Mathematical And Statistical Analysis Techniques For In

由疾病或正常大脑中各种通路的激活产生的大脑功能活动图像的变化，只有在量化成像方法所依据的生理和生化过程的速率的情况下，才能明确地解释。在使用放射性示踪剂的成像模式中，例如正电子发射断层摄影（PET），通过描述示踪剂和被示踪分子的代谢途径中的生化反应速率的数学模型来进行定量。选择最佳动力学模型至关重要，因为使用不适当的模型可能导致定量中的实质性错误和可能的结果误解。一旦选择了模型，就需要高效、鲁棒并且需要对测量误差进行最小假设的数值程序来准确估计参数。此外，还需要强有力的统计检验，以便检查实验组之间的数据是否存在显著差异。该项目的目标是开发更好的技术来解决这些相互关联的数学和统计问题;本年度在以下领域取得了进展： (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λ和rCPS也可以随时间变化，直到达到平衡。我们最近进行了一项研究，以检查rCPS的最佳扫描间隔测量。注射C-11亮氨酸后，对麻醉猴进行60分钟的动态扫描。在不同的时间间隔内估计全脑和几个感兴趣的区域的动力学模型速率常数和λ，并计算rCPS。速率常数和rCPS往往随着估计间隔的增加而降低，这表明最佳扫描间隔不应短于60 min。初步结果在核医学学会第53届年会（SNM 2006）上发表。为了确定扫描间隔必须延长多少（如果有的话）超过60分钟才能达到最佳效果，目前正在对麻醉猴进行120分钟的动态扫描。 (2)继续开展一项研究，使用C-14亮氨酸放射自显影研究的详细分布数据来估计C-11亮氨酸PET测量的精度。我们已经构建了一个三维体积从C-14亮氨酸放射自显影的一个半球的猴脑，并计算匹配的分辨率，这个体积的PET扫描仪。我们正在开发分析方法，使用该数据库来估计PET扫描仪检测脑蛋白质合成区域速率特定变化的灵敏度。部分结果发表在Nuclear Medicine and Biology（施密特and Smith，NMB 2005; 32：719-725）中。 (3)通过使用小动物PET扫描仪和连续输注5-HT 1A受体拮抗剂4-[18 F]-氟-N-{2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基}-N-（2-嘧啶基）苯甲酰胺（[18 F]FP-WAY）来评估大鼠中5-羟色胺5-HT 1A受体占有率变化的技术的开发已经完成，并且详细描述该发现的论文正在出版中（Tokugawa et al.，Eur J Nucl Med and Molecular Imaging）。 (4)在清醒大鼠中，采用C-14氟代脱氧葡萄糖和C-14脱氧葡萄糖，通过放射自显影法测定氟代脱氧葡萄糖的集总常数。所得值为0.71。这一结果在核医学学会第53届年会（SNM 2006）上发表，详细说明这一发现的论文正在出版中（Tokugawa等人，J Nucl Med）。

Changes in images of brain functional activity that are produced by disease or by activation of various pathways in the normal brain can only be unambiguously interpreted if the rates of the physiological and biochemical processes that underlie the imaging method are quantified. In imaging modalities that use radioactive tracers, e.g. positron emission tomography (PET), quantification is carried out by means of a mathematical model that describes the rates of the biochemical reactions in the metabolic pathway of the tracer and traced molecules. Selection of the best kinetic model is critical as the use of an inappropriate model can lead to substantial errors in quantification and possible misinterpretation of results. Once a model is selected, numerical procedures that are efficient, robust, and require minimal assumptions about the errors in the measurements are required to estimate accurately the parameters. Additionally, powerful statistical tests are needed so that the data can be examined for significant differences among experimental groups. The objective of this project is to develop better techniques for addressing these interrelated mathematical and statistical issues; advances in the current year were made in the following areas: (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 lamda and rCPS may also change with time until equilibrium has been achieved. We have recently undertaken a study to examine the optimal scanning interval measurement of rCPS. Anesthetized monkeys were dynamically scanned for 60 min following injection of C-11 leucine. Kinetic model rate constants and lamda were estimated over varying time intervals for whole brain and several regions of interest, and rCPS was computed. Rate constants and rCPS tended to decrease with increasing estimation interval, indicating that the optimal scanning interval should not be shorter than 60 min. Preliminary results were presented at the Society for Nuclear Medicine 53rd Annual Meeting (SNM2006). In order to determine how much, if any, the scanning interval must be extended beyond 60 min for optimality, 120-min dynamic scans of anesthetized monkeys are now ongoing. (2) Work continued on a study to use detailed distributional data from C-14 leucine autoradiographic studies to estimate the precision of PET measurements with C-11 leucine. We have constructed a three-dimensional volume from C-14 leucine autoradiograms of one hemisphere of a monkey brain, and computationally matched the resolution of this volume to that of the PET scanner. We are developing analysis methods to use this database to estimate the sensitivity of the PET scanner for detecting specific changes in regional rates of cerebral protein synthesis. Partial results were published in Nuclear Medicine and Biology (Schmidt and Smith, NMB 2005; 32:719-725). (3) Development of techniques for assessing changes in serotonin 5HT1A receptor occupancy in rats by use of a small animal PET scanner and a continuous infusion of the 5HT1A receptor antagonist 4-[18F]-fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyrimidinyl)benzamide ([18F]FP-WAY) was completed, and a paper detailing the findings is in press (Tokugawa et al., Eur J Nucl Med and Molecular Imaging). (4) The lumped constant for fluorodeoxyglucose was determined in awake rats by an autoradiographic method employing C-14 fluorodeoxyglucose and C-14 deoxyglucose. The value obtained was 0.71. This result was presented at the Society for Nuclear Medicine 53rd Annual Meeting (SNM2006), and a paper detailing the finding is in press (Tokugawa et al., J Nucl Med).