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

升级 AdaptiSPECT-C 以实现脑淋巴管和脉管系统的高空间分辨率成像，以推进阿尔茨海默病的治疗

• 批准号: 10289194
• 负责人: LARS R FURENLID
• 金额: $ 38.74万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289194
• 关键词: Aducanumab; Adverse event; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease therapy; Amyloid; Anatomy; Antibodies; Antisense Oligonucleotides; Applications Grants; Arizona; Biomedical Research; Brain; Brain Diseases; Brain imaging; Caliber; Calibration; Characteristics; Clinic; Clinical; Clinical Data; Code; Collimator; Complex; Computer software; Data; Dementia; Detection; Development; Diagnostic; Differential Diagnosis; Discipline of Nuclear Medicine; Disease; Distributional Activity; Documentation; Dose; Drug Industry; Drug Kinetics; Educational process of instructing; Face; Failure; Future; Gamma Rays; Generations; Geometry; Head; Human; Image; Image Analysis; Imaging Device; Kinetics; Label; Lead; Lesion; Lymphatic; Lymphatic System; Magnetic Resonance Imaging; Maps; Massachusetts; Mechanics; Meningeal lymphatic system; Modeling; Monitor; Motion; Names; Organ; Patient Care; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Photons; Physiology; Positron-Emission Tomography; Protocols documentation; Radiation Dose Unit; Radioisotopes; Radionuclide Imaging; Research; Research Contracts; Resolution; Rotation; Safety; Sampling; Self-Correction; Sensory Receptors; Slice; Specificity; Structure; Surface; System; Systems Analysis; Testing; Therapeutic; Tracer; United States Food and Drug Administration; Universities; Variant; attenuation; base; biomarker development; brain parenchyma; clinical application; clinical efficacy; clinical imaging; commercialization; cost; design; detector; drug clearance; flexibility; glymphatic system; high resolution imaging; human imaging; human subject; imaging agent; imaging system; improved; individual patient; kinetic model; lymphatic vasculature; lymphatic vessel; molecular imaging; parent grant; performance tests; prototype; quantitative imaging; reconstruction; response; single photon emission computed tomography; tau Proteins; tool

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.

抽象的 寻找减缓或治愈阿尔茨海默病 (AD) 的治疗方法的漫长而昂贵的斗争已经结束 一次又一次的失败；然而，我们终于在抗淀粉样蛋白抗体阿杜卡单抗中看到了一线希望， 目前正在接受美国FDA的优先审查，因此可能成为第一个批准的疾病- AD 的改良疗法随着剂量的增加而提高，但疗效也随之提高。 不良事件的发生，因此了解此类药物的生理学和动力学至关重要。 详细研究药物（包括抗体）从脑实质的清除非常困难，因为 它们通过称为淋巴/类淋巴系统的复杂系统从大脑中清除。 直到最近，传统的教导还认为人脑没有淋巴系统，因此人们可以 很容易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，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 扫描仪的标志 需要通过我们团队对解剖学和生理学的理解进行升级才能完成这项任务。 在这些 MLV 中，我们建议对 AdaptiSPECT-C 进行特定设计升级，这将允许超高 因此，“AdaptiSPECT-C+”将成为研究头顶的无与伦比的工具。 更好地了解大脑中的药物动力学将有助于清除 AD 疗法。 加速未来抗淀粉样蛋白抗体的开发，具有更广泛的治疗窗口以及其他抗体 类药物，例如抗 tau 反义寡核苷酸。

项目成果

Cerebral SPECT imaging with different acquisition schemes using varying levels of multiplexing versus sensitivity in an adaptive multi-pinhole brain-dedicated scanner.

在自适应多针孔脑部专用扫描仪中使用不同水平的多路复用与灵敏度，采用不同的采集方案进行脑 SPECT 成像。

• 发表时间: 2021
• 影响因子: 1.4
• 作者: Zeraatkar, Navid;Kalluri, Kesava S;Auer, Benjamin;May, Micaehla;Richards, R Garrett;Furenlid, Lars R;Kuo, Phillip H;King, Michael A
• 通讯作者: King, Michael A

Investigation of Axial and Angular Sampling in Multi-Detector Pinhole-SPECT Brain Imaging.

多探测器针孔 SPECT 脑成像中轴向和角度采样的研究。

• 发表时间: 2020-12
• 影响因子: 10.6
• 作者: Zeraatkar, Navid;Kalluri, Kesava S;Auer, Benjamin;Konik, Arda;Fromme, Timothy J;Furenlid, Lars R;Kuo, Phillip H;King, Michael A
• 通讯作者: King, Michael A

Mesh modeling of system geometry and anatomy phantoms for realistic GATE simulations and their inclusion in SPECT reconstruction.

系统几何和解剖模型的网格建模，用于真实的 GATE 模拟并将其包含在 SPECT 重建中。

• 发表时间: 2023-03-29
• 影响因子: 3.5
• 作者: Auer, Benjamin;Könik, Arda;Fromme, Timothy J;De Beenhouwer, Jan;Kalluri, Kesava S;Lindsay, Clifford;Furenlid, Lars R;Kuo, Philip H;King, Michael A
• 通讯作者: King, Michael A

Inclusion of quasi-vertex views in a brain-dedicated multi-pinhole SPECT system for improved imaging performance.

将准顶点视图纳入大脑专用多针孔 SPECT 系统中，以提高成像性能。

• 发表时间: 2021-01-27
• 影响因子: 3.5
• 作者: Auer, Benjamin;Zeraatkar, Navid;Goding, Justin C;Könik, Arda;Fromme, Timothy J;Kalluri, Kesava S;Furenlid, Lars R;Kuo, Phillip H;King, Michael A
• 通讯作者: King, Michael A

Improvement in sampling and modulation of multiplexing with temporal shuttering of adaptable apertures in a brain-dedicated multi-pinhole SPECT system.

在脑专用多针孔 SPECT 系统中通过自适应孔径的时间关闭来改进多路复用的采样和调制。

• 发表时间: 2021-03-02
• 影响因子: 3.5
• 作者: Zeraatkar, Navid;Auer, Benjamin;Kalluri, Kesava S;May, Micaehla;Momsen, Neil C;Richards, R Garrett;Furenlid, Lars R;Kuo, Phillip H;King, Michael A
• 通讯作者: King, Michael A