A noradrenergic mechanism of apathy and motivation deficit in MCI and AD

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SUMMARY/ABSTRACT As one of the most common symptoms, apathy frequently manifests before cognitive impairment in the spectrum of Alzheimer’s disease (AD). Persistent apathy plays an important role in rapid functional decline and significantly impacts the quality of life of individuals with AD. Yet, the neurobiological mechanisms underlying apathy remain unclear. Apathy reflects a general diminution of interest or motivation, a lack of effort in goal-directed behavior. A growing body of evidence implicates the monoaminergic circuits in motivation and effort. A recent review suggests that dopamine primarily codes for future reward and promotes reward-directed action but is less sensitive to anticipated effort. On the other hand, effort is tightly linked to heightened arousal and, with extensive projections to the thalamus and prefrontal cortex, the locus coeruleus (LC) likely plays a critical role in sustaining motivated and effortful behavior. This exploratory study aims to examine this hypothesis and distinguish the roles of the noradrenergic (NA) and dopaminergic (DA) circuits in motivated behavior and how NA and DA dysfunction may underlie apathy in individuals with mild cognitive impairment (MCI) and early stage AD, as compared to healthy controls. Specifically, the LC is a very small structure and difficult to localize with conventional structural imaging. Building on previous studies, we have taken advantage of the high neuromelanin content in the LC and ventral tegmental area/substantia nigra, pars compacta (VTA/SNc) and successfully developed a probabilistic map of the LC and VTA/SNc in individuals’ native space. By engaging participants in fMRI of a reward task we will query how the NA and DA circuits respond to timed, effortful behavior to acquire reward and to behavioral outcomes. We hypothesize that individuals with MCI and early stage AD will demonstrate reduction in neuromelanin signal contrast in the LC and diminished LC circuit activities and connectivities to support motivated behavior in link with the clinical severity of apathy. We propose to test this hypothesis in 30 patients with MCI and early stage AD and 30 age and sex matched healthy control participants (HC), with two specific aims: 1) examine whether LC and/or VTA/SNc neuromelanin signal intensity is diminished in participants with MCI and AD as compared to HC and whether the reduction in neuromelanin contrast is associated with apathy; 2) examine with fMRI whether LC and/or VTA/SNc response to reward anticipation and outcome as well as LC/VTA-SNc prefrontal cortical connectivity are reduced in participants with MCI and AD as compared to HC; and whether these changes are associated with apathy. We hope that the study will substantiate the role of noradrenergic circuits in an etiology of apathy in AD. If successful, the study may also have important implications for research of many other clinical conditions that implicate motivation dysfunction.