Cortical responses to a graded working memory challenge predict functional decline in mild cognitive impairment

Background: Early detection of progressive cognitive decline offers an opportunity for preventative interventions with enormous public health implications. Functional neuroimaging during cognitive activity in individuals at risk of dementia has the potential to advance this objective. In a prior study, we evaluated the utility of a novel functional magnetic resonance imaging paradigm that incorporated a graded working memory (WM) task to detect changes associated with mild cognitive impairment (MCI). We observed greater deactivation of posteromedial cortex (PMC) under conditions of increased WM load in MCI compared with control subjects. Our objective here is to test whether this paradigm can predict ensuing functional decline. Methods: Thirty individuals with MCI who underwent baseline functional magnetic resonance image scanning were followed clinically for 2 years. Multiple linear regression analyses were used to determine whether deactivation in PMC under increased load at baseline independently predicted decline in instrumental activities of daily living (IADL). Results: Greater deactivation in PMC to increased load predicted greater decline in IADL after controlling for baseline clinical severity, MCI subtype, apolipoprotein ε4 carrier status, gray matter, PMC and hippocampal volumes, and task performance. Conclusions: Increased deactivation observed at baseline was a harbinger of subsequent functional decline as measured by IADL in a cohort with MCI. This graded WM challenge may operate like a memory stress test by producing a threshold effect beyond which abnormal deactivation is elicited in MCI subjects who are at greatest risk of functional decline.