Association of Obstructive Sleep Apnea With White Matter Integrity and Cognitive Performance Over a 4-Year Period in Middle to Late Adulthood

Key Points Question Is obstructive sleep apnea (OSA) associated with cognition and white matter (WM) integrity over time? Findings In this cohort study of 1110 participants, OSA was associated with impaired cognition and WM integrity during 4 years of follow-up. Incident and persistent OSA were associated with accelerated attention, visual processing, and visual memory decline, which correlated with changes in fractional anisotropy of the relevant WM areas. Age and sex were associated with modifying the associations. Meaning These findings suggest that timely evaluation and adequate intervention of OSA could aid in preserving brain health, improving cognition, and reducing the risk of cognitive impairment.


Defining apnea and hypopnea on polysomnography (PSG)
Apnea was defined when airflow reduced by ≥ 90% of the baseline for at least 10 secs with ongoing respiratory efforts and hypopneas were scored when reduction of airflow at the minimum 30% for ≥ 10 sec was associated with ≥ 4% desaturation. Apnea-hypopnea index (AHI) was calculated by averaging the number of obstructive apneas and hypopneas per hour of sleep.

Neuropsychological assessment battery
Verbal memory was evaluated with Story Recall (SR) tests that has been standardized and recognized to be analogous to the Wechsler memory scale-third edition. e1 Verbal Fluency assessment consisted of phonemic (VF1) and categorical fluency (VF2) tests from the Controlled Oral Word Association Test. e2

Magnetic resonance imaging (MRI) data acquisition and processing
Magnetic resonance imaging (MRI) scanning was performed with a 1.5-Tesla scanner (General Electric, Milwaukee, WI). The interval between MRI and PSG was 8.0±16.4 days, and the cognitive assessment was performed 15.1±34.0 days after MRI. T1-weighted images were acquired with the following parameters: TR=7.7ms, TE=3.4ms, flip angle=12°, slice thickness=1.6mm. Diffusion tensor imaging (DTI) data were achieved at TR=15000ms, TE=93.8ms, 15 isotropic gradient directions with b=1000s/mm 2 , and single b=0 image acquisition.
DTI artifacts including B1 field inhomogeneity, motion artifacts, susceptibility-and eddy currentinduced distortions in DTI data were corrected by using the FSL tool (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/). e5-e7 Fractional anisotropy and diffusivity maps Fractional anisotropy (FA) measures directionality of water movement in brain tissues, indicating the microstructural integrity of brain tissues since it is sensitive to fiber number, axonal diameter, and myelination. e8-e10 Axial diffusivity (AD) and radial diffusivity (RD) assesses diffusivity in the direction parallel or perpendicular to the fiber tract, respectively. AD reflects axonal integrity and RD represents myelin integrity, both affected by intracellular/extracellular edema and changes in cellular density and array (neuronal loss, reactive gliosis). e9,e11 After creation, the FA maps were registered to the Montreal Neurological Institute space using symmetric diffeomorphic image registration algorithm provided through the Advanced Normalization Tools package. e12 T1-weighted images of each subject were registered to the individual b0 images and then the individually registered images were transformed to the template space. The resulting registration parameters were applied to corresponding maps. The registered maps were smoothed (Gaussian filter, full-width half maximum=5mm) to minimize registration errors. A population-based white matter (WM) mask image which met FA>0.2 threshold across all subjects was created.

General characteristics and covariates
Body mass index (BMI, kg/m 2 ) was calculated from height (cm) and weight (kg) measured in the morning after overnight fasting. The level of education was categorized (≤6, 7-9, 10-12, 13-16, >16 education-year). Smoking and alcohol drinking status were dichotomized (current vs. never or former). Depressive mood was evaluated with the Beck Depression Inventory. e13 Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS). e14 Scores of over 10 indicated excessive daytime sleepiness. Hypertension was diagnosed when systolic or diastolic blood pressure was equal to or above 140 or 90 mmHg, respectively, or participants took antihypertensive medications. Diabetes mellitus was defined as using oral hypoglycemic agents or insulin, or with fasting blood glucose equal to or above 126 mg dL.