Nanoparticles for detecting noradrenergic neurons in Alzheimer's Disease

摘要： 阿尔茨海默病(AD)是一种进行性神经系统疾病，其特点是 存在淀粉样蛋白斑块、神经原纤维缠结和认知缺陷。这个 这种疾病造成的经济影响令人震惊，预计将超过1万亿美元 美元，到2050年。早期诊断和治疗可以大大减少 与AD相关的经济负担。具体地说，能够评估早期病理 特定脑区的变化可能有助于诊断和治疗。这个 蓝斑(LC)，它提供去甲肾上腺素能神经支配的大部分 丘脑、皮质和海马体等区域经历了广泛的 神经退行性改变。已经描述了LC中发生的这些变化 作为在AD中观察到的最早的病理，关键的是，至少出现了十年 先于神经认知缺陷。LC去甲肾上腺素能神经元参与 调节认知、觉醒和觉醒等关键神经行为功能。 然而，评估患者在AD病程中LC的变化仍然是一项重要的工作 挑战。 第一阶段拟议研究的主要目标是开发一种有机的 纳米颗粒核磁共振显像剂无创性监测去甲肾上腺素能神经元 在LC中使用AD的临床前模型。我们的初步研究证明 这些纳米颗粒被脑干中的去甲肾上腺素能神经元摄取，并促进 成像过程。我们的具体目标是：1.评估学生的能力 纳米颗粒用于核磁共振成像LC，并与去甲肾上腺素的变化相关 级别。2.评估这些粒子是否可以用来测量退行性变 随着疾病的发展而变化。将这一点转化为更大的动物模型 进行临床前测试将是这次STTR之后的下一步。

Summary: Alzheimer's disease (AD) is a progressive neurological disorder that is marked by the presence of amyloid-ß plaques, neurofibrillary tangles and cognitive deficits. The economic impact of this disease is staggering and is expected to exceed $1 trillion dollars by the year 2050. Early diagnosis and treatment can substantially reduce the economic burden related to AD. Specifically, being able to assess early pathological changes in specific brain areas could be beneficial for diagnosis and treatment. The locus coeruleus (LC), which provides the majority of the noradrenergic innervation to areas such as thalamus, cortex and hippocampus, undergoes extensive neurodegenerative changes. These changes that occur in the LC have been described as the earliest pathologies observed in AD and, critically, appear at least a decade ahead of the neurocognitive deficits. LC noradrenergic neurons are involved in regulating key neurobehavioral functions such as cognition, arousal and wakefulness. However, assessing changes in LC over the course of AD in patients remains a major challenge. The main objective of the proposed research in phase 1 is to develop an organic nanoparticle-based MRI imaging agent to non-invasively monitor noradrenergic neurons in the LC using a preclinical model of AD. Our preliminary studies provide evidence that these nanoparticles are taken by noradrenergic neurons in the brainstem and facilitate the imaging process. Our specific aims are to 1. To assess the ability of the nanoparticles to image the LC using MRI, and correlate with changes in norepinephrine levels. 2. To assess whether these particles can be used to measure degenerative changes as the disease progresses. Translating this to larger animal models and conducting preclinical testing will be next step following this STTR.