Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Interdisciplinary Neuroscience

Department

Interdisciplinary Neuroscience

First Advisor

Peter J. Snyder

Abstract

One in three adults over 85 years old suffer from Alzheimer’s disease (AD) or other forms of dementia. This already widespread condition is expected to increase further in both incidence and prevalence in coming years. As a result, the need to understand the etiology and pathogenesis of dementia becomes ever more urgent. AD, in addition to its steep cost of care, is the most common form of dementia and the sixth leading cause of death in the United States. It is a complex disease and its mechanisms are poorly understood. The more we learn about AD, the more questions are raised about our current conceptual models of disease. Despite the rapid advancement of medical technology, reliable and sensitive diagnostic markers to identify individuals at risk to AD prior onset of clinical symptoms remain in the developmental phase resulting in inefficient diagnostic procedures. Diagnosis is further hampered by the heterogeneity of behavioral presentations, cognitive impairments, and functional statuses observed in AD, all of which may be the result of varying etiologies. Furthermore, older AD patients often suffer from comorbid medical conditions that further complicate accurate disease monitoring.

In the absence of an effective AD treatment, it is prudent to apply our current knowledge of the intersection between AD, cardiovascular disease (CVD), and cerebrovascular disease to foster efforts to delay the onset of dementia more generally. The purpose of MANUSCRIPT I is to review our current understanding of the epidemiology, genetics, and pathophysiology of AD as well as the intersection between AD and vascular causes of dementia. The epidemiology and shared risk factors and etiologies for these three disease “clusters” are explored, including shared genetic contributions and lifestyle, behavioral and environmental risk factors. In this first publication, we also explore possible mechanistic pathways of AD and the shared pathophysiology and neuropathological substrates of these three disease clusters.

CVD and cerebrovascular pathology is present for most individuals with AD, although the converse is not necessarily true. Given this relationship, it is important to address how early in the disease course those vascular changes can be observed. Such research is needed to enable early interventions to maintain quality of life in premorbid AD and reduce the burden of disease. To determine whether there is cardiovascular alteration in the early stages of AD, MANUSCRIPT II evaluated electrocardiologic measures of vagal tone for 63 adults (ages 55-75) at rest, during cognitive testing, and then again at rest. All subjects had multiple risk factors for AD, and all completed amyloid PET scans (18F-Florbetapir) to determine amyloid positivity (Aβ+). Cardiac autonomic dysfunction, specifically, an increase in sympathetic activity and a decrease in parasympathetic activity often referred to as vagal withdrawal, is prevalent among individuals with AD and is indicative of impaired autonomic function.

Preclinical AD participants (Florbetapir amyloid PET SUVr ≥ 1.1) did not consistently show changes in vagal ratio or Respiratory Sinus Arrhythmia (RSA) at any point during the experiment and they failed to demonstrate the expected response to the modest stress they experienced during cognitive task performance. Both changes are directly modulated by both muscarinic and nicotinic cholinergic autonomic neurotransmission. Because the earliest stages of AD are marked, in part, by altered function of the basal forebrain cholinergic system, with eventual degenerative changes including neuronal loss, this result suggests a link between Aβ aggregation and impaired autonomic cardiovascular function, even in the preclinical stage of AD.

Another factor that influences the lack of treatment is the absence of a reliable, affordable, and sensitive diagnostic marker to identify individuals at risk for AD before the onset of clinical symptoms. One possible marker may be found in the retina, the retina shares similar embryological origins, anatomical features, and physiological characteristics with the brain. From as early as the fourth week of gestation, the eyes, particularly the retinal nerve fiber layer (RNFL) and the optic nerve, are direct sensory extensions of the central nervous system as their axons synapse directly with several brain regions. Unlike the brain, however, retinal neuronal cell layers can be non-invasively visualized through high-resolution optical methods such as optical coherence tomography (OCT) allowing for the precise segmentation and measurement of these cell layers. For MANUSCRIPT III, more than 15 years of literature with inconsistent findings on the relationship between the morphology of retinal neuronal layers and AD were reviewed. Most papers reported RNFL and ganglion cell layer (GCL) thickness to be significantly reduced in cross sectional studies of patients with mild cognitive impairment (MCI) and mild to moderate AD. For the first time, this Manuscript explores within-subjects longitudinal change in retinal morphology during the preclinical stage of AD for all retinal neuronal layers. For this manuscript, fifty-six older adult participants (mean age = 65.36 years) from the previous manuscript completed Spectral Domain-OCT retinal imaging at baseline. Twenty-seven months later, they completed the same exams as well as an 18F-Florbetapir PET imaging and cognitive testing.

We observed a decrease over time in macular RNFL, outer nuclear layer and inner plexiform layer volumes in preclinical AD relative to controls. While the macular region of the retina is physiologically very active in healthy normal eyes, this region might have diminished activity in the preclinical stage of AD. This thinning could be due to either demyelination or loss of axons in the RNFL, both of which suggest the possibility of future degenerative changes to the cell bodies in the GCL followed by progression to deeper neuronal layers. Volume loss in the RNFL, during the preclinical stage, is not related to performance on measures of episodic memory or problem solving. However, this retinal change does appear to be modestly related to relative decrements in performance on a measure of audiovisual integration efficiency that has been recently advanced as a possible early cognitive marker of mild cognitive impairment.

In order to tie together the findings of relative changes in cardiovascular function and retinal morphological changes in preclinical AD, we decided to utilize optical coherence tomography angiography (OCTA), a new technology that makes it possible to measure retinal vascular flow. Recently, a reduction in vascular bed complexity in MCI and AD relative to healthy controls was reported by using a fractal dimension (Df) approach to summarizing OCTA imaging results. In MANUSCRIPT IV, forty-eight adults (mean age = 68.76 years) from the same sample of participants had retinal OCTA images captured using an AngioVue system (Optovue, Fremont, CA, USA). The Df was measured in linearized images of the superficial vascular plexus (SVP) to determine the space-filling linear extension of the large vessels. Our findings suggest that individuals at high-risk for preclinical AD have less density and complexity of retinal microvascular networks in the SVP of the macular region (the same region in which structural changes were observed in Manuscript III) than healthy controls. Reduced vascular density in the SVP likely leads to degradation in blood flow throughout the other parts of the retina and therefore might directly contribute to continued axonal loss as well as future GCL thinning in AD. Retinal vascular distribution and blood flow were found to be altered during the earliest stages of AD suggesting a potential cost-effective and non-invasive marker for preclinical AD.

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