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[11C]花生四烯酸（AA）已在健康志愿者16-18和阿尔茨海默病19中得到部分表征，其中观察到AA信号上调，与神经炎症有关。该配体的另一个有前途的应用是双相情感障碍（BD）的研究；AA级联调节在BD中异常的假说已经积累了大量的支持证据。在动物实验中，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不仅仅是一种普遍存在的药物反应，因为托吡amate20的阴性结果，后来被证明对双相障碍无效。在双相障碍患者中，躁狂症状的严重程度与血浆未酯化的AA11水平呈正相关；死后AA代谢指标8和神经炎症指标12升高；阿司匹林（一种AA代谢的抗炎抑制剂）可延缓临床恶化。的目标。项目目标为获取[11C]AA在BD神经病理生理学研究中的先导数据，具体目标为：1)表征[11C]AA在BD患者中的掺入特征，并与健康志愿者进行比较；2)扩展了[11C]AA放射性示踪剂的表征；3)探索基线[11C]AA脑合并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，该配体目前正用于阿尔茨海默氏症的研究。健康志愿者（n=10）和抑郁、无药物治疗的双相障碍门诊患者（n=10）将分别进行[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。六名健康志愿者将在六周后接受重复扫描，以获取测试-再测试数据。BD患者将在扫描后在NYS精神病学研究所接受6周的锂治疗。扫描将使用既定的方法进行分析。血浆AA水平将在NIH进行分析，作为分析中的协变量。的意义。双相障碍的病理生理机制尚不清楚，目前的治疗方法也不充分。这些试点数据有望阐明使用[11C]AA研究双相障碍病理生理的可行性。基线AA掺入与锂反应之间的正相关对双相障碍治疗具有重要意义：1)AA级联的分子成分可能是合理设计治疗双相障碍药物的新靶点；2)大鼠的AA级联反应可以作为一种生物测定方法，用于测试潜在的情绪稳定剂和抗抑郁药；3) AA级联异常可能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.