New molecular imaging probes specific to A2 species including soluble A2 oligomers, insoluble fibrils and plaques, are indispensable for accurate and early detection of AD pathology, as well as for drug development and treatment monitoring. NIR (near infrared imaging), MRI (magnetic resonance imaging) and PET (positron emission tomography) are the imaging modalities that currently provide capabilities for imaging A2 species. Each of these modalities has its own advantages and weaknesses;multi-modality imaging, an emerging approach that combines information from more than one modality, provides fundamental improvements for 1) accurate detection to permit early diagnosis and spatial localization;2) unambiguous information about molecular activities of a target;3) easy translation from animal study to clinical trial. To date, multi-modality imaging efforts have been focused primarily on two objectives: 1) to achieve better co-registration for accurate spatial location by constructing hybrid imaging systems or using complicated registration algorithms;2) to achieve more accurate molecular-level information of the target by developing multi-modal imaging probes. Such probes would be particularly suitable for detection and monitoring of AD and other neurodegenerative diseases. Curcumin, the principal curcuminoid of the Indian curry, has been used for ex vivo detection of amyloid deposits. However, its rapid metabolism and limited penetration across blood-brain barrier (BBB) do not allow for its use as an in vivo imaging agent. In this application we propose to create a small library of curcumin derivatives with NIR properties for in vitro and in vivo preliminary screening, and adapt the selected candidates for modification with PET and 19F MR imaging reporters for NIR/MRI/PET imaging. We will further perform NIR/PET/19F MRI multi-modality imaging of AD pathology in transgenic animals in vivo. Finally, we will attempt to conduct a limited theragnostic study with AD therapeutics using the synthesized probes for monitoring of the therapeutic outcome. In addition, several very promising PET probes such as PiB (Pittsburg compound B) and AV-45 have displayed efficacy primarily for imaging insoluble A2 plaques;however, we still fall short of a probe for imaging the soluble A2 species, the likely toxic species at early AD pathological stage. Since curcumin derivatives synthesized in our preliminary studies showed appreciable binding to monomeric species, we will investigate this phenomenon further in this application. If successful, with an arsenal of probes for detection of both insoluble plaques and soluble A2 species, we believe that eventually we will be able to monitor the full course of amyloidosis pathology of Alzheimer's disease.

Public Health Relevance

The proposed research will be beneficial for the preclinical animal study and the drug development for Alzheimer's Disease, and will have potential capability for the early and accurate clinical diagnosis of Alzheimer's Disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Quantitative Research Career Development Award (K25)
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National Institute on Aging Initial Review Group (NIA)
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Hsiao, John
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Massachusetts General Hospital
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