Depressive symptoms in cognitively unimpaired older adults are associated with lower structural and functional integrity in a frontolimbic network

Abstract

Subclinical depressive symptoms are associated with increased risk of Alzheimer's disease (AD), but the brain mechanisms underlying this relationship are still unclear. We aimed to provide a comprehensive overview of the brain substrates of subclinical depressive symptoms in cognitively unimpaired older adults using complementary multimodal neuroimaging data. We included cognitively unimpaired older adults from the baseline data of the primary cohort Age-Well (n = 135), and from the replication cohort ADNI (n = 252). In both cohorts, subclinical depressive symptoms were assessed using the 15-item version of the Geriatric Depression Scale; based on this scale, participants were classified as having depressive symptoms (>0) or not (0). Voxel-wise between-group comparisons were performed to highlight differences in gray matter volume, glucose metabolism and amyloid deposition; as well as white matter integrity (only available in Age-Well). Age-Well participants with subclinical depressive symptoms had lower gray matter volume in the hippocampus and lower white matter integrity in the fornix and the posterior parts of the cingulum and corpus callosum, compared to participants without symptoms. Hippocampal atrophy was recovered in ADNI, where participants with subclinical depressive symptoms also showed glucose hypometabolism in the hippocampus, amygdala, precuneus/posterior cingulate cortex, medial and dorsolateral prefrontal cortex, insula, and temporoparietal cortex. Subclinical depressive symptoms were not associated with brain amyloid deposition in either cohort. Subclinical depressive symptoms in ageing are linked with neurodegeneration biomarkers in the frontolimbic network including brain areas particularly sensitive to AD. The relationship between depressive symptoms and AD may be partly underpinned by neurodegeneration in common brain regions.

Fig. 1. Brain substrates of subclinical depressive symptoms in cognitively unimpaired older adults.

Results of the voxel-wise between-group differences in gray matter volume (A, green), white matter integrity (mean kurtosis) (B, blue), glucose metabolism (C, yellow) and amyloid deposition (D) in Age-Well (left panel) and ADNI (right panel). Analyses were adjusted for age, sex and education. Anxiety symptoms were added as a covariate in Age-Well. All results are presented at a p_uncorrected < 0.005 threshold combined with a cluster-level multiple comparisons correction. DepS group with subclinical depressive symptoms, NoDepS group without depressive symptoms, NS not significant, NC not collected, R right, L left.

Fig. 2. Illustration of the overlap between the brain substrates of subclinical depressive symptoms and the pattern of neurodegeneration in Alzheimer’s disease (AD).

The patterns of gray matter atrophy (at the top) and hypometabolism (at the bottom) in participants with subclinical depressive symptoms compared to those without are represented in yellow. They are overlapped on the respective patterns of gray matter atrophy (at the top) and hypometabolism (at the bottom) typically found in patients with AD and obtained here by comparing a group of 56 cognitively impaired amyloid-positive patients on the Alzheimer’s continuum to 28 controls from the IMAP + cohort ([41]; see Supplementary Material 2 for details). The superimposition allows areas of overlap to be highlighted (in orange), notably in the hippocampus, precuneus, posterior cingulate—retrosplenial area and temporoparietal region. DepS group with subclinical depressive symptoms, NoDepS group without depressive symptoms, R right, L left.