7 Tesla MRI Bolus CR Studies of Human BBB Permeability

7 人体 BBB 渗透性的特斯拉 MRI Bolus CR 研究

• 批准号: 7795817
• 负责人: WILLIAM D ROONEY
• 金额: $ 33.34万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795817
• 关键词: A-factor (Streptomyces); Accounting; Acute; Affect; Agreement; Area; Biological Markers; Biophysics; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood Volume; Blood capillaries; Bolus Infusion; Brain; Brain Pathology; Brain region; Breast Cancer Detection; Cardiomyopathies; Cell Volumes; Cerebrum; Chronic; Complement 3d Receptors; Data; Dependence; Detection; Development; Diagnostic; Dose; Drug Kinetics; Equilibrium; Exhibits; Extravasation; Generations; Goals; Gold; Grant; Histocompatibility Testing; Hour; Human; Image; Influentials; Injection of therapeutic agent; Kinetics; Knowledge; Laboratories; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measurement; Measures; Methods; Modeling; Molecular; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Myocardium; Noise; Pathology; Pathway interactions; Permeability; Physical Chemistry; Physics; Physiologic pulse; Physiology; Property; Reagent; Relaxation; Resolution; Rodent; Signal Transduction; Specificity; Speed; Stroke; Surface; Syringes; Techniques; Time; Tissues; Variant; Water; Weight; Work; capillary; disease phenotype; falls; gray matter; improved; in vivo; instrument; interest; interstitial; magnetic field; molecular mass; novel; pharmacokinetic model; public health relevance; radiotracer; research study; spatiotemporal; white matter

DESCRIPTION (provided by applicant): The long-term goal of this project is absolute quantification of (Dynamic-Contrast-Enhanced) DCE-MRI, the high spatiotemporal resolution recording of contrast reagent (CR) passage following bolus injection, via its effect on the tissue 1H2O MR signal longitudinal relaxation time constant (T1). Though applied to all tissues, the approved, low-MW Gd(III) chelate CRs are particularly sensitive probes of blood-brain-barrier (BBB) integrity. Even slight compromises of the para(endothelial)cellular pathway mainly defining BBB tightness are detected. In particular, this work exploits two recent developments - the increased availability of ultra-high magnetic field [BB0 e 7 Tesla (T)] whole-body MRI, and the introduction of the "Shutter-Speed" DCE-MRI pharmacokinetic model (SSM). The former is important because it has recently been shown that CR detectability increases with BB0: i.e., the detection threshold CR concentration decreases with increasing BB0. One consequence is that, at least by 4T, it is possible to detect monomeric Gd(III) chelate extravasation across even the normal BBB. This is contrary to conventional wisdom only because it is not easily detectable at BB0 values [d 3T] currently used clinically: it occurs in all diagnostic CR MRI examinations. The SSM corrects a significant systematic error in the almost universally used Standard DCE-MRI pharmacokinetic Model (SM). SSM incorporates the effects of equilibrium intercompartmental water exchange kinetics, which are crucial since CR detection is indirect - via its effect on 1H2O. Large systematic errors in DCE-MRI pharmacokinetic parameters, Ktrans (volume-weighted CR trans-BBB rate constant), vb (blood volume fraction), and ve (interstitial volume fraction) can occur if shutter-speed effects are ignored. [For example, such SM errors negate very high (so far perfect) specificity in SSM DCE-MRI breast cancer screening.] The SSM recognizes that DCE-MRI is an intrinsically dual probe (CR and water) technique. It is proposed here that, at high BB0 (7T), SSM will allow high-resolution mapping of the permeability coefficient capillary surface area products for CR and water (PCRS and PWS) for the whole brain. Since S is an extensive property, it increases with vb. Thus, PS maps usually show greater intensity in gray matter (GM) than white matter because of the larger GM vb value. However, it is proposed that the ratio PCRS/PWS measures the intensive property PCR/PW. This new imaging biomarker has a very large dynamic range [>10-2 (musculature) to 10-5 (normal brain)], and should be exquisitely sensitive to normal brain anatomical variations and to BBB compromise, from subtle to major. The three specific aims are to: 1.) optimize DCE-MRI at 7T, and map PCR/PW in the entire 2.) normal brain, and in the entire 3.) normal-appearing, acute lesion-containing, and chronic lesion multiple sclerosis (MS) brain. [Comparison of neutral CR0 and anionic CR2- in the normal brain will probe the PCR molecular mechanism.] This work involves aspects of physics, physical chemistry, biophysics, physiology, and relates to a number of pathologies including MS, stroke, cancer, and myocardial disease. PUBLIC HEALTH RELEVANCE: This project involves (Dynamic-Contrast-Enhanced) DCE-MRI studies of the human brain at ultra-high magnetic field, 7 Tesla (T). The new "Shutter-Speed" pharmacokinetic model (SSM) developed in the current period of this grant allows absolute quantitative analyses of DCE-MRI data. Though this project will study the normal and multiple sclerosis (MS) human brain, SSM DCE-MRI also applies to cancer in all areas of the body, to studies of normal and diseased human myocardium, and to many other pathologies.

描述(申请人提供)：这个项目的长期目标是绝对量化(动态增强)DCE-MRI，通过其对组织1H2O MR信号纵向弛豫时间常数(T1)的影响，记录对比剂(CR)在团注后通过的高时空分辨率记录。虽然适用于所有组织，但经过批准的低分子量Gd(III)螯合CRS是血脑屏障(BBB)完整性的特别敏感的探针。甚至可以检测到主要定义血脑屏障密封性的类(内皮)细胞途径的轻微损害。特别是，这项工作利用了两个最新的发展-超高磁场[BB0 e 7特斯拉(T)]全身核磁共振的可用性增加，以及“快门速度”DCE-MRI药代动力学模型(SSM)的引入。前者很重要，因为最近已表明CR可检测性随BB0的增加而增加：即检测阈值CR浓度随BB0的增加而降低。一个结果是，至少在4T时，即使是正常的血脑屏障，也可能检测到单体Gd(III)的螯合外渗。这与传统的看法相反，只是因为在目前临床使用的BB0值[d3T]下很难检测到它：它出现在所有诊断性CR MRI检查中。SSM纠正了几乎普遍使用的标准DCE-MRI药代动力学模型(SM)中的一个重大系统错误。SSM结合了平衡室间水交换动力学的影响，这是至关重要的，因为CR检测是间接的-通过其对1H2O的影响。如果忽略快门速度的影响，DCE-MRI药代动力学参数、KTrans(体积加权CR TransBBB速率常数)、Vb(血液体积分数)和Ve(间质体积分数)可能会出现较大的系统误差。[例如，这样的SM错误否定了SSM DCE-MRI乳腺癌筛查中非常高的(迄今完美的)特异性。]SSM认识到DCE-MRI本质上是一种双探头(CR和水)技术。这里提出，在高BB0(7T)下，SSM将允许高分辨率地绘制整个大脑的CR和水的渗透系数毛细血管表面积乘积(PCRS和PWS)。由于S是一个广泛的性质，它随着vb的增加而增加。因此，PS图通常显示灰质(GM)的强度比白质更强，因为GMvb值更大。然而，有人建议用PCRS/PWS比值来衡量PCRs/PW的集约性。这种新的成像生物标志物具有非常大的动态范围[&gt；10-2(肌肉系统)到10-5(正常大脑)]，应该对正常大脑解剖变化和从微小到主要的血脑屏障损害非常敏感。三个具体目标是：1.优化7T的DCE-MRI，并在整个2个时间段绘制PCR/PW图。)正常的大脑，在整个3个月中。)外观正常、含有急性病变和慢性病变的多发性硬化症(MS)脑。[通过比较中性CR0和阴离子CR2-在正常脑中的表达，探讨其分子机制。]这项工作涉及到物理学、物理化学、生物物理学、生理学的方方面面，涉及到包括多发性硬化症、中风、癌症和心肌疾病在内的许多病理学。公共卫生相关性：该项目涉及在超高磁场下对人脑进行(动态对比增强)DCE-MRI研究，7特斯拉(T)。在这笔赠款的当前时期开发的新的“快门速度”药代动力学模型(SSM)允许对DCE-MRI数据进行绝对定量分析。虽然该项目将研究正常和多发性硬化症(MS)的人脑，但SSM DCE-MRI也适用于身体所有部位的癌症、正常和患病的人类心肌的研究，以及许多其他病理学。