Associations among monoamines, tau pathology and emotional memory in aging - PROJECT SUMMARY Major lines of Alzheimer’s Disease (AD) research focus on identifying the earliest AD-related pathologic changes that occur in aging. One target of this research is monoamine-producing brainstem nuclei, where both the noradrenergic locus coeruleus (LC) and the serotonergic dorsal raphe nucleus (DRN) are among the first regions to accumulate abnormal tau, even in cognitively normal older adults. Despite the specific vulnerability of these neuromodulator systems to tau pathology, there is little AD-focused research incorporating direct measures of neuromodulator function in-vivo. Assessing the neurochemical health of these brainstem nuclei in the face of age-related tau pathology may provide insight into the mechanisms differentiating individuals who remain cognitively normal versus those who go on to develop AD. Previous postmortem neuropathology work has examined age and AD-related changes in the LC and DRN, though there is currently little in vivo research which has attempted this. This proposed research addresses this gap by using a combination of positron emission tomography (PET) methods, [18F]Fluoro-m-tyrosine ([18F]FMT) and [18F]MK-6240. [18F]FMT has been recently established as a promising PET tracer for measuring monoamine synthesis capacity in the LC and DRN simultaneously. Given limitations of currently-developed tau-PET tracers, analyses of tau pathology will focus on temporal lobe regions. The current proposal will define how tau pathology and monoamine synthesis capacity relate to performance on an emotional memory task. A focus on interactions between memory and emotion is a central component of the proposed research given the importance of monoamine systems in affective health and the growing appreciation of AD-related affective dysregulation. Aim 1 will directly relate LC and DRN [18F]FMT net tracer influx (Ki) with [18F]MK-6240 standard uptake value ratio (SUVR). Primary analyses will focus on both the amygdala and Braak I/II [18F]MK-6240 SUVR, given these regions are structurally connected with both the DRN and LC and have been implicated in negative emotional experience and memory. Aim 2 will examine how DRN/LC [18F]FMT Ki and amygdala/Braak I/II [18F]MK-6240 SUVR relate to negative and neutral memory performance. Secondary analyses in both aims will test for interactions with sex and beta-amyloid burden. This proposal will provide the applicant with unique training in (1) the neuropathology of aging and preclinical Alzheimer’s disease (2) the administration, processing, and analysis of both reversible and irreversible PET tracers, (3) the best practices for developing and administering cognitive neuroscience tasks in older adult populations, and in (4) oral and written communication and mentorship. Sponsors Dr. Anne Berry and Dr. Heidi Jacobs have extensive backgrounds and success in these four domains and are located at institutions with strong track records for training young scientists (Brandeis University and Massachusetts General Hospital, respectively). This proposed project will help the applicant pursue a career in academic research focused on defining the neural underpinnings of human behavior and the pathophysiology of neurodegenerative disease.
