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

• Applicant: Privatdozent Dr. Klaus Fließbach
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Human Cognitive and Systems Neuroscience
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 310533960

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.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Thomas Klockgether