The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study.

STUDY OBJECTIVE Examine the effects of donepezil on sleep and rapid eye movement (REM) sleep electroencephalogram (EEG) in patients with Alzheimer disease, using polysomnography, and the correlation between REM sleep EEG parameters and cognitive scores. DESIGN Randomized, double-blind, placebo-controlled design. SETTINGS Two sleep research centers, University Hospital. PARTICIPANTS Thirty-five patients with mild to moderate Alzheimer disease, allocated to 2 groups: donepezil treated (n=17) and placebo treated (n=18). INTERVENTION Patients were administered donepezil or placebo. OUTCOME MEASURES Polysomnography with REM sleep EEG spectral analysis and cognitive evaluation using the Alzheimer Disease Assessment Scale, cognitive subscale, were performed at baseline and after 3 and 6 months. Slowing ratio was the ratio between slow and fast EEG frequency bands. Cognitive and sleep data were analyzed using analysis of variance. Correlations between cognitive improvement and REM sleep EEG were also calculated. RESULTS REM sleep increased significantly after 3 and 6 months of donepezil treatment compared with baseline and placebo (p < .01). Overall theta (p = .04), frontal theta (p < .01) and frontal delta (p = .03) absolute power during REM sleep decreased after 6 months of donepezil treatment. The occipital slowing ratio decreased during treatment (p = .04). REM sleep overall and frontal and centroparietal alpha absolute power significantly correlated with the cognitive improvement rate on the Alzheimer Disease Assessment Scale, cognitive subscale (r = 0.75, r = 0.71, r = 0.78); p < .01). CONCLUSIONS Donepezil treatment enhanced REM sleep and reduced slow frequencies of REM sleep EEG, suggesting a possible action upon REM sleep-related cholinergic neurons in patients with Alzheimer disease. Furthermore, REM sleep alpha power may predict the cognitive response to donepezil.

[1]  I. Heuser,et al.  Donepezil-induced REM sleep augmentation enhances memory performance in elderly, healthy persons , 2001, Experimental Gerontology.

[2]  L. Friedhoff,et al.  The efficacy and safety of donepezil in patients with Alzheimer's disease: Results of a US multicentre, randomized, double-blind, placebo-controlled trial , 1996 .

[3]  M. Vitiello,et al.  Sleep, EEG and mental function changes in senile dementia of the Alzheimer's type , 1982, Neurobiology of Aging.

[4]  H. Boddeke,et al.  Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer's disease. , 1993, Progress in brain research.

[5]  J. Aldenhoff,et al.  Influence of the cholinesterase inhibitor galanthamine hydrobromide on normal sleep , 1994, Psychiatry Research.

[6]  C. Guilleminault,et al.  EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. , 1992, Sleep.

[7]  M Steriade,et al.  Cholinergic and noradrenergic modulation of the slow (approximately 0.3 Hz) oscillation in neocortical cells. , 1993, Journal of neurophysiology.

[8]  D. Giles,et al.  The effects of an orally administered cholinergic agonist on REM sleep in major depression , 2002, Biological Psychiatry.

[9]  M S Buchsbaum,et al.  Topographic EEG changes with normal aging and SDAT. , 1989, Electroencephalography and clinical neurophysiology.

[10]  R J Sclabassi,et al.  Computerized EEG spectral analysis in elderly normal, demented and depressed subjects. , 1986, Electroencephalography and clinical neurophysiology.

[11]  J. Haxby,et al.  Positron emission tomography in Alzheimer's disease , 1986, Neurology.

[12]  J. Backhaus,et al.  Sleep and the cholinergic rem sleep induction test in patients with primary alcoholism. , 1998, Sleep research online : SRO.

[13]  D. Wilkinson,et al.  The safety and tolerability of donepezil in patients with Alzheimer's disease. , 2004, British journal of clinical pharmacology.

[14]  T. Nielsen,et al.  Sleep in Alzheimer's disease: further considerations on the role of brainstem and forebrain cholinergic populations in sleep-wake mechanisms. , 1995, Sleep.

[15]  R. Vertes,et al.  The case against memory consolidation in REM sleep. , 2000, The Behavioral and brain sciences.

[16]  Arne Brun,et al.  PATHOLOGICAL AND POSITRON EMISSION TOMOGRAPHIC CORRELATIONS IN ALZHEIMER'S DISEASE , 1985, The Lancet.

[17]  P. Bertolucci,et al.  The cognitive subscale of the "Alzheimer's Disease Assessment Scale" in a Brazilian sample. , 2001, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[18]  J. Montplaisir,et al.  Sleep disturbances and eeg slowing in alzheimer's disease. , 1998, Sleep research online : SRO.

[19]  J. Montplaisir,et al.  Comparisons between SPECT and quantitative EEG measures of cortical impairment in mild to moderate Alzheimer's disease. , 1996, European neurology.

[20]  C. Pearlman,et al.  REM sleep and information processing: Evidence from animal studies , 1979, Neuroscience & Biobehavioral Reviews.

[21]  D. Riemann,et al.  Cholinergic neurotransmission, REM sleep and depression. , 1994, Journal of psychosomatic research.

[22]  E. Wolpert.  A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. , 1969 .

[23]  D. Braus,et al.  The value of REM sleep parameters in differentiating Alzheimer's disease from old-age depression and normal aging. , 1998, Journal of psychiatric research.

[24]  U. Hemmeter,et al.  Effects of the Novel Acetylcholinesterase Inhibitor SDZ ENA 713 on Sleep in Man , 1993, Neuropsychopharmacology.

[25]  T. Nielsen,et al.  Quantitative EEG and statistical mapping of wakefulness and REM sleep in the evaluation of mild to moderate Alzheimer's disease. , 1997, European neurology.

[26]  P. Bertolucci,et al.  Applicability of the CERAD neuropsychological battery to Brazilian elderly. , 2001, Arquivos de neuro-psiquiatria.

[27]  K. Dujardin,et al.  Sleep, brain activation and cognition , 1990, Physiology & Behavior.

[28]  P. Vitali,et al.  Quantitative EEG Changes in Alzheimer Patients during Long-Term Donepezil Therapy , 2002, Neuropsychobiology.

[29]  S. Balkan,et al.  Effect of donepezil on EEG spectral analysis in Alzheimer's disease. , 2003, Acta neurologica Belgica.

[30]  W. Fishbein,et al.  Paradoxical sleep and memory storage processes. , 1977, Behavioral biology.

[31]  J. Gillin,et al.  Induction and resetting of REM sleep rhythm in normal man by arecholine: blockade by scopolamine. , 1978, Sleep.

[32]  J. Shua-haim,et al.  ARICEPT‐INDUCED NIGHTMARES IN ALZHEIMER'S DISEASE: 2 CASE REPORTS , 1998, Journal of the American Geriatrics Society.

[33]  K. Davis.  87 CURRENT AND EXPERIMENTAL THERAPEUTICS OF ALZHEIMER DISEASE , 2002 .

[34]  J. Montplaisir,et al.  Spectral analysis of the rapid eye movement sleep electroencephalogram in right and left temporal regions: A biological marker of Alzheimer's disease , 1992, Annals of neurology.

[35]  A Z Snyder,et al.  Replication of a study of frequency analysis of the resting awake EEG in mild probable Alzheimer's disease. , 1990, Electroencephalography and clinical neurophysiology.

[36]  D. Riemann,et al.  Effect of tetrahydroaminoacridine on sleep in healthy subjects , 1996, Biological Psychiatry.

[37]  B. Feige,et al.  Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence , 2001, Biological Psychiatry.

[38]  J. Becker,et al.  EEG spectral abnormalities and psychosis as predictors of cognitive and functional decline in probable Alzheimer's disease , 1997, Neurology.

[39]  C. Perdomo,et al.  DONEPEZIL: TOLERABILITY AND SAFETY IN ALZHEIMER'S DISEASE , 2002, International journal of clinical practice.

[40]  Daniel J Buysse,et al.  Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. , 1999, Sleep.

[41]  R. Llinás,et al.  Serotonergic and cholinergic inhibition of mesopontine cholinergic neurons controlling rem sleep: An in vitro electrophysiological study , 1994, Neuroscience.

[42]  F Langevin,et al.  Scalp potential and current density mapping with an enhanced spherical spline interpolation. , 1994, Medical progress through technology.

[43]  G. Pearce,et al.  Adverse effects associated with the use of donepezil in general practice in England , 2000, Journal of psychopharmacology.

[44]  Recording and scoring leg movements. The Atlas Task Force. , 1993, Sleep.

[45]  A. Korczyn,et al.  EEG changes during long-term treatment with donepezil in Alzheimer's disease patients , 2001, Journal of Neural Transmission.

[46]  D. Knopman,et al.  An update on primary drug therapies for Alzheimer disease. , 1997, Archives of neurology.

[47]  I. Heuser,et al.  The effect of rivastigmine on sleep in elderly healthy subjects , 2000, Experimental Gerontology.

[48]  S Giaquinto,et al.  The EEG in the normal elderly: a contribution to the interpretation of aging and dementia. , 1986, Electroencephalography and clinical neurophysiology.

[49]  Elisabet Englund,et al.  Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading. , 2002, Histopathology.

[50]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[51]  Jerome M. Siegel,et al.  The REM Sleep-Memory Consolidation Hypothesis , 2001, Science.

[52]  G. Christos.  Is Alzheimer's disease related to a deficit or malfunction of rapid eye movement (REM) sleep? , 1993, Medical hypotheses.

[53]  Carlyle Smith,et al.  Sleep states and learning: A review of the animal literature , 1985, Neuroscience & Biobehavioral Reviews.

[54]  R. Stickgold,et al.  Sleep, Learning, and Dreams: Off-line Memory Reprocessing , 2001, Science.

[55]  S. Gauthier,et al.  THA does not affect sleep or EEG spectral power in Alzheimer's disease , 1993, Biological Psychiatry.

[56]  J. Born,et al.  Early sleep triggers memory for early visual discrimination skills , 2000, Nature Neuroscience.

[57]  A. Rechtschaffen,et al.  A manual of standardized terminology, technique and scoring system for sleep stages of human subjects , 1968 .