Yaffe K, Laffan AM, et al. Sleep-disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women. JAMA.2011;306(6): The study of osteoporotic fractures is supported by funding from the National Institutes of Health Sleep-Disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women Marcus Cuffie Pharm. D. Candidate Preceptor: Dr. Ali Rahimi September 16, 2011

Background Sleep-disordered breathing describes breathing problems during sleep in which insufficient oxygen reaches the lungs.  Common among older adults and affects up to 60% of elderly populations. ​  A number of adverse health outcomes including hypertension, cardiovascular disease, and diabetes have been associated with sleep- disordered breathing. Studies involving sleep-disordered breathing and cognitive impairment are often contradictory and lack the ability to draw conclusions of directionality of association. Many characteristics of disordered breathing (sleep fragmentation, hypoxia, and sleep duration) have possible negative effects on cognitive function, yet none have been carefully investigated in large longitudinal studies.

Objective To determine the prospective relationship between sleep-disordered breathing and cognitive impairment and to investigate potential mechanisms of this association.

Study Design Sleep and cognition multisite prospective cohort study women >65 years of age enrolled Study participants had an overnight polysomnography measured between January 2002 and April 2004, and a baseline cognitive assessment. After a median time of 4.7 yrs, participants underwent neuropsychological tests and had their cognitive status determined.

Study Population Women aged 65 years and older  Consisted of ambulatory participants enrolled in the Study of Osteoporotic Fractures.  Mean age of 82.3, 90% Caucasian women. Excluded if:  Diagnosed with dementia (per DSM-IV)  Use of CPAP or BiPAP in the past 3 months.  Open tracheostomy or reported use of oxygen therapy during sleep Of the 2731 women enrolled, 2271 were ineligible  461 women had in-home polysomnography  79 excluded, 70 died, and 9 terminated from the study  382 participated in ~5 yr follow-up  77 excluded due to only completing a minimal assessment visit  298 women included in final sample

Polysomnography Neuropyschological tests Monitors many body functions  EEG: brain  EOG: eye movements  EMG: skeletal muscle  ECG: heart rhythm Sleep disordered breathing  Pulse oximetry/Oxygen Saturation  Arousal index  Sudden shifts in brain wave activity  Wake after sleep onset/Total sleep time  Respiratory rate/interruptions in breathing Mini-Mental State Examination  A test of global cognition Trails B  A test of executive function California Verbal Learning Test  Test of verbal memory Digit Span  Test of numerical memory Category and verbal fluency tests Tests performed

Outcomes Apneas (complete cessation of airflow) and Hypopneas (discernible >30% reduction in airflow) were defined if occurring for 10 seconds or longer and accompanied by a 3% or greater oxygen desaturation.  Associated variables of hypoxia:  Oxygen desaturation index: The number of oxygen desaturations ≥3% per hour of sleep (coded as ≥15 or <15 events per hour)  Hypoxemia: The percentage of sleep time with oxygen saturation <90%(coded as ≥1% of sleep time or <1% sleep time with oxygen saturation <90%)  Apnea-Hypopnea index: The number of apnea plus hypopnea events per hour of sleep. (positive if ≥ 15 events per hour). Arousals from sleep were defined as an abrupt shift in electroencephalogram frequency of 3 seconds or longer.  Associated variables of sleep fragmentation:  Arousal index: The number of arousals per hour of sleep and minutes of wake after sleep onset.  Sleep duration: Total sleep time in minutes

Outcomes Cognitive impairment was determined in a 2-step process:  A. Women screened for one or more of the following criteria: (1) score of <88 on MMSE;(2) Score of <4 on the CVLT; (3) score of 3.6 or greater on Cognitive decline questionnaire; (4) previous diagnosis of dementia or use of medication for dementia;(5) residence within a nursing home.  B. Women who tested positive were reviewed by a panel blinded to results of sleep studies. The panel reviewed all patient information. A diagnosis was then made based on DSM-IV criteria.

Statistical Analysis To compare baseline characteristics of women with sleep-disordered breathing to those without, chi- square and t-tests were used. For final analysis, multivariate logistic regression models were used to control the effects of multiple confounding variables  Age, race, BMI, education level, smoking status, HTN, medication use, etc.

Results After a mean of 4.7 years of follow-up, 107 (35.9%) women developed mild cognitive impairment or dementia  Mild cognitive impairment: n = 60 (20.1%)  Dementia: n = 47 (15.8%) The presence of sleep-disordered breathing was associated with an increased odds of subsequent mild cognitive impairment or dementia (OR, 1.80; 95% CI, )  Oxygen desaturation index ≥15 events/hr: (AOR, 1.71; 95% CI, )  High sleep time in apnea or hypopnea >7%: (AOR, 2.04; 95% CI, )

Results

Conclusion Among older women, sleep-disordered breathing was associated with an increased risk of developing cognitive impairment 5 years later. 2 of 3 indices of hypoxia, but not sleep fragmentation or sleep duration, were associated with incident mild cognitive impairment or dementia This suggests that hypoxia is a likely mechanism through which sleep-disordered breathing increases risk for cognitive impairment and not sleep fragmentation

Strengths Limitations First trial to look at the long term relationship of hypoxia and risk of dementia Explored many possible mechanisms of sleep disturbances using polysomnography Raises important questions  Suggests a potential role for oxygen therapy in elderly patients with sleep disorders Polysomnography only performed for only one night  Variability Mostly Caucasian women, no males Small sample size Survival bias Evaluation

Well designed cohort Most common sleep-disordered breathing problem is obstructive sleep apnea  Patient’s more at risk for sleep apnea: diabetics, obese, male, and elderly Further trials to test:  Hypoxia and Dementia studies on a more diverse population  Including: men, younger population, and more ethnic groups  Clinical RCT on the efficacy of CPAP for patients with sleep apnea for decreasing risk of dementia.  Hypoxia vs. Hypercapnia  Longer length of study, larger sample sizes

Level of Evidence: Class IIa, Level B

References 1. Yaffe K, Laffan AM, et al. Sleep-disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women. JAMA.2011;306(6): John Dopp, Bradley Phillips. “Sleep Disorders." Pharmacotherapy: A Pathophysiologic Approach. Joseph Dipiro. New York City: McGraw-Hill Medical,