Clinical trial NCT06377332: Biomarkers of Dementia in Chronic Sleep and Breathing Disorders
Official title: Biomarkers of Dementia in Chronic Sleep and Breathing Disorders
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: COPD
Overlap Syndrome
OSA
Keywords: Biomarkers
Observational
Cross-Sectional
Lead sponsor: Woolcock Institute of Medical Research
Sponsor class: OTHER
First posted: 2024-04-22
Enrollment: 104
Sex: ALL
Minimum age (years): 40
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population involves four groups: controls, OSA, COPD and overlap syndrome (OVS). All participants will meet all inclusion criteria for their group and none of the exclusion criteria.

Brief summary: Chronic obstructive pulmonary disease (COPD), obstructive sleep apnoea (OSA) and overlap syndrome are associated with obstructions in breathing and disturbed sleep.

Chronic breathing disruptions and poor sleep may lead to cognitive impairment and brain changes linked with early neurodegenerative processes. As such, identifying early markers of cognitive impairment and dementia risk in individuals with chronic respiratory and sleep breathing disorders is crucial for understanding how these diseases may contribute to accelerated brain ageing. This study will comprehensively measure sleep, lung function, cognitive performance and blood-based markers of dementia risk and inflammation. The investigators will use innovative technologies to identify biomarkers of cognitive impairment and dementia risk in people with chronic sleep and breathing disorders. The investigators will also investigate the relationships between disrupted sleep and abnormal breathing and the brain. This research may also inform future early interventions to improve cognition and brain health in chronic sleep and respiratory disease.

Detailed description: Neurodegeneration that is present in dementia is caused, in part, by neuroinflammation, cerebral vascular damage and oxidative stress. Intermittent hypoxia and hypercapnia, as seen in patients with chronic obstructive pulmonary disease (COPD), obstructive sleep apnoea (OSA) and overlap syndrome, cause neuroinflammation and sleep fragmentation. As a result, key biomarkers of cytokine tumour necrosis factor-alpha (TNF-a), C-reactive protein (CRP), eosinophils, CD8+ and CD4+ T cells, interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1 beta (IL-1B), nuclear factor kappa beta (NF-kB) and hypoxia-inducible factor (HIF) infiltrate the central nervous system (CNS), perpetuating neuroinflammation through the presence of microglia which cause oxidative and nitrosative stress.

Key inflammatory and dementia-based biomarkers will be collected in the investigation of this association including but not limited to Aβ40/42 ratio and ptau217.

This study consists of an observational cross-sectional design with the utilisation of blood collection, lung function testing, MRI, HdEEG, fNIRS and neurocognitive assessment. Participants will be selected into the study differentially based on the target group, with OSA criteria requiring an ODI \> 15, COPD criteria requiring a GOLD 2 minimum, FEV1 ≥50%, \< 80% predicted; FEV1/FVC \< 0.7 with a 10- pack year smoking history and overlap syndrome criteria requiring a combination of ODI \> 15 and GOLD 2 minimum, FEV1 ≥50%, \< 80% predicted; FEV1/FVC \< 0.7, with a 10-pack year smoking history. Participants will be 40 to 65 years old. Controls will have no diagnosis of OSA, COPD or overlap syndrome and have an English fluency. In order to test the hypotheses, the design of a cross-sectional study will allow us to a) examine the relationships between sleep and breathing metrics and cognition and blood-based markers of dementia pathology b) examine the relationships between potential intermediates of compromised sleep and breathing with the primary cognitive and dementia risk outcomes c) compare sleep, lung function, brain health, cognition and inflammatory markers between OSA, COPD, overlap syndrome and control groups.

Eligibility criteria: Inclusion Criteria:

Control:

1. Males and females;
2. Aged 40-65 years;
3. Able to give informed consent;
4. Able to perform neuropsychological and cognitive testing;
5. Fluent in English.

OSA:

1. Males and females;
2. Aged 40-65 years;
3. Oximetry confirmed moderate to severe OSA based on the oxygen desaturation index (ODI) ≥15/hr;
4. Able to give informed consent;
5. Ability to perform neuropsychological and cognitive testing;
6. Fluent in English.

COPD:

1. Males and females;
2. Aged 40-65 years;
3. COPD confirmed by diagnosis or a positive lung function test (GOLD 2 minimum, FEV1

   ≥50%, \< 80% predicted; FEV1/FVC \< 0.7);
4. 10-pack year smoking history;
5. Able to perform neuropsychological and cognitive testing;
6. Fluent in English.

Overlap Syndrome:

1. Males and females;
2. Aged 40-65 years;
3. Oximetry confirmed moderate to severe OSA based on the oxygen desaturation index (ODI) ≥15/hr;
4. COPD confirmed by diagnosis or a positive lung function test (GOLD 2 minimum, FEV1

   ≥50%, \< 80% predicted; FEV1/FVC \< 0.7);
5. 10-pack year smoking history;
6. Able to perform neuropsychological and cognitive testing;
7. Fluent in English.

Exclusion Criteria:

1. Dementia diagnosis;
2. At home or overnight oxygen therapy;
3. Asthma diagnosis (identified with lung function bronchodilator);
4. Current antipsychotic use;
5. BMI \> 40;
6. PAP use or OSA treatment in the last 2 months;
7. Recent COPD exacerbation with change in symptomology (hospitalisation and/or steroids and/or antibiotics) within 6 weeks;
8. Awake supine oxygen saturations of \< 93%;
9. Sleep disorders including narcolepsy, idiopathic hypersomnia (IH), moderate-severe restless leg syndrome (RLS) or REM behaviour disorder (RBD);
10. Other major comorbidities (other lung diseases, neurodegenerative disease, brain injury, severe mental illness, PTSD);
11. Uncontrolled depression (impacting daily life, no use of medications or engagement with psychotherapy- dictated by physician);
12. Malignancies (basal cell carcinoma accepted);
13. Any contraindication for MRI.
14. New York Heart Association (NYHA) score of IV or hospitalisation from heart failure in the last 6 months.

Primary outcomes:
measure: Scores on the Montreal Cognitive Assessment (MoCA) neuropsychological assessment for dementia risk.
timeFrame: Cross-sectional/baseline only
measure: Blood levels of amyloid beta (Aβ40/Aβ42 ratio).
timeFrame: Cross-sectional/baseline only
Secondary outcomes:
measure: Absolute Electroencephalographic (EEG) Power During Non-Rapid Eye Movement (NREM) Sleep.
timeFrame: Cross-sectional/baseline only
measure: Brain tissue oxygenation during cognitive tasks and sleep.
timeFrame: Cross-sectional/baseline only
measure: Hypoxemia as measured by pulse oximetry.
timeFrame: Cross-sectional/baseline only
measure: Sleep Fragmentation
timeFrame: Cross-sectional/baseline only
measure: Assessment of premorbid functioning and preinjury through the Test of Premorbid Functioning (TOPF).
timeFrame: Cross-sectional/baseline only
measure: Assessment of verbal learning and memory through the Rey Auditory Verbal Learning Test (RAVLT).
timeFrame: Cross-sectional/baseline only
measure: Assessment of mild forms of cognitive dysfunction through Delis Kaplan Executive Functioning System (D-CEFS) neuropsychological assessment.
timeFrame: Cross-sectional/baseline only
measure: Assessment of speed of processing and executive functioning through the Trail Making Test (TMT).
timeFrame: Cross-sectional/baseline only
measure: Assessment of verbal fluency through the Controlled Oral Word Association Test (COWAT).
timeFrame: Cross-sectional/baseline only
measure: Assessment of attention, perceptual speed, motor speed and visual scanning through the Symbol Digits Modalities Test (SDMT).
timeFrame: Cross-sectional/baseline only
measure: Blood levels of fibrinogen.
timeFrame: Cross-sectional/baseline only
measure: Blood levels of clusterin.
timeFrame: Cross-sectional/baseline only
measure: Blood levels of 8-isoprostane
timeFrame: Cross-sectional/baseline only
measure: Blood levels of C-reactive protein (CRP)
timeFrame: Cross-sectional/baseline only
measure: Blood levels of erythrocyte sedimentation rate (ESR).
timeFrame: Cross-sectional/baseline only
measure: Blood levels of plasma tau.
timeFrame: Cross-sectional/baseline only
measure: Blood levels of neurofilament light chain (NFL).
timeFrame: Cross-sectional/baseline only
measure: Blood levels of Glial fibrillary acidic protein (GFAP).
timeFrame: Cross-sectional/baseline only
measure: Blood levels of Apolipoprotein E gene (APOE-4).
timeFrame: Cross-sectional/baseline only
measure: Blood levels of interleukin-8 (IL-8).
timeFrame: Cross-sectional/baseline only
measure: Blood levels of interleukin-6 (IL-6).
timeFrame: Cross-sectional/baseline only
measure: Blood levels of tumor necrosis factor alpha (TNFα).
timeFrame: Cross-sectional/baseline only
measure: Blood levels of amyloid beta (Aβ40/Aβ42 ratio).
timeFrame: Cross-sectional/baseline only
measure: Scores on the Montreal Cognitive Assessment (MoCA) neuropsychological assessment for dementia risk.
timeFrame: Cross-sectional/baseline only
Other outcomes:
measure: Brain structure: cortical thickness and volumetric brain maps
timeFrame: Cross-sectional/baseline only
measure: Brain structure: diffusion-weighted imaging
timeFrame: Cross-sectional/baseline only
measure: Brain function: resting-state BOLD fMRI
timeFrame: Cross-sectional/baseline only
measure: Brain pathology: T1-weighted, T2-weighted, diffusion-weighted imaging, and FLAIR
timeFrame: Cross-sectional/baseline only
measure: Assessment of sensorimotor function and comprehension through the Motor Screening Task (MOT) of CANTAB.
timeFrame: Cross-sectional/baseline only
measure: Assessment of processing and psychomotor speed through the Reaction Time (RTI) test of CANTAB.
timeFrame: Cross-sectional/baseline only
measure: Assessment of working memory and strategy through the Spatial Working Memory (SWM) test of CANTAB.
timeFrame: Cross-sectional/baseline only
measure: Assessment of visual episodic memory through the Paired Associate Learning (PAL) test of CANTAB.
timeFrame: Cross-sectional/baseline only
measure: Sleep Spindles During Non-Rapid Eye Movement (NREM) Sleep
timeFrame: Cross-sectional/baseline only
measure: Traditional sleep staging.
timeFrame: Cross-sectional/baseline only
measure: Absolute Electroencephalography (EEG) Power During Rapid Eye Movement (REM) Sleep.
timeFrame: Cross-sectional/baseline only
measure: Obstructive sleep apnoea (OSA) severity metrics
timeFrame: Cross-sectional/baseline only
measure: Lung function as measured by clinical pulmonary function tests (PFT)
timeFrame: Cross-sectional/baseline only
Locations:
city: Sydney
country: Australia
facility: The Woolcock Institute of Medical Research
state: New South Wales
Study officials:
References: