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性。为此，我们研究了与LC-NA功能相关的行为和生理参数：i)刺激检测任务中的反应时间和准确性、事件相关电位(P300b)、任务相关的瞳孔扩张和事件相关的BOLD信号(古怪范式)、ii)反应时间和准确性、事件相关电位(P300b)、注意瞬脱范式中的任务相关的瞳孔扩张。为了证明这些参数实际上依赖于去甲肾上腺素能传递，我们在28名健康的老年受试者中应用了中枢作用受体拮抗剂心得安或安慰剂后，在一项随机的、安慰剂对照的受试者设计研究中获得了这些参数。为了进一步证明阿尔茨海默病患者LC退变对这些参数的影响，我们对30例AD患者(伴有轻度认知功能障碍或轻度痴呆)和30例年龄匹配的健康对照组进行了检测。因此，我们检验了假设：i)与安慰剂相比，普萘洛尔导致行为测量的准确性降低和反应时间增加；诱发电位和瞳孔扩大的潜伏期和幅度增加；LC区的BOLD信号减少，皮质BOLD信号的延伸减少；ii)与健康对照组相比，AD患者的功能参数发生了相同方向的变化，并且这些变化随着疾病的分期(AD-痴呆和GT；AD-MCI)而增加；ii)变化的幅度随着结构MRI的变化而增加。如果我们能够验证这些假设，这些参数可以作为LC-NE完整性的替代标志物，作为下一步用于AD患者激动性药物治疗的替代标志物。

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.