Pilot PET Study Characterizing [1-11C] Arachadonic Acid in Bipolar Disorder

PET 试点研究表征双相情感障碍中的 [1-11C] 花生四烯酸

• 批准号: 8510728
• 负责人: M Elizabeth M Sublette
• 金额: $ 23.79万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510728
• 关键词: Acids; Age; Algorithms; Alzheimer' s Disease; Amygdaloid structure; Animals; Anterior; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Arachidonic Acids; Aspirin; Astrocytes; Autopsy; Biochemical Pathway; Biological Assay; Biological Markers; Bipolar Disorder; Brain; Carbamazepine; Cerebrum; Clinical; Data; Deoxyglucose; Depressed mood; Deterioration; Development; Dorsal; Dose; Drug Design; Functional disorder; Future; Glucose; Goals; Hamilton Rating Scale for Depression; Human; Individual; Institutes; Ligands; Lithium; MRI Scans; Manic; Maps; Measures; Mental Depression; Metabolic; Methods; Modeling; Molecular; Mood stabilizers; Moods; Outcome Measure; Outpatients; Participant; Patients; Pharmaceutical Preparations; Phospholipids; Plasma; Positron-Emission Tomography; Publishing; Race; Rattus; Regulation; Reporting; Reproducibility; Sample Size; Sampling; Scanning; Severities; Signal Transduction; Structure; Symptoms; Testing; Therapeutic; Thinking; Tracer; United States National Institutes of Health; base; cingulate cortex; clinical practice; cost; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose uptake; gray matter; healthy volunteer; improved; inhibitor/antagonist; interest; lamotrigine; medical schools; neuroinflammation; novel; primary outcome; public health relevance; radiotracer; regional difference; response; sex; suicide mortality; uptake; valproate

DESCRIPTION (provided by applicant): The novel positron emission tomography (PET) ligand [11C] Arachidonic Acid (AA) has been partially characterized in healthy volunteers16-18 and in Alzheimer's disease19, in which upregulated AA signaling has been observed, associated with neuroinflammation. Another promising application for this ligand is the study of Bipolar Disorder (BD); the hypothesis that regulation of the AA cascade is abnormal in BD has accumulated considerable supporting evidence. In animal studies, mood stabilizers lithium, valproate, carbamazepine, and lamotrigine downregulate the brain AA cascade5. AA is not simply a ubiquitous responder to drugs, as negative results were obtained with topiramate20, later shown to be clinically ineffective for BD. In BD patients, manic symptom severity correlates positively with levels of plasma unesterified AA11; markers of AA metabolism8 and neuroinflammation12 are increased postmortem; and clinical deterioration is retarded by aspirin, an anti- inflammatory inhibitor of AA metabolism14. Goal. The project goal is to acquire pilot data concerning use of [11C]AA to study neuropathophysiology of BD. Specific aims propose to do the following: 1) characterize [11C]AA incorporation in patients with BD and compare with healthy volunteers; 2) extend the characterization of the [11C]AA radiotracer; and 3) explore baseline [11C]AA brain incorporation as a predictor of clinical response to lithium. Methods. PET scans will take place at Weill Cornell Medical College, where the ligand is currently in use for the study of Alzheimer's. Healthy volunteers (n=10) and depressed, medication-free outpatients with BD (n=10) will each have a [11C]AA scan, a [18F]fluoro- deoxyglucose scan to measure regional brain activity, and an MRI scan. Six healthy volunteers will have repeat scans six weeks later, for test-retest data. BD patients will be treated with lithium for 6 weeks at NYS Psychiatric Institute after scanning. Scans will be analyzed using established methods16. Plasma AA levels will be analyzed at NIH for use as a covariate in analyses. Significance. The pathophysiology of BD is poorly understood, and current treatments are inadequate. These pilot data are expected to clarify the feasibility of using [11C]AA to study BD pathophysiology. Positive associations between baseline AA incorporation and lithium response would have important implications for BD treatment: 1) molecular components of the AA cascade may be novel targets for rational design of drugs to treat BD; 2) AA cascade responses in rats could be useful as a bioassay for testing potential mood stabilizers and perhaps also antidepressants; and 3) AA cascade abnormalities might serve as a biomarker for clinical response that would facilitate individualized treatment.

描述（由申请人提供）：新型正电子发射断层扫描（PET）配体[11C]蛛网膜含量（AA）在健康志愿者中部分表征了16-18和阿尔茨海默氏病19，在该志愿者中，观察到上调AA信号的上调，与神经炎症相关。该配体的另一个有希望的应用是对躁郁症（BD）的研究。 BD中AA级联反应异常的假设积累了大量支持证据。在动物研究中，情绪稳定锂，丙丙酸酯，卡马西平和拉莫三嗪下调大脑AA Cascade5。 AA不仅是对药物的无处不在响应者，因为托吡酯20获得了负结果，后来证明BD在临床上无效。在BD患者中，躁狂症状严重程度与血浆未酯化AA11的水平正相关。 AA代谢8和神经炎症的标记12增加了死后；临床恶化会受到AAS代谢的抗炎性抑制剂的阿司匹林的阻碍14。目标。项目目标是获取有关使用[11C] AA研究BD神经病理生理学的试验数据。具体目的建议进行以下操作：1）在BD患者中表征[11C] AA掺入并与健康的志愿者进行比较； 2）扩展[11C] AA radiotracer的表征； 3）探索基线[11C] AA脑掺入作为对锂的临床反应的预测指标。方法。 PET扫描将在Weill Cornell医学院进行，该学院目前正在使用配体进行研究。健康的志愿者（n = 10）和抑郁症，无BD（n = 10）的无药物门诊患者将具有[11C] AA扫描，[18F]氟脱氧葡萄糖扫描以测量区域脑活动，并进行MRI扫描。六个星期后，六名健康志愿者将重复扫描，以获取重测数据。扫描后，在NYS精神病学研究所将BD患者用锂治疗6周。将使用既定方法16分析扫描。 NIH将分析血浆AA水平，以作为分析的协变量。意义。 BD的病理生理学知之甚少，目前的治疗不足。这些试验数据有望阐明使用[11C] AA研究BD病理生理学的可行性。基线AA掺入与锂反应之间的正相关对BD处理具有重要意义：1）AA级联反应的分子成分可能是治疗BD的有理设计的新目标； 2）大鼠中的AA级联反应可作为测试潜在情绪稳定剂以及抗抑郁药的生物测定方法； 3）AA级联异常可能是临床反应的生物标志物，可以促进个性化治疗。