Biomarkers of Dementia in Chronic Sleep and Breathing Disorders

Woolcock Institute of Medical Research104 enrolled

Overview

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.

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.

Interventions

High density electroencephalogram (HdEEG)DIAGNOSTIC_TEST

High-density electroencephalography (HdEEG) will be utilised in the investigation of sleep-mediated neuronal functions in controls, OSA, COPD and overlap syndrome and the association with accelerated brain ageing and cognitive impairment.

Functional near infrared spectroscopy (fNIRS)DIAGNOSTIC_TEST

Functional near infrared spectroscopy (fNIRS) is one of the most advanced techniques in measuring brain oxygen content and hemodynamic activity. This information indirectly displays neuronal activity and provides a novel opportunity understand brain oxygenation, neurodegenerative diseases, and cognitive function.

Magnetic resonance imaging (MRI)DIAGNOSTIC_TEST

Magnetic resonance imaging (MRI) will be utilised to assess potential structural neuronal changes associated with neurodegenerative disease in those with COPD, OSA and overlap syndrome. MRI has the capacity to provide vital information regarding neuroimaging standards in cerebral vascular damage such as white matter hyperintensities (WMH), lacunes, cerebral microbleeds, brain atrophy and subcortical infarct. Through the utility of MRI sequences such as T1 and T2 weighted imaging, diffusion weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) and resting-state fMRI (rs-fMRI), the investigators will assess neurodegenerative-related structural brain changes in individuals with COPD, OSA and overlap syndrome and examine the differences between these target groups.

Blood collectionBIOLOGICAL

A fasting 50mL blood sample will be collected at the experimental visit in the morning following the overnight sleep study. Blood samples will be processed after collection and stored at -80 degrees for future batch analyses. Analyses will include markers for inflammation and dementia including but not limited to ptau217 and beta amyloid. Routine blood analyses will be conducted on 17.5mL of the sample collected for baseline measures. Routine blood analyses includes lipid profile, glucose studies, insulin, high-sensitivity C-reactive protein (hs-CRP), iron studies, thyroid function, b12/folate, homocysteine, prolactin, calcium, full blood count and biochemistry panel for the OSA, COPD and overlap syndrome groups. Routine blood analyses for controls include glucose studies, lipid profile, hs-CRP and biochemistry panel.

Neuropsychological batteryDIAGNOSTIC_TEST

A. Montreal Cognitive Assessment (MoCA): B. Test of Premorbid Functioning (TOPF): C. Rey Auditory Verbal Learning Test (RAVLT): D. D-KEFS Colour Word Interference Test (D-CWIT): E. Trail Making Test (TMT): F. Symbol Digit Modalities Test (SDMT) - Oral Version: G. RAVLT 20-minute recall H. Controlled Oral Word Association Test (COWAT):

QuestionnairesOTHER

1. Epworth Sleepiness Scale (ESS) 2. PROMIS sleep questionnaire 8a, 3. PROMIS sleep questionnaire 8b 4. EQ-5D-5L 5. Insomnia Severity Index (ISI) 6. Pittsburgh Sleep Quality Index (PSQ-I) 7. St George's Respiratory Questionnaire (SGRQ) 8. COPD Assessment Test (CAT)

Pulmonary Function Test (PFT)DIAGNOSTIC_TEST

Full pulmonary function testing will be conducted in control, COPD, OSA and overlap syndrome groups. Full lung function testing will include spirometry with pre and post bronchodilator, oscillometry, lung diffusion testing (DLCO) and lung volumes.

Cognitive AssessmentOTHER

The following cognitive assessments will be administered using a digital format on CANTAB: 1. Motor Screening Task (MOT) Used to assess sensorimotor function and comprehension and is applicable in the assessment of general cognitive function, Alzheimer's disease and cerebrovascular disease. This task acts as a practice trial for the subsequent tasks. 2. Reaction Time (RTI) Used to assess processing and psychomotor speed and is applicable in the assessment of general cognitive function and Alzheimer's disease. 3. Paired Associate Learning (PAL) Used to assess visual episodic memory and is applicable in the assessment of general cognitive function, Alzheimer's disease, Parkinson's disease and cerebrovascular disease. 4. Spatial Working Memory (SWM) Used to assess working memory and strategy and is applicable in the assessment of general cognitive function, Alzheimer's disease and cerebrovascular disease.

Polysomnogram (PSG)DIAGNOSTIC_TEST

During the sleep study, physiological signals are recorded to capture eye movements (electrooculogram, EOG) and chin muscle movements (electromyogram, EMG). A nasal airflow piece, two respiratory inductance plethysmography (RIP) bands and an oximeter probe on the finger will monitor breathing and oxygen levels in the blood. Electrocardiogram (ECG), leg movements, sleeping position and snoring are also recorded.

Eligibility

Sex: ALLMin age: 40 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Scores on the Montreal Cognitive Assessment (MoCA) neuropsychological assessment for dementia risk.

MoCA scores of 18 to 25 indicate mild cognitive impairment, 10 to 17 indicate moderate cognitive impairment and scores below 10 indicate severe cognitive impairment. Associations between MoCA and night-time hypoxemia / sleep fragmentation in the entire sample.