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: 8736483
• 负责人: Stanley I. Rapoport
• 金额: $ 39.52万
• 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/8736483
• 关键词: Acids; Acute; Aftercare; Age; Aging; Alcohol withdrawal syndrome; Alzheimer' s Disease; Amyloid; Animal Model; Arachidonic Acids; Area; Atrophic; Autopsy; Avidity; Award; Behavior; Biological; Biological Markers; Bipolar Disorder; Blood flow; Brain; Brain Diseases; Brain Injuries; Brain imaging; Cerebrovascular Circulation; Chronic; Clinical; Clinical Protocols; Cognition; Collaborations; Consumption; Cyclotrons; Data; Dementia; Depressed mood; Diffuse; Disease; Docosahexaenoic Acids; Drug Kinetics; Drug effect disorder; Fatty Acids; Functional disorder; Goals; Grant; HIV; HIV-1; Half-Life; Heavy Drinking; Human; Image; Impaired cognition; Infection; Institutes; Institutional Review Boards; Isotopes; Kinetics; Label; Ligands; Magnetic Resonance Imaging; Measures; Medicine; Membrane; Metabolic; Metabolism; Methods; Modeling; Mood stabilizers; Mus; National Institute of Allergy and Infectious Disease; National Institute of Neurological Disorders and Stroke; Neurocognitive; Neurosciences; New York; Pathologic Processes; Patients; Phospholipids; Pilot Projects; Plasma; Positron; Positron-Emission Tomography; Prevalence; Process; Protocols documentation; Psychiatry; Publishing; Radioactive; Radiochemistry; Radiolabeled; Rattus; Regenerative Medicine; Reporting; Research; Research Personnel; Research Support; Resolution; Rodent; Safety; Scientist; Severities; Site; Source; Testing; Transgenic Organisms; Translating; Traumatic Brain Injury; Treatment Efficacy; United States National Institutes of Health; Virus Diseases; Work; aging brain; antiretroviral therapy; base; brain tissue; cerebral atrophy; cohort; disease diagnosis; drinking; excitotoxicity; glucose metabolism; imaging modality; in vivo; intravenous injection; medical schools; neuroimaging; neuroinflammation; neurotransmission; non-smoking; open label; preclinical study; problem drinker; radiotracer; response; uptake

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 upregulated AA incorporation as a marker of neuroinflammation in 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 NIH-grant supported 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 accumulation (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 prolonged 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 (AA) 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). In collaboration with scientists at NIAID, we are submitting a collaborative clinical protocol to the NIAID IRB to quantify brain AA metabolism and blood flow using PET in HIV-1 infected patients, in relation to severity of neurocognitive dysfunction (M. DeMascio PI. Protocol: Imaging Neuroinflammation in HIV infection with Radiolabeled Arachidonic Acid and PET). This study should identify neuroinflammation in the course of HIV-1 infection, and to establish a surrogate biomarker for efficacy of therapy against HAND. BRAIN IMAGING IN BIPOLAR DISORDER PATIENTS. We reported that the postmortem brain from bipolar disorder (BD) demonstrated increased markers of neuroinflammation, in association with increased markers of upregulated arachidonic acid (AA) metabolism. Taken in the context of our findings that mood stabilizers used in BD downregulate rat brain AA metabolism, Dr. Elizabeth Sublette at New York Psychiatric Institute has initiated a NIH Grant-supported collaborative clinical protocol to image brain AA metabolism, using our PET method in depressed patients with BD, compared to healthy controls (Pilot PET study characterizing 1-11C AA in bipolar disorder). PET ARACHIDONIC ACID IN TRAUMATIC BRAIN INJURY. In collaboration with colleagues at the NINDS and USUHS, we are preparing a protocol for submission to conduct an open-label, proof of principle, pilot study to assess the safety and feasibility of treating patients with acute traumatic brain injury (TBI) with supplemental docosahexaenoic acid (DHA, 22:6n-3). The goal is to image the brain of human TBI subjects with PET following administration of radiolabeled arachidonic acid (AA, 20:4 n-6), 1-11CAA-PET, before and after treatment with DHA, to demonstrate changes in the incorporation of AA in brain tissue. We hypothesize that incorporation of circulating, unesterified AA will be increased in wide areas of the brain in TBI subjects with diffuse MRI abnormalities as well as regionally increased in the vicinity of focal MRI abnormalities due to neuroinflammation and brain damage. These changes can be quantified as an increase in the incorporation coefficient, K*, and the incorporation rate, Jin (K* x plasma unesterified AA concentration), by means of a validated PET method. Treatment with supplemental DHA could reduce AA incorporation thereby providing key evidence for its biological response in human brain after TBI. A grant supporting this research has been awarded from the Center for Neuroscience and Regenerative Medicine (CNRM). NEW PET LIGAND SYNTHESIS AND PHARMACOKINETICS OF FLUORINATED ARACHIDONIC ACID FOR IMAGING NEUROINFLAMMATION. 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 on 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 (1). DOCOSAHEXAENOIC ACID METABOLISM IS INCREASED IN CHRONIC ALCOHOLICS ATROPHY CORRECTED BRAIN DOCOSAHEXAENOIC ACID INCORPORATION AND BLOOD FLOW ARE INCREASED IN CHRONIC ALCOHOLICS In animal models, excessive alcohol consumption is reported to reduce brain docosahexaenoic acid (DHA) concentration, suggesting disturbed brain DHA metabolism. We hypothesized that brain DHA metabolism and regional cerebral blood flow (rCBF) also are abnormal in chronic alcoholics. We compared 15 non-smoking chronic alcoholics, studied within 7 days of their last drink, with 22 non-smoking healthy controls. Using our published neuroimaging methods with PET, we measured regional coefficients (K*) and rates (Jin) of DHA incorporation from plasma into the brain of each group using 1-11CDHA, and regional cerebral blood flow (rCBF) using 15Owater. Data were partial volume error corrected for brain atrophy. Plasma unesterified DHA concentration was quantified. Mean K* for DHA was significantly and widely elevated by 10-20%, and rCBF was elevated by 7%-34%, in alcoholics compared with controls. Unesterified plasma DHA did not differ significantly between groups nor did whole brain Jin, the product of K* and unesterified plasma DHA concentration. Significantly higher values of K* in alcoholics indicate increased brain avidity for DHA, thus a brain DHA metabolic deficit vis--vis plasma DHA availability. Higher rCBF in alcoholics suggests increased energy consumption. These changes may reflect a hypermetabolic state related to early alcohol withdrawal, or a general brain metabolic change in chronic alcoholics. (2)

神经炎症 用放射性标记的花生四烯酸对阿尔茨海默病的神经炎症进行成像：我们报道了放射性标记的花生四烯酸 (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 证实存在上调的 AA 掺入作为神经炎症的标志物 阿尔茨海默病（AD）患者（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，正在开展一项由 NIH 拨款支持的方案，以扩展这一观察范围，并使用 PET 在更大的 AD 患者队列中使用 PET 来研究 1-11CAA 的神经影像神经炎症和脑葡萄糖代谢与痴呆严重程度和脑淀粉样蛋白积累的关系（成像） 使用 11CA 花生四烯酸和 PET 治疗阿尔茨海默病的神经炎症，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% 的人在长期抗逆转录病毒治疗期间出现 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 (AA) 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）。我们与 NIAID 的科学家合作，向 NIAID IRB 提交了一份合作临床方案，使用 PET 来量化 HIV-1 感染患者的大脑 AA 代谢和血流量，并与神经认知功能障碍的严重程度相关（M. DeMascio PI。方案：用放射性标记花生四烯酸和 PET 对 HIV 感染中的神经炎症进行成像）。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。 双相情感障碍患者的脑成像。我们报道，双相情感障碍（BD）死后大脑显示神经炎症标志物增加，与花生四烯酸（AA）代谢上调标志物增加相关。 鉴于我们的发现，BD 中使用的情绪稳定剂会下调大鼠大脑 AA 代谢，纽约精神病学研究所的 Elizabeth Sublette 博士启动了一项由 NIH 资助支持的合作临床方案，以对 BD 抑郁症患者与健康对照组进行比较，使用我们的 PET 方法对大脑 AA 代谢进行成像（试点 PET 研究描述了双相情感障碍中的 1-11C AA）。 宠物花生四烯酸在脑外伤中的作用。我们正在与 NINDS 和 USUHS 的同事合作，准备一份提交方案，以进行开放标签、原理验证、试点研究，以评估补充二十二碳六烯酸（DHA，22:6n-3）治疗急性创伤性脑损伤 (TBI) 患者的安全性和可行性。 目标是在使用 DHA 治疗之前和之后，使用放射性标记的花生四烯酸（AA，20:4 n-6）、1-11CAA-PET 对人类 TBI 受试者的大脑进行 PET 成像，以证明 AA 在脑组织中掺入的变化。我们假设，在具有弥漫性 MRI 异常的 TBI 受试者中，循环中的未酯化 AA 的掺入量在大脑的广泛区域会增加，并且由于神经炎症和脑损伤，在局灶性 MRI 异常附近的区域会增加。这些变化可以通过经过验证的 PET 方法量化为掺入系数 K* 和掺入率 Jin（K* x 血浆未酯化 AA 浓度）的增加。 补充 DHA 治疗可以减少 AA 的掺入，从而为 TBI 后人脑中 AA 的生物反应提供关键证据。神经科学和再生医学中心 (CNRM) 授予了支持这项研究的拨款。 新宠物配体 用于神经炎症成像的氟化花生四烯酸的合成和药代动力学。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），限制了其在现场拥有可合成 1-11CAA 回旋加速器的研究中心的使用。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 (1)。 长期饮酒时二十二碳六烯酸代谢增加 慢性饮酒者大脑萎缩得到纠正，二十二碳六烯酸掺入和血流量增加 在动物模型中，据报道，过量饮酒会降低大脑二十二碳六烯酸 (DHA) 浓度，这表明大脑 DHA 代谢受到干扰。 我们假设慢性酗酒者的大脑 DHA 代谢和局部脑血流量 (rCBF) 也存在异常。我们将 15 名不吸烟的慢性酗酒者与 22 名不吸烟的健康对照者进行了比较，并在他们最后一次饮酒后 7 天内进行了研究。使用我们已发表的 PET 神经成像方法，我们使用 1-11CDHA 测量了各组血浆中 DHA 掺入大脑的区域系数 (K*) 和速率 (Jin)，并使用 15O 水测量了区域脑血流量 (rCBF)。数据针对脑萎缩进行了部分体积误差校正。对血浆未酯化的 DHA 浓度进行定量。与对照组相比，酗酒者的 DHA 平均 K* 显着且广泛升高 10-20%，rCBF 升高 7%-34%。未酯化血浆 DHA 在各组之间没有显着差异，全脑 Jin（K* 和未酯化血浆 DHA 浓度的乘积）也没有显着差异。酗酒者的 K* 值显着升高表明大脑对 DHA 的渴求增加，因此相对于血浆 DHA 的可用性，大脑 DHA 代谢存在缺陷。酗酒者的 rCBF 较高表明能量消耗增加。这些变化可能反映了与早期戒酒相关的代谢亢进状态，或慢性酗酒者的一般大脑代谢变化。 (2)