Probing the Intracellular Environment in Normal Aging Using Magnetic Resonance

描述（由申请人提供）：本项目拟鉴定对人类大脑衰老过程中细胞水平变化敏感的细胞内分子探针。细胞的变化包括细胞大小缩小，总树突长度减少，总树突节段数量减少。横向弛豫（T2）的MR测量对细胞体大小的减小、细胞内大分子和细胞器组成的改变以及铁含量敏感。另一方面，MR测量，表观扩散系数（ADC），对神经元空间的减少和粘度的变化很敏感。人脑中存在的代谢物主要是细胞内的，有些是细胞特异性的，例如位于神经元中的n -乙酰天冬氨酸和位于胶质细胞中的肌醇。通过测量几种代谢物的T2和ADC值，该方法将专门探测不同的细胞和亚细胞区室。N-乙酰天冬氨酸、总肌酸、总胆碱、谷氨酸和肌醇的T2和ADC值将在可能或可能不受衰老影响的多个脑区进行无创测量。其中一个目的是测量这些代谢物在年轻人和老年人大脑三个区域的T2值，以确定最近在认知正常的老年人中发现的T2值较低是否比枕叶皮层更普遍。一个互补的特定目的是测量相同脑区代谢物的ADC值。测量将在临床相关的3 t场强下进行。测量j偶联代谢物（如谷氨酸和肌醇）T2和ADC值的采集方案将作为次级目标进行优化。数据处理和分析将使用商用软件完全自动化。该项目的成功完成将确定低T2和ADC值在老年人大脑中是否普遍存在。此外，我们将了解代谢物的T2和ADC测量是否对衰老过程中发生的细胞变化敏感和特异性。从长远来看，这一提议有可能导致发现定量的、无创的、细胞内成像生物标志物，这些生物标志物可以在早期诊断、疾病进展监测和神经退行性疾病（如阿尔茨海默病）治疗方法的临床评估中发挥重要作用。

DESCRIPTION (provided by applicant): This project proposes to identify intracellular molecular probes that are sensitive to changes that take place on the cellular level during aging in the human brain. The cellular changes include shrinkage in cell size, decrease in total dendritic length, and total number of dendritic segments. MR measurement of transverse relaxation (T2) is sensitive to reduction in cell body size, modification in the intracellular macromolecular and organelle composition, and iron content. Another, MR measure, the apparent diffusion coefficients (ADC), is sensitive to decrease in neuronal space and changes in viscosity. Metabolites present in the human brain are predominantly intracellular, and some are cell specific, such as N-acetylaspartate that is located in neurons and myo-inositol located in glia. By measuring the T2 and ADC values of several metabolites, the approach will specifically probe differing cellular and subcellular compartments. The T2 and ADC values of N- acetylaspartate, total creatine, total choline, glutamate and myo-inositol will be measured noninvasively in multiple brain regions that may or may not be affected by aging. One aim is to measure T2 values of those metabolites in three brain regions in young and elderly subjects to determine whether recently found lower T2 values in cognitively normal elderly subjects are more widespread than the occipital cortex. A complementary specific aim is to measure ADC values of the metabolites in the same brain regions. The measurements will be performed at the clinically relevant field strength of 3 T. The acquisition protocols for measuring T2 and ADC values of J-coupled metabolites, such as glutamate and myo-inositol, will be optimized as sub aims. The data processing and analysis will be fully automated using commercially available software. Successful completion of this project will determine whether low T2 and ADC values are widespread in the elder human brain. Additionally, we will learn if the T2 and ADC measurements for metabolites are sensitive and specific to cellular changes that take place in aging. Long term, this proposal has the potential to lead towards the discovery of quantitative, non-invasive, intracellular imaging biomarkers which can play an important role in clinical evaluation for early diagnosis, monitoring of disease progression, and testing of therapeutic approaches for neurodegenerative disorders, such as Alzheimer's disease.