Mathematical And Statistical Analysis Techniques For In Vivo Imaging Studies

(1)我们已经验证了使用C-11亮氨酸和PET定量测定脑蛋白质合成（rCPS）局部速率的方法（见项目MH 000889）。 该方法使用动力学建模方法来估计λ，即源自动脉血浆的蛋白质合成的前体库的分数，以校正组织氨基酸的再循环（施密特et al.，JCBFM 2005; 25：617-28）。因为在异质组织中动力学模型速率常数的估计值随时间下降，直到所有前体库与动脉血浆平衡（施密特等人，JCBFM 1991; 11：10-24），估计的nlamda和rCPS也可以随时间变化，直到达到平衡。 我们目前正在研究的数据，从有意识的人类受试者动态扫描90分钟后，注射C-11亮氨酸，以确定最佳的扫描间隔测量rCPS。 动力学模型速率常数和λ已估计在不同的时间间隔为全脑和几个区域的利益和rCPS计算。 初步结果表明，60和75分钟之间的间隔可能是最佳的;这些数据在第23届脑血流和代谢国际研讨会和第8届PET脑功能定量国际会议（BrainPET 07 Abstract BO 2 - 6 U）上发表。 我们还检查了麻醉猴注射C-11亮氨酸后动态扫描120分钟的数据，以确定测量恒河猴rCPS的最佳间隔。 (2)星形胶质细胞在细胞外环境的调控、神经递质的重新合成、神经传递和血流的调节等方面具有重要作用。所有这些功能都需要能量，这表明星形胶质细胞的代谢应该随着神经元活动的变化而上升和下降。 2-14醋酸盐是星形胶质细胞优先氧化的底物，是定量放射自显影脑成像的潜在示踪剂，可在体内可视化和定量星形胶质细胞活化。 在单侧光刺激范例，这是用来测试的假设，分级的感觉刺激引起的2- 14 Caacetate的摄取系数进行性增加，醋酸盐的摄取系数下降，在去传入的视觉结构，它上升，在完整的组织在清醒的大鼠光刺激。然而，乙酸盐摄取系数的增加与刺激速率的增加不成比例，并且与所有细胞的葡萄糖利用率的增加不成比例。进行模拟研究，以调查是否醋酸盐的吸收是有限的示踪剂的组织交付。 模拟结果支持的结论是，乙酸吸收系数主要代表代谢和代谢率的变化，但随着代谢率逐渐升高，反应逐渐降低。 因此，醋酸盐代谢实际上可能比放射自显影图像所反映的程度更大。 结果已发表在Journal of Neurochemistry（Dienel，施密特and Cruz，J Neurochem，2007）上。 出版物： Dienel G，施密特KC，Cruz N（2007）. 分级光刺激过程中星形胶质细胞的体内活化。 神经化学杂志。 在线发表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