Importance of circadian rhythmicity in the cholinergic treatment of Alzheimer's disease: focus on galantamine*.
OBJECTIVE AND SCOPE: This review article used data from an extensive literature search (including MEDLINE database searches) to explore the relationships between sleep, memory and Alzheimer's disease (AD). The importance of taking into account circadian rhythmicity and acetylcholine (ACh) levels when considering acetylcholinesterase inhibitors, galantamine in particular, in the treatment of patients with AD is discussed.


RESULTS
Moderate changes of circadian rhythms may occur as part of the normal ageing process, but patients with AD exhibit circadian rhythm disturbances extending beyond those observed in non-demented elderly and this may lead to severe disruption of the sleep-wake cycle. Indeed, ACh plays an active role in maintaining a normal sleep pattern, which is important for memory consolidation. Low levels of ACh during slow-wave sleep compared with wakefulness have been shown to be critical for the consolidation of declarative memory. This suggests the existence of a circadian rhythm in central cholinergic transmission which modulates memory processes, with high ACh levels during wakefulness and reduced levels during slow-wave sleep. When using cholinesterase inhibitors to stimulate central cholinergic transmission in AD, respecting the natural circadian fluctuations of central cholinergic transmission may therefore be an important factor for patient improvement. Interfering with nocturnal cholinergic activity can add to memory problems and induce sleep disorders. Available data suggest that the type of cholinesterase inhibitor used and the time of administration may be critical with regard to the possible development of such disturbances. Plasma levels of galantamine, for example, are high during the waking day and lower at night, supporting a cholinergic stimulation that mirrors the physiological circadian rhythm of cholinergic activity. This may have beneficial implications with regard to sleep and memory.


CONCLUSIONS
The pharmacokinetic properties of cholinesterase inhibitors may need to be taken into account to avoid interference with sleep architecture and to achieve optimum benefits from treatment on cognitive processes.
Nieoullon
André
A
Université de la Méditerranée, Institut de Biologie du Développement de Marseille-Luminy, Marseille, France. andre.nieoullon@ibdml.univ-mrs.fr
Bentué-Ferrer
Danièle
D
Bordet
Régis
R
Tsolaki
Magda
M
Förstl
Hans
H
D000109:Acetylcholine / Q000378:metabolism; D000204:Activity Cycles / Q000187:drug effects*; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005702:Galantamine / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects*; D012894:Sleep Stages / Q000187:drug effects*
D002800:Cholinesterase Inhibitors; D005702:Galantamine; D000109:Acetylcholine