Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors

In this study quantitation of the degree of deficiency of the blood-brain barrier (BBB) in patients with multiple sclerosis or brain tumors, by using MRI, is shown to be possible. As a measure of permeability of the BBB to Gadolinium-DTPA (Gd-DTPA) the flux per unit of distribution volume per unit of brain mass was used. This quantity was found by introducing the longitudinal relaxation rate (R1) as a measure of concentration of Gd-DTPA in the brain tissue in the mathematical model for the transcapillary transport over the BBB. High accordance between the observed data points and the model was found, and the results were comparable to results obtained from similar studies using positron emission tomography. The improved possibility of quantitating the defect of the BBB by MRI may give new information about pathogenesis or etiology, and leads to improved methods in monitoring the efficacy of treatments in intracranial diseases.     

Differentiation of cerebral radiation necrosis from tumor recurrence by [18F]FDG and 82Rb positron emission tomography

Nine radiation-treated brain tumor patients were studied by positron emission tomography (PET) in an attempt to differentiate tumor recurrence from radiation necrosis. Rubidium-82 was used to define the region of absent or disturbed blood-brain barrier and [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) was used to evaluate the metabolic state of the brain. By comparing glucose utilization in the pathologic region with utilization in the adjacent tissue, a diagnosis of recurrent tumor (increased [18F]FDG accumulation) or necrosis (decreased FDG accumulation) was made. In the seven patients who underwent surgery the PET diagnosis was confirmed by histologic examination of resected tissue. The two patients who did not undergo surgery have had a clinical course consistent with the PET diagnosis of necrosis. Dynamic 82Rb imaging showed that the rate of 82Rb accumulation was greater in tumor than in normal brain. However, this finding alone did not differentiate tumor from necrosis, as some necrotic tissue also showed high rates of 82Rb accumulation, and washout kinetics were similarly nonspecific. The differentiation of radiation necrosis from tumor recurrence is reliably achieved by [18F]FDG PET examination and is aided by information obtained from a 82Rb PET study done immediately prior to the [18F]FDG injection.     

Comparison of 68Ga-EDTA, [1-11 C]alpha-aminoisobutyric acid, and [99mTc]sodium pertechnetate in an experimental blood-brain barrier lesion

Unilateral opening of the blood-brain barrier (BBB) in rats, induced by infusion of a hyperosmotic solution of mannitol into the left internal carotid artery, was applied to compare 68Ga-EDTA, [1-11C]alpha-aminoisobutyric acid (using the long-lived 14C-labeled analog), and [9mTc]sodium pertechnetate as agents for diagnosis of BBB disruption. Of the three agents and two time intervals studied, 68Ga-EDTA at 30 min postinjection gave the highest target-to-nontarget ratio. In addition, 68Ga-EDTA, unlike commonly used [99mTc]sodium pertechnetate, can be used in conjunction with positron emission tomography, which could make possible earlier and better assessment of BBB defects using 68Ga-EDTA.     

Simplified, noninvasive PET measurement of blood-brain barrier permeability

Blood-brain barrier (BBB) permeability to [68Ga]EDTA was measured by positron emission tomography (PET) in four normal volunteers and in 11 patients with brain tumors. A unidirectional transfer constant, Ki, was calculated applying multiple-time graphical analysis (MTGA). This method allows the detection of backflux from brain to blood and, by generalization, the measurement of the constant Kb (brain to blood). Furthermore, the need for an independent measurement of the intravascular tracer is obviated: MTGA itself provides an estimate of the cerebral plasma volume (Vp). In the four normal volunteers the Ki was 3.0 +/- 0.8 X 10(-4) ml g-1 min-1 (mean +/- SD) and the Vp 0.034 +/- 0.007 ml g-1. A net increase in Ki up to a maximum of 121.0 X 10(-4) ml g-1 min-1 (correspondent value of Kb = 0.025 min-1) as well as an increase of Vp was observed in malignant tumors. The input function was calculated using both the [68Ga]EDTA concentration in sequential arterial blood samples and, noninvasively, the activity derived from the superior sagittal sinus image. The values of Ki and Vp from these two calculations were in good agreement. The application of MTGA to PET permits the evaluation of passage of substances across the BBB without making assumptions about the compartments in which the tracer distributes.     

SPECT studies of brain tumors with L-3-[123I] iodo-alpha-methyl tyrosine: comparison with PET, 124IMT and first clinical results

L-3-[123I]iodo-alpha-methyltyrosine (123IMT) like tyrosine has been reported previously to have a high affinity for a transport system in the blood-brain-barrier (BBB). We examined the kinetic behavior of 124IMT in brain and plasma in two patients with glioblastoma using dynamic positron emission tomography (PET). 124IMT accumulated in brain and tumor tissue, reaching a maximum after 15 min, with a washout of 20% to 35% at 60 min postinjection. Animal experiments confirmed the accumulation of the intact tracer in murine brain, but there was no incorporation into proteins. SPECT studies with 123IMT in patients with different types of brain tumors showed increased uptake in 26 of 32 tumors. Although nonspecific uptake in tumors must be considered, the accumulation of IMT in normal brain and in some tumors with intact BBB suggests a specific uptake of IMT. As transport is the main determinant of initial amino acid uptake, 123IMT appears to be a suitable SPECT tracer of amino acid uptake although it is not incorporated into protein.     

A prospective comparison of rubidium-82 PET and thallium-201 SPECT myocardial perfusion imaging utilizing a single dipyridamole stress in the diagnosis of coronary artery disease

The purpose of the present study is to prospectively compare myocardial perfusion imaging with rubidium-82 (82Rb) by positron emission tomography (PET) with thallium-201 (201Tl) imaging by single-photon emission tomography (SPECT) by recording both studies with a single dipyridamole handgrip stress, and reading both sets of images with the same display technique. In a series of 202 patients with previous coronary arteriography, the sensitivity, specificity, and accuracy of 82Rb PET were 93%, 78%, and 90% and for 201Tl SPECT 76%, 80%, and 77%, respectively. When 70 patients with previous therapeutic interventions were excluded, the remaining 132 patients showed a sensitivity, specificity, and accuracy of 95%, 82% and 92% for 82Rb PET and 79%, 76%, and 78% for 201Tl SPECT. The improved contrast resolution of PET resulted in markedly superior images and a more confident identification of defects.     

Measurement of cardiac output with first-pass determination during rubidium-82 PET myocardial perfusion imaging

In addition to providing useful clinical information, cardiac output determined during rubidium-82 positron emission tomography (PET) myocardial perfusion studies can be used in the measurement of absolute regional myocardial blood flow using Sapirstein's method. This investigation was conducted to compare cardiac output values obtained by post-processing data acquired in a list mode PET myocardial perfusion study with those obtained using a technetium-99m-labeled red blood cell method on the same patients. Results from 14 patients showed that cardiac output can be accurately measured simultaneously in a⁸²Rb PET myocardial study, allowing determination of multiple perfusion and functional parameters of the heart, thus improving the cost-effectiveness of the⁸²Rb PET study.     

犬颅脑枪弹伤后血脑屏障的改变及意义

目的　探讨犬脑枪弹伤后血脑屏障 (BBB)通透性改变及意义。方法　杂种犬 12只 ,随机分成正常对照、脑贯通伤 (PCI)15min、1h、6h组 (n=3) ,采用德国小口径步枪 (子弹型号 5 5 6mm ,弹头质量 2 5 7g)按上述分组要求致伤。硝酸镧心内灌注法固定犬脑 ,透射电镜下观察BBB改变。结果　犬脑枪弹伤后 15min、1h组均出现BBB改变 ,紧密连接开放 ,血管基膜外以至组织间隙内存在硝酸镧颗粒 ,后者更明显 ;至 6h组BBB改变愈加严重 ,可见大量硝酸镧颗粒经BBB进入组织间隙 ,与 15min、1h组比较差异有统计学意义 (P <0 0 5 )。结论　BBB的开放是造成颅脑火器伤后早期脑水肿的原因之一。     

The use of 123I-iodoamphetamine and single-photon emission computed tomography to assess local cerebral blood flow

N-Isopropyl 123I P-iodoamphetamine (IMP) is a radiopharmaceutical that is lipid-soluble, penetrates the normal blood-brain barrier, and has a high first-pass extraction efficiency in brain. Initial IMP distribution is proportional to local cerebral blood flow and is stable for at least 1 hr after administration. When combined with single-photon emission computed tomography (SPECT), regional activity can be quantified. Eighty-three studies were performed to aid in understanding the clinical utility of this radiotracer. In control subjects, brain activity followed expected regional perfusion patterns. Physiologic maneuvers produced altered perfusion patterns corresponding to those demonstrated by positron tomography. Perfusion abnormalities in stroke patients were visualized earlier than structural changes detected by transmission computed tomography (CT), and the area of altered IMP activity generally exceeded that suggested by standard CT examination. Seizure foci were identified by local abnormalities of cerebral blood flow. Primary brain tumors failed to demonstrate IMP activity even when shown by angiography to be highly vascular.     

Essentials of a rubidium-82 generator for nuclear medicine

The use of generator-produced ⁸²Rb for positron emission tomography studies in clinical nuclear medicine requires a number of factors to be considered. These include ⁸²Sr availability, methods of recharging the generator with fresh ⁸²Sr, adequate elution yield of ⁸²Rb, low breakthrough of ^82–85Sr, simple and reliable operation of the generator, and delivery of a sterile and pyrogen free eluate of ⁸²Rb.     

Dynamic study of supratentorial gliomas with L-methyl-11C-methionine and positron emission tomography

The regional kinetics of intravenously injected L-methyl-11C-methionine (11C-L-methionine) in the brain was investigated by positron emission tomography (PET) in 14 patients with gliomas. In both tumor and unaffected brain the tracer uptake reached a nearly constant level in 5 min or less. The ratio between the uptake of 11C-L-methionine by high-grade tumors and the uptake by unaffected brain was 1.9-4.8. In two cases of low-grade astrocytoma the ratio was 0.8-1.0. High uptakes of 11C-L-methionine occurred in gliomas even in the absence of blood-brain barrier defects as observed by other methods. This indicates that besides active transport of amino acid, a larger extracellular space in tumor as compared with unaffected brain tissue may also contribute to the increased uptake of 11C-L-methionine--derived radioactivity. In some patients delineation of the tumors was improved by use of PET with 11C-L-methionine as compared with computed tomography, angiography, and, in some instances, PET with 68Ga-EDTA. PET with 11C-L-methionine permits better evaluation of the tumor extent and may affect preoperative grading.     

Single-photon emission computed tomography in the evaluation of brain tumors and the diagnosis of relapse vs radiation necrosis

Morphologic characterization of brain tumors by magnetic resonance imaging and computed tomography is well established. However, functional metabolic imaging by single-photon emission tomography (SPET) and positron emission tomography are also increasingly important imaging tools for noninvasive assessment of brain tumors. Brain SPET is useful in the differentiation of tumor recurrence from radiation necrosis, in the non-invasive assessment of gliomas and meningiomas aggressiveness, in differentiating neoplastic from non neoplastic intracerebral haemorrhage, in monitoring therapy response and in the evaluation of other types of brain tumors. Our own experience is presented supporting the above.     

亚低温对颅脑损伤后脑血管内皮细胞紧密连接开放的影响

目的　观察颅脑损伤后早期亚低温治疗对脑毛细血管内皮细胞紧密连接开放的影响 ,阐明亚低温降低伤后血脑屏障通透性的可能机制。　方法　Wistar大鼠 90只 ,随机分为常温对照组 (10只 )、常温损伤组 (40只 )和亚低温治疗组 (40只 )。在镧示踪法电镜下分别观察亚低温及常温条件下颅脑损伤后内皮细胞紧密连接的开放及其程度 ;用干 -湿重法测定常温损伤组及亚低温治疗组伤后不同时相脑组织含水量并行统计学分析。　结果　常温损伤组伤后 3h紧密连接初步开放 ,2 4～ 4 8h紧密连接开放达高峰 ,72h紧密连接仍大量开放。亚低温治疗组紧密连接仅轻度开放 ;亚低温治疗组脑组织含水量较常温损伤组明显减少 ,伤后 3,2 4 ,72h差异有显著性意义(P <0 .0 5 ) ,伤后 4 8h差异有非常显著性意义 (P <0 .0 1)。　结论　亚低温有减轻颅脑损伤后血脑屏障毛细血管内皮细胞紧密连接的开放程度及减轻脑水肿的作用 ,亚低温减轻伤后内皮细胞紧密连接开放是降低伤后血脑屏障通透性机制之一。     

Evaluation of primary brain tumors with FLT-PET: usefulness and limitations

PURPOSE OF THE REPORT: The purpose of this report was to investigate the potential of positron emission tomography using F-18 fluorodeoxythymidine (FLT-PET) in evaluating primary brain tumors. MATERIALS AND METHODS: FLT-PET was performed in 25 patients with primary brain tumors. FLT uptake in the lesion was semiquantitatively evaluated by measuring the maximal standardized uptake value (SUVmax) and the tumor-to-normal tissue ratio (TNR). SUVmax and TNR were compared with the histologic grade and the expression of the proliferation marker (Ki-67). RESULTS: FLT uptake in normal brain parenchyma was very low, resulting in the visualization of brain tumors with high contrast. Both SUVmax and TNR significantly correlated with the malignant grade of brain gliomas, in which high SUVmax/TNR was obtained for high-grade gliomas. Patients with primary lymphoma also showed SUVmax/TNR equivalent to glioblastoma. There was a positive correlation between SUVmax/TNR and the Ki-67 index. In contrast, spuriously high SUVmax and TNR were obtained in 3 of 6 patients with suspected recurrent tumors (2 patients with recurrent grade 2 glioma and one patient with postoperative granuloma), all of which showed lesion enhancement on MRI after Gd administration. CONCLUSIONS: FLT-PET can be used to evaluate the malignant grade and proliferation activity of primary brain tumors, especially malignant brain tumors. However, the presence of benign lesions showing blood-brain barrier disruption cannot be distinguished from malignant tumors and needs to be carefully evaluated.     

Rubidium-82 myocardial uptake and extraction after transient ischemia: PET characteristics

The effects of transient regional ischemia on monovalent cation uptake and extraction by the myocardium were studied in seven open chest dogs. Following a 10-20% stenosis of the left anterior descending coronary artery to prevent reactive hyperemia, the regional myocardial uptake of the monovalent cation 82Rb (ml/min/g X extraction) was measured before, during, and at 10, 30, and 60-80 min after a 10 min total occlusion of the left anterior descending coronary artery using positron emission tomography. Regional myocardial blood flow was also measured at the same time interval using radiolabeled carbonized microspheres. The regional myocardial extraction of 82Rb was calculated as uptake/flow. In normally perfused myocardial regions there was an inverse relationship between 82Rb extraction and blood flow [extraction = -0.56 (In flow) + 0.46, r = 0.93] over a range of flow from 0.3 to 4 ml/min/g. During the prolonged recovery of 82Rb uptake in the transiently ischemic region, flow had returned to normal levels but 82Rb extraction at a given value of flow was significantly decreased at the 30 and 60-80 min times after release of the occlusion compared with normally perfused regions. Thus, prolonged abnormalities in the 82Rb uptake and extraction occur in myocardium recovering from transient ischemia.     

急性冷暴露对大鼠血脑屏障通透性的影响及木樨草素的保护作用

目的:对大鼠进行急性冷暴露,探讨冷暴露对大鼠血脑屏障(BBB)通透性的影响及木樨草素对大脑保护的可能性。方法:建立大鼠冷暴露模型,用比色法测定脑组织中伊文思兰(EB)含量关系及干-湿重法检测脑组织含水量变化,反映大鼠BBB通透性的影响。结果:冷暴露后大鼠脑组织水分含量和伊文思兰明显增高,BBB通透性明显增加,添加木樨草素的防护组则通透性受到不同程度的改变。结论:脑组织在冷暴露下BBB通透性增高,木樨草素有一定的保护作用。     

Myocardial metabolism of fluorodeoxyglucose compared to cell membrane integrity for the potassium analogue rubidium-82 for assessing infarct size in man by PET

Potassium loss from damaged myocardial cells is linearly related to CPK enzyme loss reflecting extent of necrosis. The potassium analog, rubidium-82 (82Rb), is extracted after i.v. injection and retained in viable myocardium but is not trapped or washed out of necrotic regions. To compare myocardial cell metabolism with membrane dysfunction as indicators of necrosis/viability, 43 patients with evolving myocardial infarction and coronary arteriography had positron emission tomography using fluorodeoxyglucose (FDG) and the potassium analog 82Rb. Percent of heart showing FDG defects and 82Rb washout on sequential images indicating failure to retain the potassium analogue were visually assessed and quantified by automated software. Infarct size based on rubidium kinetics correlated closely with size and location on FDG images (visual r = 0.93, automated r = 0.82), suggesting that loss of cell membrane integrity for trapping the potassium analog 82Rb parallels loss of intracellular glucose metabolism, both comparable quantitative markers of myocardial necrosis/viability.     

Iodine-122-labeled amphetamine derivative with potential for PET brain blood-flow studies

The positron emitter 122I (t1/2 3.6 min) was collected from a xenon-122/iodine-122 (122Xe/122I) generator and incorporated into an amphetamine analog, 2,4-dimethoxy-N,N-dimethyl-5-[122I]iodophenylisopropylamine (5-[122I]-2,4-DNNA). The remote synthesis was achieved in 3 min with a 50% radioincorporation yield and a product radiopurity of greater than 98%. 5-[122I]-2,4-DNNA was injected into a beagle dog and a brain section imaged with positron emission tomography (PET). The uptake and retention of 5-[122I]-2,4-DNNA was compared to that of 82Rb+ in the same animal. Dynamic PET activity data were obtained 0-20 min postinjection of 5-[122I]-2,4-DNNA and showed rapid uptake by brain and good cerebral/extracerebral tissue distinction. A whole-body scan of a dog was also obtained with 5-123I-2,4-DNNA showing uptake in brain, lung, and other body organs. The feasibility of incorporating 122I into an extracted brain perfusion agent for use with PET is demonstrated.     

Contrast material for CT of the liver and spleen--an experimental study on the safety of lipiodol-iopamidol emulsion

Iodinated oil (Lipiodol Ultra-Fluid) emulsified by non-ionic contrast material (Iopamidol) featuring much iodine and surface activity, was developed for computed tomography (CT) of the liver and spleen. The stability study revealed that Lipiodol-Iopamidol Emulsion (LIE, 1-6 microns in diameter) stored 2 weeks under refrigeration showed no visible change in globule size distribution. The biodistribution study in six rabbits revealed that LIE injected into the vein was accumulated in the liver, spleen, and lung, which have reticuloendothelial cells, however not accumulated in the brain, kidney, and serum, which have no reticuloendothelial cells. The disruption to the blood brain barrier (BBB) was assessed using Evans' Blue dye as a visual marker. After the coarse emulsion (larger than 8 microns in diameter) was injected into the internal carotid artery of three rats, the permeability of BBB increased. However, after the injection of LIE, no increased permeability of BBB was noted. Our results suggest that LIE will have a clinical application in the detection of focal hepatic and splenic lesions.     

Quantitative micro-SPECT/CT for detecting focused ultrasound-induced blood–brain barrier opening in the rat

IntroductionFocused ultrasound has been discovered to be able to locally and reversibly increase the permeability of the blood–brain barrier (BBB). The purpose of this study was to investigate the feasibility of micro-single photon emission computed tomography/ computed tomography (micro-SPECT/CT) and 99mTc diethylenetriamine pentaacetate (99mTc-DTPA) for identifying disruption of the BBB induced by focused ultrasound in a rat model. We also assessed the amount of radiotracer that had crossed the BBB using various intensity levels of ultrasound energy.MethodsImmediately after sonication, three Sprague–Dawley rats were scanned for 2 h to determine the optimum time for data acquisition. Static SPECT with 1.5-h acquisition time was then performed in 12 rats sonicated with focused ultrasound pressure amplitudes of 0.78–2.45 MPa. Radiotracer and blue dye were used for lesion delineation. SPECT images were evaluated quantitatively and compared to results of histology and autoradiography. Terminal deoxynucleotidyl transferase biotin-desoxyuridine 5'-triphosphate (dUTP) nick end labeling staining was used to examine hemorrhage and tissue damage.ResultsThe disruption to nondisruption radioactivity ratio showed a gradual increase from dynamic SPECT images, reaching a peak at 1.5 h post injection. The extent and intensity of radioactivity showed a good correlation with autoradiographic distribution and blue dye staining. SPECT measures correlated significantly with quantitative autoradiographic results (r²=0.90). According to SPECT findings, high acoustic powers allowed the delivery of larger amounts of radiotracer [0.001±0.002%ID (percent injected dose) under 0.78 MPa vs. 0.036±0.022%ID under 2.45 MPa]. Brain hemorrhage and tissue damage occurred at pressure amplitudes higher than 1.9 MPa.ConclusionsOur data demonstrate the usefulness of ^99mTc-DTPA micro-SPECT/CT for detecting focused ultrasound-induced BBB disruption in the rat. This method may be used in vivo in combination with quantitative analysis for evaluating the amount of BBB opening.