Frontostriatal volumes and anterior thalamic mediation of late-life depressive symptoms across the cognitive spectrum from normal aging to Alzheimer's disease: A structural equation modelling study

BACKGROUND: Late-life depression has been linked to cortico-striato-thalamo-cortical (CSTC) dysfunction. We examined whether the volumes of the thalamic subregions, frontal cortex, and striatum are related to depressive symptoms across cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD) groups. METHODS: Fifty-four psychotropic-naïve older adults (CN:16; MCI:19; AD:19) underwent T1-weighted MRI, neuropsychological assessments, and Geriatric Depression Scale (GDS) ratings. Cortical and subcortical volumes were obtained using FreeSurfer, and the thalamic nuclei were segmented using the Iglesias Probabilistic Atlas and grouped into six subregions. The intracranial volume-adjusted regional volumes were compared across the groups. Stepwise regression identified volumetric predictors of the GDS, and structural equation modelling tested CSTC-based pathways linking cognition, regional volumes, and depressive symptoms. RESULTS: Thalamic subregional volumes did not differ significantly between groups, whereas the frontal and subcortical regions showed diagnostic effects. Lower volumes of the anterior thalamic subregions, frontal gyrus, and putamen were associated with higher GDS scores. Path analysis showed excellent fit and demonstrated that frontal and putaminal atrophy had direct effects on the GDS, whereas anterior thalamic volume indirectly influenced the GDS via its association with these frontostriatal nodes. CONCLUSION: These findings suggest a CSTC network account of late-life depression, wherein frontostriatal atrophy show proximal associations with depressive symptoms, whereas anterior thalamic volume shows an indirect association. Future longitudinal, multimodal studies are needed to determine temporal ordering and causality, including whether protecting anterior thalamic integrity or enhancing frontostriatal function might be associated with attenuation of depressive symptoms in older adults.