Brain-cognition relationships and treatment outcome in treatment-resistant late-life depression

Older adults with treatment-resistant depression are at significant risk for cognitive impairment. The relationship between treatment response and cognitive function in this population is not well-established. We examined neural correlates of executive and memory function, and their relationship with prospective treatment outcomes. In the context of a longitudinal biomarker study embedded within a multi-center randomized controlled trial for late-life treatment-resistant depression, 397 participants completed baseline neuropsychological testing, and of these 234 adults successfully completed a baseline MRI scan. Multivariate regressions were used to test for brain-cognition associations between memory and executive function and brain functional connectivity, white matter integrity, and gray matter structure. Further, we employed regularized elastic net regressions to identify biomarkers predicting depression remission (MADRS≤10) in the clinical trial. Among participants who completed neuroimaging better cognition was associated with lower connectivity between components of the default mode and the frontoparietal networks and within the frontoparietal network (multivariate r=0.37, p<0.01). Using diffusion imaging data, lower tract integrity in a distributed set of tracts was associated with poorer executive function (multivariate r=0.27, p<0.05). Additionally, gray matter structure was positively associated with cognition (multivariate r=0.38, p<0.05). Education and better structural brain maintenance but not overall health were associated with better cognition. Ongoing treatment resistance was predicted by poorer cognition and gray matter structure. We identified distinct cross-sectional associations between specific neural circuits and variation in cognitive function in people with treatment-resistant late-life depression. We also found worse cognitive function and gray matter structure predicted ongoing treatment resistance to medication offered in the clinical trial.