The Effect of OSA on Brain Waste Clearance

NCT05606991 | Enrolling By Invitation

• 1 other identifier: BrainOSA-0522
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Obstructive Sleep Apnea; Dementia; Cognitive Impairment

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Changes in sleep-wake amplitudes (peak-trough) of blood levels of Aβ

  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.

  Pre- and 2 weeks post-intervention

Secondary Outcomes (7)

• Changes in NREM slow wave parietal cortex activity

  Pre- and 2 weeks post-intervention

• Changes in brain tissue oxygenation during sleep

  Pre- and 2 weeks post-intervention

• Changes in brain blood volume during sleep

  Pre- and 2 weeks post-intervention

• Changes in sympathetic and parasympathetic activity during wake and sleep periods

  Pre- and 2 weeks post-intervention

• Changes in sleep-wake amplitudes (peak-trough) of blood levels of p-tau-217

  Pre- and 2 weeks post-intervention

Study Arms (2)

CPAP on

NO INTERVENTION

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

CPAP off

EXPERIMENTAL

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

Other: CPAP Withdrawal

Interventions

CPAP Withdrawal OTHER

Complete withdrawal of continuous positive airway pressure (CPAP) therapy for a 2-week period.

CPAP off

Eligibility Criteria

• Age: 35 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Established CPAP use for treatment of OSA with compliance of \> 3 months, with ≥ 5 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Woolcock Institute of Medical Research: lead
• National Health and Medical Research Council, Australia: collaborator

Study Sites (1)

Woolcock Institute of Medical Research

Macquarie Park, New South Wales, 2113, Australia

Location

Related Publications (9)

• Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019 Feb 22;363(6429):880-884. doi: 10.1126/science.aav2546. Epub 2019 Jan 24.

  PMID: 30679382 BACKGROUND

• Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. doi: 10.1126/science.1180962. Epub 2009 Sep 24.

  PMID: 19779148 BACKGROUND

• Bubu OM, Andrade AG, Umasabor-Bubu OQ, Hogan MM, Turner AD, de Leon MJ, Ogedegbe G, Ayappa I, Jean-Louis G G, Jackson ML, Varga AW, Osorio RS. Obstructive sleep apnea, cognition and Alzheimer's disease: A systematic review integrating three decades of multidisciplinary research. Sleep Med Rev. 2020 Apr;50:101250. doi: 10.1016/j.smrv.2019.101250. Epub 2019 Dec 12.

  PMID: 31881487 BACKGROUND

• Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012 Aug 15;4(147):147ra111. doi: 10.1126/scitranslmed.3003748.

  PMID: 22896675 BACKGROUND

• Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224.

  PMID: 24136970 BACKGROUND

• Bucks RS, Olaithe M, Rosenzweig I, Morrell MJ. Reviewing the relationship between OSA and cognition: Where do we go from here? Respirology. 2017 Oct;22(7):1253-1261. doi: 10.1111/resp.13140. Epub 2017 Aug 4.

  PMID: 28779504 BACKGROUND

• Leng Y, McEvoy CT, Allen IE, Yaffe K. Association of Sleep-Disordered Breathing With Cognitive Function and Risk of Cognitive Impairment: A Systematic Review and Meta-analysis. JAMA Neurol. 2017 Oct 1;74(10):1237-1245. doi: 10.1001/jamaneurol.2017.2180.

  PMID: 28846764 BACKGROUND

• Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, Ancoli-Israel S, Stone KL. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA. 2011 Aug 10;306(6):613-9. doi: 10.1001/jama.2011.1115.

  PMID: 21828324 BACKGROUND

• Ju YS, Zangrilli MA, Finn MB, Fagan AM, Holtzman DM. Obstructive sleep apnea treatment, slow wave activity, and amyloid-beta. Ann Neurol. 2019 Feb;85(2):291-295. doi: 10.1002/ana.25408. Epub 2019 Jan 17.

  PMID: 30597615 BACKGROUND

MeSH Terms

Conditions

Sleep Apnea, Obstructive; Dementia; Cognitive Dysfunction

Condition Hierarchy (Ancestors)

Sleep Apnea Syndromes; Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Brain Diseases; Central Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Study Officials

• Keith Wong, MBBS FRACP

  Woolcock Institute of Medical Research

  PRINCIPAL INVESTIGATOR

• Svetlana Postnova, PhD

  University of Sydney

  PRINCIPAL INVESTIGATOR

• Mark Butlin, PhD

  Macquarie University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized controlled crossover trial

Study Record Dates

• First Submitted: July 12, 2022
• First Posted: November 7, 2022
• Study Start: July 18, 2023
• Primary Completion: April 1, 2026
• Study Completion: April 1, 2026
• Last Updated: June 27, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)