Association between insomnia and cognitive performance, gray matter volume, and white matter microstructure in cognitively unimpaired adults

Abstract

Background: Mounting evidence links poor sleep quality with a higher risk of late-life dementia. However, the structural and cognitive correlates of insomnia are still not well understood. The study aims were to characterize the cognitive performance and brain structural pattern of cognitively unimpaired adults at increased risk for Alzheimer's disease (AD) with insomnia.

Methods: This cross-sectional study included 1683 cognitively unimpaired middle/late-middle-aged adults from the ALFA (ALzheimer and FAmilies) study who underwent neuropsychological assessment, T1-weighted structural imaging (n = 366), and diffusion-weighted imaging (n = 334). The World Health Organization's World Mental Health Survey Initiative version of the Composite International Diagnostic Interview was used to define the presence or absence of insomnia. Multivariable regression models were used to evaluate differences in cognitive performance between individuals with and without insomnia, as well as potential interactions between insomnia and the APOE genotype. Voxel-based morphometry and tract-based spatial statistics were used to assess between-group differences and potential interactions between insomnia and the APOE genotype in gray matter volume and white matter diffusion metrics.

Results: Insomnia was reported by 615 out of 1683 participants (36.5%), including 137 out of 366 (37.4%) with T1-weighted structural imaging available and 119 out of 334 (35.6%) with diffusion-weighted imaging. Individuals with insomnia (n = 615) performed worse in executive function tests than non-insomniacs and displayed lower gray matter volume in left orbitofrontal and right middle temporal cortex, bilateral precuneus, posterior cingulate cortex and thalamus, higher gray matter volume in the left caudate nucleus, and widespread reduction of mean and axial diffusivity in right hemisphere white matter tracts. Insomnia interacted with the APOE genotype, with APOE-ε4 carriers displaying lower gray matter volumes when insomnia was present, but higher volumes when insomnia was not present, in several gray matter regions, including the left angular gyrus, the bilateral superior frontal gyri, the thalami, and the right hippocampus.

Conclusions: Insomnia in cognitively unimpaired adults at increased risk for AD is associated to poorer performance in some executive functions and volume changes in cortical and subcortical gray matter, including key areas involved in Alzheimer's disease, as well as decreased white matter diffusivity.

Keywords: Alzheimer disease; Diffusion-weighted imaging; Inflammation; Insomnia; Magnetic resonance imaging; Neurocognitive disorders; Neuropsychology; Sleep; Voxel-based morphometry.

Fig. 1

Participants’ selection flow-chart. ^aThis sample was used for analyses assessing associations between the presence of insomnia and performance in neuropsychological tests (NPS). ^bThis sample was used for analyses assessing associations between the presence of insomnia and gray matter volume. ^cThis sample was used for analyses assessing associations between the presence of insomnia and white matter diffusion imaging parameters

Fig. 2

Effect of insomnia on gray matter volume. a Blue-green colored regions show areas with significantly lower volume in participants with insomnia compared with controls (p_uncorrected< 0.005; k = 100). b Red-yellow colored areas show areas with significantly higher brain volume in participants with insomnia compared with controls. L, left hemisphere; R, right hemisphere

Fig. 3

Interactions between APOE-ε4 status and insomnia in gray matter volume. a Gray matter areas where a significant interaction between APOE-ε4 status and insomnia was found (puncorrected < 0.005; k = 100, only the additive model is shown). Graphs b–e show how the association between APOE status and gray matter volume is modulated by the presence of insomnia in four representative brain regions. L, left hemisphere; R, right hemisphere

Fig. 4

Effect of insomnia on white matter microstructure. Significant white matter clusters derived from tract-based spatial statistics are represented in red-yellow over the skeletonized white matter tracts (green). Individuals with insomnia showed significantly reduced values of mean (a) and axial (b) diffusivity (FWE corrected p value < 0.05), and a trend for radial diffusivity (c) (FWE corrected p value between 0.05 and 0.1), compared with normal sleepers. L, left hemisphere; R, right hemisphere