In addition to the characteristic deficits in explicit memory for facts or past events, patients with Alzheimer's disease also demonstrate an underappreciated impairment in repetition priming, an essential form of implicit memory. Priming refers to a performance enhancement that occurs simply due to repeated exposure to a stimulus, and occurs without conscious recollection of the stimulus. Priming is preserved in patients with explicit memory deficits due to circumscribed damage to the medial temporal lobe (MTL) explicit memory system (e.g. patient ?H.M.?), but is impaired in a modality-specific manner with lesions of cortex supporting processing of that modality. While AD pathology spreads widely throughout the cortex in the later stages of disease progression, priming impairments appear in patients with Mild Cognitive Impairment (a precursor to AD) and even in the preclinical stages of disease - long before pathology has spread to affect other cortical functions. Alternatively, recent work suggests that before affecting the cortex, AD pathology begins in brainstem nuclei such as the locus coeruleus (LC) ? the sole source of norepinephrine (NE) for the majority of the neocortex ? regulating arousal and attention, and providing a steady-state level of ?cortical tonus.? It has been proposed that early subcortical damage to this LC-NE system in AD compromises this tonic cortical activation to a degree that is unable to support priming in the initial stages of disease, but until recently probing the integrity of the NE system in vivo was technically challenging. The recent development of Fast Spin Echo (FSE) T1-weighted MR imaging techniques to utilize the natural contrast properties of neuromelanin, a product of NE metabolism, has allowed the reliable identification of the LC in vivo. The neuromelanin contrast intensity of the structure on FSE MRI has been pathologically validated as a measure of LC cell loss, and has been found to relate to cognitive function in AD. Similarly, pupillary response under cognitive load and measurement of salivary alpha-amylase (SAA) have recently been used as proxies of NE system function and integrity. I propose to utilize these novel techniques to test the hypothesis that the priming deficit in AD stems from early LC dysfunction by administering a perceptual open- closed figure priming task along with a conceptual word-stem completion priming task to participants on the aging-MCI-AD spectrum who are participating in a multi-modal imaging and pupillometry studies of the LC. Using recent advances in techniques for the acquisition and analysis of both diffusion-weighted and resting- state functional MRI, I will further test whether the structural and functional connectivity of the LC to modality- specific cortical regions implicated in conceptual and perceptual repetition priming are separately related to our conceptual and perceptual tasks. This work will not only expand our understanding of the biological basis of implicit memory, but also further characterize the nature of the early pathologic disruption of this underappreciated implicit memory process in early Alzheimer's disease.
In addition to difficulty with explicit memory for past events, patients with Alzheimer's disease (AD) also have impairments in unconscious forms of implicit memory that may be some of the earliest signs of disease. This project investigates whether the implicit memory deficit in patients with AD is the result of damage to the norepinephrine (NE) neuromodulatory system known to regulate attention and cortical arousal. This study will utilize state-of-the-art neuroimaging and other markers of the NE system, to assess the contributions of the integrity and connectivity of the system in AD with impairment in repetition priming ? a form of implicit memory.
