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

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) 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.

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.

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):

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)

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.

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.

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.

Brain tissue oxygenation during sleep as measured by oxygenated and deoxygenated hemoglobin using functional Near Infrared Spectroscopy (fNIRS). Associations between brain tissue oxygenation and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Overnight hypoxemia measured by pulse oximetry through nocturnal readings of blood oxygen saturation (SpO2). Associations between night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

EEG arousal index (events per minute of total sleep time) measured during polysomnography. Associations between night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Neuropsychological Test: A z-score of -0.75 indicates low-average premorbid functioning, z= -1.40 indicates borderline poor premorbid functioning and inferior premorbid functioning spans from z=-2.05 to -3.65. Associations between TOPF scores and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Neuropsychological Test: RAVLT scores between groups. Scores ≤ z= -1.0 across two domains indicate poor performance. Immediate verbal learning is assessed by summing trials 1 to 5, Learning is assessed from trial 5 minus trial 1, and Forgetting is assessed through trial five minus the delayed recall trial. Associations between RAVLT scores and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Neuropsychological Test: Differences in scores between groups across the four trials. Greater time taken to complete the trials results in higher scores which indicate worse performance. Associations between D-CEFS scores night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Neuropsychological Test: Differences in TMT scores between groups. Greater time taken to complete the tests results in higher scores which indicate worse performance. A TMT trial A score of ≥78 seconds and a TMT trial B score of ≥273 seconds indicates deficiency. Associations between TMT scores night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Neuropsychological Test: Differences in the COWAT scores between groups. The more acceptable words stated across all four trials, the better the performance in the test. Associations between COWAT scores and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Neuropsychological Test: Differences in the scores on the SDMT between groups. Scores on the SDMT range from 1 to 110, with higher scores indicating better performance over the 90-second trial. Associations between SDMT scores and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of fibrinogen between groups. Associations between fibrinogen and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of clusterin between groups. Associations between clusterin and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of 8-isoprostane between groups. Associations between 8-isoprostane and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of CRP between groups. Associations between CRP and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of ESR between groups. Associations between ESR and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of plasma tau between groups. Associations between plasma-tau and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of NFL between groups. Associations between NFL and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of GFAP between groups. Associations between GFAP and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of APOE-4 between groups. Associations between APOE-4 and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of IL-8 between groups. Associations between IL-8 and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of IL-6 between groups. Associations between IL-6 and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Differences in the blood levels of TNFα between groups. Associations between TNFα and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Associations between blood levels of Aβ (Aβ40/Aβ42 ratio) and night-time hypoxemia / sleep fragmentation between groups.

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 between groups.

Brain MRI: Diffusion-weighted imaging will be analysed to obtain individual fractional anisotropy (FA) and mean diffusivity (MD) maps. Associations of FA and MD and night-time hypoxaemia / sleep fragmentation will be tested using permutation analysis of linear models on each voxel of the white-matter brain map, and corrected for multiple comparisons, in the entire sample and between groups.

Brain fMRI: Resting-state BOLD fMRI will be subjected to dual-regression independent component analysis to obtain individual spatial maps of multiple resting-state brain networks. The component weights of individual voxels will be associated with night-time hypoxaemia / sleep fragmentation using permutation analysis of linear models and corrected for multiple comparisons, in the entire sample and between groups.

Brain MRI: Structural scans will be used to identify potential brain pathology including, white-matter hyper- and hypo-intensities, lacunes, and potential infarcts or other potential ischaemic lesions. The number, type and anatomical location of these potential pathologies will be scored and associated with night-time hypoxaemia / sleep fragmentation using linear mixed models, in the entire sample and between groups.

CANTAB: Differences in scores on the MOT as measured by MOTML (the mean latency from display of a stimulus to the correct response). Greater scores indicate worse performance. Associations between MOT scores and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

CANTAB: Differences in scores on the RTI as measured by RTIFMDRT (the median time taken for the subject to select the target stimulus after releasing the button, calculated across all trials). Higher scores indicate worse performance. Associations between RTI scores night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

CANTAB: Differences in scores on the SWM as measured by SWMTE (total errors during the trials). Higher scores indicate worse performance. Associations between SWM scores and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

CANTAB: Differences in scores on the PAL as measured by PALTEA (The number of times the subject chose the incorrect box for a stimulus on assessment problems (PALTE), plus an adjustment for the estimated number of errors they would have made on any problems, attempts and recalls they did not reach). Higher scores indicate worse performance. Associations between PAL scores and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Sleep spindle and slow oscillation events in NREM sleep from in-laboratory overnight polysomnography. A sleep spindle and slow oscillation detection algorithm will be applied to electroencephalography (EEG) signals from polysomnography after artefacts are detected and removed. Associations between sleep spindles and slow oscillation events and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Proportion of the sleep opportunity scored at the 5 stages (wake, and N1, N2, N3, and REM sleep) between lights out and lights on, and sleep onset, REM onset, sleep efficiency, measured using overnight in-laboratory polysomnography with high-density electroencephalogram (HdEEG), scored by a polysomnographic technician in accordance with American Academy of Sleep Medicine (AASM) Sleep Scoring criteria. Associations between traditional sleep staging and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Spectral power of delta (1-4.5 Hz), theta (4.5-8 Hz), alpha (8-12 Hz), sigma (12-15 Hz), beta (15-25 Hz), and gamma (25-40 Hz) frequency ranges. Power spectral analysis will be applied to EEG signals from polysomnography after artefacts are detected and removed. Associations between absolute Electroencephalography (EEG) Power During Rapid Eye Movement (REM) Sleep and night-time hypoxemia / sleep fragmentation in the entire sample and between groups.

Apnoea-hypopnea index (AHI), oxygen desaturation index (ODI; 3%), oxygen saturation nadir, electroencephalogram (EEG) arousal index (number of arousals per hour of sleep). Associations between OSA severity metrics and night-time hypoxaemia/ sleep fragmentation in the entire sample and between groups.

Pulmonary functioning as measured by traditional PFT (spirometry with pre and post bronchodilator, diffusing capacity of the lungs for carbon monoxide (DLCO), lung volumes and respiratory impedance (oscillometry) as dictated by the American Thoracic Society (ATS). Associations between lung function and night-time hypoxaemia/ sleep fragmentation in the entire sample and between groups.