Mathematical And Statistical Analysis Techniques For In Vivo Imaging Studies

(1)我们验证了一种用C-11亮氨酸和PET定量测定大脑蛋白质合成(RCPS)区域速率的方法(见项目MH000889)。该方法使用动力学建模方法来估计Lamda，来自动脉血浆的蛋白质合成前体池的分数，以校正组织氨基酸的循环(Schmidt等人，JCBFM 2005；25：617-28)。由于在异质组织中对动力学模型速率常数的估计随着时间的推移而下降，直到所有前体池与动脉血浆达到平衡(Schmidt等人，JCBFM 1991；11：10-24)，估计的nlamda和RCPS也可能随着时间而变化，直到达到平衡为止。我们目前正在检查有意识的受试者在注射C-11亮氨酸后动态扫描90分钟的数据，以确定RCP的最佳扫描间隔测量。对于整个大脑和几个感兴趣的区域，在不同的时间间隔内估计了动力学模型的速率常数和Lamda，并计算了RCPS。初步结果表明，60至75分钟的时间间隔可能是最佳的；这些数据是在第23届脑血流与代谢国际研讨会和第8届国际PET脑功能量化会议(BrainPET07 Abstract BO2-6U)上公布的。我们还检查了注射C-11亮氨酸后动态扫描120分钟的麻醉猴子的数据，以确定测量恒河猴RCP的最佳间隔。 (2)星形胶质细胞在控制细胞外环境、神经递质的从头合成、神经传递和血流调节等方面具有重要作用。所有这些功能都需要能量，这表明星形细胞的新陈代谢应该随着神经元活动的变化而起伏。2-14乙酸乙酯是星形胶质细胞优先氧化的底物，是一种潜在的示踪剂，可用于脑成像和定量放射自显影，以可视化和定量体内星形胶质细胞的激活。在单侧光刺激范式中，被用来检验分级感觉刺激导致2-14C乙酸酯摄取系数逐渐增加的假说，在清醒大鼠的光刺激过程中，醋酸盐摄取系数在去传入的视觉结构中下降，在完整组织中上升。然而，醋酸盐摄取系数的增加与刺激率的增加不成比例，也与所有细胞对葡萄糖利用率的增加不成比例。进行模拟研究，以调查醋酸盐摄取是否受到向组织输送示踪剂的限制。模拟结果支持醋酸盐吸收系数主要代表新陈代谢，并对代谢率的变化做出响应，但随着代谢率的升高，响应逐渐降低。因此，醋酸盐代谢的增加实际上可能比放射自显影图像所反映的程度要大得多。研究结果已发表在《神经化学杂志》(Dienel，Schmidt and Cruz，J Neurochem，2007)上。 出版物： Dienel G，Schmidt KC，Cruz N(2007)。分级光刺激下星形胶质细胞在体内的激活。J神经化学。在线发布doi：10.1111/j.1471-4159.2007.04859.x

(1) We have validated a method for quantitative determination of regional rates of cerebral protein synthesis (rCPS) with C-11 leucine and PET (see project MH000889). The method uses a kinetic modeling approach to estimate lamda, the fraction of the precursor pool for protein synthesis derived from arterial plasma, in order to correct for recycling of tissue amino acids (Schmidt et al., JCBFM 2005; 25:617-28). Because estimates of kinetic model rate constants decline with time in heterogeneous tissues until all precursor pools equilibrate with arterial plasma (Schmidt et al., JCBFM 1991; 11:10-24), estimated nlamda and rCPS may also change with time until equilibrium has been achieved. We are currently examining data from conscious human subjects dynamically scanned for 90 min after injection of C-11 leucine in order to determine the optimal scanning interval measurement of rCPS. Kinetic model rate constants and lamda have been estimated over varying time intervals for whole brain and several regions of interest and rCPS computed. Preliminary results suggest that an interval between 60 and 75 min may be optimal; these data were presented at the 23rd International Symposium on Cerebral Blood Flow & Metabolism and 8th International Conference on Quantification of Brain Function with PET (BrainPET07 Abstract BO2-6U). We are also examining data from anesthetized monkeys dynamically scanned for 120 min following injection of C-11 leucine in order to determine the optimal interval for measurement of rCPS in rhesus monkeys. (2) Astrocytes have important roles in control of extracellular environment, de novo synthesis of neurotransmitters, and regulation of neurotransmission and blood flow. All of these functions require energy, suggesting that astrocytic metabolism should rise and fall with changes in neuronal activity. 2-14Cacetate is a substrate preferentially oxidized by astrocytes and is a potential tracer for brain imaging with quantitative autoradiography to visualize and quantify astrocytic activation in vivo. In a unilateral photic stimulation paradigm that was used to test the hypothesis that graded sensory stimuli cause progressive increases in the uptake coefficient of 2-14Cacetate, the acetate uptake coefficient fell in deafferented visual structures and it rose in intact tissue during photic stimulation of conscious rats. The increase in the acetate uptake coefficient, however, was not proportional to the increase in stimulus rate and was not proportional to increases in the rate of glucose utilization by all cells. Simulation studies were undertaken to investigate whether acetate uptake was limited by delivery of tracer to the tissue. Simulation results support the conclusion that acetate uptake coefficients represent mainly metabolism and respond to changes in metabolic rate, but with progressively lower responses at progressively higher metabolic rates. Therefore, acetate metabolism may actually increase to a much greater extent than is reflected in autoradiographic images. Results have been published in the Journal of Neurochemistry (Dienel, Schmidt and Cruz, J Neurochem, 2007). Publications: Dienel G, Schmidt KC, Cruz N (2007). Astrocyte activation in vivo during graded photic stimulation. J Neurochem. published online doi:10.1111/j.1471-4159.2007.04859.x