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.

Association of white matter hyperintensities and clinical vascular burden with depressive symptoms in Black older adults

“…It is notable that the relationship between cerebrovascular disease and depressive symptoms is present at the level of subthreshold depression. This result is consistent with findings from the broader literature indicating that individuals with subthreshold depression experience white matter microstructural changes 50,51 and WMHs 52 similar to those observed in major depressive disorder, and have greater functional impairment (e.g., impairment in activities of daily living) 53 and increased risk of mortality compared to their healthy, same-aged peers. 54 Subthreshold depressive symptoms have also recently been linked to the presence of clinical vascular conditions in mid-to-late life, including elevated blood pressure variability 55 and an estimate of overall cardiovascular health that includes modifiable vascular risk factors such as body weight, blood glucose, total cholesterol, blood pressure, and frequency of physical activity.…”

Human tau-overexpressing mice recapitulate brainstem involvement and neuropsychiatric features of early Alzheimer’s disease

“…In our study, we found a significant reduction in 5-HT innervation of the EC, and since these 5-HT neurons project to other cortical regions there is likely 5-HT denervation in the PFC and OFC as well. The EC, PFC, cingulate, insula and temporoparietal cortex have all been implicated with depression and negative affect in older adults [ 75 , 76 ], so loss of 5-HT input to any one of these regions may be sufficient to drive depression in AD.…”

The taxonomy of subjective cognitive decline: proposal and first clinical evidence from the Geneva memory clinic cohort

“…[24] Moreover, a recent study reported that subclinical depressive symptoms are not associated with brain amyloidosis in cognitively healthy older adults. [25] This could result in a lower risk of developing Alzheimer's disease dementia in the Psy subgroup.…”