Abstract
Pupillary responses during cognitive tasks are linked to functioning of the locus coeruleus (LC). The LC is an early site of abnormal tau deposition, which may contribute to key aspects of Alzheimer's disease (AD) pathophysiology. We previously found attenuation of pupillary responses to increases in cognitive load in individuals with mild cognitive impairment (MCI), suggesting pupillary responses may provide a biomarker of early risk for AD associated with LC dysfunction. The LC modulates cortical activity through two modes of operation: tonic and phasic. Early LC damage has been predicted to result in a state of persistent high tonic LC activity that may disrupt task-related phasic activity. To further examine whether pupillary responses are associated with early LC dysfunction, we measured pupil dilation during a digit span task as a measure of phasic activity, and low frequency BOLD variance (LFBV) during resting-state fMRI in key nodes of the ventral attention network (VAN) as a measure of cortical reactivity related to LC tonic activity in 358 middle-aged men. Individuals with greater LFBV in VAN nodes, i.e., higher tonic brain activity at rest, showed a smaller increase in pupil dilation from low to moderate cognitive loads. Thus, higher tonic LFBV activity at rest was related to reduced task-appropriate phasic dilation increases. The results support predictions from prominent models of LC functioning in which early LC dysfunction leads to persistent high tonic rates of activity during rest and lower signal-to-noise of phasic responses during task performance. Taken together with previous findings of early AD pathophysiology in LC and reduced phasic dilation responses to increased cognitive load in individuals with MCI, the present results suggest that pupillary responses may index early LC dysfunction and should receive further study as a potential biomarker of risk for AD.