Principal Investigator: Meryl Butters, Ph.D.
OPTIMUM is the largest ever study of treatment-resistant LLD, which provides an unprecedented opportunity to study whether those with treatment-resistant late-life depression (TRLLD) are at higher risk of cognitive decline and progression to dementia compared to those with treatment-responsive LLD. The OPTIMUM-NEURO Study has been funded by the National Institute of Mental Health to carry out longitudinal neuroimaging, neurocognitive assessment, and peripheral biomarker testing in the OPTIMUM sample, with the aim of characterizing the pathways of Alzheimer’s Disease risk in treatment-resistant LLD.
Efforts to prevent or delay dementia have been largely unsuccessful. However, major depressive disorder in late life (“late-life depression”, LLD) has been identified as one of six treatable risk factors for dementia, especially Alzheimer’s Disease and vascular dementia. The depression-dementia relationship may be magnified in older adults who do not respond to antidepressant treatment and experience persistent symptoms. Thus, resolving whether those with treatment-resistant late-life depression (TRLLD) are at higher risk of cognitive decline and progression to dementia compared to those with treatment-responsive LLD is critically important.
The OPTIMUM NEURO Trial will map neurocognitive and neuroimaging biomarkers associated with progression to dementia in people with persistent LLD (i.e., TRLLD) compared to those whose LLD remits with treatment. We anticipate enrolling 750 elders with LLD and characterizing their symptomatic trajectory over 24 months. We will assess each participant at three time points with neurocognitive and advanced neuroimaging. Based on our recent findings that inflammatory and related molecular markers can differentiate those with neurocognitive impairment and LLD from those with LLD alone, we will build a predictive multivariate model combining baseline neurocognitive, neuroimaging, and plasma protein data to determine who is at greatest risk for cognitive decline and dementia. If successful, our work can accelerate therapeutic efforts and innovation targeting the depression- dementia pathway and reduce suffering for large numbers of elders and their families.
Using advanced neurocognitive, neuroimaging, and molecular approaches, we will determine whether people with persistent, treatment resistant late-life depression experience accelerated decline in cognitive performance and brain circuits that increase risk for dementia, compared to those who respond to treatment. Our proposed study will also develop a predictive tool combining neurocognitive, neuroimaging, and protein data to identify who with late-life depression is at highest risk of cognitive decline and dementia. The goal of the study is to clarify the risk mechanisms via which people with resistant depression in late-life may progress to dementia, and whether effective treatment of such depression mitigates that risk.
