Review
Effects of acetylcholinesterase inhibitors and memantine on resting-state electroencephalographic rhythms in Alzheimer’s disease patients

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Abstract

Acetylcholinesterase inhibitors (AChEIs) are the most widely used symptomatic treatment for mild to severe Alzheimer’s disease (AD) patients, while N-methyl-d-aspartic acid (NMDA) receptor antagonist memantine is licensed for use in moderate to severe AD patients. In this article, the effect of these compounds on resting state eyes-closed electroencephalographic (EEG) rhythms in AD patients is reviewed to form a knowledge platform for the European Innovative Medicine Initiative project “PharmaCog” (IMI Grant Agreement No. 115009) aimed at developing innovative translational models for drug testing in AD. Indeed, quite similar EEG experiments and the same kind of spectral data analysis can be performed in animal models of AD and in elderly individuals with prodromal or manifest AD. Several studies have shown that AChEIs affect both resting state EEG rhythms and cognitive functions in AD patients. After few weeks of successful treatment, delta (0–3 Hz) or theta (4–7 Hz) rhythms decrease, dominant alpha rhythms (8–10 Hz) increase, and cognitive functions slightly improve. Beneficial effects of these rhythms and cognitive functions were also found in AD responders to the long-term successful treatment (i.e. 6–12 months). In contrast, only one study has explored the long-term effects of memantine on EEG rhythms in AD patients, showing reduced theta rhythms. The present review enlightens the expected effects of AChEIs on resting state EEG rhythms in AD patients as promising EEG markers for the development of translational protocols both within the PharmaCog project and for wider use.

Highlights

Symptomatic treatment options for Alzheimer’s disease (AD) are currently limited to two therapeutic classes namely, acetylcholinesterase inhibitors (AChEIs) and memantine. ► The present review clarifies the effects of AChEIs and memantine on resting-state electroencephalographic (EEG) rhythms and cognitive function in AD patients to identify EEG markers useful for drug development. ► Based on the field literature, the patient’s EEG rhythms most reactive to AChEIs are those at delta (0–3 Hz), theta (4–7 Hz) and alpha (8–12 Hz); the effects of memantine generate a reduction of pathological theta rhythms.

Section snippets

Towards the discovery of new markers and drugs for Alzheimer’s disease: the PharmaCog project

Alzheimer’s disease (AD) is the most prevalent form of dementia seen in the elderly population, and is characterised by memory loss and cognitive and other behavioural abnormalities. AD is related to neurodegeneration within the basal forebrain, parietal, prefrontal, entorhinal cortices, amygdala and hippocampus. It is characterised by an impairment of the cholinergic neurotransmission associated with a pathological production of beta amyloid (Abeta) and phosphorylated tau (Daulatzai, 2010,

Assessment of the cognitive and functional status in AD patients

The quantitative evaluation of the cognitive and functional deficits in AD patients (i.e., basic and instrumental activities of daily living, hobbies, professional duties and so on) play a key role in the diagnosis or therapy monitoring in clinical trials and are a crucial reference for the evaluation of surrogate instrumental markers to be used in these trials. As far as the assessment of the cognitive deficits is concerned, neuropsychological studies have shown that quantitative and

Standard symptomatic drugs for AD

There have been numerous preclinical and clinical studies published that report positive cognitive symptomatic effects in small-scale clinical studies in AD patients. However, these have failed to translate into significant efficacy in later stage clinical development. Despite decades of research, only two classes of pharmacological agents are currently approved for AD: the AChEIs (approved for all stages of the disease) and the NMDA receptor antagonist, memantine (approved for the later

Electroencephalographic techniques for research on AD

EEG measures brain electrical activity recorded from electrodes placed on the surface of the head. Spontaneous on-going scalp EEG rhythms reflect synchronous extracellular ion flow due to excitatory and inhibitory postsynaptic potentials in large populations of cortical pyramidal neurons (Nunez, 2000). It is also commonly accepted that scalp EEG voltages mainly correspond to the local field potentials generated in superficial cortical layers; conversely, potentials deriving from deeper cortical

Acetylcholine effects on EEG rhythms: cellular mechanisms

Cellular mechanisms at the basis of Ach effects on EEG rhythms can be summarised as follows. During slow, synchronised EEG rhythms, cortical pyramidal cells displayed low-frequency intracellular membrane oscillations and pronounced, longlasting inhibitory after-hyperpolarisations following spike discharge (Buzsáki and Gage, 1989, Metherate et al., 1992). Extracellular currents associated with these slow, synchronised membrane electrophysiological events are believed to summate in the

Pharmacological modulation of resting-state EEG rhythms in human subjects: the effects of AChEIs and memantine

Experiments on the effects of donepezil and memantine on EEG markers in humans have gained great interest owing to biochemical and pharmacological evidence of the crucial role of ACh in cognitive functions. As such, other therapeutic approaches aimed at boosting the cholinergic system are tested in clinical trials. AChEIs sustain the availability of the natural transmitter by limiting its removal from the synapse. Other approaches include administering exogenous agonists that may substitute for

Conclusions

AChEIs (especially donepezil) are the most important symptomatic treatments for mild-to-severe AD patients, while the NMDA-receptor antagonist memantine is licensed for the administration to moderate-to-severe AD patients. Here, the literature on the effects of these compounds on the resting-state eyes-closed EEG rhythms recorded in AD patients is reviewed as a knowledge platform for the identification of spectral EEG markers to be used for the development of innovative translational models for

Acknowledgements

The activity leading to the present review has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) for the Innovative Medicine Initiative under Grant Agreement No. 115009 (Prediction of cognitive properties of new drug candidates for neurodegenerative diseases in early clinical development, PharmaCog). For further information on the PharmaCog project, please refer to http://www.pharmacog.org. We thank the staff of University of Foggia for their help in the

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