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Optical probe and instrumentation development for in vivo near-infrared fluorescence imaging of Alzheimer's disease

Award Number: K01AG072046
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Optical probe and instrumentation development for in vivo near-infrared fluorescence imaging of Alzheimer's disease - PROJECT SUMMARY / ABSTRACT The main neuropathological hallmarks of Alzheimer's disease (AD) are the extracellular accumulation of amyloid plaque deposits and intracellular formation of neurofibrillary tangles (NFTs). To enable the study of disease progression and the effect of therapeutics in preclinical mouse models of AD, there is an urgent need for non- invasive methods of imaging both hallmarks in the living brain. The most established non-invasive imaging approaches at the whole animal level are magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT). However, only optical techniques like near- infrared (NIR) fluorescence imaging have the theoretical spatial resolution to image individual amyloid plaques and NFTs. In contrast to PET and SPECT, NIR fluorescence has the additional advantage of using safe, non- ionizing radiation. Previous NIR fluorescence probes for AD have mostly emitted in the 600-650 nm wavelength range. While these probes can be used to provide low resolution, bulk estimates of AD pathology burden in vivo and to distinguish between AD mice and wildtype controls, they lack the ability to provide absolute quantitation and cannot be used to image non-invasively with microscopic resolution. To enable non-invasive optical imaging through the intact scalp and intact skull of mice, the wavelength of the fluorescent probe needs to be shifted into the NIR-II spectrum (1,000-1,700 nm). At these longer wavelengths, the penetration depth through tissue is increased dramatically while the background caused by intrinsic autofluorescence is minimized. Here we propose to develop and identify candidate probes for NIR-II imaging by employing two complimentary strategies. In the first approach, we will modify the chemical structure of a promising candidate probe, with existing affinity for amyloid plaques and NFTs to enhance its binding affinity and NIR-II fluorescence emission. In the second approach, we will screen an existing chemical library of > 650 NIR fluorophores using chemical structure-activity modeling and in vitro and in vivo characterization. To image our candidate NIR-II fluorophores in vivo, we will build a custom multi-modal microscope combining NIR confocal and multiphoton microscopy and fully characterize its performance with simulations and experimental validation. We will conduct longitudinal, in vivo imaging studies in AD mice to validate our developed probes and instrumentation and demonstrate for the first time non-invasive monitoring of AD pathology with microscopic resolution. The excellent scientific environment and world-class resources provided by the Massachusetts General Hospital and Harvard Medical School, as well as the internationally recognized leadership of the applicant's mentors, along with the expertise of the proposed collaborators, will be key to the successful completion of the proposed research. This K01 award will be instrumental for the applicant to strengthen his skillset with training in optical probe development and in vivo imaging in AD mice and to take the next steps towards becoming an independent researcher.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $127,320 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	5	1/21/2026	NON-COMPETING CONTINUATION	$127,320
														Subtotal = $127,320

Issue Date FY: 2025 ( Subtotal = $127,320 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	4	12/23/2024	NON-COMPETING CONTINUATION	$127,320
														Subtotal = $127,320

Issue Date FY: 2024 ( Subtotal = $127,320 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	3	1/31/2024	NON-COMPETING CONTINUATION	$127,320
														Subtotal = $127,320

Issue Date FY: 2023 ( Subtotal = $127,320 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	2	2/2/2023	NON-COMPETING CONTINUATION	$127,320
														Subtotal = $127,320

Issue Date FY: 2022 ( Subtotal = $127,320 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Aging Research	000	1	1/24/2022	NEW	$127,320
														Subtotal = $127,320

Grand Total All Awards = $636,600

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Optical probe and instrumentation development for in vivo near-infrared fluorescence imaging of Alzheimer's disease

Award Number: K01AG072046

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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