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 成像涉及多巴胺的人脑信号传导 多巴胺能功能障碍已报道在阿尔茨海默氏病和人类衰老中。为了解决这个问题，我们开发了一种新的方法，使用正电子发射断层扫描（PET）和1-11碳化四烯酸（1-11CAA）以及区域脑血流量（RCBF）对人脑中的多巴胺能神经传递对人脑进行了成像。我们在健康男性中测量了AA和RCBF的区域掺入系数K*，鉴于多巴胺能D1/D2受体激动剂（10或20 mg/kg S.c.）磷灰石或盐水在用三甲苯甲酰胺预处理后，以预防恶性。我们通过观察到血清生长激素的显着增加以及AA掺入的显着增加和减少，在RCBF的RCBF中使用PET显着增加和减少，我们证明了对阿哌汀的强劲中心多巴胺能反应。 AA掺入变化反映了与与磷脂酶A2相连的D2样受体激活相关的神经元信号传导。 RCBF变化代表了D1/D2受体激活的一般功能效应。 1-11CAA PET方法对于研究帕金森氏病，阿尔茨海默氏病和其他疾病的多巴胺能神经传递的干扰应很有用。（3） 神经炎症 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等，J NuclMedicine。200849：1414-21）。 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阿尔茨海默氏病，有11个豆氨酸烯酸和宠物，OHSR豁免＃5877）。 在HIV-1感染受试者中成像神经炎症 全世界有300万人感染了人类免疫缺陷病毒（HIV）-1；在抗逆转录病毒疗法的同时，大约30-50％的人患有HIV-1相关的神经认知障碍（手），手的患病率随着年龄的增长而增加，并导致与阿尔茨海默氏病相互作用。 因此，HIV-1感染是NIA的主要关注点。我们假设HIV-1患者的认知功能障碍会因并发神经炎症而加剧。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（Basselin et al。成像上调脑芳族芳基芳烃芳族芳族酸代谢型在HIV-1 Transgenic Rats。在此基础上，我们正在与NIAID一起编写合作临床方案，该方案与神经认知功能障碍的严重程度有关HIV-1感染患者的PET使用PET量化脑蛛网膜酸代谢和血流。这项研究应在HIV-1感染过程中确定神经炎症，并建立替代生物标志物来抗手的疗效。 氟化蛛网膜酸的合成和体内药代动力学：对人类成像神经炎症的影响。神经炎症期间，蛛网膜酸（AA）从膜磷脂中释放出来，我们报告了使用1-11CAA和PET的阿尔茨海默氏病（AD）患者中神经炎症（AD）患者中神经炎症的生物标志物上调作为神经炎症的生物标志物。但是，11C的放射性半衰期短（20分钟），限制了其用于研究中心的研究中心，该中心具有一个可以合成1-11CAA的旋转器位点。作为开发临床上有用的（18）F-氟核酸（（18）F-FAA）的第一步，其长期放射性半衰期为109.8分钟，可以在多个地点合成或从商业来源传递，我们开发了一种高幼型立体观念方法，用于非降低radioActive actricative consthettical consthettical consthettical consective notradioactive consthetthe for radioactive actractive consthettical overaintive f-f-ai。在未经干燥的小鼠中静脉注射后，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，将我们的立体选择性合成方法转换为（19）F-FAA将正电子发射（18）f-FAA形象化以形象AD和其他神经炎性疾病中的Brain AA代谢形象，并且可以在多种临床中进行较高的临床基础，以比11C-2C-AA（2）进行常规的临床中心。 Docosahexaenoic酸代谢 将Docosahexaenoic Acid（DHA）掺入人脑中，作为脑脂质代谢和神经传递的脑部生物标志物。 Docosahexaenoic Acid（DHA，22：6N-3）对于维持正常的脑结构和功能至关重要，被认为是神经保护作用。在阿尔茨海默氏病患者中，已经对DHA补充剂进行了测试，据报道，此类患者的血浆浓度降低。它的大脑浓度取决于饮食中的N-3前体Alpha-Linolenicac的饮食DHA含量和肝转化。我们使用定量放射自显影和静脉注射放射性标记的DHA开发了一种体内方法，以测量DHA掺入大脑，并表明掺入率等于脑代谢DHA的消耗率。然后，我们扩展了使用正电子发射断层扫描（PET）的人类使用的方法（Umhau等人，使用正电子发射断层扫描术J. Lipid Res，50，1259，2009）将循环docosahexaenoic成像掺入人脑中。现在，我们正在使用PET来量化慢性酒精中毒和不同脑部疾病患者的脑DHA掺入。 葡萄糖代谢 葡萄糖代谢减少在患阿尔茨海默氏病风险的受试者中的作用。在批判性综述中，我们指出，在患有阿尔茨海默氏病风险的人（AD）的人们的认知能力下降开始之前，可能存在较低的脑葡萄糖代谢。脑缺作可能是先前的，并导致神经病理学级联反应导致认知能力下降。 AD中的神经退行性过程进一步降低了大脑葡萄糖代谢，因为突触功能降低并减少了能量需求，从而完成了恶性循环。通过破坏此周期来降低AD风险的策略应（1）通过改善系统性葡萄糖利用来提高胰岛素敏感性，或使用安全诱导轻度，可持续的酮症（1）的方法旁路旁路恶化脑葡萄糖代谢。