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. 2025 Jan 6;17(1):9.
doi: 10.1186/s13195-024-01643-0.

Depressive symptoms in older adults are associated with changes in stress-related markers, functional connectivity and brain volume

Edelweiss Touron  1 , Robin de Flores  1 , Laurent Coulbault  1   2 , Cassandre Palix  1 , Anne Chocat  1 , Elizabeth Kuhn  1 , Brigitte Landeau  1 , Florence Mézenge  1 , Daniel Roquet  1 , Léa Chauveau  1 , Sacha Haudry  1 , Denis Vivien  1   3 , Vincent de La Sayette  4 , Natalie L Marchant  5 , Gaël Chételat  1 , Géraldine Poisnel  6 ; Medit-Ageing Research Group
Collaborators, Affiliations

Depressive symptoms in older adults are associated with changes in stress-related markers, functional connectivity and brain volume

Edelweiss Touron et al. Alzheimers Res Ther. .

Abstract

Background: Subclinical depressive symptoms increase the risk of developing Alzheimer's disease (AD). The neurobiological mechanisms underlying this link may involve stress system dysfunction, notably related to the hippocampus which is particularly sensitive to AD. We aimed to investigate the links between blood stress markers and changes in brain regions involved in the stress response in older adults with or without subclinical depressive symptoms.

Methods: This cross-sectional study was conducted using baseline data from the Age-Well trial. Cognitively unimpaired (CU) older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15-item Geriatric Depression Scale) were included in the analyses. Blood cortisol, epinephrine and norepinephrine were measured; as well as the resting-state functional connectivity (rs-FC) between, and gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields. Blood stress markers levels and neuroimaging measures were compared between groups; then regression analyses were conducted between these measures.

Results: DepS participants showed higher plasma epinephrine levels, which was associated with greater rs-FC between the CA1 and Subiculum hippocampal subfields and the hypothalamus. Lower GM volume in the CA1 and DG/CA2-3-4 subfields was also found in DepS. No between-group differences were observed for blood cortisol and norepinephrine.

Conclusions: Our findings show that subclinical depressive symptoms are associated with increased sympatho-adrenomedullary axis activity, together with lower GM volume in a hippocampal subfield (i.e., CA1) particularly sensitive to AD. While causation cannot be inferred, these results suggest that screening and treating subclinical depressive symptoms in CU older adults could reduce AD risk.

Trial registration: ClinicalTrials.gov Identifier: NCT02977819, Registration Date: 2016-11-25.

Keywords: Aging; Catecholamines; Cortisol; Depressive symptoms; Hippocampal subfields; Hypothalamus.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to the examinations, and the Age-Well randomized clinical trial was approved by the ethics committee (Comité de Protection des Personnes Nord-Ouest III, Caen, France; trial registration number: EudraCT: 2016–002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819; registration date: 2016–11-25). Consent for publication: Not applicable. Competing interests: Dr Touron reported grant from French Ministry of Higher Education and Research (PhD grant). Dr Kuhn reported grant from the French Ministry of Higher Education and Research (PhD grant), and support from INSERM (PhD). Dr Marchant, Dr Chételat and Dr Poisnel reported grants from European Union’s Horizon 2020 Research and Innovation Program under grant agreement No 667696 during the conduct of the study. Dr Marchant reported grants from a Senior Fellowship from the Alzheimer’s Society (AS-SF-15b-002). Dr Chételat reported grants, personal fees and nonfinancial support from Institut National de la Santé et de la Recherche Médicale (INSERM); personal fees from Fondation Entrepreneurs MMA, grants and personal fees from Fondation Alzheimer, grants from Région Normandie, grants from Fondation Recherche Alzheimer, grants from Association France Alzheimer, outside the submitted work. No other disclosures were reported.

Figures

Fig. 1
Fig. 1
Flow diagram of the inclusion process. DHEA, Dehydroepiandrosterone; MRI, Magnetic Resonance Imaging
Fig. 2
Fig. 2
Between-group differences in blood stress markers: plasma epinephrine (A), plasma norepinephrine (B) and serum cortisol (C). ANCOVAs were adjusted for age, sex, education and anxiety symptoms, with a statistical significance set to p < 0.05 (*p < 0.05). The black dot represents the mean value for each group. NoDepS, Group without depressive symptoms; DepS, Group with subclinical depressive symptoms
Fig. 3
Fig. 3
Associations between epinephrine and hippocampal-hypothalamic functional connectivity within participants with or without subclinical depressive symptoms. Reported statistics were obtained from Pearson’s partial correlations adjusted for age, sex, education and anxiety symptoms. Raw values are plotted and linear trends and confidence intervals (95%) are represented according to participants with (turquoise) and without (gray) subclinical depressive symptoms. NoDepS, Group without depressive symptoms; DepS, Group with subclinical depressive symptoms; CA, Cornu Ammonis; RS, Resting-state; FC, Functional connectivity
Fig. 4
Fig. 4
Hippocampal 3D surface view of lower gray matter volume (voxelwise method) in participants with subclinical depressive symptoms (DepS) compared with those without symptoms (NoDepS) (A). Areas of lowest gray matter volume in DepS compared to NoDepS are mainly located in the CA1 and DG/CA2-3–4 subfields, represented here in warm colors (red). A schematic representation of the hippocampal subfields obtained from manual delineation is shown on the 3D surface view of the hippocampi in (B). For the sake of comparison, gray matter atrophy in Alzheimer’s disease (AD) patients and across normal aging are shown on the same hippocampal views (C) (figure adapted from [55]). Note that the different effects are illustrated in color using different scales. NoDepS, Group without depressive symptoms; DepS, Group with subclinical depressive symptoms; Alzheimer’s disease, AD; DG, Dentate Gyrus; CA, Cornu Ammonis
Fig. 5
Fig. 5
Overview of the results suggesting increased sympatho-adrenomedullary axis activity in participants with subclinical depressive symptoms and a compensatory response through upregulation of hippocampal-hypothalamic functional connectivity. (1) Higher SAM axis activity, through hypothalamus activation, results in higher release of epinephrine in the blood from the adrenal medulla (2). This higher epinephrine release is associated with increased functional connectivity between the hippocampus (CA1 and Subiculum subfields) and the hypothalamus (3). As the hippocampus is thought to exert an inhibitory influence on the hypothalamus [10, 11], it is possible that this increased hippocampal-hypothalamic functional connectivity reflects an attempt to downregulate hypothalamus and SAM axis activities as a compensatory response towards reducing the elevated release of epinephrine in the blood in participants with subclinical depressive symptoms
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