Biomedical subjects
Publications and source records attributed to J R Ballinger.
The combination of diamagnetic barium sulfate and superparamagnetic iron oxide (SPIO) in one suspension produces a macroscopic cancellation of positive and negative magnetic susceptibility components that can potentially eliminate susceptibility artifacts even with gradient echo pulse sequences. The relaxation properties that make the SPIO suspension a useful negative contrast agent are retained.
The purposes of this study are to evaluate the utility of kit formulation, the basic in vivo characteristics, and clinical usefulness of dopamine D2 receptor imaging with 123I-(S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrodinyl)m ethyl]- benzamide (123I-IBZM). We studied 22 normal controls, 3 early symptomatic Huntington's disease patients, and 1 patient with visual hallucination on and off neuroleptics. 123I-IBZM could be conveniently prepared with a high degree of purity from a kit, but with relatively low radiochemical yield. We demonstrated 123I-IBZM receptor binding equilibrium by performing serial SPECT scanning in a normal volunteer. The basal ganglia/frontal cortex (BG/FC) ratios plateaued after the specific binding reached equilibrium approximately 60 minutes after injection. The BG/FC ratio declined significantly with age. The ratios for the Huntington's disease patients were significantly lower than those for normal controls. The images of the patient off neuroleptic therapy showed dramatically increased BG activity compared with those obtained while on therapy. The BG/FC ratio provides an estimate of Bmax/Kd and hence the receptor density. It appears important to perform SPECT early in the equilibrium phase and at a fixed time after injection to obtain significantly high signal to noise ratios. 123I-IBZM is an ideal tracer for SPECT including a rotating gamma camera type which can provide estimates of the receptor density objectively by calculating the BG/FC ratio, and is a promising agent for the investigation of dopamine D2 receptors in clinical conditions.
The individual components of two commercially available barium sulfate (BaSO4) suspensions, Liquid HD and E-Z-paque (E-Z-EM Inc., Westbury, NY), were investigated to determine their contribution to relaxation. Longitudinal and transverse relaxation times of suspensions and solutions of the different BaSO4 particles and the vehicle used to keep them in suspension were measured separately at 2.0 T. A multiple echo Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence was used for T2 determinations with different values of the echo spacing 2 tau. Longer values of 2 tau resulted in significant shortening of the calculated T2 relaxation times, indicating that the major mechanism leading to signal loss in BaSO4 suspensions is the diffusion of water molecules through susceptibility gradients in the vicinity of suspended particles. At higher BaSO4 concentrations, decreased water proton density also produces significant signal loss. Viscosity has little effect on the relaxation. A combination of larger and smaller BaSO4 particle sizes was found to be more effective than smaller sizes only in enhancing signal decay.
Huntington's disease (HD) is pathologically characterized by neuronal loss and neuroreceptor alterations in the striatum, including a reduction in dopamine receptor density. We evaluated the clinical usefulness of 123I-iodobenzamide (IBZM) D2 receptor SPECT imaging and 99mTc-hexamethylpropyleneamineoxime (HMPAO) brain perfusion SPECT imaging by studying four early symptomatic HD patients, 20 asymptomatic subjects at risk for HD and 22 controls. Striatal D2 receptor binding and perfusion were measured semiquantitatively by calculating striatum-to-frontal cortex IBZM and HMPAO uptake ratios, respectively. The control IBZM ratio (1.58 +/- 0.06) declined with age at 1.5% per decade (r = -0.58, p < 0.005), whereas the HMPAO ratio (1.15 +/- 0.05) did not. All four symptomatic patients had decreased IBZM ratios and three patients also had decreased HMPAO ratios. Five of 20 at-risk subjects had decreased IBZM ratios and two subjects also had decreased HMPAO ratios. Three of the five at-risk subjects showed subtle nonchoreic neurological abnormalities. Decreased striatal D2 receptor binding thus may be detected by IBZM-SPECT in the asymptomatic as well as symptomatic groups, and these changes were more marked than perfusion deficits detected by HMPAO-SPECT. IBZM-SPECT thus appears to be a promising method for early diagnosis and preclinical detection of HD.
The accumulation of 99mTc-glucarate, an agent recently reported to localize in acutely infarcted myocardium, zones of acute cerebral injury and tumors, has been compared with 99mTc-gluconate in an in vitro system of cultured Chinese hamster ovary fibroblasts. The effects on accumulation of hypoxia and competition with fructose have been studied. Both labeled glucose analogs showed a two- to threefold enhanced accumulation in hypoxic cells relative to aerobic cells. No such enhanced accumulation under hypoxia was observed for the nonsugar tracers pertechnetate and 99mTc-DTPA. The presence of 20 mM fructose reduced the accumulation of 99mTc-glucarate by 30% (p = 0.067) and 99mTc-gluconate by 40% (p < 0.05) in hypoxic cells, but had no significant effect in aerobic cells. These results suggest that both compounds at least partially share a common mechanism of uptake and/or accumulation with fructose.
Static imaging of lung ventilation in multiple views or with SPECT requires a 99mTc aerosol which does not wash out during imaging. Commercially available 99mTc colloids have suitable physical properties but are inefficiently delivered from jet nebulizers. An in vitro system was used to compare the delivery of various 99mTc radiopharmaceuticals from nebulizer solutions. Delivery of noncolloidal agents (pertechnetate, pentetate, imidodiphosphate, albumin) was much greater than that of colloids. However, addition of phosphate buffer to an in-house 99mTc-tin colloid produced an agent that was delivered as efficiently as the noncolloidal tracers and which shows promise for clinical use.
In this in vitro study of a potential oral MRI contrast agent, barium sulfate suspension (BSS), the object was to examine the effect of varying barium sulfate concentration on signal intensity while keeping suspension additives the same; and to optimize the concentration of a specific preparation of BSS. A phantom was used to test suspensions with concentrations of barium sulfate ranging from 90% to 220% w/v. T1-weighted, T2-weighted, and gradient echo sequences all showed a decrease in signal as concentration was increased to 170%. Between 170% and 220%, the signal intensity was constant on the T1-weighted and T2-weighted sequences. With the proton density and gradient echo sequences, there was a slower rate of decline in the signal intensity in the 170 to 220% range of BSS concentrations. We conclude that BSS with a concentration in the range of 170% to 220% w/v is optimum for the specific preparation used. We speculate that the behavior of the signal-to-noise ratio with changing concentration is explained by factors including proton density, T1 relaxation enhancement, diffusion effects, and magnetic field inhomogeneity, depending on the particular pulse sequence used.
Monoclonal antibodies can be labelled with technetium-99m by prereduction of the antibody with 2-mercaptoethanol, then reduction of pertechnetate with an aliquot of a stannous kit, resulting in greater than 97% labelling without the need for further purification. The present work shows that equally high labelling can be obtained with a variety of weak ligands and that the optimum quantity of stannous chloride is 2-4 micrograms. Although the label was stable to challenge with excess DTPA, cysteine was able to remove a portion of the label. We have also shown that this technique works with the IgG2a isotype in addition to the previously reported IgG1 isotype. This approach is simple, convenient and reproducible, and warrants further clinical evaluation.
Red blood cells were labelled with 67Ga oxine prepared from 67Ga citrate, a routinely available and relatively inexpensive radiopharmaceutical which is suitable for dual-isotope imaging with 99mTc. Labelling efficiency was 88 +/- 1%, 24-h in vitro stability was 93 +/- 5% in saline at room temperature and 68 +/- 4% in whole blood at 37 degrees C, and the method could be performed within 20-30 min.
The diagnosis and localization of inflammation and infection by nuclear medicine techniques continue to improve. The past year has seen a number of innovations and improvements in both commonly used radiopharmaceuticals and those still in the research phase. A good, in-depth knowledge of the many pathophysiologic changes that can occur at various sites and with different etiologies remains important in understanding and choosing which tests are most likely to provide useful clinical information. A number of important publications over the past year are reviewed.
Leukocytes can be labelled with 99mTc using HMPAO and gentisic acid methods. We compared the two methods with respect to labelling efficiency on mixed leukocytes and isolated polymorphonuclear (PMN) and mononuclear (MN) cells, and the in vitro stability of the label. HMPAO produced approximately 70% labelling efficiency on mixed or PMN cells and the label was stable in saline or plasma. Labelling efficiency on MN was only 14% and was less stable. Gentisic acid produced a labelling efficiency of 52% on PMN and 35% on MN; both were stable in saline but less stable in plasma. In conclusion, HMPAO produces higher labelling efficiency and the label shows greater in vitro stability in plasma. However, gentisic acid is much less expensive to use, allows labelling of MN cells, and should result in more favourable microdosimetry. Preliminary clinical results suggest that gentisic acid is equivalent to HMPAO but has the advantage of being much cheaper.
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Standard labelling methods using 111In-tropolonate in plasma resulted in lower labelling efficiency (LE) with pig granulocytes than with human cells. Addition of acid-citrate-dextrose (ACD) to cell-free plasma in a ratio of 1:10 tripled the LE to a value which was not significantly different from that obtained in saline. Under optimized conditions, LE was 67 +/- 2% (mean +/- SE) with pig granulocytes, which remained lower than that obtained with human cells but was adequate for nuclear imaging studies of granulocyte deposition in the pig.
A pretinning method for labelling erythrocytes with technetium-99m (99mTc) in vitro has been developed using a kit which contains stannous chloride stabilized with gentisic acid. Labelling efficiency was 97.3% (SD 1.4%) for 80 patients. The method requires less time than the Brookhaven kit and results in a smaller volume for reinjection but provides equivalent clinical results. We have previously shown that leukocytes labelled with 99mTc using the same gentisic acid kit are clinically equivalent to those labelled with HMPAO; thus, the kit is versatile and cost-effective.
Thirteen patients with cerebral trauma were studied for cerebral perfusion by the use of Tc-99m HMPAO scanning. CT imaging was performed on nine patients. Because of their clinical condition, four patients were scanned only in the planar mode to help establish the diagnosis of brain death. Other indications for study included gunshot wound and blunt or sharp object trauma with or without skull fracture. In all cases, HMPAO scans showed defects with a quality equivalent to or greater than that demonstrated by CT. Our initial results suggest that HMPAO may predict the degree of permanent damage and which patients may develop post-traumatic headache. A diagnosis of brain death can be established without the withdrawal of medical therapy.
Variability in the quality of [99mTc]HM-PAO images of the brain has been attributed to differences between kits and the addition of excessive amounts of pertechnetate to the kits. A retrospective study showed no significant differences between batches of kits with respect to radiochemical purity (RCP) or image quality. Up to 3000 MBq (81 mCi) pertechnetate could be added to the kit without adversely affecting RCP or image quality. It was shown that image quality was directly affected by RCP at time of injection and dropped sharply when RCP fell below 85%. Interstitial injection and mixing with blood prior to injection also resulted in poor image quality. Pretreatment with perchlorate reduced uptake of activity in the parotid glands; this improved image quality and reduced the influence of RCP.
Spiperone dithiocarbamate (SPDC) was prepared by reacting spiperone with carbon disulfide followed by sodium hydroxide. SPDC was labelled with 99mTc by reduction of pertechnetate with formamidine sulfinic acid or sodium dithionite at alkaline pH, resulting in approximately 40% incorporation of 99mTc. The lipophilic complex was conveniently isolated at high specific activity and high radiochemical purity by extraction into dichloromethane, which was then evaporated and the residue was redissolved in a 1:3 mixture of ethanol and saline containing 0.1 mg/mL gentisic acid. Biodistribution studies following i.p. injection in rats showed low uptake of radioactivity in the brain, but striatum/cortex and striatum/cerebellum ratios were reduced by pretreatment with haloperidol. This agent may allow imaging of dopamine D-2 receptors using single-photon emission computed tomography (SPECT).
The manufacturer recommends that the radiochemical purity of 99mTc-MIBI be determined with alumina TLC plates developed in ethanol, but for routine use this is slow and requires care. After comparing a variety of systems, we obtained equivalent results using ITLC-SG strips developed with saline to determine [99mTc]pertechnetate and with acetone to determine 99mTc colloid; % 99mTc-MIBI was determined by difference from 100%. These separations are the opposite of those obtained with the routine polar 99mTc radiopharmaceuticals. Equivalent results were obtained even more rapidly by extracting 99mTc-MIBI from water into chloroform.