基于“肾生髓”理论应用fMRI技术探讨补肾法治疗Alzheimer病的机理

The traditional Chinese theory of "Kidney Generating Marrow" considers that kidney is the foundation of life, behavior and brain activity. The basic pathogenesis of Alzheimer's disease (AD) is brain disfunction induced by "the insufficiency of kidney essence and decreasing of kidney function". Based on this theory, kidney is the target of treating AD patients in traditional Chinese medicine. It has been reported that Bushen medicine (e.g."Zuogui pills" and "Yougui pills") could improve AD petients' symptoms and delay AD progress in clinical practice. ..This study is guided by the theory of "Kidney Generating Marrow". The subjects with AD of renal deficiency type will be recruited and divided into two groups, which are the deficiency of kidney-YIN group and the deficiency of kidney-YANG group, respectively. Non-invasive brain functional MR imaging techniques will be used to measure the volume of the hippocampus, thickness of gray matter, integrity of white matter, brain perfusion and cognitive task-induced activity in AD before and after using "Zuogui pill" or "Yougui pill". The purpose of this study is: (1) to observe the relationship between brain structure, function and the patterns of syndrome with fMRI, compared with the normal aged people as the control group; (2) to evaluate the clinical effects of Bushen medicine in AD; and (3) to investigate the mechanism of Bushen method in treating AD with fMRI based on the theory of "Kidney Generating Marrow".

中医"肾生髓"理论认为肾藏精, 精生髓，脑为髓之海。Alzheimer病(AD)的基本病性为本虚标实，"肾精亏虚、髓海渐空"是AD的基本病机，因此从肾论治是中医药治疗AD的根本。补肾中药"左归丸"、"右归丸"能够显著改善AD患者的临床症状，延缓病程进展。本研究在"肾生髓"理论指导下，以肾虚髓减型AD偏肾阴虚患者和偏肾阳虚患者为研究对象，以正常老年人为对照，采用无创的MR脑功能成像技术（弥散张量成像、动脉自旋标记灌注及血氧水平依赖对比成像），分别在左归丸或右归丸治疗前、后检测两组证型AD患者的海马体积、全脑皮层厚度、脑白质完整性、脑血流灌注状态及认知任务刺激下的脑功能活动，揭示中医证型与脑组织结构和功能的关系，并以MMSE和中医证候评分为标准，分别在脑形态和功能两方面评价补肾中药对AD的疗效，进而从影像学角度探讨"肾生髓"理论指导下补肾法治疗AD的作用机理。

本研究在“肾生髓”理论指导下，联合应用多模态MRI成像技术，包括脑结构和功能成像（3D脑结构成像、弥散张量成像、动脉自旋标记灌注及MR波谱成像），以肾虚髓减型AD偏肾阴虚患者和偏肾阳虚患者为研究对象，并以简易精神状态量表评分和中医证候评分为对照，于左归丸或右归丸治疗前、后分别检测AD患者的全脑白质完整性、脑血流灌注状态及代谢物水平，揭示AD中医证型与脑组织结构和功能的关系并从影像学角度探讨“肾生髓”理论指导下补肾法治疗AD的作用机理。主要研究结果如下：1、偏肾阴虚和偏肾阳虚组患者脑质结构间不存在显著差异，尽管MRS提示在右额叶能量代谢物(Cr)两组间存在显著差异，但不足以引起脑功能及血流灌注的不同。2、比较补肾中药治疗前、后两种中医证型脑结构及功能发现，①AD患者脑白质FA值平均值在双侧额叶、颞叶、顶叶、枕叶较治疗前略增加，ADC值平均值在额叶、颞叶有所下降，但均无统计学差异，而在顶叶，治疗后ADC值较前明显降低。提示补肾中药能够改善顶叶脑白质完整性。其中经左归丸治疗后，肾虚髓减型偏肾阴虚组AD患者FA值在额叶、颞叶及顶叶有所上升，但未达统计学水平；ADC值在额叶、颞叶、顶叶及后扣带回均有不同程度下降，但未达统计学水平。提示左归丸能够在一定程度上提高肾虚髓减型偏肾阴虚AD患者的脑白质完整性，从而降低脑白质ADC值，升高FA值，尤其是在额叶、颞叶、顶叶及后扣带回。经补肾中药右归丸治疗后，肾虚髓减型偏肾阳虚组AD患者FA值在顶、枕叶及前扣带回有不同程度升高，其中前扣带回FA值较治疗前明显升高，ADC值在顶、枕叶及前扣带回有不同程度下降，但未达统计学水平。提示右归丸能够在一定程度上提高肾虚髓减型偏肾阳虚AD患者顶、枕叶及前扣带回的脑白质完整性，从而降低该部位ADC值，升高FA值。② 经补肾中药左归丸、右归丸治疗后，脑白质血流灌注CBF平均值在右侧额叶、前扣带回及左侧顶叶、枕叶有所增加，但无统计学差异。提示补肾中药能够在一定程度上增加脑血流量，但对于两侧大脑半球的血流作用并不完全一致。③ 比较补肾中药治疗前后脑内代谢物的变化发现，经补肾中药治疗后，在前扣带回Cho/Cr比值较前明显升高，提示细胞膜代谢合成较前旺盛造成Cho升高所致；两侧额叶NAA、Cr及右额叶Cho均较前增高，但未达到统计学差异水平，提示补肾中药左、右归丸能够在一定程度上提高神经元活性、细胞膜合成及能量代谢