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.     

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。     

The blood-brain barrier

The blood-brain barrier (BBB) is present on three sites: the brain vessels, the choroid plexus and the arachnoid membrane. It is made of nonfenestrated endothelial or epithelial cells interconnected by tight junctions. Biochemically, the BBB is formed by bimolecular layers of phospholipids into which globular proteins are inserted. Exchanges through the BBB depend on whether the substances exchanged are soluble in water or in lipids. Hydrosoluble substances are largely excluded from the brain by the BBB; liposoluble substances pass the barrier easily by passive or active mechanisms. Water movements through the BBB are related to variations in osmolality. These data are of the utmost importance in all brain diseases with rupture of the BBB and in all neuroradiological procedures using contrast media.     

反复下体负压致意识丧失对大鼠血脑屏障通透性的影响

为阐明多次发生＋Ｇｚ致意识丧失对脑的影响及其机制，观察了反复下体负压（ＬＢＮＰ）致意识丧失对大鼠血脑屏障（ＢＢＢ）通透性的影响。雄性ＳＤ大鼠，麻醉后置于－４．０ｋＰａ的下体负压舱内，至脑电波消失２ｍｉｎ后恢复常压。分别于一次和三次ＬＢＮＰ作用后１ｈ利用硝酸镧示踪法观察ＢＢＢ通透性的变化。一次ＬＢＮＰ致意识丧失组大鼠脑皮层组织变化不明显；三次ＬＢＮＰ致意识丧失组大鼠脑皮层组织中大部分毛细血管内皮细胞     

Contrast‐enhanced in vivo magnetic resonance microscopy of the mouse brain enabled by noninvasive opening of the blood‐brain barrier with ultrasound

The use of contrast agents for neuroimaging is limited by the blood‐brain barrier (BBB), which restricts entry into the brain. To administer imaging agents to the brain of rats, intracarotid infusions of hypertonic mannitol have been used to open the BBB. However, this technically challenging approach is invasive, opens only a limited region of the BBB, and is difficult to extend to mice. In this work, the BBB was opened in mice, using unfocused ultrasound combined with an injection of microbubbles. This technique has several notable features: it (a) can be performed transcranially in mice; (b) takes only 3 min and uses only commercially available components; (c) opens the BBB throughout the brain; (d) causes no observed histologic damage or changes in behavior (with peak‐negative acoustic pressures of 0.36 MPa); and (e) allows recovery of the BBB within 4 h. Using this technique, Gadopentetate Dimeglumine (Gd‐DTPA) was administered to the mouse brain parenchyma, thereby shortening T₁ and enabling the acquisition of high‐resolution (52 × 52 × 100 micrometers³) images in 51 min in vivo. By enabling the administration of both existing anatomic contrast agents and the newer molecular/sensing contrast agents, this technique may be useful for the study of mouse models of neurologic function and pathology with MRI. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

碱性成纤维细胞生长因子对受照后大鼠血脑屏障的影响

目的评价定量检测放射性血脑屏障（BBB）破坏的不同方法，探讨碱性成纤维细胞生长因子（bFGF）对放射性BBB破坏的保护作用。方法60只急性放射性脑损伤模型大鼠（直线加速器6MeV电子束单次照射25Gy）分为单纯照射组和照射前尾静脉注射bFGF组（250ng／kg），并设未照射对照组；分别于照射后2、7和30d采用脑干-湿重法检测脑含水量，并用单次静脉注射3mg／kg伊文氏蓝（EB）后脑组织的EB含量法评估BBB破坏情况。结果照射后脑组织含水量和EB含量均较对照组明显增高，注射bFGF组脑组织含水量和EB含量均低于单纯照射组（P〈0．05）。受照后不同日期的脑组织EB含量差异有统计学意义（P〈0．05），而脑含水量差异没有统计学意义。结论注射EB后检测脑组织，浓度法较干湿重法测脑含水量能更好地反映BBB的破坏情况；bFGF对受照后BBB破坏有保护作用。     

H7在脑损伤后血脑屏障损害中的作用

目的 探讨蛋白激酶Ｃ（ＰＫＣ）抑制剂Ｈ７在脑损伤后血脑屏障损害中的作用。方法 雄性ＳＤ大鼠４８只,随机分为正常对照组、假手术组、脑损伤组织和治疗组。治疗组于大鼠脑损伤后０．５小时腹腔注射ＰＫＣ抑制Ｈ７（１ｍｇ／ｋｇ）,１２小时重复注射１次,伤后２４应用分光光度计定量检测伊文氏兰渗出。结果 脑损伤后伊文氏兰明显渗出,治疗组渗出明显减少。结论 应用ＰＫＣ抑制剂Ｈ７能明显阻止血脑屏障开放,可望在血脑屏障     

Magnetic resonance imaging enhanced by superparamagnetic iron oxide particles: Usefulness for distinguishing between focused ultrasound‐induced blood–brain barrier disruption and brain hemorrhage

Purpose

To investigate the usefulness of a fully flow‐compensated heavy T2*‐weighted imaging enhanced by superparamagnetic iron oxide (SPIO) particles for distinguishing between focused ultrasound‐induced disruption of blood–brain barrier (BBB) and brain hemorrhage.

Materials and Methods

Focused ultrasound (frequency: 1.5 MHz) was used to induce disruption of the BBB in 39 rats. Two T2*‐weighted images were obtained before and after SPIO administration. Preenhanced T2*‐weighted images were used to detect hemorrhage. Detection of BBB disruption was performed on SPIO‐enhanced images. Thirty‐four rats were sacrificed after magnetic resonance (MR) scanning for histological confirmation of brain lesions. Theremaining five animals were followed up for 35 days. Prussian blue staining was performed on histological sections to detect SPIO particles in the brain.

Results

After SPIO injection the areas of BBB disruption in rat brain were significantly enlarged. The area of mismatch between the T2*‐weighted images indicated a safe region where BBB opening occurred without hemorrhagic complications. In the longitudinal study, removal of SPIO occurred at a faster rate in hemorrhagic areas, albeit being closer to that occurring in the liver. The presence of SPIO was confirmed by Prussian blue staining in brain parenchyma and capillary endothelial cells in areas of BBB disruption.

Conclusion

T2*‐weighted images—either with and without SPIO enhancement—may differentiate focused ultrasound‐induced BBB disruption from brain hemorrhage. J. Magn. Reson. Imaging 2009;29:31–38. © 2008 Wiley‐Liss, Inc.     

急性中、重度低压缺氧对大鼠血脑屏障通透性的影响

目的 观察急性中、重度低压缺氧条件下,大鼠血脑屏障通透性的变化特点,为阐明低压缺氧作用下脑功能障碍的可能机理提供生理学依据。方法 选择雄性ＳＤ大鼠１８只,随机分为对照组、５０００ｍ及８０００ｍ急性低压缺氧暴露组。实验组动物于低压舱内,以２０ｍ／ｓ的速率上升,至５０００ｍ（或８０００ｍ）,停留５ｈ,而后以２０ｍ／ｓ的速率下降至地面,出舱后立即经心脏灌注硝酸镧固定液,开颅取脑,制成切片,置透射电镜下观     

A model of blood-brain barrier permeability to water: accounting for blood inflow and longitudinal relaxation effects.

A noninvasive technique for measuring the permeability of the blood-brain barrier (BBB) to water could help to evaluate changes in the functional integrity of the BBB that occur in different pathologies, such as multiple sclerosis or growth of brain tumor. Recently, Schwarzbauer et al. (Magn Reson Med 1997;37:769-777) proposed an MR method to measure this permeability based on the T(1) reductions induced by injecting various doses of paramagnetic contrast agent. However, this method may be difficult to implement in a clinical environment. Described here is a two-point technique, in which a spatially selective inversion is used to measure T(1) prior to and after injection of an intravascular contrast agent. Measurements made in the rat brain are compared to numerical simulations generated with a physiological model that accounts for blood flow and includes two different blood volumes: nonexchanging and exchanging blood volumes. Our results suggest that BBB permeability could be evaluated from the change in T(1) caused by the vascular contrast agent. This technique might provide an approach for monitoring changes in BBB permeability to water in clinical studies.     

Evaluation of blood-brain barrier permeability changes in rhesus monkeys and man using 82Rb and positron emission tomography

Dynamic positron tomography of the brain with 82 Rb, obtained from a portable generator [82Sr (25 days) - 82 Rb (76 sec)], provides a means of studying blood-brain barrier (BBB) permeability in physiological and clinical investigations. The BBB in rhesus monkeys was opened unilaterally be intracarotid infusion of 3 M urea. This osmotic barrier opening allowed entry into the brain of intravenously administered rubidium chloride. The BBB opening was demonstrated noninvasively using 82Rb and positron emission tomography and corroborated by the accumulation of 86Rb in tissue samples. Positron emission tomography studies can be repeated every 5 min and indicate that dynamic tomography or static imaging can be used to study BBB permeability changes induced by a wide variety of noxious stimuli. Brain tumors in human subjects are readily detected because of the usual BBB permeability disruption in and around the tumors.     

镧示踪法观察大鼠颅脑损伤后血脑屏障形态学变化

目的：颅脑损伤后血脑屏障（ｂｌｏｏｄ－ｂｒａｉｎｂａｒｒｉｅｒ，ＢＢＢ）通透性的变化，是导致外伤性脑水肿的最直接的因素．研究脑ＢＢＢ改变对探讨颅脑损伤脑水肿发生发展过程有重要意义．方法：本实验采用镧示踪法观察大鼠脑损伤后ＢＢＢ超微结构的变化，同时定量检测了伤区脑组织脑水肿发展过程．结果：研究发现伤后１０分钟组，已可见ＢＢＢ开放，伤后２４～４８小时组渗出最为严重，伤后７天组ＢＢＢ功能尚未完全恢复．颅脑损伤后伤区脑组织伊文氏蓝（ｅｖａｎｓｂｌｕｅ，ＥＢ）含量及伤区脑组织含水量的变化过程与ＢＢＢ的改变相一致．结论：对颅脑损伤后脑水肿的治疗应从早期开始，并持续１周以上．     

A physiological barrier distal to the anatomic blood-brain barrier in a model of transvascular delivery

BACKGROUND AND PURPOSE: Osmotic disruption of the blood-brain barrier (BBB) provides a method for transvascular delivery of therapeutic agents to the brain. The apparent global delivery of viral-sized iron oxide particles to the rat brain after BBB opening as seen on MR images was compared with the cellular and subcellular location and distribution of the particles. METHODS: Two dextran-coated superparamagnetic monocrystalline iron oxide nanoparticle contrast agents, MION and Feridex, were administered intraarterially in rats at 10 mg Fe/kg immediately after osmotic opening of the BBB with hyperosmolar mannitol. After 2 to 24 hours, iron distribution in the brain was evaluated first with MR imaging then by histochemical analysis and electron microscopy to assess perivascular and intracellular distribution. RESULTS: After BBB opening, MR images showed enhancement throughout the disrupted hemisphere for both Feridex and MION. Feridex histochemical staining was found in capillaries of the disrupted hemisphere. Electron microscopy showed that the Feridex particles passed the capillary endothelial cells but did not cross beyond the basement membrane. In contrast, after MION delivery, iron histochemistry was detected within cell bodies in the disrupted hemisphere, and the electron-dense MION core was detected intracellularly and extracellularly in the neuropil. CONCLUSION: MR images showing homogeneous delivery to the brain at the macroscopic level did not indicate delivery at the microscopic level. These data support the presence of a physiological barrier at the basal lamina, analogous to the podocyte in the kidney, distal to the anatomic (tight junction) BBB, which may limit the distribution of some proteins and viral particles after transvascular delivery to the brain.     

Intravascular contrast media and the blood-brain barrier. Testing the new nonionic agent ioxilan

The effects of diatrizoate, iohexol, and ioxilan on the blood-brain barrier (BBB) were investigated in normal and hypertensive rats. Anesthetized Wistar rats received 14C-inulin as an indicator for BBB disruption. Diatrizoate, iohexol, or ioxilan (350 and 175 mgI/mL) or normal saline was then injected into the carotid artery (2 mL in 30 seconds). Twenty minutes later, the cardiovascular system was flushed, the brain removed, and each hemisphere was digested. BBB disruption, expressed as counts/minute/mg protein, was compared for each hemisphere in each group by analysis of variance. BBB damage in the diatrizoate-350 group was significantly greater than that in all other groups. No significant BBB damage resulted from iohexol or ioxilan relative to normal saline.     

信号转导机制在大鼠脑损伤后血脑屏障损害中的作用

为探讨信号转导系统在脑损伤后血脑屏障损害中的作用，取雄性SD大鼠75只，随机分为正常对照组、假手术组、脑损伤组、毛喉素组和H7组，用荧光显微镜定性观察、分光光度计定量检测伊文蓝渗出。结果显示，脑损伤后伊文蓝明显渗出，毛喉素组和H7组渗出明显减少，提示毛喉素和H7能阻止血脑屏障开放，可望为血脑屏障保护提供新的治疗途径。     

Factors contributing to blood-brain barrier disruption following intracarotid injection of nonionic iodinated contrast medium for cerebral angiography: experimental study in rabbits

Purpose This study was performed to investigate the role of injection methods and conditions under a fixed dose of radiographic contrast medium (CM) in respect to promoting blood–brain barrier (BBB) disruption. Materials and methods A total of 44 white rabbits (average body weight 2.7 ± 0.4 kg) were used, and their carotid injection was performed with nonionic CM. The variables assessed for the carotid injections included the following: iodine content (300 or 150 mg I/ml), liquid temperature (37° or 24°C), and the injection time duration (1 or 30 s). The rabbits were divided into five groups. To evaluate BBB disruption, pre- and post-contrast-enhanced magnetic resonance (MR) studies were performed. Results Abnormal enhancement of the brain parenchyma in MRI was noted in only one group, which consisted of high-iodine concentration CM injected at a low temperature over a short injection interval. Statistically significant increased values for the percentage of relative enhancement (RE%) were demonstrated (P < 0.05) in comparison with the saline-injected control group. Conclusion This result suggests variables that may need to be carefully considered to prevent BBB injury induced by nonionic CM for cerebral angiography, especially in the setting of a neurointerventional procedure.     

镧示踪法观察常规分割外照射后血脑屏障的超微结构改变

目的 观察Sprague-Dawley(SD)大鼠全脑常规外照射后血脑屏障(BBB)的超微结构变化特点及其规律。方法 SD大鼠20只,分为5个实验组,60Coγ射线全脑常规分割外照射,各组受照后16h以硝酸镧为示踪剂,用透射电镜观察BBB超微结构变化。结果 对照组镧颗粒分布在血管腔内,BBB结构完整;10Gy组少量镧颗粒通过开放的毛细血管内皮细胞间的紧密连接,沉积于基底膜,但未入脑组织;20Gy组见大部分紧密连接开放,镧颗粒弥漫性分布于神经细胞间隙,细胞内无镧颗粒沉积;30Gy神经细胞质内见大量、核内见少量镧颗粒沉积;40Gy组部分毛细血管内皮细胞及神经细胞失去正常形态,结构破坏,大量镧颗粒沉积在细胞核内、外。结论 放射线具有降低及破坏BBB功能的作用,且与照射剂量呈正相关;30Gy后BBB完全开放,此时进行化疗为最佳时机;照射40Gy后不易再全脑追加剂量,否则会导致不可逆性放射性脑损伤。     

高原脑损伤血脑屏障变化的实验研究

目的：了解高原条件下颅脑损伤后血脑屏障（ｂｌｏｏｄ－ｂｒａｉｎｂａｒｉｅｒ，ＢＢＢ）变化的特点．方法：采用自由落体致伤法（致伤冲量为１２００ｇ·ｃｍ）造成颅脑损伤模型．ＢＢＢ变化的定性测定采用伊文氏蓝（ｅｖａｎｓｂｌｕｅ，ＥＢ）染色，利用荧光比色法测定组织中ＥＢ含量来定量代表ＢＢＢ通透性变化，同时电镜观察毛细血管的病理改变．结果：高原脑损伤后局部损伤区出现蓝染带较早且范围宽．脑组织中ＥＢ含量较平原损伤时含量有非常显著的增高．脑组织中毛细血管损伤严重，以基底膜破坏明显，其周围有大量的水肿液．结论：高原低压低氧条件可加重颅脑ＢＢＢ损伤破坏，通透性增高．     

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。