DAT1 and BDNF polymorphisms interact to predict Aß and tau pathology.

Previous work has associated polymorphisms in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) and brain derived neurotrophic factor gene (Val66Met in BDNF) with atrophy and memory decline. However, it is unclear whether these polymorphisms relate to atrophy and cognition through associations with Alzheimer's disease pathology. We tested for effects of DAT1 and BDNF polymorphisms on cross-sectional and longitudinal ß-amyloid (Aß) and tau pathology (measured with positron emission tomography (PET)), hippocampal volume, and cognition. We analyzed a sample of cognitively normal older adults (cross-sectional n = 321) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). DAT1 and BDNF interacted to predict Aß-PET, tau-PET, and hippocampal atrophy. Carriers of both "non-boptimal" DAT1 C and BDNF Met alleles demonstrated greater pathology and atrophy. Our findings provide novel links between dopamine and neurotrophic factor genes and AD pathology, consistent with previous research implicating these variants in greater risk for developing AD.

Interactive effects of locus coeruleus structure and catecholamine synthesis capacity on cognitive function.

Background: The locus coeruleus (LC) produces catecholamines (norepinephrine and dopamine) and is implicated in a broad range of cognitive functions including attention and executive function. Recent advancements in magnetic resonance imaging (MRI) approaches allow for the visualization and quantification of LC structure. Human research focused on the LC has since exploded given the LC's role in cognition and relevance to current models of psychopathology and neurodegenerative disease. However, it is unclear to what extent LC structure reflects underlying catecholamine function, and how LC structure and neurochemical function are collectively associated with cognitive performance. Methods: A partial least squares correlation (PLSC) analysis was applied to 19 participants' LC structural MRI measures and catecholamine synthesis capacity measures assessed using [18F]Fluoro-m-tyrosine ([18F]FMT) positron emission tomography (PET). Results: We found no direct association between LC-MRI and LC-[18F]FMT measures for rostral, middle, or caudal portions of the LC. We found significant associations between LC neuroimaging measures and neuropsychological performance that were driven by rostral and middle portions of the LC, which is in line with LC cortical projection patterns. Specifically, associations with executive function and processing speed arose from contributions of both LC structure and interactions between LC structure and catecholamine synthesis capacity. Conclusion: These findings leave open the possibility that LC MRI and PET measures contribute unique information and suggest that their conjoint use may increase sensitivity to brain-behavior associations in small samples.

Poorer aging trajectories are associated with elevated serotonin synthesis capacity.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [18F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and ß-amyloid (Aß) pathology using cross-sectional [18F]Flortaucipir and [11C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [18F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging.

Higher neuroticism is a risk factor for Alzheimer's disease (AD), and is implicated in disordered stress responses. The locus coeruleus (LC)-catecholamine system is activated during perceived threat and is a centerpiece of developing models of the pathophysiology of AD, as it is the first brain region to develop abnormal tau. We examined relationships among the "Big 5" personality traits, LC catecholamine synthesis capacity measured with [18F]Fluoro-m-tyrosine PET, and tau burden measured with [18F]Flortaucipir PET in cognitively normal older adults (n = 47). ß-amyloid (Aß) status was determined using [11C]Pittsburgh compound B PET (n = 14 Aß positive). Lower LC catecholamine synthesis capacity was associated with higher neuroticism, more depressive symptoms as measured by the Geriatric Depression Scale, and higher amygdala tau-PET binding. Exploratory analyses with other personality traits revealed that low trait conscientiousness was also related to both lower LC catecholamine synthesis capacity, and more depressive symptoms. A significant indirect path linked both high neuroticism and low conscientiousness to greater amygdala tau burden via their mutual association with low LC catecholamine synthesis capacity. Together, these findings reveal LC catecholamine synthesis capacity to be a promising marker of affective health and pathology burden in aging, and identifies candidate neurobiological mechanisms for the effect of personality on increased vulnerability to dementia.

Associations among locus coeruleus catecholamines, tau pathology, and memory in aging.

The locus coeruleus (LC) is the brain's major source of the neuromodulator norepinephrine, and is also profoundly vulnerable to the development of Alzheimer's disease (AD)-related tau pathology. Norepinephrine plays a role in neuroprotective functions that may reduce AD progression, and also underlies optimal memory performance. Successful maintenance of LC neurochemical function represents a candidate mechanism of protection against the propagation of AD-related pathology and may facilitate the preservation of memory performance despite pathology. Using [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure catecholamine synthesis capacity in LC regions of interest, we examined relationships among LC neurochemical function, AD-related pathology, and memory performance in cognitively normal older adults (n = 49). Participants underwent [11C]Pittsburgh compound B and [18F]Flortaucipir PET to quantify ß-amyloid (n = 49) and tau burden (n = 42) respectively. In individuals with substantial ß-amyloid, higher LC [18F]FMT net tracer influx (Kivis) was associated with lower temporal tau. Longitudinal tau-PET analyses in a subset of our sample (n = 30) support these findings to reveal reduced temporal tau accumulation in the context of higher LC [18F]FMT Kivis. Higher LC catecholamine synthesis capacity was positively correlated with self-reported cognitive engagement and physical activity across the lifespan, established predictors of successful aging measured with the Lifetime Experiences Questionnaire. LC catecholamine synthesis capacity moderated tau's negative effect on memory, such that higher LC catecholamine synthesis capacity was associated with better-than-expected memory performance given an individual's tau burden. These PET findings provide insight into the neurochemical mechanisms of AD vulnerability and cognitive resilience in the living human brain.

Elevated Dopamine Synthesis as a Mechanism of Cognitive Resilience in Aging.

Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system's cortical targets, and reductions in the density of dopamine receptors. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age. We measured individual differences in striatal dopamine synthesis capacity in cognitively normal older adults using [18F]Fluoro-l-m-tyrosine positron emission tomography cross-sectionally and tested relationships with longitudinal reductions in cortical thickness and working memory decline beginning up to 13 years earlier. Consistent with a compensation account, older adults with the highest dopamine synthesis capacity were those with greatest atrophy in posterior parietal cortex. Elevated dopamine synthesis capacity was not associated with successful maintenance of working memory performance overall, but had a moderating effect such that higher levels of dopamine synthesis capacity reduced the impact of atrophy on cognitive decline. Together, these findings support a model by which upregulation of dopamine synthesis represents a mechanism of cognitive resilience in aging.