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Brain Aging Across the Lifespan in Neurodevelopmental Disorders

Award Number: R01MH133068
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/20/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Brain Aging Across the Lifespan in Neurodevelopmental Disorders - ABSTRACT Autism spectrum disorder (ASD) is typically described as a disorder of childhood; however, challenges in socioemotional behavior and cognition persist across the lifespan. Nearly 6 million adults in the United States currently live with ASD, with prevalence more than doubling in the last 10 years. Recent studies suggest that adults with ASD are twice as likely to develop dementia, and have an increased prevalence of age-related physical and psychiatric conditions. While brain and behavioral differences are well researched in children with ASD, a major gap in knowledge exists for the adult brain. The brains of individuals with ASD undergo an atypical developmental trajectory, marked by initial excess in volume, neuron density, and connectivity in childhood that is followed by a progressive reduction in cell number, myelin thickness, and synapses into adulthood. We propose that early neuronal excess and local over-connectivity, in concert with systemic neuroimmune dysregulation, may render the ASD brain vulnerable to age-related pathological and pro- inflammatory processes beginning in early adulthood that may ultimately lead to cellular dysfunction and later cognitive decline. Here we aim to determine the cell types affected as individuals with ASD age through adulthood and identify neuroinflammatory markers specific to those cells. We will utilize a unique sample of clinically and genetically characterized human postmortem adult brains, examining regions implicated in the socioemotional and neurobiological impairments of ASD and aging. We hypothesize that aberrant immune activation of pro-inflammatory processes contribute to the altered trajectory of brain development, as well as deleterious neuropathogenic protein aggregations associated with cognitive decline. We will utilize unbiased transcriptomic methods to determine which genes may be differentially expressed in specific cell groups, and assays to determine which proteins, including cytokines, may be disproportionately affected with age in ASD (Aim 1). Informed by these results, we will carry out a systematic examination of the expression of high-priority markers in specific cell types with preserved spatial information in brain tissue sections (Aim 2). Finally, we will examine the effects of neuroinflammation and aging in ASD on the synaptic connections between neurons (Aim 3). These critical, discovery-driven studies will serve as an essential first step to characterize cellular and molecular processes associated with brain aging in ASD, and provide a fundamental platform upon which mechanistic studies and animal models can be built. This project will define the neuropathological features associated with brain aging in ASD and correlate these variables with extensive clinical and genetic information for each subject, in support of precision medicine. Ultimately, we aim to shift the mindset of autism research toward the view of adulthood not as an endpoint, but as part of a trajectory of brain development across the lifespan, with the goal of promoting healthy aging in the rapidly growing population of adults living with ASD.


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 = $803,128 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	3	1/23/2026	NON-COMPETING CONTINUATION	$803,128
														Subtotal = $803,128

Issue Date FY: 2025 ( Subtotal = $800,542 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	2	11/20/2024	NON-COMPETING CONTINUATION	$680,461
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	001	2	9/18/2025	NON-COMPETING CONTINUATION	$120,081
														Subtotal = $800,542

Issue Date FY: 2024 ( Subtotal = $798,830 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	1	11/20/2023	NEW	$718,947
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	001	1	5/31/2024	NEW	$79,883
														Subtotal = $798,830

Grand Total All Awards = $2,402,500

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Brain Aging Across the Lifespan in Neurodevelopmental Disorders

Award Number: R01MH133068

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/20/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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