Acetylcholine esterase inhibitor donepezil improves dynamic cerebrovascular regulation in Alzheimer patients

Alzheimer's disease (AD) leads to a degeneration of the nucleus basalis of Meynert and thus to decreased cholinergic tonus in the brain. The transcription of endothelial nitric oxide synthase depends on an adequate cholinergic innervation of microvessels and vasoregulative abnormalities have been reported in AD. We investigated activation-flow coupling to study the role of acetylcholine esterase inhibition (AChEI) on vasoregulative function.

A functional transcranial Doppler approach was used to measure the visually evoked flow velocity response in the posterior cerebral artery in AD patients who had no vascular risk factors. The diagnosis of AD was made according to the ICD10/DSMIIIR-criteria. After baseline recording the effect of four weeks 5mg donepezil and then four weeks 10 mg was investigated. Doppler data were evaluated with a control system approach to obtain dynamic properties of vasoregulation and were compared with a healthy control group.

AD patients showed an increased damping (0.64 +/- 0.2; p = 0.007 vs. control) in evoked responses and lower resting flow velocity levels (40 +/- 13 cm/s; p = 0.06 vs. control), which were restored in a dose-dependent manner under AChEI (0.4 +/- 0.2; 44 +/- 11 cm/s).

AD is associated with a functional vasoregulative deficit possibly due to decreased levels of the endothelial nitric oxide synthase. Augmenting levels with AChEI normalized flow regulation possibly leading to a better blood supply to active neurons.