Association of Melanopsin Retinal Ganglion Cell Response and Central Visual System Atrophy with Circadian Rhythm Disturbances and Neuropsychiatric Symptoms in Alzheimer's Disease

Abstract

Background: It is well established that Alzheimer's Disease (AD) affects the visual system, with specific disease-related changes to structures involved in visual perception and circadian rhythm (i.e., melanopsin retinal ganglion cells (mRGCs)). Although it is known that associations between AD and ocular structures exist, the relationship between ocular pathology and circadian rhythm disturbances (CRD) and neuropsychiatric symptoms (NS) in AD is an emerging field. Objectives: Using secondary and primary data, I: (1) determined if atrophy in selected visual brain regions of interest (ROIs) was associated with NS; (2) determined if mRGC response was associated with CRD using objective measures; and (3) discussed specific considerations and challenges for including AD participants in ophthalmology research. Outcomes were developed into three papers. Methods: Paper One: Using the Alzheimer's Disease Neuroimaging Initiative (ADNI), atrophy was estimated using magnetic resonance imaging (MRI) measures (volume and thickness) in visual ROIs. Neuropsychiatric Inventory (NPI) scores and relevant sub-domains estimated NS. Paper Two: AD and control participants completed a comprehensive ophthalmic exam and pupillometry (to assess mRGC response). Questionnaires assessed participants' NS. An actigraphy watch measured circadian rhythm. Paper Three: I presented several considerations for study design, complexity of tasks, recruitment, and physical exam environment specific to AD participants involved with ophthalmology research. Results: Paper One included n=143 AD and n=283 control subjects. Volumes and thicknesses of all ROIs were significantly lower in the AD group compared with controls (p<.05) but were not associated with NS in either group. Paper Two included n=10 AD and n=18 control participants. Groups did not differ on mRGC responses or actigraphy outcomes. In the AD group only: immediate mRGC response was associated with increased wakening after sleep onset (WASO) and decreased sleep efficiency; and sustained response was associated with increased total sleep time (p<.05). Paper Three revealed several considerations that may improve data collection and recruitment. Conclusions: Some AD-related ocular pathology appears to be associated with CRD but not with NS. There were no significant findings in either sample in the age-matched control groups, suggesting the associations are specific to AD. AD participants require special considerations to optimize participation in ophthalmological studies.