Upgrading AdaptiSPECT-C for High Spatial Resolution Imaging of Brain Lymphatics and Vasculature to Advance Therapies for Alzheimer’s Disease

摘要 为了找到延缓或治愈阿尔茨海默病(AD)的治疗方法，这场漫长而昂贵的战斗已经 经历了一次又一次的失败，然而，我们终于在抗淀粉样抗体阿杜卡努单抗中看到了一线希望， 目前正在接受美国食品和药物管理局的优先审查，因此可能成为第一个被批准的疾病- 改良治疗阿尔茨海默病。阿杜卡那单抗的临床疗效随着剂量的增加而提高，但其发生率也随剂量的增加而增加 因此，了解这类药物的生理学和动力学是至关重要的。 从脑实质清除药物，包括抗体，是非常困难的详细研究，因为 它们通过一个名为淋巴/淋巴系统的复杂系统从大脑中清除。事实上， 直到最近，传统的教学方法还认为，人脑没有淋巴系统，所以人们可以 不难想象，需要工具来研究这个新发现的器官。这些大脑的小口径 淋巴管被称为脑膜淋巴管(MLV)，需要高灵敏度和高分辨率 成像，这是革命性的AdaptiSPECT-C扫描仪的特点。即便如此，AdaptiSPECT-C 需要升级才能完成此任务。通过我们团队对解剖学和生理学的理解 在这些MLV中，我们建议对AdaptiSPECT-C进行特定的设计升级，这将允许超高- 在头顶进行分辨率成像。因此，“AdaptiSPECT-C+”将成为研究 从大脑中清除AD疗法。对大脑中药物动力学的更好理解将 加快未来抗淀粉样蛋白抗体的开发，具有更广泛的治疗窗口和其他 类药物如反义tau反义寡核苷酸。

Abstract The long and expensive battle to find a treatment to slow or cure Alzheimer’s disease (AD) has witnessed failure after failure; however, we finally see a ray of hope in the anti-amyloid antibody, aducanumab, which is currently under priority review by the USFDA and thus may become the first approved disease- modifying therapy for AD. Clinical efficacy of aducanumab improves with increasing dose but so does the rate of adverse events, thus understanding the physiology and kinetics of this class of drugs is paramount. Clearance of drugs including antibodies from the brain parenchyma is incredibly difficult to study in detail since they clear from the brain through a complex system called the lymphatic/glymphatic system. Indeed, the traditional teaching until just recently was that the human brain did not have a lymphatic system, so one can easily imagine the need for tools to research this newly discovered organ. The small caliber of these brain lymphatics, known as meningeal lymphatic vessels (MLVs), demand high sensitivity and high-resolution imaging, which are the hallmarks of the revolutionary AdaptiSPECT-C scanner. Even so, AdaptiSPECT-C requires an upgrade to accomplish this task. Through our team’s understanding of the anatomy and physiology of these MLVs, we propose a specific design upgrade to AdaptiSPECT-C, which will allow super high- resolution imaging at the top of the head. “AdaptiSPECT-C+” will thus become an unparalleled tool to study the clearance from the brain of AD therapies. An improved understanding of drug kinetics in the brain will accelerate the development of future anti-amyloid antibodies with a wider therapeutic window and also other classes of drugs such as anti-tau anti-sense oligonucleotides.