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

项目摘要 预计到2050年，美国阿尔茨海默氏症(AD)患者的数量将达到近1400万， 强调迫切需要生物标志物来监测和预测疾病进展，特别是在疾病早期 各阶段。现有的“AT(N)”框架包括对AD的三个关键特征进行成像：淀粉样β蛋白(Aβ)斑块 (A)和tau神经原纤维缠结(T)，使用正电子发射断层扫描(PET)；和神经变性(N)， 采用结构磁共振容积测定仪和氟脱氧葡萄糖PET。这些AT(N)标记提供了至关重要的能力 AD期，但不能完全预测疾病的进展，特别是在早期疾病。 AD中受损的其他重要分子过程和动态平衡网络的成像生物标记物， 因此需要补充AT(N)框架。 该项目建议使用基于磁共振的细胞内粘度生物标记物，这是 对于正常的细胞功能至关重要，并且与AD的病理生理学密切相关。我们最近 开创了一种名为磁共振光谱指纹识别(MRSF)的快速而强大的技术， 它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是这样做的 通过测量两种细胞型特定代谢物：N-乙酰天冬氨酸(NAA)的松弛时间(T1，T2)， 仅限于神经元和肌醇(MI)，后者仅限于星形胶质细胞。我们已经得到了来自 NIA资助的纽约大学AD研究中心将我们的MRSF序列纳入他们的常规tau-PET/MRI 协议。这将允许对一大批认知正常的人和轻度精神病患者进行连续随访。 认知障碍。两组受试者都将接受年度神经认知评估，血浆Aβ和 血浆tau评估；两年一次的β-PET、tau-PET和mri+mrsf扫描。该项目具有以下内容 假设：(H1)NAA松弛时间减少，MI松弛时间增加将预测 AD进展：认知功能衰退、萎缩和tau蓄积。(H2)这些放松时间，以及NAA 和MI浓度，将提高β-PET、tau-PET和磁共振萎缩预测未来认知能力的能力 拒绝。(H3)用经济实惠且易于收集的血浆A-β和血浆取代H2中的A-β和tau-PET Tau将提供相同或更好的统计能力来预测认知能力下降。 这项工作的预期结果是一组神经元和星形胶质细胞内粘度的新标记物。 它们有可能成为早期预测AD患者神经变性和认知功能下降的生物标志物。 解决AT(N)网络当前成像设备中的空白。

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.