Sex-specific hippocampus volume changes in obstructive sleep apnea

Abstract

Introduction: Obstructive sleep apnea (OSA) patients show hippocampal-related autonomic and neurological symptoms, including impaired memory and depression, which differ by sex, and are mediated in distinct hippocampal subfields. Determining sites and extent of hippocampal sub-regional injury in OSA could reveal localized structural damage linked with OSA symptoms.

Methods: High-resolution T1-weighted images were collected from 66 newly-diagnosed, untreated OSA (mean age ± SD: 46.3 ± 8.8 years; mean AHI ± SD: 34.1 ± 21.5 events/h;50 male) and 59 healthy age-matched control (46.8 ± 9.0 years;38 male) participants. We added age-matched controls with T1-weighted scans from two datasets (IXI, OASIS-MRI), for 979 controls total (426 male/46.5 ± 9.9 years). We segmented the hippocampus and analyzed surface structure with "FSL FIRST" software, scaling volumes for brain size, and evaluated group differences with ANCOVA (covariates: total-intracranial-volume, sex; P < .05, corrected).

Results: In OSA relative to controls, the hippocampus showed small areas larger volume bilaterally in CA1 (surface displacement ≤0.56 mm), subiculum, and uncus, and smaller volume in right posterior CA3/dentate (≥ - 0.23 mm). OSA vs. control males showed higher bilateral volume (≤0.61 mm) throughout CA1 and subiculum, extending to head and tail, with greater right-sided increases; lower bilateral volumes (≥ - 0.45 mm) appeared in mid- and posterior-CA3/dentate. OSA vs control females showed only right-sided effects, with increased CA1 and subiculum/uncus volumes (≤0.67 mm), and decreased posterior CA3/dentate volumes (≥ - 0.52 mm). Unlike males, OSA females showed volume decreases in the right hippocampus head and tail.

Conclusions: The hippocampus shows lateralized and sex-specific, OSA-related regional volume differences, which may contribute to sex-related expression of symptoms in the sleep disorder. Volume increases suggest inflammation and glial activation, whereas volume decreases suggest long-lasting neuronal injury; both processes may contribute to dysfunction in OSA.

Keywords: AHI, apnea-hypopnea index; Autonomic; CA, cornu ammonis; Inflammation; Intermittent hypoxia; Neuroimaging; OSA, obstructive sleep apnea; Oxidative stress.

Fig. 1

Hippocampal subfields based on the Winterburn atlas [subject 1; 37]. Left panel shows 45° rotations around anterior-posterior axis for surfaces of left and right hippocampi. Right panel shows right hippocampus dorsal (left) and ventral (right) representations, and the center shows coronal slices along anterior-posterior axis with the subregions overlaid onto the subject's high-resolution T1-weighted anatomical scan included with the Winderburn atlas.

Fig. 2

Reconstruction of average of 1045 right hippocampal segmentations, illustrating shape and size of the “template” hippocampus against which individual surface displacements are measured.

Fig. 3

OSA hippocampal volume changes relative to controls in a mixed group (males and females). Regions of significant displacement (P < .05, corrected for multiple comparisons) are color-coded according to average displacement. Warm colors reflecting outward displacement, i.e., volume increases, and cool colors reflect inward displacement, i.e., volume decreases (key at top). The model includes age, sex and TIV as covariates. The left hippocampus is on the left side of the figure, and the right hippocampus on the right of the figure. The panel shows views with the structure rotation about the anterior-posterior axis. The large images are 90° rotations and the smaller middle images are 15° rotations.

Fig. 4

Female OSA hippocampal volume changes relative to controls, with age and TIV as covariates. Figure conventions as in Fig. 3.

Fig. 5

Male OSA hippocampal volume changes relative to controls, with age and TIV as covariates. Figure conventions as in Fig. 3.

Fig. 6

Variance of residuals in mm², illustrating higher variability in the tail, moderate variability in the head, and low variability in the body. The right side showed higher variability than the left, and males showed higher variability than females.

Fig. 7

Sex differences in control and OSA groups. Areas of significantly higher volume in female vs male in controls are shown in top row (P < .05). Effect sizes for all differences are shown for control (middle row) and OSA (bottom row). See Table 1 for subject details.

Supplementary Fig. 1

Platform variations in measures of brain volume (Brainvol), total intracranial volume (TIV), and age.