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Modeling Axonal Density and Inflammation-Associated Cellularity in Alzheimer?s Disease Using Hybrid Diffusion Imaging

Award Number: R01AG053993
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Abstract Alzheimer's disease (AD) affects as many as 5 million individuals over the age of 65 in the United States (US) and 35 million worldwide. Because of the aging population, the prevalence of AD will disproportionately increase in future years if no effective early interventions are developed. Converging evidence suggests that the pathophysiologic processes in the brains of AD patients begin decades before symptoms occur. The long preclinical phase of AD provides a valuable window for early intervention with disease-modifying therapy, if we are able to understand the underlying mechanisms of AD by identifying reliable biomarkers. Diffusion MRI (dMRI) probes microstructures of the human brain by measuring water diffusion properties at the cellular level in vivo and non-invasively, which is especially suitable for preclinical screening and monitoring disease progression for AD. Microstructural features with links to specific biologic targets, e.g., axons, glia, or extracellular substrates may provide direct insight into the pathophysiologic changes underlying neurodegenerative disorders. In theory, diffusion MRI provides significant advances for objectively detecting and characterizing the mechanisms of brain changes in AD. Current approaches using diffusion tensor imaging (DTI), however, have not achieved this potential. A very recent advance in the use of dMRI to image the human brain is the development of a method to reflect axonal density and volume fraction of glial cells (cellularity) among other microstructural features. These biologic specific diffusion metrics can be obtained by parametric analysis of the diffusion data via diffusion compartment modeling. We will use the hybrid diffusion imaging (HYDI) developed by the PI to acquire diffusion data with at least five diffusion-weighting b-value shells to sensitize diffusion compartments (e.g., axons, glia, and extracellular substrates) with different diffusivities. A novel feature of HYDI is its versatility for various diffusion model analyses and computational approaches. In the proposed research, we will use two diffusion modeling approaches: (1) neurite orientation dispersion and density imaging (NODDI) to extract the diffusion metric for axonal density, and (2) diffusion basis spectrum imaging (DBSI) to extract the cellularity of glial cells reflecting inflammatory processes. The goals of the proposed research are to determine the sensitivity (Aim 1), discrimination (Aim 2), and predictive power (Aim 3) of the diffusion metrics of axonal density and inflammation-associated cellularity cross-sectionally (Aims 1 and 2) and longitudinally (Aim 3) in a cohort of healthy control and preclinical (at-risk) older adults, and patients with early mild cognitive impairment (MCI), late MCI, and AD. The success of the proposed research will lead to the development of non-invasive differential diagnostic tools and reveal the micromechanisms of the pathophysiologic changes that occur in the early stages of AD.


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: 2025 ( Subtotal = $0 )
2025	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	5	10/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	5	5/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	5	4/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $389,248 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	5	6/17/2020	NON-COMPETING CONTINUATION	$389,248
														Subtotal = $389,248

Issue Date FY: 2019 ( Subtotal = $468,263 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	4	7/12/2019	NON-COMPETING CONTINUATION	$468,263
														Subtotal = $468,263

Issue Date FY: 2018 ( Subtotal = $469,838 )
2018	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	3	5/7/2018	NON-COMPETING CONTINUATION	$469,838
														Subtotal = $469,838

Issue Date FY: 2017 ( Subtotal = $391,310 )
2017	2017	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	2	6/19/2017	NON-COMPETING CONTINUATION	$391,310
														Subtotal = $391,310

Issue Date FY: 2016 ( Subtotal = $319,565 )
2016	2016	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Aging Research	000	1	8/14/2016	NEW	$319,565
														Subtotal = $319,565

Grand Total All Awards = $2,038,224

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Modeling Axonal Density and Inflammation-Associated Cellularity in Alzheimer?s Disease Using Hybrid Diffusion Imaging

Award Number: R01AG053993

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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