The Locus Coeruleus Catecholamine System in Aging: Implications for Understanding Alzheimer’s Disease
Creators: name: Parent, Jourdan
Publisher: name: Brandeis University
Year: 2024
Subjects: Alzheimer's disease
Emotional Memory
Functional Connectivity
Locus coeruleus
Tau
Neuroimaging

description: Early detection of Alzheimer’s disease (AD) pathological trajectories in aging is critical for developing therapeutic interventions for the neurodegenerative disease. A growing body of research has focused on the locus coeruleus (LC), which is one of the first brain regions to develop tau pathology, and may be an “epicenter” from which tau pathology spreads throughout the brain. The LC produces catecholamines norepinephrine and dopamine and is an important modulator of arousal, memory and stress responses. Most in vivo neuroimaging studies rely on structural magnetic resonance imaging (MRI) measures of the LC to measure the LC “structural integrity.” My dissertation research developed methods for positron emission tomography (PET) imaging of the LC to measure the neurochemical health of the LC. Specifically, I used irreversible tracer [18F]Fluoro-meta-tyrosine ([18F]FMT) to measure catecholamine synthesis capacity within the LC. My dissertation research examined relationships between LC catecholamine synthesis capacity and AD-related pathology, cognition, and functional network activity. Together, my research suggests higher LC catecholamine synthesis capacity is optimal in aging and is associated with lower temporal lobe tau pathology and lower risk of developing AD. Additionally, my research identifies elevated LC catecholamine function as a candidate mechanism of cognitive resilience as it may help maintain intact cognition despite existing tau burden. Study 1 established methods for measuring [18F]FMT net tracer influx (Ki) in the LC and demonstrated proof-of-concept associations between LC [18F]FMT Ki measures of catecholamine synthesis capacity, AD-related pathology and memory performance in a sample of 49 cognitively normal older adults. These participants completed a battery of standard neuropsychological assessments, and PET scans to measure LC catecholamine synthesis capacity, tau pathology, and beta-amyloid pathology. Study 2 used the same cohort of cognitively normal older adults to assess how LC synthesis capacity was associated with known affective risk factors for AD – neuroticism and depression – and also how it relates to tau burden in the amygdala, a brain region understood to support affective function. In study 3, I used the same cohort of older adults, who also underwent a 5-minute resting-state functional magnetic resonance imaging session (fMRI), to test whether LC catecholamine synthesis capacity is associated with functional alterations in an LC network and whether pathology moderated these associations. Finally, study 4 sought to examine age-related alterations in cognitive function known to be supported by LC neuromodulator function by testing the effects of older age and emotion on memory quality.
description: Study 1 found that in individuals with substantial beta-amyloid burden (beta-amyloid positive), higher LC synthesis capacity was associated with both lower cross-sectional tau burden and less tau accumulation over time in the temporal lobe, which is broadly consistent with complementary research using MRI measures of LC structural integrity. Additionally, I found LC synthesis capacity attenuated the negative impact of tau burden of memory where individuals with higher LC synthesis capacity had better-than-expected memory given their level of tau burden. These findings support a model of LC synthesis capacity as a mechanism of cognitive resilience. In study 2, I found that lower LC synthesis capacity was associated with higher trait neuroticism, a higher number of depression symptoms, and greater amygdala tau burden and that LC synthesis capacity significantly mediated the relationship between neuroticism and amygdala tau burden, suggesting that LC synthesis capacity may impact AD pathology pathogenesis through affect-related disruptions. In study 3, I found that for individuals with substantial beta-amyloid burden, higher amygdala tau burden was associated with greater LC-network functional connectivity, which is consistent with complementary research linking network hyperactivity with higher AD-related pathology. Additionally, those individuals with highest risk for developing AD had higher LC-network functional connectivity with lower LC catecholamine synthesis capacity. Moreover, I found that those individuals with higher tau burden had worse memory performance with higher LC-network functional connectivity. Together, these findings suggested that higher LC-functional connectivity is linked to poorer pathological and cognitive outcomes but may be dampened in high AD-risk individuals with higher LC catecholamine function. For study 4, Participants (n = 37 older adults; n = 34 young adults) studied emotionally negative and neutral images that varied in color saturation and luminance, and reconstructed the visual salience of the images in a subsequent memory test. I calculated salience bias (mean salience error) and precision (SD of salience error), which I compared with participants’ subjective ratings of memory vividness for each image. I found correlations between subjective memory vividness and objective measures of remembered visual salience were reduced in older adults. Additionally, I found age-by-emotion interactions consistent with accounts that memory benefits for negative emotional stimuli are reduced in older adults. Significant age effects and interactions were limited to precision measures and were not observed for salience bias. Together these findings identify age-related differences in emotional memory, which is purported to be modulated by the LC-catecholamine inputs to the temporal lobe. These behavioral findings lay critical groundwork for follow-up research incorporating neuroimaging. Together, my dissertation research supports the value of [18F]FMT PET for shedding light on individual differences in AD vulnerability and provides new mechanistic insight into the role of the LC-catecholamine system in memory and affective function in aging.
description: