?Deposition of amyloid plaques in the brain represents a universal feature of many neurodegenerative diseases and precedes their clinical symptoms by several years. Currently, diagnosis of amyloid-associated dementias in individuals showing symptoms of cognitive decline is extremely difficult, requiring multiple modes of testing over months to years. Early, pre-symptomatic diagnosis is even more challenging, if not impossible, with currently available technology. Among the more difficult problems with proper diagnosis of neurodegeneration is the inability to discern between diseases with vastly different etiology but similar symptomatic characteristics. Since the plaques that are characteristic of different amyloid-associated diseases are comprised primarily of distinctly different proteins, a simple and reliable method to identify the protein makeup of amyloid deposits in living patients could significantly aid in conclusive disease diagnosis, allowing the opportunity for disease-modifying therapeutic intervention. We will investigate the use of a new family of fluorescent probes that can label amyloids in tissue. Importantly, this class of compounds can be tuned in a way that allows not only enhanced visualization of amyloids but also colorimetric discrimination of the amyloids as a function of their protein composition. Such discriminating ability may enable accurate diagnosis/monitoring of specific neurodegenerative diseases, thereby aiding in selection of a proper course of treatment. This proposal will screen a library of novel fluorescent probes, evaluate their formulation for systemic delivery, and evaluate their utility to image neurodegenerative diseases in living systems. The output of this proposal will be a lead diagnostic candidate capable of imaging neurodegenerative diseases in the eye.
Public Health Relevance Statement: Public Health Relevance: Many neurodegenerative diseases are characterized by the deposition of insoluble protein aggregates in the brain that are referred to as amyloids. Recently, these amyloids have been identified in retinal tissue in diseased individuals. The proposed research aims evaluate a systemically-delivered diagnostic agent to image amyloid-deposits in a neurodegenerative disease model.
NIH Spending Category: Acquired Cognitive Impairment; Aging; Alzheimer's Disease; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Brain Disorders; Dementia; Emerging Infectious Diseases; Eye Disease and Disorders of Vision; Infectious Diseases; Neurodegenerative; Neurosciences; Rare Diseases; Transmissible Spongiform Encephalopathy (TSE)
Project Terms: accurate diagnosis; age related; Alzheimer's Disease; Amyloid; Amyloid deposition; amyloid imaging; Amyloid Proteins; Amyloidosis; base; Binding (Molecular Function); Brain; Characteristics; Chemicals; Clinical; clinical application; Color; Creutzfeldt-Jakob Syndrome; Dementia; Deposition; design; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Diagnostic tests; Discrimination (Psychology); Disease; disease diagnosis; Disease model; Disease Progression; drug candidate; Drug Formulations; Drug Kinetics; Early Diagnosis; effective therapy; Etiology; Eye; Family; Fluorescence; Fluorescent Probes; Image; Imagery; Impaired cognition; improved; in vivo; Individual; intravenous administration; Label; Lead; Libraries; Life; Methods; Monitor; Morphology; mouse model; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; novel; Optical Methods; Organism; Oryctolagus cuniculus; Output; Parkinson Disease; Pathogenesis; Patients; Physiological; prevent; Prion Diseases; Property; protein aggregate; protein aggregation; Proteins; public health relevance; Reporting; Research; research study; Retina; Retinal; Senile Plaques; Series; small molecule; Staining method; Stains; Symptoms; Technology; Testing; Therapeutic Intervention; Time; Tissues; tool; tool development; Translating; Work
