Marcus Cuffie Pharm. D. Candidate Preceptor: Dr. Ali Rahimi September 16, 2011

1. Sleep-Disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women 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):613-619. The study of osteoporotic fractures is supported by funding from the National Institutes of Health Marcus Cuffie Pharm. D. Candidate Preceptor: Dr. Ali Rahimi September 16, 2011

2. 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.

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

4. Study Design • Sleep and cognition multisite prospective cohort study. • 2731 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.

5. 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

6. Tests performed 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

7. 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

8. 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.

9. 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.

10. 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, 1.10-2.93) • Oxygen desaturation index ≥15 events/hr: (AOR, 1.71; 95% CI, 1.04-2.83) • High sleep time in apnea or hypopnea >7%: (AOR, 2.04; 95% CI, 1.10-3.78)

11. Results

12. 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

13. Evaluation 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

14. 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

15. Level of Evidence: Class IIa, Level B

16. References • 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):613-619. • John Dopp, Bradley Phillips. “Sleep Disorders." Pharmacotherapy: A Pathophysiologic Approach. Joseph Dipiro. New York City: McGraw-Hill Medical, 2008. 1191-1200