Small Animal In vivo quantification of cerebral glucose metabolic rate

描述（由申请人提供）：正电子发射断层扫描（PET）广泛用于绘制大脑葡萄糖代谢率（CMRG）图，并广泛用于指示临床竞技场中的认知和结局状态。然而，在临床相关的小动物疾病模型中使用这种成像模式仍然不常见，并且大多数microPET成像研究仍然是非定量的。更广泛使用定量microPET的主要障碍包括血液采样要求。解决方法学问题，限制了小动物PET成像的实用性，准确和重复的定量测量CMRG将提供一个重要的工具，以加强在各种疾病状态的研究。提出了通过将小动物microPET与微流控血浆采样技术相结合来改善CMRG的体内多时间点定量的研究。将使用该自动化微流体方法测定的体内CMRG值与使用相同动物中的传统手动取样方法测定的CMRG值进行比较。第二项microPET研究将确定同时测量血液和大脑葡萄糖同位素浓度的微创方法的准确性和实用性。由于PET成像在神经外科临床中被广泛用于监测创伤性脑损伤（TBI）患者，我们将使用我们第二项microPET研究中确定的最佳microPET方法进行原理验证研究，以量化CMRG的急性损伤后抑郁及其在大鼠轻中度单侧TBI实验模型中的恢复。将基于microPET的CMRG值的准确性和可靠性与终点标准放射自显影方法得出的值进行比较。成功完成拟议的研究将使小动物的多时间点定量microPET成像安全且常规可行。这将代表这一重要转化研究工具的实用性的重大进展，并应加强监测和开发用于治疗TBI和其他中枢神经系统疾病的潜在疗法的进展。公共卫生相关性：将进行这些研究以提高安全性和可靠性，并减少在小动物中进行脑葡萄糖利用定量成像所需的侵入性程序的数量。一种新的自动血浆采样装置，能够采取非常小的血液样本，以及从血细胞分离血浆将被开发和集成到目前的脑成像程序。将计算脑葡萄糖使用率，比较使用血浆样本或单一血浆样本结合心脏和脑中葡萄糖摄取成像计算所得的值。最佳成像方法将用于监测实验性创伤性脑损伤大鼠脑葡萄糖使用随时间的变化。该项目完成后，研究人员将可使用一种新的成像工具，在生理稳定的条件下以最小的辐射照射研究大脑功能。

DESCRIPTION (provided by applicant): Positron emission tomography (PET) is widely used to map the cerebral metabolic rate of glucose (CMRG) and is widely used to indicate cognitive and outcome status in the clinical arena. However, use of this imaging modality in clinically relevant small animal models of disease remains infrequent, and the majority of microPET imaging studies remain non-quantitative. Major impediments to more wide-spread use of quantitative microPET include blood sampling requirements. Solving the methodological issues that have limited the utility of small animal PET imaging for accurate and repeated quantitative measurements of CMRG will provide an important tool to enhance research in a variety of disease states. Studies are proposed to improve in vivo, multi-time-point quantification of CMRG by integrating small animal microPET with microfluidic plasma sampling technology. In vivo CMRG values determined using this automated microfluidics methodology will be compared against those determined using traditional, manually drawn sampling methods in the same animals. A second microPET study will determine the accuracy and utility of a minimally-invasive method of simultaneous measurement of blood and brain glucose isotope concentration. Since PET imaging is used so extensively in the neurosurgical clinic to monitor patients with traumatic brain injury (TBI) we will conduct a proof-of-principle study using the optimal microPET methods determined in our second microPET study to quantify the acute post-injury depression of CMRG and its recovery in an experimental model of mild-moderate unilateral TBI in rats. The accuracy and reliability of microPET-based CMRG values will be compared against values derived from end-point standard autoradiography methods. Successful completion of the proposed research will make multi-time-point, quantitative microPET imaging of small animals safe and routinely feasible. This will represent a major advance in the utility of this important translational research tool and should enhance progress in the monitoring and development of potential therapies for treatment of TBI and other diseases of the central nervous system. PUBLIC HEALTH RELEVANCE: The studies will be performed to improve the safety and reliability and to reduce the number of invasive procedures needed to conduct quantitative imaging of brain glucose utilization in small animals. A new automated plasma sampling device that is capable of taking very small samples of blood as well as separating plasma from the blood cells will be developed and integrated into current brain imaging procedures. Rates of brain glucose use will be calculated, comparing the values obtained in calculations using blood plasma samples or a single plasma sample in combination with imaging glucose uptake in both heart and brain. The optimal imaging method will be used to monitor changes in brain glucose use over time in rats with experimental traumatic brain injury. Upon completion of this project a new imaging tool will be available to researchers to study brain function under physiologically stable conditions with minimal radiation exposure.