The Effect of OSA on Brain Waste Clearance

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.

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); PLUSA 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; ORFor 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.