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

摘要

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.