Sustained Use of CPAP Slows Deterioration of Cognition, Sleep, and Mood in Patients with Alzheimer's Disease and Obstructive Sleep Apnea: A Preliminary Study

Abstract

Introduction:

Obstructive sleep apnea (OSA) is common among patients with Alzheimer's disease (AD). Untreated OSA exacerbates the cognitive and functional deficits. Continuous positive airway pressure (CPAP) has recently been shown to have beneficial effects on cognition in AD. Little attention has focused on the long-term benefits of CPAP in these patients.

Methods:

This was an exploratory study of sustained CPAP use (mean use = 13.3 months, SD = 5.2) among a subset of participants from an initial 6-week randomized clinical trial (RCT) of CPAP in patients with mild to moderate AD. Follow-up included 5 patients who continued CPAP (CPAP+) after completion of the RCT and 5 patients who discontinued CPAP (CPAP−), matched by time of completion of the initial study. A neuropsychological test battery and sleep/mood questionnaires were administered and effect sizes were calculated.

Results:

Even with a small sample size, sustained CPAP use resulted in moderate-to-large effect sizes. Compared to the CPAP− group, the CPAP+ group showed less cognitive decline with sustained CPAP use, stabilization of depressive symptoms and daytime somnolence, and significant improvement in subjective sleep quality. Caregivers of the CPAP+ group also reported that their own sleep was better when compared to the final RCT visit and that their patients psychopathological behavior was improved.

Conclusion:

The results of this preliminary study raise the possibility that sustained, long-term CPAP treatment for patients with AD and OSA may result in lasting improvements in sleep and mood as well as a slowing of cognitive deterioration. Prospective randomized controlled research trials evaluating these hypotheses are needed.

Citation:

Cooke JR; Ayalon L; Palmer BW; Loredo JS; Corey-Bloom J; Natarajan L; Liu L; Ancoli-Israel S. Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer's disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med 2009;5(4):305-309.

Obstructive sleep apnea (OSA) is common among patients with Alzheimer's disease (AD), with prevalence rates reported to be greater than 40% in those who are institutionalized.¹ Untreated OSA itself can have deleterious effects on cognition and daytime functioning,^2–4 and may exacerbate the primary cognitive and functional deficits associated with AD.^5–7 The most effective treatment of OSA is continuous positive airway pressure (CPAP).⁸ Our laboratory recently showed that, in a 6-week randomized placebo controlled clinical trial (RCT) of CPAP in patients with mild-moderate AD and OSA, CPAP improved OSA, objective sleep parameters, and daytime sleepiness, and resulted in modest improvements in measures of cognitive functioning.^9–11 Some participants were so pleased with the effects of CPAP that they purchased their own CPAP machines in order to continue treatment after completing the 6-week RCT. Although long-term follow-up evaluation was not part of the original study design, the continued use of CPAP by some patients presented the opportunity to explore the potential benefits of prolonged CPAP use in AD patients with OSA and to ask the question whether the positive effects on sleep, mood and cognition were maintained with sustained CPAP use.

METHODS

Subjects

Five patients who continued CPAP (CPAP+), and five patients who chose to discontinue CPAP (CPAP−) at the end of the 6-week RCT were included in these analyses. Sleep and mood of the patients' caregivers were also evaluated. Details of the RCT are described in Ancoli-Israel et al.,⁹ including inclusion/exclusion criteria; briefly, all participants (n = 52) in the RCT had a diagnosis of AD, a Mini Mental Status Examination (MMSE)¹² score ≥ 18, an available caregiver, and an apnea-hypopnea index (AHI; number of apneas plus hypopneas per hour of sleep) ≥ 10 (based on polysomnography). All participants and caregivers signed consent forms for the initial RCT and for this follow-up visit, which were approved by the University of California San Diego Human Research Protections Program.

Methods and Measures

In 2004, 3 years into the RCT study, a telephone interview was conducted with all participants who had already completed the RCT to determine if any had chosen to continue CPAP use. Those study participants who reported continued CPAP use were asked if they would be interested in taking part in the follow-up study. All follow-up assessments were conducted in the home and each participant completed the same neuropsychological test battery (described below) as in the RCT. Both the participant and caregiver also completed the same sleep/mood questionnaires administered during the initial RCT study. As each participant carried the diagnosis of AD, caregivers assisted participants with these questionnaires. Each participant in the CPAP+ group was matched by time of completion of the initial RCT to participants who had chosen to discontinue CPAP use.

The procedure for overnight in-home polysomnography (PSG) was previously described,¹³ and the same procedure was repeated for this follow-up evaluation for the CPAP+ group. Repeat PSG was not conducted in the CPAP− group, as most were not willing to repeat the sleep recording. The total number of apneas (defined as an 80% airflow decrease from baseline for ≥ 10 sec) and hypopneas (defined as a 30% to 80% airflow decrease ≥ 10 sec associated with a desaturation ≥ 3% or with an arousal) were scored and divided by the total sleep time to calculate the AHI.

Patients and caregivers completed the Pittsburgh Sleep Quality Index (PSQI),¹⁴ the Epworth Sleepiness Scale (ESS),¹⁵ the Functional Outcomes of Sleep Questionnaire (FOSQ),¹⁶ and the Cornell Scale for Depression (CSD) in Dementia.¹⁷ Caregivers also completed the Neuropsychiatric Inventory (NPI).¹⁸

Participants completed the same neuropsychological test battery from the RCT, described in detail in Ancoli-Israel et al.⁹ Briefly, tests chosen evaluated cognitive abilities of particular relevance to AD (learning/ memory), to OSA-related hypoxia and/or its treatment (learning/memory, and “frontal/ executive skills”), to sleepiness/ sleep disturbance (attention, vigilance), as well as to normal aging (mental processing speed). The test battery included: (1) Global cognition (overall score from the Mattis' Dementia Rating Scale [DRS])¹⁹; (2) Basic attention and vigilance (total correct on the Digit Cancellation task)²⁰; (3) Psychomotor speed (time to complete [seconds] the Trail Making Test Parts A,²¹ raw scores from the Wechsler Adult Intelligence Scale–Third Edition [WAIS-III],²² and Digit Symbol and Symbol Search subtests); (4) Verbal episodic memory (total recall on learning trials 1 through 3 from the Hopkins Verbal Learning Test–Revised [HVLT-R])^23,24; and (5) tests sensitive to various aspects of executive functioning (Trail Making Part B [seconds to complete],²¹ conceptual level responses from the 64-card version of the Wisconsin Card Sorting Test [WCST-64],^25,26 total words completed on the Color-Word Interference trial of the Stroop Color and Word Test,²⁷ and total correct words generated on the Letter fluency [FAS] test and on the Category [Animals] Fluency test).^28,29

Data Analysis

Due to the small sample size, effect sizes were used to quantify differences in sleep, mood, and neuropsychological measures between the CPAP+ and CPAP− groups. The effect-size for each measure was computed as standardized mean differences in change score between final RCT and follow-up visit, namely, (d₁-d₂)/δ_p (d₁ and d₂ are the change scores in the CPAP+ and CPAP− groups respectively, and δ_p is the pooled standard deviation of the change score). For the sake of completeness, despite the small sample size, we also conducted 2 sample Student's t-test and Mann-Whitney test for the mean change scores (between the final RCT and follow-up visits). For the DRS measure which was only given at the initial RCT study entry, the Student's t-test and Mann-Whitney test were performed on the RCT baseline and the follow-up visit scores.

RESULTS

Participants: Ten participants (7 men and 3 women) and 9 caregivers (one patient had moved into an assisted living facility and therefore that caregiver was not included) participated in the follow-up evaluation. The mean follow-up time from completing the RCT was 13.3 months (SD = 5.2, range = 6−21 months). There were no meaningful differences between the 2 groups on any demographic measures at follow-up. Participants had a mean age of 75.7 years (SD = 5.9, range = 65−84), had moderate dementia (mean follow-up MMSE = 22.6, SD = 4.5, range = 16−27), were mildly overweight (mean BMI = 25.9, SD = 3.1, range = 21−31) and on average had ≥ 14 years of education (mean = 14.6 years, SD = 2.7, range = 12−20 years). The majority of patients (9 of 10) were Caucasian. At follow-up, the CPAP+ group had a mean AHI of 1.6 (SD = 2.3, range = 0.2–5.7) while using CPAP.

Follow-Up Questionnaire Results: At the end of the RCT, the participants had comparable scores for sleep and mood. Even with the study's small sample size, there were several noteworthy results.

As can be seen in Figure 1, the CPAP+ group's depressive symptoms (based on CSD), daytime sleepiness (based on ESS) and subjective sleep quality (based on PSQI) either showed less deterioration or improved from the end of the RCT to follow-up compared to the CPAP− group.

Figure 1.

Changes in the CPAP+ and CPAP− groups from the end of the RCT to follow-up on the depression, daytime sleepiness and sleep quality scales. CSD: Although neither group had depressive symptoms at the end of the RCT, at follow-up, the CPAP+ group continued having no depressive symptoms (CSD < 6) (effect size = 1.3) while the CPAP− group showed an increase in CSD scores suggesting deterioration in mood (CSD > 6); ESS: Neither group had evidence of daytime somnolence at the end of the RCT; however, at follow-up, the CPAP+ group's ESS result was unchanged while the CPAP− group's ESS score was consistent with clinically significant daytime sleepiness (effect size = 0.8); PSQI: CPAP+ group showed a significant clinical and statistical improvement in PSQI while the CPAP− group showed a clinical and statistical deterioration (effect size = 1.8, p < 0.05 by both Student's t-test and Mann-Whitney test).

There were no differences between groups in the amount of change in either the FOSQ (effect size = −0.2) or the MMSE (effect size = 0.1).

Follow-Up Neuropsychological Results: Similar to the sleep/mood scores, at the end of the RCT, the participants had comparable scores on the individual tests in the neuropsychological battery.

As with the sleep mood questionnaires, there were some notable results. As assessed by the DRS, there was a moderate effect on global cognition with the CPAP+ group having less deterioration when compared to the CPAP− group (effect size = 0.4).

In addition, as shown in Table 1, the CPAP+ group showed evidence of improvement in executive functioning as assessed by WCST (effect size = 0.7), Stroop Color-Word Score (effect size = −0.8), Trails B (effect size = −0.3) and FAS Total Letter Score (effect size = −0.7) while the CPAP− group appeared to deteriorate on these tests. Sustained CPAP use also appeared to have positive effects on psychomotor speed (WAIS effect size = −1.9; Trails A effect size = −0.5) with the CPAP+ group showing evidence of improvement while the CPAP− group appeared to deteriorate.

Table 1.

Neuropsychological Measures

Variable	CPAP+ (n = 5) Mean (SD)		CPAP− (n = 5) Mean (SD)		Effect size
	End of RCT	Follow-Up	End of RCT	Follow-Up
HVLT	15.2 (7.2)	14.0 (7.9)	13.8 (6.4)	12.8 (4.9)	0.1
WAIS**	19.3 (2.5)	17.0 (8.2)	15.4 (4.6)	12.3 (7.4)	−1.9
Trails A	86.6 (120.1)	96.2 (115.3)	67.6 (26.9)	100.0 (64.5)	0.5
Trails B	95.8 (25.8)	87.8 (71.1)	247.8 (96.3)	249.6 (78.9)	−0.3
WCST	43.6 (13.4)	33.6 (25.4)	35.8 (9.4)	28.8 (22.2)	0.7
Stroop	8.0 (4.1)	18.8 (16.0)	5.3 (3.0)	2.8 (12.1)	−0.8
FAS Letter	24.6 (16.3)	25.4 (26.3)	26.4 (16.2)	19.8 (9.8)	−0.7
FAS Animal	13.2 (9.2)	11.4 (12.6)	11.6 (6.1)	9.2 (5.5)	−0.1
Digit Cancel	18.4 (9.0)	16.2 (14.3)	13.7 (1.5)	11.0 (5.8)	−0.2

*Higher HVLT score implies more recall; Higher WAIS speed implies completing the task faster; Lower Trails A score implies completing the task faster; Lower Trails B score implies completing the task faster; Higher WCST score implies completing more of the task; Higher Stroop score implies being able to read more color/words; Higher FAS letter score implies the ability to think of more words; Higher FAS animal score implies the ability to think of more words; Higher Digit cancellation score implies completing more of the task.

^**p value = 0.06 from the Student's t-test and Mann-Whitney test.

Caregivers: Caregivers of the CPAP+ group reported stabilization of the patients' psychopathology symptoms (based on the caregivers' scoring of the NPI) while the CPAP- caregivers noted worsening symptoms (effect size = −1.5, p = 0.07 by Mann-Whitney test). Compared to the caregivers of the CPAP− group, the CPAP+ caregivers' subjective sleep quality based on the PSQI remained stable, while the caregivers of the CPAP− group showed evidence of deterioration (effect size = −1.3, p = 0.02 by Mann-Whitney test). In addition, there were moderate effects in the caregivers own depression ratings (CSD effect size = −0.3) and their own quality of life ratings (FOSQ effect size = 0.5) scores.

DISCUSSION

The results of this study suggested that continued use of CPAP may be associated with some sustained benefits in sleep, mood, and cognitive functioning. The CPAP+ group either remained stable or showed improvement (i.e., changed in the direction of improvement) on almost all measures while the CPAP− group continued to deteriorate, as would be expected over time in patients with AD. The sustained use of CPAP also appeared to benefit these patients' caregivers who reported that their own sleep quality improved, their own mood remained stable, and the patients' psychopathology was stabilized.

This study focused on the sustained effects of CPAP use and did not include any analysis of changes from baseline (i.e., pre-CPAP treatment) to follow-up, as each participant received CPAP treatment during the initial RCT and showed similar benefits on all measures. Rather the study focused on the long-term effect of CPAP use vs. discontinuation of treatment.

To our knowledge, there have been no published reports describing the pattern of cognitive functioning among AD patients using CPAP over several months. Likewise, there have been no reports of how sustained CPAP treatment might affect mood and sleep in this patient population although most studies in non-demented subjects have found that long-term CPAP use improved general sense of well-being and reduced daytime sleepiness.^30–35

Despite our positive findings, there are several limitations that warrant discussion. First, it is impossible to make causal inferences given the small sample size and lack of random assignment to group (continued use versus discontinuation of CPAP). In addition, selection bias should be considered as the CPAP+ and CPAP− groups may have had intrinsic unmeasured differences which resulted in their choice to continue or discontinue CPAP. As follow-up evaluations were not a part of the parent study design, there are no objective measures of CPAP compliance; nevertheless, the CPAP+ group did continue to have AHI levels < 5 suggesting that they did indeed continue to use their CPAP. Finally, these subjects were matched by time of completion of the initial RCT, not by other potentially important variables such as gender, body mass index, severity of OSA, or baseline cognitive function. More rigorous matching was not possible due to the available small sample size. Because of these study limitations, the results should be interpreted with caution and need to be confirmed.

These findings do however raise the interesting possibility that the sustained, long-term use of CPAP may result in a slowing in the rate of cognitive deterioration and in improvements in sleep and mood in patients with mild to moderate AD and OSA. In this study, even with a very small sample size, we found moderate-to-large effect sizes with statistically significant improvements in sleep quality for those participants who continued to use CPAP. Given the potential positive impact that CPAP use may have on cognition as well as mood and sleep measures in AD patients and their caregivers, these possibilities should be evaluated through prospective randomized controlled trials.

DISCLOSURE STATEMENT

This was not an industry supported study. Dr. Ancoli-Israel has consulted for and/or is on the advisory board of Ferring Pharmaceuticals, GlaxoSmithKline, Orphagen Pharmaceuticals, Pfizer, Respironics, Sanofi-Aventis, Sepracor, and Schering-Plough and has received research support from Sepracor and Litebook, Inc. The other authors have indicated no financial conflicts of interest.