Functional consequences of the degeneration of the locus coeruleus-norepinephrine-system in Alzheimer's disease

本项目研究阿尔茨海默病（AD）蓝斑-去甲肾上腺素（LC-NE）系统退化的功能相关因素。为此，我们研究了被认为与lc - na功能相关的行为和生理参数：1)刺激检测任务（古怪范式）中的反应时间和准确性、事件相关电位（P300b）、任务相关瞳孔扩张和事件相关bold信号；2)注意眨眼范式中的反应时间和准确性、事件相关电位（P300b）、任务相关瞳孔扩张。为了证明这些参数实际上取决于去甲肾上腺素能传递，我们在28名健康老年受试者中应用中枢作用ß-受体拮抗剂心得安或安慰剂后，在随机、安慰剂对照的受试者设计研究中获得了这些参数。为了进一步证明这些参数受到AD中众所周知的LC退行性变的影响，我们在30名AD患者（轻度认知障碍或轻度痴呆）和30名年龄匹配的健康对照中获得了这些参数。因此，我们检验了以下假设：i)与安慰剂相比，心得安导致行为测量的准确性降低和反应时间增加；潜伏期增加，诱发电位和瞳孔扩张幅度减小；LC区BOLD信号减弱，皮层BOLD信号延伸减弱；ii)与健康对照相比，AD患者的功能参数发生相同方向的改变，并且这些变化随着疾病分期（AD-痴呆>AD- mci）而增加；ii)变化幅度随MRI结构变化而增加。如果我们能够验证这些假设，这些参数可以用作lc - ne完整性的替代标记物，可以作为下一步在AD患者的激动性药物操作中使用。

This projects investigates functional correlates of the degeneration of the locus coeruleus-norepinephrine (LC-NE)-system in Alzheimer's disease (AD). For this purpose we investigate behavioral and phyiological parameters which are supposed to be correlates of LC-NA-functionality: i) reaction times and accuracy, event related potential (P300b), task related pupilar dilatation and event related BOLD-signal in a stimulus detection task (oddball paradigm), ii) reaction times and accuracy, event related potential (P300b), task related pupilar dilatation in an attential blink paradigm. In order to demonstrate that these parameters actually depend on noradrenergic transmission we obtain them in a randomized, placebo-controlled within-subject-design study after application of the central acting ß-receptor anatgonist Propranolol or Placebo in 28 healthy older subjects. In order to further demonstrate that the parameters are affected by the well known degeneration of the LC in AD we obtain them in 30 AD-patients (with mild cognitive impairment or mild dementia) and 30 age-matched healthy controls. We thereby test the hypothesis that: i): Propranolol compared to placebo leads to decreased accuracy and increased reaction times in the behavioral measures; increased latency and decreased amplitude in evoced potentials and pupil dilatation; decreased BOLD signal in the LC area and in decreased extension of the cortical BOLD signal; ii) the functional parameters are altered in the same direction in AD patients as compared to healthy controls, and that these changes increases with disease stage (AD-dementia>AD-MCI); ii) the magnitude of the changes increases with structural MRI changes. If we can verify these hypotheses the parameters can be used as surrogate markers of LC-NE-integrity which can be used in agonistic pharmacomanipulations in AD patients as a next step.