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Understanding dynamics of brain network in TDP-43 related neurodegeneration

Award Number: R21AG085492
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Understanding dynamics of brain network in TDP-43 related neurodegeneration - Mislocalization of TDP-43 is a common pathological feature of several neurodegenerative diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Many studies support the loss-of-function mechanism caused by TDP-43 nuclear clearance as a major pathogenesis pathway toward neurodegeneration. It is of great importance to understand the dynamics of disease progression in TDP-43 knockout mouse models. Functional microcircuits are at the heart of the information processing capability of the brain. Calcium imaging is a powerful tool to study functional microcircuits. Calcium imaging can generate high-dimensional longitudinal datasets, which are collected at multiple time points over a temporal process (each observation time point is a wave). Longitudinal analysis models the evolving temporal process. However, existing analysis methods are primarily designed to process cross-sectional data, which provides a static view of the brain network. As a result, existing methods have limited capability to model complex dynamic network patterns for high- dimensional data. Lack of advanced longitudinal analysis methods is a bottleneck for using calcium imaging to study the dynamics of brain networks in TDP-43 knockout mouse models. This project seeks to develop a Bayesian computational system to model longitudinal functional microcircuits and use it to examine microcircuit changes in a TDP-43 knockout mouse model. The developed system is referred to as Bayesian Longitudinal Microcircuit Analysis (BLMA). The Specific Aims are: Aim 1. Develop a computational system for longitudinal microcircuit modeling. The proposed system, BLMA, will include these components: preprocessing, microcircuit construction, feature extraction, and Bayesian multivariate mixed modeling. Aim 2. Understand microcircuit changes in a TDP-43 knockout mouse model. We will apply BLMA to an existing longitudinal calcium imaging dataset of pyramidal neurons of the prefrontal cortex (PFC) from awake behaving Tdp-43F/F mice. We will compare the control and knockout groups to determine whether the knockout group exhibits abnormal PFC microcircuit trajectories. This project will develop BLMA to advance the state-of-the-art in data analysis and modeling for longitudinal calcium imaging. It leverages Bayesian machine learning to address critical challenges in longitudinal calcium imaging data analysis: shared information across waves and high dimensionality. This project is innovative because it will develop a novel Bayesian system to model microcircuit changes based on calcium imaging data and delineate a unique brain network mechanism leading to TDP-43 related neurodegeneration. At the completion of this project, we will have delineated a unique brain network mechanism in TDP-43 related neurodegeneration.


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 = $200,093 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	000	2	6/4/2025	NON-COMPETING CONTINUATION	$200,093
														Subtotal = $200,093

Issue Date FY: 2024 ( Subtotal = $238,968 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Aging Research	000	1	9/9/2024	NEW	$238,968
														Subtotal = $238,968

Grand Total All Awards = $439,061

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Understanding dynamics of brain network in TDP-43 related neurodegeneration

Award Number: R21AG085492

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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