Brain Imaging In Human Aging, Alzheimer Disease And Other Disorders

人类衰老、阿尔茨海默病和其他疾病的脑成像

• 批准号: 8552321
• 负责人: Stanley I. Rapoport
• 金额: $ 7.49万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552321
• 关键词: Acids; Address; Age; Aging; Agonist; Alcoholism; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Animal Model; Apomorphine; Arachidonic Acids; Behavior; Biological Markers; Blood flow; Brain; Brain Diseases; Brain imaging; Bypass; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Clinical Protocols; Cognition; Collaborations; Consumption; Cyclotrons; Dementia; Diet; Disease; Docosahexaenoic Acids; Dopamine; Dopamine D2 Receptor; Drug Kinetics; Drug effect disorder; Fatty Acids; Functional disorder; Glucose; Goals; HIV-1; Half-Life; Hepatic; Human; Image; Impaired cognition; Infection; Institutional Review Boards; Isotopes; Kinetics; Label; Lipids; Magnetic Resonance Imaging; Measurable; Measures; Medicine; Membrane; Metabolic; Metabolism; Methods; Modeling; Mus; National Institute of Allergy and Infectious Disease; Nausea; Nerve Degeneration; Neurocognitive; Neurons; Parkinson Disease; Pathologic Processes; Patients; Phospholipase A2; Phospholipids; Plasma; Positron; Positron-Emission Tomography; Prevalence; Process; Protocols documentation; Psychiatry; Quantitative Autoradiography; Radioactive; Radiochemistry; Radiolabeled; Rattus; Receptor Activation; Reporting; Research; Research Personnel; Resolution; Rodent; Role; Saline; Serum; Severities; Signal Transduction; Site; Somatotropin; Source; Structure; Supplementation; Synapses; Testing; Time; Transgenic Organisms; Translating; Treatment Efficacy; Work; Writing; aging brain; alpha-Linolenic Acid; antiretroviral therapy; base; cohort; disease diagnosis; excitotoxicity; glucose metabolism; imaging modality; improved; in vivo; insulin sensitivity; intravenous injection; lipid metabolism; medical schools; men; neuroimaging; neuroinflammation; neurotransmission; novel; preclinical study; prevent; radiotracer; receptor coupling; response; trimethobenzamide; uptake

DOPAMINE SIGNALING IMAGING HUMAN BRAIN SIGNALING INVOLVING DOPAMINE Dopaminergic dysfunction has been reported in Alzheimer disease and human aging. To address this issue, we developed a novel method to image dopaminergic neurotransmission in the human brain using positron emission tomography (PET) and 1-11Carachidonic acid (1-11CAA), as well as regional cerebral blood flow (rCBF) with 15Owater. We measured regional incorporation coefficients K* for AA, and rCBF, in healthy men given the dopaminergic D1/D2 receptor agonist (10 or 20 mg/kg s.c.) apomorphine or saline, after pretreatment with trimethobenzamide to prevent nausea. We demonstrated a robust central dopaminergic response to apomorphine by observing significant increases in serum growth hormone, and significant increases and decreases in AA incorporation plus increments in rCBF with PET. The AA incorporation changes reflected neuronal signaling associated with activation of D2-like receptors coupled to phospholipase A2. The rCBF changes represented general functional effects of D1/D2 receptor activation. The 1-11CAA PET method should be useful for studying disturbed dopaminergic neurotransmission in Parkinson disease, Alzheimer disease and other disorders.(3) NEUROINFLAMMATION IMAGING NEUROINFLAMMATION IN ALZHEIMER DISEASE WITH RADIOLABELED ARACHIDONIC ACID: We reported that brain uptake of radiolabeled arachidonic acid (1-14CAA) could be used to assess neuroinflammation in different animal models, and confirmed using PET and the positron-emitting isotope 1-11CAA the presence of neuroinflammation in the brain of Alzheimer disease (AD) patients (Esposito et al., J Nucl Medicine. 2008 49:1414-21). Based on this work, in collaboration with researchers at the Departments of Psychiatry at NYU School of Medicine and of Radiochemistry at Weill Cornell Medical College, we are conducting a protocol to extend this observation and to neuroimage neuroinflammation with 1-11CAA and brain glucose metabolism using PET in a larger cohort of AD patients in relation to dementia severity and brain amyloid distribution (Imaging Neuroinflammation in Alzheimer's Disease with 11CArachidonic Acid and PET, OHSR Exemption #5877). IMAGING NEUROINFLAMMATION IN HIV-1 INFECTED SUBJECTS Thirty million people worldwide are infected with Human Immunodeficiency Virus (HIV)-1; some 30-50% develop HIV-1 associated neurocognitive disorder (HAND) while on antiretroviral therapy, and the prevalence of HAND increases with age and causes interaction with Alzheimer disease. Thus, HIV-1 infection is of major concern to the NIA. We hypothesized that cognitive dysfunction in HIV-1 patients is exacerbated by concurrent neuroinflammation. To test this hypothesis, we first confirmed neuroinflammation as upregulated brain arachidonic acid metabolism in a noninfectious transgenic HIV-1 rat model, using our in vivo fatty acid imaging method (Basselin et al. Imaging upregulated brain arachidonic acid metabolism in HIV-1 transgenic rats. J Cereb Blood Flow Metab Jul 28 2010). On this basis, we now are writing a collaborative clinical protocol with the NIAID to quantify brain arachidonic acid metabolism and blood flow using PET in HIV-1 infected patients for the first time, in relation to severity of neurocognitive dysfunction. This study should identify neuroinflammation in the course of HIV-1 infection, and to establish a surrogate biomarker for efficacy of therapy against HAND. SYNTHESIS AND IN VIVO PHARMACOKINETICS OF FLUORINATED ARACHIDONIC ACID: IMPLICATIONS FOR IMAGING NEUROINFLAMMATION IN HUMANS. Arachidonic acid (AA) is released from membrane phospholipid during neuroinflammation, and we have reported upregulated brain AA metabolism as a biomarker of neuroinflammation in Alzheimer disease (AD) patients using 1-11CAA and PET. However, the radioactive half-life of 11C is short (20 minutes), limiting its use to research centers having a cyclotron oon site that can synthesize 1-11CAA. As a first step to develop a clinically useful (18)F-fluoroarachidonic acid ((18)F-FAA) with a long radioactive half-life of 109.8 min, which could be synthesized at multiple sites or delivered from a commercial source, we developed a high-yield stereoselective synthetic method for nonradioactive 20-(19)F-FAA. After intravenous injection in unanesthetized mice, its brain uptake, distribution and kinetics were identical to uptake of the natural AA (as measured with 1-14CAA). These results suggest that it would be feasible to translate our stereoselective synthetic method for (19)F-FAA to synthesize positron-emitting (18)F-FAA to image brain AA metabolism in AD and other neuroinflammatory disorders, and that imaging could be conducted routinely in multiple clinical centers with high resolution than 11C-AA (2). DOCOSAHEXAENOIC ACID METABOLISM INCORPORATION OF DOCOSAHEXAENOIC ACID (DHA) INTO HUMAN BRAIN AS BIOMARKER OF DISTURBED BRAIN LIPID METABOLISM AND NEUROTRANSMISSION. Docosahexaenoic acid (DHA, 22:6n-3) is critical for maintaining normal brain structure and function, and is considered neuroprotective. Dietary DHA supplementation has been tested in patients with Alzheimer disease, and its plasma concentration is reported reduced in such patients. Its brain concentration depends on dietary DHA content and hepatic conversion from its dietary derived n-3 precursor, alpha-linolenic acid. We developed an in vivo method in rats using quantitative autoradiography and intravenously injected radiolabeled DHA to measure DHA incorporation into brain, and showed that the incorporation rate equals the rate of brain metabolic DHA consumption. We then extended the method for use in humans with positron emission tomography (PET) (Umhau et al., Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography J. Lipid Res, 50, 1259, 2009). We are now using PET to quantify brain DHA incorporation in patients with chronic alcoholism and different brain diseases. GLUCOSE METABOLISM ROLE OF REDUCED GLUCOSE METABOLISM IN SUBJECTS AT RISK FOR ALZHEIMER DISEASE. In a critical review, we pointed out that lower brain glucose metabolism may be present before the onset of measurable cognitive decline in people at risk for Alzheimer disease (AD). Cerebral hypometabolism likely precedes and contributes to the neuropathological cascade leading to cognitive decline. The neurodegenerative processes in AD further decreases brain glucose metabolism because of reduced synaptic functionality and hence reduced energy needs, thereby completing a vicious cycle. Strategies to reduce risk of AD by breaking this cycle should aim to (1) improve insulin sensitivity by improving systemic glucose utilization, or (2) bypass deteriorating brain glucose metabolism using approaches that safely induce mild, sustainable ketonemia (1).

多巴胺信号传导 涉及多巴胺的人脑信号传导成像 据报道，多巴胺能功能障碍与阿尔茨海默病和人类衰老有关。为了解决这个问题，我们开发了一种新方法，使用正电子发射断层扫描 (PET) 和 1-11 花生四烯酸 (1-11CAA) 以及使用 15O 水的局部脑血流 (rCBF) 对人脑中的多巴胺能神经传递进行成像。我们测量了健康男性在接受多巴胺能 D1/D2 受体激动剂（皮下注射 10 或 20 mg/kg）阿扑吗啡或生理盐水后，在用三甲氧苯甲酰胺预处理以预防恶心后，AA 和 rCBF 的区域掺入系数 K*。通过观察血清生长激素的显着增加，以及 AA 掺入的显着增加和减少以及 rCBF 的增加，我们证明了对阿扑吗啡的强烈中枢多巴胺能反应。 AA 掺入变化反映了与磷脂酶 A2 偶联的 D2 样受体激活相关的神经元信号传导。 rCBF 变化代表 D1/D2 受体激活的一般功能影响。 1-11CAA PET 方法应可用于研究帕金森病、阿尔茨海默病和其他疾病中多巴胺能神经传递紊乱。(3) 神经炎症 使用放射性标记花生四烯酸对阿尔茨海默病中的神经炎症进行成像：我们报道了放射性标记花生四烯酸 (1-14CAA) 的大脑摄取可用于评估不同动物模型中的神经炎症，并使用 PET 和正电子发射同位素 1-11CAA 证实阿尔茨海默病 (AD) 患者大脑中存在神经炎症 (Esposito 等人，J Nucl Medicine.2008 49:1414-21)。基于这项工作，我们与纽约大学医学院精神病学系和威尔康奈尔医学院放射化学系的研究人员合作，正在开展一项方案，以扩展这一观察结果，并使用 PET 在更大的 AD 患者队列中使用 1-11CAA 和脑葡萄糖代谢对痴呆症严重程度和脑淀粉样蛋白分布进行神经成像神经炎症（神经炎症成像） 使用 11CA 花生四烯酸和 PET 治疗阿尔茨海默病，OHSR 豁免#5877）。 HIV-1 感染者的神经炎症成像 全球有三千万人感染人类免疫缺陷病毒（HIV）-1；大约 30-50% 的人在接受抗逆转录病毒治疗时会出现 HIV-1 相关神经认知障碍 (HAND)，并且 HAND 的患病率随着年龄的增长而增加，并导致与阿尔茨海默病的相互作用。 因此，HIV-1 感染是 NIA 重点关注的问题。我们假设 HIV-1 患者的认知功能障碍会因并发的神经炎症而加剧。为了检验这一假设，我们首先使用我们的体内脂肪酸成像方法，在非感染性转基因 HIV-1 大鼠模型中证实神经炎症是脑花生四烯酸代谢上调的结果（Basselin 等人，成像上调 HIV-1 转基因大鼠脑花生四烯酸代谢。J Cereb Blood Flow Metab，2010 年 7 月 28 日）。在此基础上，我们现在正在与 NIAID 编写一份合作临床方案，首次使用 PET 量化 HIV-1 感染患者的脑部花生四烯酸代谢和血流量，并与神经认知功能障碍的严重程度相关。这项研究应确定 HIV-1 感染过程中的神经炎症，并建立 HAND 治疗效果的替代生物标志物。 氟化花生四烯酸的合成和体内药代动力学：对人类神经炎症成像的影响。神经炎症期间，花生四烯酸 (AA) 从膜磷脂中释放出来，我们使用 1-11CAA 和 PET 报告，大脑 AA 代谢上调作为阿尔茨海默病 (AD) 患者神经炎症的生物标志物。然而，11C的放射性半衰期很短（20分钟），限制了其在具有可合成1-11CAA的回旋加速器站点的研究中心的使用。作为开发临床上有用的 (18)F-氟花生四烯酸 ((18)F-FAA) 的第一步，该酸具有 109.8 分钟的长放射性半衰期，可以在多个地点合成或从商业来源提供，我们开发了一种非放射性 20-(19)F-FAA 的高产率立体选择性合成方法。未麻醉小鼠静脉注射后，其脑摄取、分布和动力学与天然 AA 的摄取相同（用 1-14CAA 测量）。这些结果表明，将我们的 (19)F-FAA 立体选择性合成方法转化为合成正电子发射 (18)F-FAA 来成像 AD 和其他神经炎症性疾病中的脑 AA 代谢是可行的，并且可以在多个临床中心以比 11C-AA 更高的分辨率常规进行成像 (2)。 二十二碳六烯酸代谢 将二十二碳六烯酸 (DHA) 纳入人脑，作为脑脂质代谢和神经传递紊乱的生物标志物。二十二碳六烯酸（DHA，22:6n-3）对于维持正常的大脑结构和功能至关重要，并且被认为具有神经保护作用。膳食 DHA 补充剂已在阿尔茨海默病患者中进行了测试，据报道，此类患者的血浆浓度有所降低。它的大脑浓度取决于膳食 DHA 含量以及膳食衍生的 n-3 前体 α-亚麻酸的肝脏转化。我们开发了一种大鼠体内方法，使用定量放射自显影术和静脉注射放射性标记的 DHA 来测量 DHA 掺入大脑的情况，并表明掺入率等于大脑代谢 DHA 消耗的速度。然后，我们通过正电子发射断层扫描 (PET) 将该方法扩展到人类（Umhau 等人，使用正电子发射断层扫描将循环二十二碳六烯酸成像纳入人脑，J. Lipid Res, 50, 1259, 2009）。我们现在使用 PET 来量化慢性酒精中毒和不同脑部疾病患者大脑中 DHA 的掺入情况。 葡萄糖代谢 葡萄糖代谢减少在阿尔茨海默病风险对象中的作用。在一篇批判性评论中，我们指出，对于有阿尔茨海默病 (AD) 风险的人来说，在可测量的认知能力下降之前，可能就存在较低的大脑葡萄糖代谢。大脑代谢低下可能先于神经病理级联反应，并导致导致认知能力下降。 AD 中的神经退行性过程进一步降低了大脑葡萄糖代谢，因为突触功能减少，从而减少了能量需求，从而完成了恶性循环。通过打破这一循环来降低 AD 风险的策略应旨在 (1) 通过改善全身葡萄糖利用率来提高胰岛素敏感性，或 (2) 使用安全诱导轻度、可持续酮血症的方法绕过恶化的脑葡萄糖代谢 (1)。