Cellular Viscosity as a Marker for Alzheimer’s Disease Pathology: A Combined Multiparametric MR Spectroscopy and PET Study

细胞粘度作为阿尔茨海默病病理学的标志物：多参数 MR 波谱和 PET 联合研究

• 批准号: 10739995
• 负责人: Ivan Ivanov Kirov
• 金额: $ 75.55万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739995
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease pathology; American; Amyloid beta-Protein; Appearance; Astrocytes; Atrophic; Axonal Transport; Basic Science; Biochemistry; Biological Markers; Brain; Cell physiology; Cells; Clinical; Cognitive; Complement; Cytoskeleton; Data; Deposition; Disease; Disease Progression; Evaluation; Exhibits; Fingerprint; Functional disorder; Funding; Future; Homeostasis; Hypertrophy; Image; Impaired cognition; Impairment; Individual; Inflammation; Life; Link; Liquid substance; Longitudinal Studies; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Metabolic Marker; Methods; Mitochondria; Molecular; Monitor; Motivation; N-acetylaspartate; Names; Nerve Degeneration; Neurocognitive; Neurons; Outcome; Pathology; Patients; Phase Transition; Plasma; Positron-Emission Tomography; Process; Property; Proteins; Protocols documentation; Relaxation; Reproducibility; Research; Research Design; Scanning; Signal Transduction; Solid; Structure; Techniques; Testing; Time; Variant; Viscosity; Work; abeta accumulation; cell type; cognitive function; cohort; comparison control; cost effective; disease prognosis; early detection biomarkers; fluorescence imaging; fluorodeoxyglucose positron emission tomography; follow-up; imaging biomarker; improved; in vivo; mild cognitive impairment; myoinositol; neurocognitive test; neuroinflammation; novel; novel marker; predictive marker; prognostication; response; routine imaging; tau Proteins; tau aggregation; uptake

Project Summary The number of Americans with Alzheimer’s Disease (AD) is projected to reach almost 14 million by 2050, highlighting the urgent need for biomarkers to monitor and predict disease progression, especially at its early stages. The existing “AT(N)” framework includes imaging of three key AD hallmarks: amyloid beta (Aβ) plaques (A) and tau neurofibrillary tangles (T), using Positron Emission Tomography (PET); and neurodegeneration (N), using structural MRI volumetry and Fluorodeoxyglucose PET. These AT(N) markers provide the crucial ability to stage AD, but are not fully capable of robust prognostication of disease progression, especially in early disease. Imaging biomarkers for other important molecular processes and homeostatic networks impaired in AD, are therefore needed to complement the AT(N) framework. This project proposes the use of magnetic resonance-based biomarkers of intracellular viscosity, which is of fundamental importance for proper cellular function, and is closely linked to AD pathophysiology. We recently pioneered a rapid and robust technique termed Magnetic Resonance Spectroscopic Fingerprinting (MRSF), which can quantify changes to intracellular viscosity separately within neurons and astrocytes. MRSF does so by measuring the relaxation times (T1, T2) of two cell-type specific metabolites: N-acetyl-aspartate (NAA), which is confined to neurons, and myo-inositol (mI), which is confined to astrocytes. We have received approval from the NIA-funded NYU AD Research Center to include our MRSF sequence within their routine tau-PET/MRI protocol. This will allow a serial follow-up of a large cohort of cognitively normal individuals and patients with mild cognitive impairment. Both sets of subjects will undergo yearly neurocognitive assessments, plasma Aβ and plasma tau evaluations; and biennial Aβ-PET, tau-PET, and MRI+MRSF scans. The project has the following hypotheses: (H1) Reduced NAA relaxation times, and elevated mI relaxation times will predict the hallmarks of AD progression: cognitive decline, atrophy and tau accumulation. (H2) These relaxation times, alongside NAA and mI concentrations, will improve the ability of Aβ-PET, tau-PET and MRI atrophy to predict future cognitive decline. (H3) Replacing Aβ-PET and tau-PET in H2 by cost-effective and easy-to-collect plasma Aβ and plasma tau will provide the same or better statistical power for predicting cognitive decline. The expected outcome of this work is a set of novel markers for neuronal and astrocytic intracellular viscosity which will potentially become biomarkers for early prediction of neurodegeneration and cognitive decline in AD, addressing gaps in the current imaging armamentarium of the AT(N) network.

项目摘要 到2050年，患有阿尔茨海默病（AD）的美国人预计将达到近1400万， 强调迫切需要生物标志物来监测和预测疾病进展，特别是在其早期 阶段现有的“AT（N）”框架包括三个关键AD标志的成像：淀粉样β（Aβ）斑块 (A)和tau神经元缠结（T），使用正电子发射断层扫描（PET）;和神经变性（N）， 使用结构MRI容积法和氟脱氧葡萄糖PET。这些AT（N）标记物提供了关键的能力， AD期，但不能完全可靠地预测疾病进展，尤其是在早期疾病中。 AD中其他重要分子过程和稳态网络受损的成像生物标志物， 因此，需要补充AT（N）框架。 该项目提出使用基于磁共振的细胞内粘度生物标志物， 对于适当的细胞功能至关重要，并且与AD病理生理学密切相关。我们最近 开创了一种快速而强大的技术，称为磁共振光谱指纹（MRSF）， 其可以分别量化神经元和星形胶质细胞内细胞内粘度的变化。MRSF这样做 通过测量两种细胞类型特异性代谢物的弛豫时间（T1，T2）：N-乙酰基-天冬氨酸（NAA）， 局限于神经元，而肌醇（mI）局限于星形胶质细胞。我们已获得批准， NIA资助的纽约大学AD研究中心将我们的MRSF序列纳入其常规tau-PET/MRI中 议定书这将允许对认知正常个体和轻度认知障碍患者的大队列进行连续随访。 认知障碍两组受试者将接受年度神经认知评估，血浆Aβ和 血浆tau评价;以及两年一次的Aβ-PET、tau-PET和MRI+MRSF扫描。该项目有以下内容 假设：（H1）NAA弛豫时间减少和mI弛豫时间升高将预测以下特征： AD进展：认知下降、萎缩和tau蛋白蓄积。(H2)这些放松时间，以及NAA 和mI浓度，将提高Aβ-PET、tau-PET和MRI萎缩预测未来认知功能的能力。 下降(H3)用具有成本效益且易于收集的血浆Aβ和血浆替代H2中的Aβ-PET和tau-PET tau将提供相同或更好的预测认知衰退的统计功效。 这项工作的预期成果是一组新的神经元和星形胶质细胞细胞内粘度的标志物 其将潜在地成为早期预测AD中的神经变性和认知下降的生物标志物， 解决AT（N）网络的当前成像设备中的差距。