Use of novel fluorescent tracers to develop a comprehensive retinal biomarker database that maps the heterogeneity of Alzheimer's pathogenesis

使用新型荧光示踪剂开发综合视网膜生物标志物数据库，绘制阿尔茨海默病发病机制的异质性

• 批准号: 10821965
• 负责人: Stella Sarraf
• 金额: $ 170.44万
• 依托单位: AMYDIS DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10821965
• 关键词: ALS patients; Address; Advanced Development; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amyloid; Amyloid beta-Protein; Angiography; Artificial Intelligence; Binding; Biological Markers; Blinded; Blood; Blood Vessels; Bolus Infusion; Brain; Cadaver; Caring; Categories; Characteristics; Clinical; Clinical Research; Clinical Trials; Cognitive; Contrast Media; Data; Databases; Dementia; Deposition; Detection; Development; Diagnostic; Diagnostic tests; Dimensions; Disease; Dose; Enrollment; Equilibrium; Equipment; Evaluation; Exhibits; Exposure to; Eye; Fluorescence; Foundations; Freeze Drying; Freezing; Functional disorder; Fundus; Future; Goals; Heterogeneity; Hippocampus; Human; Image; Individual; Injections; Label; Lead; Light; Maps; Measures; Medical; Metabolic; Mission; Modality; Mutation; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurofibrillary Tangles; Optical Coherence Tomography; PET positivity; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Perfusion; Pharmaceutical Preparations; Phase Ib Clinical Trial; Physicians; Population; Positioning Attribute; Positron-Emission Tomography; Process; Property; Proteins; Radial; Radiation; Reading; Reporting; Research Personnel; Retina; Retinal Diseases; Safety; Senile Plaques; Signal Transduction; Standardization; Structure; Symptoms; Technology; Testing; Tissues; Tracer; Variant; Vial device; Visit; Water; abeta accumulation; alpha synuclein; analytical tool; beta pleated sheet; clinical candidate; clinical diagnosis; clinical practice; cognitive testing; cohort; commercial application; commercialization; cost; design; diagnostic technologies; disease heterogeneity; familial Alzheimer disease; fluorescence imaging; high resolution imaging; hyperphosphorylated tau; imaging biomarker; imaging modality; in vivo; individual patient; individualized medicine; knowledge integration; limbic-predominant age-related TDP-43 encephalopathy; multimodality; neurofilament; novel; novel diagnostics; open label; ophthalmic examination; patient subsets; precision medicine; protein TDP-43; protein biomarkers; reconstitution; recruit; research clinical testing; retinal imaging; small molecule; tau Proteins; tau-1; therapeutically effective

Project Summary Alzheimer’s disease (AD), the most common form of dementia, has traditionally been defined by the accumulation of amyloid beta (Aβ) in neuritic plaques and hyperphosphorylated tau in neurofibrillary tangles. However, recent evidence indicates that AD is better viewed as a continuum of disease with a broader degree of mechanistic and pathological heterogeneity. For example, ~15% of AD patients are negative for Aβ and most AD patients have “mixed pathology”, with large subsets exhibiting accumulation of additional neurodegenerative biomarkers such as α-synuclein (α-syn) and the TDP-43. Hippocampal and amygdalar deposits of TDP-43 have recently been characterized as defining a disease state that overlaps heavily with AD: Limbic-predominant, Age- related TDP-43 Encephalopathy (LATE). At present, AD diagnosis relies on clinical evaluation of symptoms and PET imaging of Aβ and Tau load. However, this is costly, involves exposure to radiation, and does not have the ability to detect broader dimensions of AD heterogeneity, such as the presence of pathological α-syn and TDP- 43 deposits that define large subsets of the AD continuum. There is an unmet medical need for an antemortem diagnostic that can reliably identify mechanistic heterogeneity in individual AD patients, ideally one that can detect multiple disease-related biomarkers simultaneously and non-invasively in CNS tissue. Amydis is leveraging the retina as a “window to the brain” to address this unmet need by developing an ocular contrast agent – i.e. a “retinal tracer – that can be used to fluorescently label α-syn, TDP-43, and Aβ in patients suspected of having AD. The retinal tracer, AMDX-2011P, currently in human clinical trials, has these remarkable capabilities and is designed to have fluorescent properties amenable for use with standard retinal imaging equipment found in the eye care office, making this technology widely accessible. In this proposal, Amydis will take the first clinical steps towards developing transformative new diagnostic technology in AD focusing on the biomarker Aβ in AD patient retinas. The specific aims of the project are: (1) to develop a lyophilized product of AMDX-2011P for i.v. delivery; (2) to complete a Phase 1B clinical trial of AMDX-2011P in patients with a clinical diagnosis of FAD (known FAD mutation and dementia) who have a positive Aβ PET scan (N=12), subjects with known FAD mutation but without clinical evidence of dementia (N=12) and healthy subjects (N=8) to determine if the tracer reliably reports on Aβ status; and, (3) to begin constructing a database of AD and normal retinal images for use in developing automated, AI-assisted retinal biomarker analytics tools for physicians and researchers. Completion of these aims will advance the development of our in vivo ocular diagnostic test, getting us one step closer to our mission of providing an antemortem, simple, and affordable diagnostic to parse the heterogeneity of AD. Future studies will integrate knowledge obtained from ongoing clinical studies of AMDX- 2011P as a marker of a-syn and TDP-43 and assess whether the tracer can report on the co-occurrence and variability of these critical biomarkers in individual patients.

项目总结