Upregulated Norepinephrine Synthesis Capacity in Aging

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Project summary The locus coeruleus (LC) is a small nucleus in the brainstem that is vulnerable to the accumulation of abnormal tau protein, a neuropathological hallmark of Alzheimer’s disease (AD). The LC is structurally connected to the temporal lobe and may play a role in transmitting abnormal tau through trans-neuronal spread. The LC is the primary producer of the neuromodulator norepinephrine. Norepinephrine is essential for normal attention and memory function. Beyond a role in cognition, norepinephrine serves a myriad of neuroprotective roles which include inhibition of oxidative stress, maintenance of the blood brain barrier, and anti-inflammatory processes. The occurrence of hyperphosphorylated tau in the LC has been linked with loss of norepinephrine-producing LC neurons. The targeting and neurodegeneration of LC is particularly insidious due to the combined loss of cognition-enhancing neuromodulation and loss of neuroprotective functions thus paving the way for disease acceleration and propagation. Despite insults to the LC, there is evidence for upregulation of norepinephrine metabolism in healthy aging, mild cognitive impairment, and AD. We propose upregulation of norepinephrine synthesis in the LC cells remaining represents a mechanism of neurochemical compensation that, in some individuals, wards off cognitive decline and protects against disease spread. In healthy older adult humans, we will define relationships between LC structural integrity, and norepinephrine synthesis levels (Aim 1). We will determine the extent to which elevated norepinephrine synthesis confers a benefit to memory performance (Aim 2). Finally, we will test the hypothesis that elevated norepinephrine synthesis is associated with reduced tau accumulation longitudinally (Aim 3). This multimodal study will combine state-of-the-art magnetic resonance imaging (MRI) to measure LC structural integrity, [18F]Fluoro-m-tyrosine positron emission tomography (PET) to measure norepinephrine/dopamine synthesis capacity, [18F]MK-6240 PET to measure tau pathology, and plasma measures of Ab42/40. If successful, this research will provide new understanding of the neurochemical basis of individual differences in disease progression and will launch a novel avenue of investigation into the role of norepinephrine in disease resilience (supporting maintenance of cognitive function despite pathology) and disease resistance (combatting disease spread).