The Effect of OSA on Brain Waste Clearance

April 17, 2024 updated by: Woolcock Institute of Medical Research

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.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

38

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • New South Wales
      • Glebe, New South Wales, Australia, 2095
        • Woolcock Institute of Medical Research

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

35 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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.
  • 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.

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:

    1. 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
    2. 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
    3. 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Screening
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: CPAP on
Participants will continue with their usual continuous positive airway pressure (CPAP) therapy as advised by their treating physician.
Experimental: CPAP off
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
Complete withdrawal of continuous positive airway pressure (CPAP) therapy for a 2-week period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in sleep-wake amplitudes (peak-trough) of blood levels of Aβ
Time Frame: Pre- and 2 weeks post-intervention
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in NREM slow wave parietal cortex activity
Time Frame: Pre- and 2 weeks post-intervention
Differences between the CPAP on and CPAP off conditions in NREM slow wave parietal cortex activity as measured by high-density EEG (HD-EEG).
Pre- and 2 weeks post-intervention
Changes in brain tissue oxygenation during sleep
Time Frame: Pre- and 2 weeks post-intervention
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).
Pre- and 2 weeks post-intervention
Changes in brain blood volume during sleep
Time Frame: Pre- and 2 weeks post-intervention
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).
Pre- and 2 weeks post-intervention
Changes in arterial stiffness indices during sleep
Time Frame: Pre- and 2 weeks post-intervention
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.
Pre- and 2 weeks post-intervention
Changes in central aortic blood pressure during sleep
Time Frame: Pre- and 2 weeks post-intervention
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.
Pre- and 2 weeks post-intervention
Changes in pulse wave velocity (PWV)
Time Frame: Pre- and 2 weeks post-intervention
Differences between the CPAP on and CPAP off conditions in pulse wave velocity (m/sec), as measured using the SphygmoCor XCEL device.
Pre- and 2 weeks post-intervention
Changes in sympathetic and parasympathetic activity during wake and sleep periods
Time Frame: Pre- and 2 weeks post-intervention
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.
Pre- and 2 weeks post-intervention
Changes in sleep-wake amplitudes (peak-trough) of blood levels of p-tau-180
Time Frame: Pre- and 2 weeks post-intervention
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.
Pre- and 2 weeks post-intervention
Changes in sleep-wake amplitudes (peak-trough) of blood levels of p-tau-217
Time Frame: Pre- and 2 weeks post-intervention
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.
Pre- and 2 weeks post-intervention
Changes in sleep-wake amplitudes (peak-trough) of blood levels of glial fibrillary acidic protein (GFAP)
Time Frame: Pre- and 2 weeks post-intervention
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.
Pre- and 2 weeks post-intervention
Changes in sleep-wake amplitudes (peak-trough) of blood levels of neurofilament light chain (NfL)
Time Frame: Pre- and 2 weeks post-intervention
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.
Pre- and 2 weeks post-intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Woolcock Institute of Medical Research

Collaborators

National Health and Medical Research Council, Australia

Investigators

  • Principal Investigator: Keith Wong, MBBS FRACP, Woolcock Institute of Medical Research
  • Principal Investigator: Svetlana Postnova, PhD, University of Sydney
  • Principal Investigator: Mark Butlin, PhD, Macquarie University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 18, 2023

Primary Completion (Estimated)

September 1, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

July 12, 2022

First Submitted That Met QC Criteria

October 30, 2022

First Posted (Actual)

November 7, 2022

Study Record Updates

Last Update Posted (Actual)

April 18, 2024

Last Update Submitted That Met QC Criteria

April 17, 2024

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BrainOSA-0522

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Cognitive Impairment

Clinical Trials on CPAP Withdrawal

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Pakistan

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe