The long-term goal of this proposal is to develop a functional measure of risk for neurodegenerative disease, based on locus coeruleus (LC) function. The LC is the brainstem source of the neurochemical norepinephrine (NE). The proposed work may identify potential LC- or NE-related targets for prevention of neurodegenerative disease. This is highly relevant to the National Institute on Aging's mission to improve the health of older Americans, since neurodegenerative diseases like AD and PD represent a very significant and growing burden to older individuals and to the healthcare system at large. The particular goal of this proposal is to establish links between task-evoked pupillary responses (which are a known proxy for LC neuronal activity), neuronal density in the LC, naturally-occurring genetic polymorphisms which increase NE signaling in the LC, and global cognitive functioning.
The specific aims for this proposal are to: 1) to determine whether the amplitude of task- evoked pupillary responses during an auditory attention task is related to cognitive performance among older adults; 2) determine the shared and unique contributions of neuromelanin MRI signal intensity in the LC and the amplitude of task-evoked pupillary response to predicting global cognition scores, attention scores, and cognitive reserve; and 3) to determine whether either task-evoked pupillary responses or neuromelanin MRI signal intensity differ between individuals with and without a deletion variant of adra2b, the ?2B adrenoceptor. To achieve these aims, we propose to recruit, test and genotype 100 individuals aged 65-85. This population will include approximately 50 individuals with the adra2b deletion variant. We will assess cognitive function using the NIH Toolbox Cognitive Battery and the Cognitive Reserve Scale and measure the amplitude of task- evoked pupillary responses during a simple attention task. Finally, individuals will be given a neuromelanin MRI scan. We hypothesize that the amplitude of task-evoked pupillary responses will be positively correlated with neuronal density in the LC, and larger pupillary responses and more neuromelanin will both be linked to better cognitive performance and higher cognitive reserve. Furthermore, we hypothesize that individuals with the adra2b deletion variant will have larger pupillary responses, more neuromelanin and better cognitive performance than those without.
Despite decades of high-quality research, neurodegenerative diseases such as Alzheimer's disease remain incurable and fatal with only palliative treatments available, underscoring the need for alternative approaches to treatment. The locus coeruleus is a brainstem region recently identified as one of the first sites of damage in the progression of Alzheimer's and other neurodegenerative diseases. We propose to establish a link between locus coeruleus functioning and cognitive performance in the elderly, which may not only lead to the development of a very early marker of Alzheimer's disease, but potentially also disease-modifying targets for treatment.
