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Retinal Imaging of Alzheimer's Disease Pathology

阿尔茨海默病病理学的视网膜成像

基本信息

批准号：
9744410
负责人：
Maya Koronyo-Hamaoui
金额：
$ 34.27万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9744410
关键词：
Affect Affect Age Age Alzheimer&apos s Disease Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Amyloidosis Amyloidosis Appearance Appearance Autopsy Autopsy Biological Markers Biological Markers Blood Vessels Blood Vessels Blood flow Blood flow Brain Brain Brain Diseases Brain Diseases Brain Pathology Brain Pathology Cadaver Cadaver Cells Cells Cerebral Amyloid Angiopathy Cerebral Amyloid Angiopathy Cerebrum Cerebrum Circadian Rhythms Clinical Clinical Clinical Data Clinical Data Clinical Research Clinical Research Clinical Trials Clinical Trials Cognitive Cognitive Curcumin Curcumin Data Data Deposition Deposition Detection Detection Development Development Diagnosis Diagnosis Disease Disease Disease Progression Disease Progression Early Diagnosis Early Diagnosis Encephalitis Encephalitis Exhibits Exhibits Follow-Up Studies Follow-Up Studies Future Future Goals Goals Histologic Histologic Human Human Image Image Imaging technology Imaging technology Immunotherapy Immunotherapy Impaired cognition Impaired cognition Inflammation Inflammation Inflammatory Inflammatory Label Label Lead Lead Location Location Measures Measures Methods Methods Monitor Monitor Mus Mus Nerve Degeneration Nerve Degeneration Nerve Fibers Nerve Fibers Neurodegenerative Disorders Neurodegenerative Disorders Neurofibrillary Tangles Neurofibrillary Tangles Neuroglia Neuroglia Non-Invasive Cancer Detection Pathologic Pathologic Pathology Pathology Patients Patients Peptides Peptides Photoreceptors Photoreceptors Population Population Populations at Risk Populations at Risk Process Process Publishing Publishing Research Research Resolution Resolution Retina Retina Retinal Retinal Diseases Retinal Diseases Retinal Ganglion Cells Retinal Ganglion Cells Risk Risk Rodent Model Rodent Model Screening procedure Screening procedure Senile Plaques Senile Plaques Severities Severities Site Site Spatial Distribution Spatial Distribution Specificity Specificity Structure Structure Synapses Synapses Tauopathies Tauopathies Technology Technology Thinness Thinness Tissues Tissues Transgenic Organisms Transgenic Organisms abeta accumulation abeta accumulation amyloid imaging amyloid imaging astrogliosis astrogliosis base base brain cell brain cell circadian cranium cranium design design diencephalon diencephalon disorder control disorder control early screening early screening high resolution imaging high resolution imaging hyperphosphorylated tau hyperphosphorylated tau imaging approach imaging approach imaging modality imaging modality in vivo in vivo melanopsin melanopsin mild cognitive impairment mild cognitive impairment mouse model mouse model neuron loss neuron loss neurosensory neurosensory non-invasive monitor novel novel novel strategies novel strategies optical imaging optical imaging protein oligomer protein oligomer response response retinal ganglion cell degeneration retinal ganglion cell degeneration retinal imaging retinal imaging tau Proteins tau Proteins tau-1 tau-1 tissue degeneration tissue degeneration treatment response treatment response β-amyloid burden

项目摘要

ABSTRACT The central goal of this proposal is to explore pathological hallmarks of Alzheimer’s disease (AD) in the retina and evaluate retinal amyloid imaging as a novel approach for diagnosis and monitoring of AD. There is growing evidence that AD affects the neurosensory retina, a developmental outgrowth of the brain and the only CNS tissue directly accessible for high-resolution imaging. The retina exhibits a wide spectrum of pathologies in AD patients, including thinning of the nerve fiber layer, vascular and blood flow changes, and degeneration of retinal ganglion cells (RGCs). The hallmark pathological signs of AD – amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) comprised of hyperphosphorylated tau protein (ptau) – have long been described in the brain. However, Aβ deposits in the retina of human AD patients, including early stage cases, were only recently discovered. Further studies have found ptau, Aβ-like deposits, and elevated Aβ42 peptides in postmortem AD retinas. Notably, a loss of a subtype of RGCs, melanopsin-containing RGCs, was associated with accumulation of Aβ inside and around these cells. Preliminary data from our group indicate manifestation of vascular amyloidosis and retinal inflammation (e.g. astrogliosis and microgliosis) surrounding Aβ fibrils and NFT-like structures, which are specific to the retinas of AD patients. These changes appear to be exacerbated during disease progression. In order to visualize AD pathology, a noninvasive retinal amyloid imaging method has been developed to facilitate repeated monitoring of retinal Aβ deposits with high resolution and specificity in living transgenic rodent models of AD. Pilot clinical trials implementing this retinal curcumin imaging technology demonstrate its capacity to quantitatively detect retinal Aβ deposits in living AD patients. Our studies using this retinal amyloid optical imaging in mouse models demonstrate the feasibility to track subtle changes in retinal amyloid plaques during disease progression, and in response to immune-based therapy. Based on the published and preliminary data collected, the following research objectives are proposed: 1) To determine the existence and distribution of amyloid deposits, vascular amyloidosis, intracellular Aβ oligomers, and tauopathy in the retinas of AD and Mild Cognitive Impairment (MCI) patients; 2) To examine retinal inflammation and degeneration, and evaluate possible correlations with brain pathology and cognitive status in MCI and AD patients, and 3) To noninvasively monitor formation, appearance and clearance of retinal Aβ deposits in live mouse models of AD, during disease progression and in response to immunotherapy. Results from these studies stand to markedly increase the understanding of how AD affects the retina, and whether retinal amyloid imaging can reliably indicate brain pathology or cognitive status. Given the accessibility of the retina for direct and noninvasive high resolution imaging, targeting this tissue may provide an invaluable approach to identify new biomarkers and screen populations to facilitate prediction of risk, diagnosis and monitoring of AD.

摘要