The Locus Coeruleus, Norepinephrine and Cognitive Aging

Unfortunately, most people are personally familiar with the devastating consequences of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). The number of older adults with neurodegenerative disease is expected to rise as the baby boomer generation ages, with 28 million baby boomers developing AD. This, in turn, is expected to cost $328 billion dollars, or 24% of total Medicare spending. Despite decades of research into the causes of AD, there are only 5 FDA-approved treatments, all of which are supportive, non-disease-modifying drugs. Of the treatments that have been tested for AD, 99.6% have failed. Accordingly, new approaches to neurodegenerative disease - a better understanding of their causes and better targets for treatment - are desperately needed.

The locus coeruleus (LC) has recently been identified as one of the earliest sites of damage in AD and PD, with pathological lesions appearing as early as the mid-20s. A brain region of 40,000-60,000 neurons located in the brainstem, the LC is the source of the neurochemical norepinephrine (NE, also known as noradrenaline). The LC has widespread projections throughout the nervous system and plays an important role in arousal, attention, memory, mediation of emotional and stress responses, and some aspects of motor control. Damage to the LC, and the resulting decrease in protective NE signaling throughout the brain, is proposed to be an important mechanism in the progression of neurodegeneration. The LC has even been proposed by some to be the primary mediator of cognitive reserve, predicting the relative preservation of cognitive performance despite neuropathological insult. Despite the possibility that decreased NE signaling from the LC may serve as the earliest warning flag of dementia, few studies link LC function and cognitive performance. Remarkably, neither has the relationship between LC function and LC neuronal loss been examined. A promising new technique, neuromelanin-sensitive magnetic resonance imaging (MRI), will allow us to estimate the amount of neuromelanin-containing tissue in the LC. Neuromelanin MRI has been shown to be quantitative, highly correlated with the number of LC neurons, and reproducible, with high inter-rater reliability. The investigators have been using this innovative technique to establish a correlation between LC neuromelanin density and attention across the lifespan, which may provide a non-invasive, functional measure of neurodegeneration risk that may be valid well before the onset of clinical symptoms. Furthermore, using modern MRI analysis techniques, it is now possible to measure the function of the LC with functional MRI.

As an even less invasive measure of LC function, the investigators propose to assess task-evoked pupillary responses during auditory and visual vigilance tasks. Light-evoked pupillary responses - changes in pupil size due to changes in illumination - are well known to be abnormal in AD, but task-evoked pupillary responses may represent an early sign of future cognitive decline. Pupil diameter, under constant light conditions, is a well-established correlate of neuronal activity in LC neurons. Measuring pupil changes with a non-invasive eyetracker is an ideal assay for this purpose.

To further characterize the relationship between LC integrity, LC function, and cognitive function the investigators will administer a broad neuropsychological battery to measure cognitive performance. The laboratory makes use of a variety of classic neuropsychological tests such as the Montreal Cognitive Assessment and Trail-Making Test, in addition to the NIH Toolbox Cognition and Emotion Batteries, blood pressure and other cardiovascular health measurements, a retrospective report of traumatic childhood experiences, and a variety of custom-designed attention tasks for use with the MRI scanner and eyetracking components of the study.

There is intriguing neurogenetic evidence that individual differences in NE signaling may protect against AD. A common polymorphism (small genetic change) in the adrenergic receptor alpha 2b gene (a molecule in the brain that binds to norepinephrine, "adra2b deletion variant") likely results in significantly increased NE signaling from the LC. The lab has previously shown that individuals with this polymorphism attend to and later recall emotional events better than those without, and experience greater perceptual vividness. Crucially - others have shown that individuals with this polymorphism are less likely to have AD or mild cognitive impairment. These phenomena are likely all related to the role that the LC plays in attention, arousal and, in combination, support healthy cognitive aging.

Finally, the investigators will also attempt to modulate LC activity using non-invasive transcutaneous auricular vagus nerve stimulation for very short periods (~15 to 45 minutes) to discover if it is possible to alter, and potentially improve, LC function variables. Previously, this technique has been shown to directly activate the LC through the vagus nerve.