A POSITRON EMISSSION TOMOGRAPHY STUDY OF 5-HT1A RECEPTORS IN ALZHEIMER'S DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 虽然5-羟色胺能系统的改变在阿尔茨海默病(AD)中已被广泛证明，但5-HT1A受体的变化从未得到适当的研究。最近出现了可以安全用于人类的5-HT1A拮抗剂，这使得这一点成为可能。已知5-HT1a受体与认知和行为有关，而这两者在AD中都被破坏了。此外，动物研究表明，5-HT1A拮抗剂可能通过调节葡萄糖物质系统在AD中发挥治疗作用。因此，重要的是要确定5-HT1a受体在AD中是否被破坏，以及这些变化的幅度和时间进程。因此，我们的目标是用正电子发射断层扫描(PET)来确定5-HT1a受体在早期AD中是否减少。10名符合NINCDS-ADRDA诊断标准的轻度至中度症状的可能AD患者入选。所有患者都将接受全面的神经精神评估，包括一般功能能力、认知功能和非认知功能的测量。还从社区招募了同样数量的年龄和性别匹配、认知完整的对照组。在研究开始之前，患者和对照组没有服用5-HT1A特异性药物。在筛选纳入后，每组接受10mCi静脉注射5-HT1A拮抗剂[11C]WAY100635，然后在注射75分钟后进行PET扫描。受试者和对照组都接受了MRI扫描，这与PET扫描是共同登记的。核磁共振被用来确定感兴趣区域的位置，并调整参与者的脑萎缩。除了使用组之间广泛的感兴趣区域分析(即双侧额叶、颞叶、顶叶和枕叶皮质的比较)外，还通过逐个像素的分析来比较较小的区域，如河马区，以确定是否存在局部差异。在AD中识别5-HT1A功能障碍是阐明该系统在AD中的作用并确定其作为治疗靶点的第一步。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although alterations in the serotonergic system have been broadly demonstrated in Alzheimer's disease (AD), changes in the 5-HT1A receptor has never been properly studied. The recent emergence of 5-HT1A antagonists that can be safely used in humans now makes this possible. The 5-HT1A receptor is known to be involved with cognition and behaviour, both of which are disrupted in AD. Furthermore, animal studies suggest that 5-HT1A antagonists may play a therapeutic role in AD via modulation of the gluatmatergic system. As a result, it is important to ascertain whether or not 5-HT1A receptors are disrupted in AD and the magnitude and time course of these changes. Therefore, we aimed to determine if 5-HT1A receptors are decreased in early AD using positron emission tomography (PET). Ten patients who meet NINCDS-ADRDA criteria for probable AD with mild to moderate symptomatology were recruited. All patients will had a full neuropsychiatric assessment that includes measures of general functional capacity, cognitive function and noncognitive function. An equal number of age- and sex-matched controls with intact cognition were also recruited from the community. Patients and controls were free from 5-HT1A-specific medications prior to initiation of the study. After screening for inclusion, each group was administered a 10mCi intravenous injection of the 5-HT1A antagonist, [11C] WAY100635, followed by a PET scan 75 minutes post-injection. Both subjects and controls also underwent an MRI scan that was co-registered with the PET scan. The MRI was be used to determine the location of the regions of interest and to adjust for brain atrophy in the participants. In addition to using a broad region of interest analysis between groups (i.e., comparison of bilateral frontal, temporal, parietal and occipital cortices) smaller areas, such as the hipppocampus, was be compared through a pixel-by-pixel analysis to determine whether local differences exist. Identifying 5-HT1A dysfunction in AD is the first step in elucidating the role of this system in AD and determining its potential as a therapeutic target.