Date Approved

2016

Document Type

Dissertation

Degree Name

PhD in Cell and Molecular Biology

Department

Cell Biology

College

Graduate School of Biomedical Sciences

First Advisor

Robert Nagele, PhD

Committee Member 1

Kingsley Yin, PhD

Committee Member 2

Bernd Spur, PhD

Committee Member 3

John Pastorino, PhD

Committee Member 4

Venkataswar Venkataraman, PhD

Committee Member 5

Gary Goldberg, PhD

Subject(s)

Autoantibodies, Biomarkers, Neurodegenerative Diseases, Early Diagnosis, Neurocognitive Disorders, Nervous System Diseases, Autoimmune Diseases of the Nervous System

Disciplines

Biological Phenomena, Cell Phenomena, and Immunity | Cell Biology | Immune System Diseases | Life Sciences | Molecular Biology | Nervous System Diseases | Organismal Biological Physiology

Abstract

Autoantibodies are self-reactive antibodies that have been widely implicated as causal agents of autoimmune diseases. They are found in the blood of all human sera, regardless of age, gender, or the presence or absence of disease. While the underlying reason for their ubiquity remains unknown, it has been hypothesized that they participate in the clearance of blood-borne cell and tissue debris generated in both healthy and diseased individuals on a daily basis. Although much evidence supports this debris clearance role, recent studies also suggest a causal role for autoantibodies in disease. My thesis work has focused on this "cause and/or effect" role of autoantibodies and recent technological advancements in their detection to exploit autoantibodies as sensitive and specific biomarkers useful for the detection and diagnosis of various neurodegenerative diseases. Briefly, utilizing human protein microarrays as a diagnostic platform, we have developed discrete, blood-borne autoantibody biomarker panels from patient sera that are capable of accurately diagnosing and staging early-stage Alzheimer's disease (AD) known as Mild Cognitive Impairment (MCI), early-stage Parkinson's disease (PD), and Multiple Sclerosis (MS). Lastly, we have also developed a generalized panel of autoantibody biomarkers capable of detecting broad neurodegeneration, regardless of disease. We believe this panel can be used as a primary screening tool for patients suspected of having neurodegenerative diseases in their earliest stages when symptoms might not be obvious or readily observable.

Blood-borne biomarkers are currently heralded as the "gold standard" in diagnostic biomarker development. Blood draws are simple and less invasive to collect than other biofluids, and substantially less expensive than neuroimaging, which is restricted geographically and therefore not widely available. The development of diagnostic blood tests for MCI, early-stage PD, and MS are important advancements in not only treating these diseases, but also in elucidating the potential mechanisms underlying their pathology. Disease diagnosis at the earliest detectable stage allows patients to begin treatment earlier than ever before possible, with the potential to greatly improve their quality of life. Additionally, early-stage diagnosis allows not only for validation of patients enrolled in clinical trials, but also for sensitive and specific monitoring of drug-efficacy throughout trials. We believe this strategy can potentially be used to create the first ever inexpensive, non-invasive, and highly accurate multi-disease diagnostic test platform utilizing blood-borne autoantibody biomarkers.

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