Obstructive sleep apnea and structural and functional brain alterations: a brain-wide investigation from clinical association to genetic causality

Abstract

Background: Obstructive sleep apnea (OSA) is linked to brain alterations, but the specific regions affected and the causal associations between these changes remain unclear.

Methods: We studied 20 pairs of age-, sex-, BMI-, and education- matched OSA patients and healthy controls using multimodal magnetic resonance imaging (MRI) from August 2019 to February 2020. Additionally, large-scale Mendelian randomization analyses were performed using genome-wide association study (GWAS) data on OSA and 3935 brain imaging-derived phenotypes (IDPs), assessed in up to 33,224 individuals between December 2023 and March 2024, to explore potential genetic causality between OSA and alterations in whole brain structure and function.

Results: In the cohort study, OSA patients exhibited significantly lower fractional amplitude of low-frequency fluctuation and regional homogeneity in the right posterior cerebellar lobe and bilateral superior and middle frontal gyrus, while showing higher levels in the left occipital lobe and left posterior central gyrus. Decreased fractional anisotropy (FA) but increased apparent diffusion coefficient (ADC) was shown in the bilateral superior longitudinal fasciculus. According to the results of Affiliation file 2: table s6, it is the ADC value of right superior longitudinal fasciculus was shown a positive correlation with the lowest oxygen saturation. In the Mendelian randomization analyses, the area of left inferior temporal sulcus (OR: 0.89; 95% CI: 0.82-0.96), rfMRI connectivity ICA100 edge 893 (OR: 0.88; 95% CI: 0.82-0.96), ICA100 edge 951 (OR: 0.89; 95% CI: 0.82-0.97), and ICA100 edge 1213 (OR: 0.89; 95% CI: 0.82-0.96) were significantly decreased in OSA. Conversely, mean thickness of G-front-inf-Triangul in right hemisphere (OR: 1.14; 95% CI: 1.05-1.23), mean orientation dispersion index in right tapetum (OR: 1.13; 95% CI: 1.04-1.23), and rfMRI connectivity ICA100 edge 258 (OR: 1.13; 95% CI: 1.04-1.22) showed opposite results.

Conclusions: Nerve fiber damage and imbalances in neuronal activity across multiple brain regions caused by hypoxia, particularly the frontal lobe, underlie the structural and the functional connectivity impairments in OSA.

Keywords: Brain structure and function; Mendelian randomization; Neuroimaging; Obstructive sleep apnea.

Fig. 1

Flowchart of the analyses conducted in the present study. Stage 1, the observational study. Stage 2, the Mendelian randomization study design. There are three principal assumptions in Mendelian randomization design: (A) instrumental variables (IVs) must be strongly associated with exposure, (B) IVs are not related to confounding factors, and (C) IVs affect outcome risk only through the risk factor rather than any other ways; OSA, obstructive sleep apnea; HCs, healthy controls; T2- FLAIR, T2-fluid attenuated inversion recovery; 3D-T1WI, three-dimensional T1-weighted images; rfMRI, resting-state fMRI; DTI, diffusion tensor imaging; BMI, body mass index; IVs, instrumental variables; SNP, single-nucleotide polymorphisms; LD, linkage disequilibrium

Fig. 2

Difference of fALFF and ReHo values in the OSA patients. A Compared with healthy controls (HCs), OSA patients decreased fALFF in the right posterior cerebellar lobe, the bilateral superior and middle frontal gyrus, and the left anterior, middle, and posterior cingulate gyrus but increased fALFF in the left occipital lobe. B Compared with HCs, OSA patients decreased ReHo in the right posterior cerebellar lobe, left superior and middle frontal gyrus, and right superior and middle frontal gyrus but increased ReHo in the left posterior central gyrus. Red colors show brain regions with increased values; blue colors indicate brain regions with decreased values

Fig. 3

Correlation analysis between significantly different diffusion tensor imaging (DTI) and LSaO2 in OSA patients. SLF, superior longitudinal fasciculus; LSaO2, lowest oxygen saturation

Fig. 4

The forest plot of the Mendelian randomization analyses results about causal associations of OSA on 3935 brain imaging derived phenotypes (IDPs). OR, odds ratio; CI, confidence interval; Significant threshold was set at p-value < 0.05 for the inverse variance weighted method (IVW)