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Is Brain Function Impaired in Moderate Sleep Apnoea: Before and After Six Months of APAP. by Russ J. Buckley A thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy (Medicine) in the University of Otago, Christchurch, New Zealand July 2021 Abstract The physiological impact of severe levels of obstructive sleep apnoea and the benefits of treatment are well documented. Yet more of the population suffer sleep apnoea of moderate severity. However, we still have substantial gaps in our understanding on the physiological impact and treatment of people with sleep apnoea of moderate severity. Our study addressed whether moderate obstructive sleep apnoea (OSA) had an impact on cerebral blood flow, cognition, or microsleeps. It also explored the effect of 6–7 months of auto-titrating positive airway pressure (APAP) therapy on physiological measurements and quality-of-life in persons with moderate OSA. Twenty-four patients aged 32–79 years (median age 59, 10 female), who had previously presented to the Christchurch Hospital Sleep Unit and subsequently diagnosed with sleep apnoea of moderate severity consented to our study. Following a Level II polysomnography to confirm their suitability to participate, thirteen of these participants, aged 43–79 years (median age 59, 4 female), were placed on APAP therapy, with instructions to use it for at least 4 hr per night for 70% or more of the nights. The remaining 11 participants aged 32–79 years (median age 62, 6 female), were placed in an untreated cohort. Placement in the treated cohort was dependent on order of presentation with those first recruited offered a place in the treated cohort. A third group of seven healthy controls aged 42–73 years (median age 62, 4 female) with an apnoea, hypopnea index (AHI) < 5 were recruited from a database of normal volunteers. The absence of sleep apnoea’s was confirmed by polysomnography in all seven participants. All three groups underwent an MRI ASL scan of cerebral perfusion, completed cognitive tests covering five cognitive domains – attention, executive functioning, memory, speed of processing, and visuospatial – and undertook a 30-minute task in which they were required to continuously track a constantly moving target for the purpose of detecting microsleeps. This behavioural data, along with video recordings of eye movement and closure, were visually rated to identify microsleeps. Finally, the Epworth sleepiness scale (ESS), Pittsburgh sleep quality index (PSQI), and Short-form 36 Health survey questionnaire (SF-36) were completed. All measurements were repeated after the intervention period of 6–7 months during which time the treated cohort received APAP therapy. Global cerebral perfusion did not differ at baseline between participants with sleep apnoea of moderate severity and healthy controls (mean 49.26 ml/100g/min vs 48.73 respectively, p = .899, d = 0.06). Furthermore, global cerebral perfusion rates at follow-up for the treated cohort, were not significantly different to baseline (mean 51.64 vs 48.56, p = .150, d =0.42). Although a comparison of regional perfusion, as shown in the multi-sliced images, between the treated cohort, the untreated cohort, and the control group show a positive effect of change in the treated cohort over the other two, particularly in the right cerebral cortex/cingulate gyrus region and the right angular/supramarginal gyri, no statistically significant distinct regions of improved cerebral perfusion were identified. i The normalized and standardized composite cognitive score also did not differ at baseline between moderate OSA and healthy controls (median 0.26 vs 0.73, p = .166, d = -0.62). Repeat testing of cognition at the completion of 6–7 months of APAP therapy found no evidence of a difference between baseline and follow-up on total cognition (mean = 0.22 vs 0.36, p = .560, d = -0.17. However, despite memory showing a significant improvement (p = .001) there was a clear test-retest effect in all three groups. Microsleep was also tested at baseline. Participants with moderate OSA (0–126 microsleeps, median 0) and healthy controls (0–2 microsleeps, median 0) displayed a similar propensity to microsleeps (p = .253, d = 2.1). No difference in microsleeps were observed between participants compliant with APAP treatment compared to their baseline result (median 0, range 0–5, vs. median 0, range 0–13, p = .344). Several markers of day-time sleepiness and quality of live improved in our treatment cohort: Epworth Sleepiness Scale (median 8 down from 11, p = .003, d =1.96), PSQI (mean 15.69 up from 14.23, p = .046, d = 0.94) and Minnesota Short Form 36 (mean 76.31 up from 66.09, p = .035, d = 0.93). This research was unable to demonstrate any change in cerebral perfusion, cognition, or microsleeps following 6-7 months of APAP treatment. However, improvements in daytime sleepiness, sleep quality and quality of life are consistent with the observation that most participants who used APAP in this study wished to continue its use past its conclusion. This indicates a clinical benefit in treating moderate OSA not otherwise supported. ii Acknowledgements A work of this nature would be difficult, if not impossible to achieve were it not for the effort of others. The assistance given and friendship offered to me by my supervisors, Professor Richard Jones, Professor Lutz Beckert, Dr. Carrie Innes and Dr. Paul Tudor Kelly, all deserve special mention. Also, I want to acknowledge the contribution of Dr. Michael Hlavac who was an enthusiastic member of the research team. Although I have been challenged at times by their considerable intellect and knowledge, their constant encouragement and patience, unrelenting enthusiasm, considerable support, and sound practical advice has provided me with a sound platform from which I could complete this study. Special recognition of the considerable contribution made by those patient souls who volunteered for this study needs acknowledgement. Without people who are prepared to put their hand up when asked to participate in these studies, meaningful research would be limited. I asked a lot from those who participated. They had to undergo overnight sleep studies, tolerate the MRI scanner, be subjected to two and a half hours of cognitive and microsleep testing, not once but twice. In addition, those participants assigned to the treated cohort had to undertake six-months of APAP treatment which involved wearing a mask while they sleep. That they did that was an extraordinary display of tolerance, which on behalf of the sciences I applaud. Also, I want to thank the Canterbury District Health Board Sleep Health Services team, who in addition to their normal workload, undertook the Sleep Studies and Pacific Radiology staff members who undertook the MRI ASL scans, often in the weekends. I would also like to recognize their friendship and encouragement both of which were much appreciated as was their interest in what this study was doing. I am also appreciative of the friendship, help, and feedback extended to me by my colleagues at the New Zealand Brain Research Institute. Dr Tracy Melzer deserves special mention for his assistance with ASL processing. It is also appropriate that I thank the University of Otago for its institutional support and for recognising the merit of this study and providing financial support. I was very privileged to benefit from an Otago University Doctoral Scholarship and can only hope that this study has done it justice. Finally, I must recognise the encouragement, contribution, and sacrifice made by my wife Raewyn throughout the course of my studies. Without her unwavering support and tolerance, this study would not have been possible. Her belief in me at all times has been remarkable. Thank-you love. iii Table of Contents Abstract ................................................................................................................................................... i Acknowledgements .............................................................................................................................. iii Table of Contents ................................................................................................................................. iv Preface ................................................................................................................................................... ix Table of Abbreviations ......................................................................................................................... x Chapter 1 Introduction ......................................................................................................................... 1 1.1 The problem .................................................................................................................................. 2 1.2 Solution ......................................................................................................................................... 4 1.3 Research Questions and Hypotheses ............................................................................................. 4 Chapter 2 The cerebrovascular sequalae of moderate OSA whilst awake ...................................... 7 2.1 Introduction ................................................................................................................................... 7 2.2 Definitions....................................................................................................................................