Brain Imaging In Human Aging, Alzheimer Disease And Other Disorders

阿尔茨海默病神经炎症的影像学表现 尸检研究证明了阿尔茨海默病的神经炎症标志物，但我们在体内对人类神经炎症进行成像的能力有限。基于对神经炎症大鼠模型的研究，我们预测阿尔茨海默病患者静脉注射放射性标记的花生四烯酸（AA）的脑摄取会升高。我们使用正电子发射断层扫描（PET）在8名轻度-重度痴呆阿尔茨海默病患者和8名年龄匹配的对照组中证实了这一预测。AA掺入升高，已知有高密度的老年性神经炎斑块和激活的小胶质细胞的新皮层脑区。相比之下，这些区域的脑血流量减少。我们的PET方法，在确认后，可用于检查阿尔茨海默病和其他疾病中神经炎症的进展，以及疾病对药物的反应（参考文献1）。 健康志愿者突触功能的胆碱能调节 额叶皮质血流量，测量使用PET和15 O-水，升高与工作记忆任务的困难，在年轻的健康志愿者的反应时间的延长。抗胆碱酯酶药毒扁豆碱的管理，防止这些变化。因此，突触传递的胆碱能调节增强了记忆能力，减少了额叶皮层中的费力突触募集。这些变化可能与阿尔茨海默病患者抗胆碱酯酶治疗的有效性有关（参考文献2和3）。 多巴胺脑信号成像 我们正在与NIMH进行PET协议，以通过AA成像大脑信号转导，与多巴胺能传递有关，在成人注意力缺陷多动障碍（ADHD）和年龄匹配的对照组中。阿扑吗啡是一种多巴胺D2/D3受体激动剂，经临床前研究证实，可通过D2受体激活AA信号传导。我们假设，这种信号将在ADHD患者中受到干扰，基于他们改变的多巴胺受体和转运蛋白等位基因的遗传证据。我们已经完成了6名正常志愿者的扫描，并正在评估结果。 人脑二十二碳六烯酸区域显像 DHA是脑细胞膜中营养必需的多不饱和脂肪酸，参与许多脑代谢过程。能够将其消费与人类健康和疾病联系起来将是有益的。我们正在与NIAAA研究人员一起进行PET协议，以量化健康志愿者的大脑DHA信号传导和消耗，基于我们的临床前研究。对于整个大脑，从血浆中掺入DHA的平均速率等于3.8 mg/天（参考文献4）。 多巴胺脑信号成像 我们与NIMH启动了一项PET协议，通过花生四烯酸对注意缺陷多动障碍（ADHD）成年人和年龄匹配的对照组中与多巴胺能传递相关的脑信号转导进行成像。阿扑吗啡是一种多巴胺D2/D3受体激动剂，经临床前研究证实，可通过D2受体激活花生四烯酸信号传导。我们假设，这种信号将在ADHD患者中受到干扰，基于他们改变的多巴胺受体和转运蛋白等位基因的遗传证据。我们已经完成了6名正常志愿者的扫描，并正在评估结果。 人脑二十二碳六烯酸区域显像 二十二碳六烯酸（DHA）是脑细胞膜中一种营养必需的多不饱和脂肪酸，参与多种脑代谢过程。能够将其消费与人类健康和疾病联系起来将是有益的。我们正在与NIAAA研究人员一起进行PET协议，以量化健康志愿者的大脑DHA信号传导和消耗，基于我们的临床前研究。对于整个大脑，从血浆中掺入DHA的平均速率等于3.8 mg/天。我们正在准备一份关于这项研究的手稿。

IMAGING NEUROINFLAMMATION IN ALZHEIMER DISEASE Postmortem studies demonstrate neuroinflammatory markers in Alzheimer disease, but our ability to image neuroinflammation in humans in vivo is limited. Based on studies in a rat model of neuroinflammation, we predicted that brain uptake of intravenously injected radiolabeled arachidonic acid (AA) would be elevated in patients with Alzheimer disease. We confirmed this prediction using positron emission tomography (PET) in 8 mildly-severely demented Alzheimer disease patients compared with 8 aged-matched controls. AA incorporation was elevated in neocortical brain regions known to have high densities of senile neuritic plaques and activated microglia. Cerebral blood flow was reduced by comparison in these regions. Our PET method, after confirmation, might be used to examine progression of neuroinflammation in Alzheimer and other diseases in which it plays a role, and disease response to medication (Ref. 1). CHOLINERGIC MODULATION OF SYNAPTIC FUNCTION IN HEALTHY VOLUNTEERS Frontal cortex blood flow, measured using PET and 15O-water, was elevated in relation to working memory-task difficulty in young healthy volunteers, in relation to prolongation of reaction time. Administration of the anticholinesterase, physostigmine, prevented these changes. Thus, cholinergic modulation of synaptic transmission enhanced memory performance and reduced effortful synaptic recruitment in the frontal cortex. These changes may be related to the usefulness of anticholinesterase treatment in patients with Alzheimer disease (Ref. 2 and 3). IMAGING HUMAN BRAIN SIGNALING INVOLVING DOPAMINE We are conducting a PET protocol with the NIMH to image brain signal transduction via AA, related to dopaminergic transmission, in adults with Attention Deficit Hyperactivity Disorder (ADHD) and age-matched controls. Apomorphine, a dopamine D2/D3 receptor agonist, is administered to activate AA signaling via D2 receptors, as proven in preclinical studies. We hypothesize that this signaling will be disturbed in ADHD patients, based on genetic evidence of their altered dopamine receptor and transporter alleles. We have completed scans on 6 normal volunteers and are evaluating the results. REGIONAL DOCOSAHEXAENOIC ACID IMAGING IN THE HUMAN BRAIN DHA is a nutritionally essential polyunsaturated fatty acid in brain cell membranes and participates in many brain metabolic processes. Being able to image its consumption in human health and disease would be useful. We are conducting a PET protocol together with NIAAA investigator to quantify brain DHA signaling and consumption in healthy volunteers, based on our preclinical studies. For the entire brain, the mean rate of DHA incorporation from plasma equals 3.8 mg/day (Ref. 4). IMAGING HUMAN BRAIN SIGNALING INVOLVING DOPAMINE We initiated a PET protocol with the NIMH to image brain signal transduction via arachidonic acid, related to dopaminergic transmission, in adults with Attention Deficit Hyperactivity Disorder (ADHD) and age-matched controls. Apomorphine, a dopamine D2/D3 receptor agonist, is administered to activate arachidonic acid signaling via D2 receptors, as proven in preclinical studies. We hypothesize that this signaling will be disturbed in ADHD patients, based on genetic evidence of their altered dopamine receptor and transporter alleles. We have completed scans on 6 normal volunteers and are evaluating the results. REGIONAL DOCOSAHEXAENOIC ACID IMAGING IN THE HUMAN BRAIN Docosahexaenoic acid (DHA) is a nutritionally essential polyunsaturated fatty acid in brain cell membranes and participates in many brain metabolic processes. Being able to image its consumption in human health and disease would be useful. We are conducting a PET protocol together with NIAAA investigator to quantify brain DHA signaling and consumption in healthy volunteers, based on our preclinical studies. For the entire brain, the mean rate of DHA incorporation from plasma equaled 3.8 mg/day. We are preparing a manuscript on this research.