehavioral task batteries.

A technique is described that provides information about relative cerebral responses to differing neurobehavioral tasks in normal subjects studied with positron computed tomography and oxygen-15-labeled water. Simulation studies demonstrate that this technique is sensitive to changes in true local CBF within a physiological range and tends to underestimate relative flow changes at high flow values (>30 ml min−1 100 g−1) and to overestimate these changes for flow values of <25 ml min−1 100 g−1. Image acquisition times of 60 s following the arrival of oxygen-15-labeled water in the brain were the most accurate for identifying such relative changes between radioisotope administrations and were not limited by statistical noise from total image counts. Studies in normal volunteers indicate that the technique is highly reproducible, demonstrating a coefficient of variation for small (<2 cm2) regions of 2.98 between studies in the same state. Visual stimulation studies in normal volunteers demonstrated relative radioisotope concentration changes between control and stimulated states that are in good agreement with similar results obtained using the same stimulation paradigm but with the use of fluorodeoxyglucose to determine cerebral glucose metabolism.

Myocardial Extraction of Labeled Long-Chain Fatty Acid Analogs

Summary The single circulation myocardial extraction of terminally iodinated hexadecenoic acid (77 ± 11.0%) is approximately two times the extraction of 18 carbon fatty acids (33 ± 5.2%) prepared by iodination of double bonds. The results compare favorably with natural 18 carbon stearic (70 ± 7.5%) and oleic (61 ± 7.8%) acids labeled with carbon-11 in the carboxyl group. It is concluded that terminally radioiodinated long chain fatty acids can be used as substitutes for in vivo investigations of fatty acid distribution and in particular may be useful as a regional myocardial blood flow indicator. The authors are indebted to Mrs. Alice Lee, Mr. Carl Selin, and Mr. Joe Takahashi for technical assistance.

The C15O2 Build-up Technique to Measure Regional Cerebral Blood Flow and Volume of Distribution of Water:

A new method to measure regional CBF (rCBF) and volume of distribution of water is presented. It centres on recording the tissue build-up and retention of 15O-labelled water during the continuous inhalation of 15O-labelled carbon dioxide. Simultaneously, the arterial concentration is continuously monitored, and corrections for delay and dispersion in the recorded response are made by curve fitting. The values for the volume of distribution of water obtained in four normal subjects were close to reported in vitro values. Using the same fixed distribution volumes for both build-up and steady-state studies resulted in comparable rCBF values for both techniques.

NEW APPROACHES TO THE PROBLEM OF OSTEOPOROSIS

1. Individuals who are normal and not osteoporotic seem to show retention of cortical bone at successive decades of life in proportion to the total lean body-mass. In patients with osteoporosis the weight of the skeleton decreases at a rate exceeding the physiological rate of atrophy of muscle, tendon and bone tissue that occurs with the time-dependent process of ageing. 2. Six patients representing the typical forms of osteoporosis commonly found in orthopaedic practice were investigated intensively over a period of three years and compared with individuals in whom there was no osteoporosis by studies of metabolic balance, Sr85 osteograms, and tetracycline deposition. 3. Studies of metabolic balance in patients with osteoporosis showed normal or negative calcium balances, but an equilibrium for the metabolism of nitrogen and phosphorus. Increased intake of calcium in the diet produced retention of calcium but not sufficient phosphorus, nitrogen or gain in weight to prove that the patient had made new bone and healed the osteoporosis. 4. Radio-isotope osteograms showed high, normal or low rates of change of uptake of Sr85 and the accretion rate was calculated to be normal or low in individuals with osteoporosis. High uptake of tetracycline by a small mass of bone tissue and by a relatively small percentage of the total number of osteons suggested that in an adult human being the calcium reserve in the skeleton is enormous. Thirty to 50 per cent of the total bone mass was sufficient to turn over 0·5 to 1·0 gramme, the amount of calcium utilised in twenty-four hours by the human adult. This was accomplished by structural or old bone throughout the entire skeleton, and by labile or newer bone located in approximately 10 per cent of the total number of Haversian cylinders or osteons. 5. Some of the unclosed or half-closed osteons were hyperactive in osteoporotic bones. In the process of remodelling of cortical bone a significant quantity of bone tissue was incompletely restored and there were, presumably as a result, intermittently large or small negative calcium balances. Osteoporosis may have been the cause, rather than the result, of the negative calcium balance. 6. The experimental and clinical literature of the past ten years, and studies on patients described in this critical review, were interpreted to indicate that prolonged calcium deficiency, castration, hyperadrenal corticoidism or a sedentary life may precipitate, accentuate and accelerate osteoporosis in individuals who are genetically predisposed to develop it. Sometimes high calcium intake or sex hormones, or both, may have slowed the rate of resorption but did not replace the deficit in cortical bone. 7. Further research is necessary to find the chief etiological factor and to produce the cure for this increasingly common disorder of the skeleton.

MOVEMENT OF CALCIUM IN BOTH DIRECTIONS ACROSS THE PRIMATE PLACENTA.

Summary Transfer of Ca from mother to fetus concurrent with transfer from fetus to mother was studied in 3 pregnant rhesus monkeys. Ca45 was injected into a fetal inter-placental vessel simultaneously with intravenous injection of Ca47 into the anesthetized mother. Samples of maternal blood (MB), fetal blood (FB), and amniotic fluid (AF) were assayed for Ca45, Ca47 and non-radioactive Ca. Initial loss of Ca47 from MB was matched by rapid initial appearance in FB (t 1/2 ≤ 6 min) and somewhat slower entry into AF. Similarly, Ca45 appeared in MB at a rate almost equal to the initial rate of loss from FB. The quantity of Ca crossing the placenta daily was at least 6–10 times that required for fetal skeletal growth.

Methods for compact cyclotron production of indium-111 for medical use.

Abstract The Medical use of indium-111 for diagnostic scintigraphic visualization of bone marrow, spinal fluid and cerebral cisternae, and certain tumors is growing rapidly. Its physical properties are favorable for these purposes; a physical half-life of 2·83 days, decay by electron capture to stable 111Cd, with the emission of gamma rays of 0·171 and 0·245 MeV, which are accompanied by total internal conversions of about 10% and 6% respectively. Two general methods for its preparation in the carrier-free state have been reported—the bombardment of silver with doubly ionized helium-4,(1–3) or of cadmium with protons.(4–7) Experimental values for the cross sections for these reactions as a function of energy of the bombarding particle have been published for silver (8) and for cadmium targets. (9) Two additional direct routes are; helium-3 bombardment of silver, and deuteron bombardment of cadmium. We have made a comparative study of all four of these routes to 111In to determine the one best suited for compact, multiparticle, moderate energy cyclotrons, currently operating in a number of medical centers. To meet the demands for 111In for clinical investigations most economically, it was desirable to minimize initial cost of targets and to avoid tedious chemical recovery of isotopically enriched target material after bombardment. Therefore, only commercially available, natural silver and cadmium foils with a purity of at least 99·95% were employed.

The varying tissue distribution of L-glutamic acid labelled at three different sites☆

Methods using 5 and 6 enzymes were devised to synthesize L-[11C]glutamic acid (GA), labeled on the carboxyl group of either the alpha-(AGA) or gamma-(GGA) carbon atom. The distribution of the 11C-labeled AGA or GGA in rabbits was compared with that of L-[13N]glutamic acid. The results show that AGA was rapidly decarboxylated with loss of the 11C-label, and that GGA was also decarboxylated, but to a lesser degree. Thus, the radiolabel distribution may not reflect the distribution of the original compound. The results also demonstrate that positron labeled pharamaceuticals may be rapidly synthesized via complex enzymatic pathways.

Enzymatic synthesis of 11C-pyruvic acid and 11C-L-lactic acid

Abstract L -Lactic acid is formed as the end product of glycolysis under anaerobic conditions in all cells, but this reaction is of special significance in the myocardium. L -Lactic acid is reversibly formed from and is in equilibrium with myocardial pyruvic acid, which is its sole metabolic pathway. 11C-Pyruvic acid is synthesized from 11C carbon dioxide using pyruvate-ferredoxin oxidoreductase and coenzymes. The 11C-pyruvic acid is then converted to 11C- L -lactic acid by lactic acid dehydrogenase. The availability of 11C-pyruvic acid and 11C- L -lactic acid will permit the in vivo investigation of lactate metabolism.

Evaluation of left ventricular function (ejection fraction and segmental wall motion) by single pass radioisotope angiography

Changes in ejection fraction (EF) and segmental wall motion (SWM) have been shown to be sensitive indicators of left ventricular (LV) function. This information is only obtainable by contrast angiography or gated blood pool scans. Gated studies assume a fixed geometry for the LV for EF determinations, are lengthy and limited primarily to the LAO projection. We correlated contrast and Tc-99m pertechnetate angiograms by singl pass radioisotope angiography (immediately preceding the contrast study) in 12 patients. EF was calculated from the LV time/activity curve and values ranged from .21 to .72. Angiographic correlation yielded r = 0.97. Regional LV wall motion was evaluated by dividing a summated cardiac cycle into 16 frames and dynamically and sequentially displaying these frames. Regional wall motion evaluation of four LV quadrants correlated well with angiography (r = 0.97). For quantitation these images were divided into four anterior and four inferior segments and the areas of respective segments were compared and expressed as a shortening fraction. SWM compared favorably with angiographic determinations (r ranged from 0.70 to 0.99). Thus, single pass radioisotopic determinations of EF and SWM in the RAO projection correlated well with the angiographic values and provide essential quantitative information of LV function otherwise unobtainable at the bedside.