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

描述（由申请人提供）：新型正电子发射断层扫描（PET）配体[11 C]花生四烯酸（AA）已在健康志愿者16 -18和阿尔茨海默病19中部分表征，其中观察到AA信号传导上调，与神经炎症相关。该配体的另一个有前途的应用是双相情感障碍（BD）的研究;在BD中AA级联调节异常的假设已经积累了相当多的支持证据。在动物研究中，情绪稳定剂锂、丙戊酸盐、卡马西平和拉莫三嗪下调大脑AA级联反应5。AA不仅仅是药物的普遍应答者，因为托吡酯20获得了阴性结果，后来证明对BD临床无效。在BD患者中，躁狂症状的严重程度与血浆未酯化AA的水平正相关11; AA代谢8和神经炎症12的标志物在死后增加;并且临床恶化被AA代谢的抗炎抑制剂阿司匹林延缓14。目标.该项目的目标是获取有关使用[11 C]AA研究BD神经病理生理学的试验数据。具体目标建议进行以下操作：1）表征BD患者中的[11 C]AA掺入，并与健康志愿者进行比较; 2）扩展[11 C]AA放射性示踪剂的表征; 3）探索基线[11 C]AA脑掺入作为锂临床反应的预测因子。方法. PET扫描将在威尔康奈尔医学院进行，该配体目前用于阿尔茨海默氏症的研究。健康志愿者（n=10）和抑郁、无药物治疗的BD门诊患者（n=10）将分别进行[11 C]AA扫描、[18 F]氟脱氧葡萄糖扫描以测量局部脑活动和MRI扫描。六周后，六名健康志愿者将接受重复扫描，以获得重测数据。扫描后，BD患者将在纽约州精神病学研究所接受为期6周的锂治疗。将使用已建立的方法分析扫描16。将在NIH分析血浆AA水平，用作分析中的协变量。意义BD的病理生理学知之甚少，目前的治疗是不够的。这些初步数据有望阐明使用[11 C]AA研究BD病理生理学的可行性。基线AA掺入和锂反应之间的正相关性将对BD治疗具有重要意义：1）AA级联的分子组分可能是合理设计治疗BD的药物的新靶点; 2）大鼠中的AA级联反应可用作测试潜在的情绪稳定剂和抗抑郁药的生物测定; AA级联反应异常可作为临床反应的生物标志物，有助于个体化治疗。

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.