0
Original Research |

Donepezil Improves Obstructive Sleep Apnea in Alzheimer Disease*: A Double-Blind, Placebo-Controlled Study FREE TO VIEW

Walter Moraes, MD, PhD; Dalva Poyares, MD, PhD; Lucia Sukys-Claudino, MD; Christian Guilleminault, MD, PhD; Sergio Tufik, MD, PhD
Author and Funding Information

*From the Psychobiology Department (Drs. Moraes, Poyares, Sukys-Claudino, and Tufik), Universidade Federal de São Paulo, São Paulo, Brazil; and Human Sleep Research Center (Dr. Guilleminault), Department of Psychiatry and Behavioral Science, School of Medicine, Stanford University, Palo Alto, CA.

Correspondence to: Walter Moraes, MD, PhD, R. Manuel de Paiva, 313-São Paulo-SP, 04106-020, Brazil; e-mail: waltermoraes@giro.com.br


Chest. 2008;133(3):677-683. doi:10.1378/chest.07-1446
Text Size: A A A
Published online

Background: There is an association between Alzheimer disease and sleep-disordered breathing. Donepezil is the drug most frequently used to treat cognitive symptoms in Alzheimer disease. This study evaluates the effects of donepezil on obstructive sleep apnea in patients with Alzheimer disease.

Methods: Randomized, double-blind, placebo-controlled design. Twenty-three patients with mild-to-moderate Alzheimer disease and apnea-hypopnea index (AHI) > 5/h were allocated to two groups: donepezil treated (n = 11) and placebo treated (n = 12). Polysomnography and cognitive evaluation using Alzheimer disease assessment scale-cognitive (ADAS-cog) subscale were performed at baseline and after 3 months. Cognitive and sleep data were analyzed using analysis of variance.

Results: AHI and oxygen saturation improved significantly after donepezil treatment compared to baseline and placebo (p < 0.05). Rapid eye movement (REM) sleep duration increased after donepezil treatment (p < 0.05). ADAS-cog scores improved after donepezil treatment, although they did not correlate with REM sleep increase and sleep apnea improvement (p < 0.01).

Conclusions: Donepezil treatment improved AHI and oxygen saturation in patients with Alzheimer disease. Treatment also increased REM sleep duration and reduced ADAS-cog scores.

Trial registration: ClinicalTrials.gov Identifier: NCT00480870.

Figures in this Article

The association between Alzheimer disease and sleep-disordered breathing has been frequently studied.15 The presence of apolipoprotein E epsilon 4 seems to be linked to the occurrence of both conditions, suggesting a genetic basis.3,6Central-acting cholinesterase inhibitors are the first primary pharmacologic treatments approved for Alzheimer disease, for which donepezil is the most frequently used.7 Multicenter studies710 have found little toxicity, and its side effects (diarrhea, nausea, vomiting, nightmares, among others) are mild and transient. Donepezil is a reversible inhibitor of the acetyl-cholinesterase enzyme, thus enhancing cholinergic transmission.11 Its half-life is approximately 70 h.11 It is excreted intact in the urine and metabolized into four major metabolites, two of which are known to be active.11

Cholinergic activity also influences the upper airway opening via central and peripheral mechanisms.1215 Decreased thalamic pontine cholinergic projections may affect respiratory drive, leading to both central and obstructive apnea at least in certain degenerative conditions.1415 Since impairment of cholinergic transmission is a putative pathophysiologic mechanism for Alzheimer disease, it is expected that cholinergic-related respiratory disturbances may occur.78,16 However, donepezil has been shown to augment rapid eye movement (REM) sleep in patients with Alzheimer disease, a sleep stage during which sleep apnea events are more frequent.7,1719 Such conflicting effects make it difficult to know a priori whether improvement of sleep apnea is likely to occur during donepezil treatment.,1415 Mindful of the above, the authors hypothesized the following: (1) donepezil may influence respiratory variables during sleep in patients with obstructive sleep apnea-Alzheimer disease (OSA-AD), and (2) there is a correlation between cognitive improvement and sleep respiratory changes.

Population

Forty patients with mild-to-moderate Alzheimer disease were consecutively recruited from geriatric and neurologic clinics at the University Hospital of the Universidade Federal de São Paulo. Thirty of them had obstructive sleep apnea (OSA) and presented with apnea-hypopnea index (AHI) > 5/h according to American Academy of Sleep Medicine (AASM) criteria.20 OSA was not previously diagnosed or treated in these patients. There were technical problems in the polysomnography of seven patients due to frequent patient-movement artifacts. The final sample consisted of the remaining 23 patients who were randomly allocated to two groups: donepezil treated (n = 11) and placebo treated (n = 12).

The diagnosis of Alzheimer disease was based on the probability criteria of the Alzheimer’s Disease and Related Disorders Association.21Patients were rated 1 and 2 (mild-to-moderate level) on the Brazilian version of the clinical dementia rating (CDR), and the more severe cases were excluded.22Potential subjects were evaluated by history, physical examination, mini-mental state examination (MMSE), Alzheimer disease assessment scale-cognitive (ADAS-cog) subscale,23 brain MRI, and laboratory tests (hematologic evaluation, renal and liver functions, vitamin B12, folic acid, thyroid hormones, fasting glycemia, venereal disease research test, and urine sediment). .Exclusion criteria were the presence of other causes of dementia; MRI compatible with other etiology of dementia; and pulmonary, cardiac, and other current severe medical or psychiatric diseases. No psychoactive drugs other than the experimental drug were taken during the trial or the preceding 1-month period. Alcohol and sleep medications were not permitted during the trial and the preceding 1-month period. Caregivers were instructed to take note of the use of any nonpsychoactive drugs in daily sleep diaries.

Drugs and Administration

Tablets containing placebo were prepared and packed in the same fashion as those with 5 mg of donepezil. Donepezil and placebo were administered in a single dose at bedtime. The dosage was one tablet per day in the first month and two tablets per day for the next 2 months. After completion of the protocol, patients were referred to our sleep clinic to have OSA treated.

Randomization

Each medication-containing box was packed by a standard pharmacy service. Boxes were coded as A or B, indicating placebo or donepezil (the signification of the codes was kept in a closed envelope). A random number list with uniform distribution from 0 to 1 was generated using software (Statistica; Statsoft; Tulsa, OK). Patients were consecutively allocated to two treatment groups according to the random number list: ≤ 0.5 to group A and > 0.5 to group B. Researchers were blind to patient conditions when recording and scoring parameters. Codes were opened and assigned to each patient when statistical analysis was performed.

Polysomnography and Scoring

Patients were submitted to 2 nights of polysomnography for habituation purposes, followed by a baseline recording before the onset of treatment and a second recording after 3 months of treatment. The minimum duration of polysomnography was 7 h.

Polysomnography was performed in the sleep laboratory of the Psychobiology Department at Universidade Federal de São Paulo using a 32-channel device (Sonolab; Meditron; Sao Paulo, Brazil): resolution, 256 Hz; 22 EEG; 2 electro-oculogram, 1 chin electromyogram, 1 leg electromyogram, 1 ECG, 1 tracheal microphone, 1 oronasal thermistor, 1 nasal pressure transducer (Pro-Tech Services; Mukilteo, WI), 2 chest and abdominal effort sensors, and 1 pulse oximeter (Nellcor; Pleasanton, CA). Two researchers scored the recordings visually using Rechtshaffen and Kales and AASM criteria for respiratory parameters and microarousals.2426

Apneas and hypopneas were scored according to AASM criteria.20 Variables analyzed were total sleep time, sleep efficiency (sleep time/recording time × 100), sleep latency (time from lights off to sleep onset), REM sleep latency (time from sleep onset to REM sleep onset), wake after sleep onset (WASO), REM and non-REM sleep percentage, microarousal index (microarousals per hour), overall AHI, obstructive AHI, central AHI, mixed AHI, REM AHI, non-REM AHI, average oxygen saturation, and percentage of sleep time with oxygen saturation < 90%. Apnea-hypopnea improvement ratio was calculated was calculated as follows: AHI improvement = initial AHI − final AHI/initial AHI. Caregivers answered a Portuguese language-modified version of Stanford Sleep Disorders Questionnaire after polysomnography to rule out other major sleep disorders.27

Psychometric Testing

The ADAS-cog subscale evaluates multiple cognitive functions including word evocation, verbal fluency, understanding of simple commands, constructive praxis, ideational praxis, temporospatial orientation, word recognition, verbal fluency, vocabulary, and understanding. Scores range from 0 to 70, with higher scores indicating more cognitive deterioration. The Brazilian version of ADAS-cog22 was applied before donepezil treatment and again after 3 months.

Ethics

Subjects or caregivers signed informed consent forms that explained possible side effects of donepezil and assured them that they could leave the trial at any moment. All subjects were assured that they would receive clinical treatment. The Ethics Committee at Universidade Federal de São Paulo authorized the study.

Statistical Analysis

One-way analysis of variance (ANOVA) was used to compare all variables for donepezil and placebo groups during the baseline recording night. Polysomnographic and cognitive data at baseline and after 3 months of treatment were analyzed using two-way ANOVA for repeated measures with treatment group and treatment time as the main factors and time/treatment interaction effect followed by Bonferroni test, with p ≤ 0.01 comparing data. The Spearman correlation test was used to assess possible correlations between cognitive, body mass index (BMI) and sleep respiratory parameters in the donepezil-treated group.

General

Table 1 shows that there were no significant differences in age, gender, BMI, MMSE, and CDR scores between the donepezil and placebo groups before treatment. There was no significant correlation between AHI improvement ratio and BMI. MRI scan showed brain atrophy. Results of other laboratory tests were within normal range.

Adverse Effects

Mild and transitory side effects involving nausea and headache occurred in three patients receiving donepezil. There were no reports of nightmares or worsening of sleep when caregivers were questioned.

Sleep Polysomnographic Variables

REM sleep percentage increased after 3 months of donepezil treatment, as seen in Table 2 . There was a significant improvement in the following respiratory parameters after 3 months of donepezil treatment: AHI, obstructive AHI, mixed AHI, lowest oxygen saturation, and time spent with oxygen saturation < 90% (Table 2). Central AHI did not improve significantly after donepezil treatment (Table 2, Fig 1 ). There was also a significant reduction in non-REM AHI after donepezil treatment (interaction factor F[1,21] = 5.39, p = 0.03) [Table 2]. Although there was a trend toward reduction of REM AHI, it was not significant (interaction factor F[1,21] = 3.47 p = 0.07) [Table 2]. Microarousal index decreased significantly after donepezil treatment due to a reduction in respiratory-related microarousals (Table 2). Nine donepezil-treated patients (81%) had improvement of AHI (Fig 1). Six patients (54%) spent > 1% sleep time with oxygen saturation < 90% before donepezil treatment (Fig 1). Five of these patients (83%) improved after donepezil treatment (Fig 1). There were no significant differences between donepezil and placebo groups in the following polysomnographic parameters: total sleep time, sleep efficiency, sleep latency, REM sleep latency, WASO, and percentage of non-REM sleep stages. There was no significant difference in percentage of time spent in supine position within and between groups (Table 2).

Psychometric Variables

ADAS-cog scores significantly decreased after 3 months of donepezil treatment (Table 2). Correlations between ADAS-cog scores, AHI, average oxygen saturation, time of oxygen saturation spent < 90%, microarousal index, and other polysomnographic variables did not reach statistical significance in the donepezil-treated group before and after therapy.

The main finding of the present study was the significant improvement in AHI and oxygen saturation of OSA-AD patients treated with donepezil. No previous polysomnographic studies on the effect of donepezil on sleep apnea in Alzheimer disease have been undertaken. As expected, donepezil was well tolerated and no major side effects occurred.1011 No evidence of worsening of sleep or nightmares was found in this study. This is in accordance with the findings of other authors11 who have studied larger samples in general practice. Acetylcholinesterase inhibitors elevate central and peripheral acetylcholine levels. However, the distribution of donepezil varies between different brain and peripheral tissues.28 An increase in REM sleep proportion after donepezil treatment was an expected finding.7

In contrast to the prolific literature on physical and surgical treatments for sleep apnea, there is a dearth of effective pharmacologic approaches.2932 Most drugs previously tested for this purpose acted on monoaminergic and adenosinergic systems and showed unsuccessful or ambiguous results.2932 Hedner and colleagues12 published the only previous report on a cholinergic pharmacologic treatment in humans using an IV infusion of the anticholinesterase drug physostigmine in sleep-disordered breathing patients, improving both obstructive and central respiratory events mostly during REM sleep. However, that study12 focused on the acute effect of a drug that does not sustain plasma levels during the entire night. We have selected a cholinergic drug already approved by many regulatory agencies for the treatment of Alzheimer disease and that has been extensively studied and shown to be safe and pharmacologically stable.10 Taking advantage of the characteristics of this drug, we were able to show that the beneficial respiratory effect is maintained after long-term use, possibly adding to its therapeutic spectrum. In contrast to this previous report,12 we found that overall AHI improvement was due to a reduction in obstructive and mixed respiratory events. In addition, we did not find a significant improvement in AHI during REM sleep, although there was a nonsignificant trend toward reduction. These results suggest that AHI improvement after donepezil treatment is related to cholinergic mechanisms involved in obstructive and mixed apnea and is not specifically dependent on REM AHI reduction. OSA-AD patients showed different individual responses to donepezil. We found no parameter that could predict individual treatment outcome. Future studies are needed to explain individual differences in response to cholinergic drugs for OSA treatment. As expected, there was a high degree of variability in respiratory parameters of the control group and no clear tendency to worsening.3334 Besides respiratory effects, donepezil increased REM sleep, and decreased microarousal index and ADAS-cog scores after 3 months of donepezil treatment, confirming findings of previous research.7,1718 Hedner et al35 reported a similar finding in non-Alzheimer OSA patients in abstract form.

As previously mentioned, it was expected that the REM sleep increase would be associated to the worsening of OSA because respiratory events are more frequent during this sleep stage.12,19 However, cholinergic drugs display more complex effects on respiration. Available evidence demonstrates that cholinergic stimulation has potent excitatory effects on medullary respiratory neurons and respiratory motoneurones.14 It also affects the central chemosensitive drive of the respiratory control system.14 Upper airway dilating muscle activity is characterized by an early peaking pattern that serves to dilate the upper airway at the time when the greatest negative intraluminal pressure is generated by contraction of the chest wall muscles and diaphragm.36 An experimental study36showed an increase in hypoglossus nerve activity with consequent opening of the upper airway following carbachol pontine injection in cats. Physostigmine administered to cholinergic neurons located in the rostral ventrolateral medulla of anesthetized vagotomized and artificially ventilated cats resulted in elongation of the hypoglossal-to-phrenic nerve firing interval resulting in improved oxygenation.37It also antagonizes respiratory depression induced by fentanyl in rats.38Furthermore, physostigmine stimulates saliva production, resulting in reduced superficial tension that increases upper airway stability, which may represent another mechanism for improving OSA.3940 Cholinergic stimulation of the respiratory center and the carotid body increases sensitivity to hypoxia improving the chemoreflex response.12,1415,41 Such effects may contribute to the cholinergic-induced improvement of the peripheral and central components of respiratory regulation during sleep.12,1415,3742 In our study, most of the reduction of the microarousal index in the donepezil group was attributable to a significant decrease in respiratory-related microarousals, even though cholinergic drugs may elicit arousal.4344

Donepezil-related cognitive improvement measured by ADAS-cog subscale did not correlate with respiratory parameters, suggesting independence between cognition and sleep respiratory symptoms in patients with Alzheimer disease.1 However, further clarification is required as to whether or not OSA contributes to cognitive deterioration in Alzheimer disease.35

In summary our results support the concept that cholinergic transmission is involved in the pathogenesis of OSA in Alzheimer disease, suggesting a possible target for pharmacologic intervention. Larger placebo-controlled studies are needed to confirm these results.

Abbreviations: AASM = American Academy of Sleep Medicine; ADAS-cog = Alzheimer disease assessment scale-cognitive; AHI = apnea-hypopnea index; ANOVA = analysis of variance; BMI = body mass index; CDR = clinical dementia rating; MMSE = mini-mental state examination; OSA = obstructive sleep apnea; OSA-AD = obstructive sleep apnea-Alzheimer disease; REM = rapid eye movement; WASO = wake after sleep onset

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo and Associação Fundo de Incentivo à Psicofarmacologia.

The authors have no conflicts of interest to disclose.

Table Graphic Jump Location
Table 1. Sociodemographic Data*
* 

Data are presented as mean ± SD (range) or No.

 

p < 0.05, ANOVA.

Table Graphic Jump Location
Table 2. Cognitive and Polysomnographic Findings*
* 

Data are presented as mean ± SD.

 

p < 0.05, ANOVA.

Figure Jump LinkFigure 1. AHI before (1) and after (2) donepezil (top left, A) or placebo (top right, B) treatment, and time spent with oxygen saturation < 90% before (1) and after (2) donepezil (bottom left, C) or placebo (bottom right, D) treatment. An outlier (Subject 12) is not presented (top right, B) due to scale: AHI was 81 events/h at entry and 87 events/h after placebo.Grahic Jump Location

The authors thank Dr. Robert Skomro for his comments.

Hoch, CC, Reynolds, CF, III, Nebes, RD, et al (1989) Clinical significance of sleep-disordered breathing in Alzheimer’s disease: preliminary data.J Am Geriatr Soc37,138-144
 
Reynolds, CF, III, Kupfer, DJ, Taska, LS, et al Sleep apnea in Alzheimer’s dementia: correlation with mental deterioration.J Clin Psychiatry1985;46,257-261
 
Bliwise, DL Sleep apnea, APOE4 and Alzheimer’s disease: 20 years and counting?J Psychosom Res2002;53,539-546
 
Bliwise, DL Sleep disorders in Alzheimer’s disease and other dementias.Clin Cornerstone2004;6(suppl 1A),S16-S28
 
Abrams, B Add Alzheimer’s to the list of sleep apnea consequences.Med Hypotheses2005;65,1201-1202
 
Kadotani, H, Kadotani, T, Young, T, et al Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults.JAMA2001;285,2888-2890
 
Moraes, WAS, Poyares, DR, Guilleminault, C, et al The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study.Sleep2006;29,199-205
 
Pratt, RD, Perdomo, CA, Surick, IW, et al Donepazil: tolerability and safety in Alzheimer’s disease.Int J Clin Pract2002;56,710-717
 
Rogers, SL, Friedhoff, LT The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial.Dementia1996;7,293-303
 
Dunn, NR, Pearce, GL, Shakir, AW Adverse effects associated with the use of donepezil in general practice in England.J Psychopharmacol2000;14,406-408
 
Davis, KL Current and experimental therapeutics of Alzheimer’s disease. Davis, KL Charney, D Coyle, JTet al eds.Neuropsychopharmacology: the fifth generation of progress.2002,1243-1252 Lippincott, Williams and Wilkins. Philadelphia, PA:
 
Hedner, J, Kraiczi, H, Peker, Y, et al Reduction of sleep-disordered breathing after physostigmine.Am J Respir Crit Care Med2003;168,1246-1251
 
O’Donnell, CP, Schwartz, AR, Smith, PL Upper airway collapsibility: the importance of gender and adiposity.Am J Respir Crit Care Med2000;162,1606-1607
 
Bellingham, MC, Ireland, MF Contribution of cholinergic systems to state dependent modulation of respiratory control.Respir Physiol Neurobiol2002;131,135-144
 
Gilman, S, Chervin, RD, Koeppe, RA, et al Obstructive sleep apnea is related to a thalamic cholinergic deficit in MSA.Neurology2003;61,35-39
 
Brun, A, Englund, E Regional pattern of degeneration in Alzheimer’s disease: neuronal loss and histopathological grading.Histopathology1981;5,459-564
 
Kanbayashi, T, Sugiyama, T, Aizawa, R, et al Effects of donepezil (Aricept) on the rapid eye movement sleep of normal subjects: psychiatryClin Neurosci2002;56,307-308
 
Schredl, M, Weber, B, Leins, ML, et al Donepezil-induced REM sleep augmentation enhances memory performance in elderly, healthy persons.Exp Gerontol2001;36,353-361
 
Wiegand, L, Zwillich, CW, Wiegand, D, et al Changes in upper airway muscle activation and ventilation during phasic REM sleep in normal men.J Appl Physiol1991;71,488-497
 
AASM Task Force report.. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research.Sleep1999;22,667-690
 
McKhann, G, Drachman, D, Folstein, M, et al Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease.Neurology1984;34,939-944
 
Bertolucci, PHF, Okamoto, IV, Brucki, SMD, et al Applicability of the CERAD Neuropsychological Battery to Brazilian elderly.Arq Neuropsiquiatr2001;59,532-536
 
Schulz, RR, Siviero, MO Bertolucci PHF. The cognitive subscale of the Alzheimer’s Disease Assessment Scale in a Brazilian sample.Braz J Med Biol Res2001;34,1295-1302
 
Rechtschaffen, A, Kales, A. A manual of standardized terminology, techniques and scoring system for sleep states of human subjects. 1968; US Government Printing Office. Washington, DC:.
 
American Sleep Disorders Association.. EEG arousals: scoring rules and examples: a preliminary report from Sleep Disorders Atlas Task Force of the American Sleep. Disorders Association.Sleep1992;15,173-184
 
ASDA Atlas Task Force.. Recording and scoring leg movements.Sleep1993;16,748-759
 
Braz, S, Neumann, BG, Tufik, S Avaliação dos distúrbios do sono: elaboração e validação de um questionário.Revista da ABP-APAL (Revista Brasileira de Psiquiatria)1987;9,9-14
 
Kasa, P, Papp, H, Kasa, P, Jr, et al Donepezil dose-dependently inhibits acetylcholinesterase activity in various areas and in the presynaptic cholinergic and the postsynaptic cholinoceptive enzyme-positive structures in the human and rat brain.Neuroscience2000;101,89-100
 
Loube, DI Treatment algorithm for OSA.Chest1997;111,528-529
 
Henderson, JH, II, Strollo, PJ, Jr Medical management of obstructive sleep apnea.Prog Cardiovasc Dis1999;41,377-386
 
Smith, I, Lasserson, TJ, Wright, J Drug therapy for obstructive sleep apnoea in adults.Cochrane Database Syst Rev2006;2,CD003002
 
Abad, VC, Guilleminault, C Pharmacological management of sleep apnoea.Expert Opin Pharmacother2006;7,11-23
 
Bliwise, DL, Benkert, RE, Ingham, RH Factors associated with nightly variability in sleep-disordered breathing in the elderly.Chest1991;100,973-976
 
Pendlebury, ST, Pépin, JL, Veale, D, et al Natural evolution of moderate sleep apnoea syndrome: significant progression over a mean of 17 months.Thorax1997;52,872-878
 
Hedner, J, Kraiczi, H, Peker, Y, et al Reduction of sleep apnea after the orally available cholinesterase inhibitor donepezil [abstract].Sleep Med2005;6,S54-S55
 
Haxhiu, MA, Cherniack, NS, Mitra, J, et al Nonvagal modulation of hypoglossal neural activity.Respiration1992;59,65-71
 
Willette, RN, Doorley, BM, Sapru, HN Activation of cholinergic mechanisms in the medulla oblongata reverse intravenous opioid-induced respiratory depression.J Pharmacol Exp Ther1987;240,352-358
 
Liu, X, Sood, S, Liu, H, et al Opposing muscarinic and nicotinic modulation of hypoglossal motor output to genioglossus muscle in ratsin vivo.J Physiol2005;565,965-980
 
Jokic, R, Klimaszewski, A, Mink, J, et al Surface tension forces in sleep apnea: the role of a soft tissue lubricant: a randomized double-blind, placebo-controlled trial.Am J Respir Crit Care Med1998;157,1522-1525
 
Hedner, E, Birkhed, D, Hedner, J, et al Stimulation of minor salivary glands by intraoral treatment with the cholinesterase inhibitor physostigmine in man.Eur J Oral Sci2001;109,371-374
 
Fitzgerald, RS, Shirahata, M, Wang, HY Acetylcholine is released from in vitro cat carotid bodies during hypoxic stimulation.Adv Exp Med Biol2000;475,485-494
 
Kubin, L, Kimura, H, Tojima, H, et al Suppression of hypoglossal motoneurons during the carbachol-induced atonia of REM sleep is not caused by fast synaptic inhibition.Brain Res1993;611,300-312
 
Martin, SE, Brander, PE, Deary, IJ, et al The effect of clustered versus regular sleep fragmentation on daytime function.J Sleep Res1999;8,305-311
 
Phillips, AJ, Robinson, PA A quantitative model of sleep-wake dynamics based on the physiology of the brainstem ascending arousal system.J Biol Rhythms2007;22,167-179
 

Figures

Figure Jump LinkFigure 1. AHI before (1) and after (2) donepezil (top left, A) or placebo (top right, B) treatment, and time spent with oxygen saturation < 90% before (1) and after (2) donepezil (bottom left, C) or placebo (bottom right, D) treatment. An outlier (Subject 12) is not presented (top right, B) due to scale: AHI was 81 events/h at entry and 87 events/h after placebo.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Sociodemographic Data*
* 

Data are presented as mean ± SD (range) or No.

 

p < 0.05, ANOVA.

Table Graphic Jump Location
Table 2. Cognitive and Polysomnographic Findings*
* 

Data are presented as mean ± SD.

 

p < 0.05, ANOVA.

References

Hoch, CC, Reynolds, CF, III, Nebes, RD, et al (1989) Clinical significance of sleep-disordered breathing in Alzheimer’s disease: preliminary data.J Am Geriatr Soc37,138-144
 
Reynolds, CF, III, Kupfer, DJ, Taska, LS, et al Sleep apnea in Alzheimer’s dementia: correlation with mental deterioration.J Clin Psychiatry1985;46,257-261
 
Bliwise, DL Sleep apnea, APOE4 and Alzheimer’s disease: 20 years and counting?J Psychosom Res2002;53,539-546
 
Bliwise, DL Sleep disorders in Alzheimer’s disease and other dementias.Clin Cornerstone2004;6(suppl 1A),S16-S28
 
Abrams, B Add Alzheimer’s to the list of sleep apnea consequences.Med Hypotheses2005;65,1201-1202
 
Kadotani, H, Kadotani, T, Young, T, et al Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults.JAMA2001;285,2888-2890
 
Moraes, WAS, Poyares, DR, Guilleminault, C, et al The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study.Sleep2006;29,199-205
 
Pratt, RD, Perdomo, CA, Surick, IW, et al Donepazil: tolerability and safety in Alzheimer’s disease.Int J Clin Pract2002;56,710-717
 
Rogers, SL, Friedhoff, LT The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial.Dementia1996;7,293-303
 
Dunn, NR, Pearce, GL, Shakir, AW Adverse effects associated with the use of donepezil in general practice in England.J Psychopharmacol2000;14,406-408
 
Davis, KL Current and experimental therapeutics of Alzheimer’s disease. Davis, KL Charney, D Coyle, JTet al eds.Neuropsychopharmacology: the fifth generation of progress.2002,1243-1252 Lippincott, Williams and Wilkins. Philadelphia, PA:
 
Hedner, J, Kraiczi, H, Peker, Y, et al Reduction of sleep-disordered breathing after physostigmine.Am J Respir Crit Care Med2003;168,1246-1251
 
O’Donnell, CP, Schwartz, AR, Smith, PL Upper airway collapsibility: the importance of gender and adiposity.Am J Respir Crit Care Med2000;162,1606-1607
 
Bellingham, MC, Ireland, MF Contribution of cholinergic systems to state dependent modulation of respiratory control.Respir Physiol Neurobiol2002;131,135-144
 
Gilman, S, Chervin, RD, Koeppe, RA, et al Obstructive sleep apnea is related to a thalamic cholinergic deficit in MSA.Neurology2003;61,35-39
 
Brun, A, Englund, E Regional pattern of degeneration in Alzheimer’s disease: neuronal loss and histopathological grading.Histopathology1981;5,459-564
 
Kanbayashi, T, Sugiyama, T, Aizawa, R, et al Effects of donepezil (Aricept) on the rapid eye movement sleep of normal subjects: psychiatryClin Neurosci2002;56,307-308
 
Schredl, M, Weber, B, Leins, ML, et al Donepezil-induced REM sleep augmentation enhances memory performance in elderly, healthy persons.Exp Gerontol2001;36,353-361
 
Wiegand, L, Zwillich, CW, Wiegand, D, et al Changes in upper airway muscle activation and ventilation during phasic REM sleep in normal men.J Appl Physiol1991;71,488-497
 
AASM Task Force report.. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research.Sleep1999;22,667-690
 
McKhann, G, Drachman, D, Folstein, M, et al Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease.Neurology1984;34,939-944
 
Bertolucci, PHF, Okamoto, IV, Brucki, SMD, et al Applicability of the CERAD Neuropsychological Battery to Brazilian elderly.Arq Neuropsiquiatr2001;59,532-536
 
Schulz, RR, Siviero, MO Bertolucci PHF. The cognitive subscale of the Alzheimer’s Disease Assessment Scale in a Brazilian sample.Braz J Med Biol Res2001;34,1295-1302
 
Rechtschaffen, A, Kales, A. A manual of standardized terminology, techniques and scoring system for sleep states of human subjects. 1968; US Government Printing Office. Washington, DC:.
 
American Sleep Disorders Association.. EEG arousals: scoring rules and examples: a preliminary report from Sleep Disorders Atlas Task Force of the American Sleep. Disorders Association.Sleep1992;15,173-184
 
ASDA Atlas Task Force.. Recording and scoring leg movements.Sleep1993;16,748-759
 
Braz, S, Neumann, BG, Tufik, S Avaliação dos distúrbios do sono: elaboração e validação de um questionário.Revista da ABP-APAL (Revista Brasileira de Psiquiatria)1987;9,9-14
 
Kasa, P, Papp, H, Kasa, P, Jr, et al Donepezil dose-dependently inhibits acetylcholinesterase activity in various areas and in the presynaptic cholinergic and the postsynaptic cholinoceptive enzyme-positive structures in the human and rat brain.Neuroscience2000;101,89-100
 
Loube, DI Treatment algorithm for OSA.Chest1997;111,528-529
 
Henderson, JH, II, Strollo, PJ, Jr Medical management of obstructive sleep apnea.Prog Cardiovasc Dis1999;41,377-386
 
Smith, I, Lasserson, TJ, Wright, J Drug therapy for obstructive sleep apnoea in adults.Cochrane Database Syst Rev2006;2,CD003002
 
Abad, VC, Guilleminault, C Pharmacological management of sleep apnoea.Expert Opin Pharmacother2006;7,11-23
 
Bliwise, DL, Benkert, RE, Ingham, RH Factors associated with nightly variability in sleep-disordered breathing in the elderly.Chest1991;100,973-976
 
Pendlebury, ST, Pépin, JL, Veale, D, et al Natural evolution of moderate sleep apnoea syndrome: significant progression over a mean of 17 months.Thorax1997;52,872-878
 
Hedner, J, Kraiczi, H, Peker, Y, et al Reduction of sleep apnea after the orally available cholinesterase inhibitor donepezil [abstract].Sleep Med2005;6,S54-S55
 
Haxhiu, MA, Cherniack, NS, Mitra, J, et al Nonvagal modulation of hypoglossal neural activity.Respiration1992;59,65-71
 
Willette, RN, Doorley, BM, Sapru, HN Activation of cholinergic mechanisms in the medulla oblongata reverse intravenous opioid-induced respiratory depression.J Pharmacol Exp Ther1987;240,352-358
 
Liu, X, Sood, S, Liu, H, et al Opposing muscarinic and nicotinic modulation of hypoglossal motor output to genioglossus muscle in ratsin vivo.J Physiol2005;565,965-980
 
Jokic, R, Klimaszewski, A, Mink, J, et al Surface tension forces in sleep apnea: the role of a soft tissue lubricant: a randomized double-blind, placebo-controlled trial.Am J Respir Crit Care Med1998;157,1522-1525
 
Hedner, E, Birkhed, D, Hedner, J, et al Stimulation of minor salivary glands by intraoral treatment with the cholinesterase inhibitor physostigmine in man.Eur J Oral Sci2001;109,371-374
 
Fitzgerald, RS, Shirahata, M, Wang, HY Acetylcholine is released from in vitro cat carotid bodies during hypoxic stimulation.Adv Exp Med Biol2000;475,485-494
 
Kubin, L, Kimura, H, Tojima, H, et al Suppression of hypoglossal motoneurons during the carbachol-induced atonia of REM sleep is not caused by fast synaptic inhibition.Brain Res1993;611,300-312
 
Martin, SE, Brander, PE, Deary, IJ, et al The effect of clustered versus regular sleep fragmentation on daytime function.J Sleep Res1999;8,305-311
 
Phillips, AJ, Robinson, PA A quantitative model of sleep-wake dynamics based on the physiology of the brainstem ascending arousal system.J Biol Rhythms2007;22,167-179
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543