The Effect of OSA on Brain Waste Clearance

The Impact of 2 Weeks CPAP Withdrawal on Brain Waste Clearance in Adults With Severe Obstructive Sleep Apnoea - A Randomised Controlled Crossover Trial

Recent ground-breaking research has shown that clearance of toxic neuro-metabolites from the brain including the proteins β-Amyloid (Aβ) and tau that form dementia causing plaques and tangles is markedly impaired when sleep is disturbed. This suggests that dementia risk may be increased in people with sleep disorders such as obstructive sleep apnea (OSA). Longitudinal studies have linked OSA with a 70-85% increased risk for mild cognitive impairment and dementia. Despite this strong link, little is known about the OSA-specific mechanistic underpinnings. It is not fully understood as to how sleep disturbance in OSA inhibit brain glymphatic clearance. However, it is known that OSA inhibits slow wave sleep, profoundly activates sympathetic activity, and elevates blood pressure - particularly during sleep. These disturbances have, in turn, been shown to independently inhibit glymphatic function. Previous studies have attempted to sample human cerebrospinal fluid (CSF) involved in glymphatic clearance for dementia biomarkers during sleep. However, these studies were severely limited by the need for invasive CSF sampling. To address this problem, a set of newly available, highly sensitive blood based SIMOA assays will be used to study glymphatic function in people treated for severe OSA who undergo CPAP withdrawal. Furthermore, novel methods will be utilized to capture changes in slow wave sleep, blood pressure and brain blood flow together with sleep-wake changes in blood levels of excreted neuro-metabolites to define the pathophysiological mechanisms that inhibit brain cleaning in OSA.

Dementia is a neurodegenerative disease characterized by cognitive dysfunction affecting aspects of memory and learning. Although the mechanisms that underlie the pathophysiology of dementia are still unclear, in the past decade there has been a focus on the adverse impact of sleep disturbance on brain waste disposal via the glymphatic system. The glymphatic system is a recently discovered brain-wide perivascular passageway that transports toxic neuro-metabolites (e.g.: amyloid beta, or Aβ) out of the brain to the blood via the cerebrospinal fluid. Newer research has shown that the glymphatic system becomes particularly active during sleep, clearing metabolites twice as fast compared with wakefulness. Obstructive sleep apnea (OSA), a sleep disorder characterized by periods of intermittent hypoxia and sleep fragmentation due to obstructed breathing, has traditionally been causatively linked to the development of hypertension and cognitive dysfunction. Further to this, recent epidemiological studies have also linked OSA to an increased risk for both dementia and its prodromal state - mild cognitive impairment. There is emerging evidence to suggest that OSA might chronically impair glymphatic clearance of Aβ42 from the brain and facilitate the formation of Aβ plaques that characterize Alzheimer's Disease. Recent ground-breaking research has shown that clearance of toxic neuro-metabolites from the brain including the proteins Aβ and tau that form dementia causing plaques and tangles is markedly impaired when sleep is disturbed. This suggests that dementia risk may be increased in people with sleep disorders such as OSA. Longitudinal studies have linked OSA with a 70-85% increased risk for mild cognitive impairment and dementia. Despite this strong link, little is known about the OSA-specific mechanistic underpinnings. It is not fully understood as to how sleep disturbance in OSA inhibit brain glymphatic clearance. However, it is known that OSA inhibits slow wave sleep, profoundly activates sympathetic activity, and elevates blood pressure - particularly during sleep. These disturbances have, in turn, been shown to independently inhibit glymphatic function. Previous studies have attempted to sample human cerebrospinal fluid (CSF) involved in glymphatic clearance for dementia biomarkers during sleep. However, these studies were severely limited by the need for invasive CSF sampling. To address this problem, this proposed study will use a set of newly available, highly sensitive blood based SIMOA assays to study glymphatic function in people treated for severe OSA who undergo CPAP withdrawal. Furthermore, novel methods will be utilized to capture changes in slow wave sleep, blood pressure and brain blood flow together with sleep-wake changes in blood levels of excreted neuro-metabolites to define the pathophysiological mechanisms that inhibit brain cleaning in OSA.

Obstructive sleep apnea, Brain waste clearance, Glymphatic system, Continuous positive airway pressure therapy, CPAP, Dementia, Cognitive impairment

Participants will continue with their usual continuous positive airway pressure (CPAP) therapy as advised by their treating physician.

Participants will be weaned off their usual continuous positive airway pressure (CPAP) therapy and enter a 2-week period of non-treatment.

Difference between the CPAP on and CPAP off conditions in sleep-wake amplitudes (peak-trough) of blood levels of Aβ (Aβ40/Aβ42 ratio), as measured by SIMOA blood neuro-metabolite assays.

Differences between the CPAP on and CPAP off conditions in NREM slow wave parietal cortex activity as measured by high-density EEG (HD-EEG).

Differences between the CPAP on and CPAP off conditions in brain tissue oxygenation, as measured by oxygenated and deoxygenated hemoglobin using functional Near Infrared Spectroscopy (fNIRS).

Differences between the CPAP on and CPAP off conditions in brain blood volume during sleep, estimated by changes in total hemoglobin using functional Near Infrared Spectroscopy (fNIRS).

Differences between the CPAP on and CPAP off conditions in arterial stiffness during sleep, as measured by the Augmentation Index (%) using pulse wave analysis (PWA) of finger blood pressure waveforms from the Finapres Nova device.

Differences between the CPAP on and CPAP off conditions in peripheral and central aortic systolic, diastolic and mean blood pressure (mmHg) during sleep using pulse wave analysis (PWA) of finger blood pressure waveforms from the Finapres Nova device.

Differences between the CPAP on and CPAP off conditions in pulse wave velocity (m/sec), as measured using the SphygmoCor XCEL device.

Differences between the CPAP on and CPAP off conditions in sympathetic and parasympathetic activity during wake and sleep periods, as measured by heart rate variability (HRV) analysis of electrocardiogram (ECG) readings.

Difference between the CPAP on and CPAP off conditions in sleep-wake amplitudes (peak-trough) of blood levels of p-tau-180, as measured by SIMOA blood neuro-metabolite assays.

Difference between the CPAP on and CPAP off conditions in sleep-wake amplitudes (peak-trough) of blood levels of p-tau-217, as measured by SIMOA blood neuro-metabolite assays.

Changes in sleep-wake amplitudes (peak-trough) of blood levels of glial fibrillary acidic protein (GFAP)

Difference between the CPAP on and CPAP off conditions in sleep-wake amplitudes (peak-trough) of blood levels of GFAP, as measured by SIMOA blood neuro-metabolite assays.

Difference between the CPAP on and CPAP off conditions in sleep-wake amplitudes (peak-trough) of blood levels of NfL, as measured by SIMOA blood neuro-metabolite assays.

Inclusion Criteria: Community dwelling adults aged 35-65 years. Polysomnography-confirmed severe OSA with apnea hypopnea index (AHI) ≥ 30/hour, with Non-Rapid Eye Movement (NREM) AHI ≥ 15/hour, within the past 2 years. Established CPAP use for treatment of OSA with compliance of > 3 months, with ≥ 6 hours use per night for > 5 nights per week. Willing to withdraw from CPAP use for 14 nights. Able to give informed verbal and written consent. Fluent in spoken, and comprehension of English. Exclusion Criteria: Commercial drivers (e.g.: drivers of heavy vehicles, public passenger vehicles, or vehicles requiring dangerous goods driver license). History of severe cardiovascular disease (e.g.: stroke, myocardial infarction, atrial fibrillation). Presence of cognitive impairment and/or established diagnosis of dementia. Regular use of medications which affect sleep (e.g.: benzodiazepines, opioids, stimulants, sedating antihistamines). Regular 24-hour shift workers, presence of jetlag, or history of trans-meridian travel (crossing 2 or more time zones) in the past 2 weeks. Advice against withdrawal of CPAP treatment, as determined by the participant's treating physician or study physician. Vulnerable to driving impairment without CPAP therapy/upon withdrawal of CPAP therapy, as assessed by: (a) positive response(s) to screening questions in the modified ASTN-Motor Vehicle Accident Questionnaire, reporting driving accidents and/or impairments prior to established CPAP therapy; AND/OR (b) the participant's treating physician. Prior history of severe COVID-19 infection involving significant neurological symptoms (e.g.: reduced level of consciousness, delirium, encephalopathy) - warranting hospitalization. Current COVID-19 infection and/or experience of ongoing symptoms/sequelae following a recent COVID-19 infection. Not up to date with the COVID-19 vaccination schedule - as per the current Australian Technical Advisory Group on Immunization (ATAGI) definition for individuals aged 16 years and over - at the time of writing this Protocol, defined as having: Received 2 primary doses of any Therapeutic Goods Administration (TGA)-approved or TGA-recognized COVID-19 vaccine at least 14 days apart (except for the Janssen COVID-19 vaccine, where only 1 primary dose is required); PLUS A booster dose of a TGA-approved COVID-19 vaccine (Pfizer, Moderna or AstraZeneca) at a recommended interval of 3-6 months after the receipt of 2nd primary dose; OR For severely immunocompromised individuals: received 3 primary doses of any TGA-approved or TGA-recognized COVID-19 vaccine, with dose 3 administered within 6 months of receiving dose 2. Other medical conditions deemed by study physicians to warrant exclusion.

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