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Defining the Role of Post-TBI Sleep Disruption in the Development of CTE and Alzheimer's Disease-Related Neuropathology

Award Number: R01NS128966
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Defining the Role of Post-TBI Sleep Disruption in the Development of CTE and Alzheimer's Disease-Related Neuropathology - ABSTRACT Mild traumatic brain injury (mTBI, concussion) has emerged as a risk factor for the development of neurodegenerative disorders such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy, which are characterized by the aberrant aggregation of tau within neural cells. However, the mechanisms linking mTBI to AD-related pathology later in life remain unknown. Disruption of the sleep-wake cycle (SWD) is a frequent chronic complaint after mTBI and also accompanies the development of AD. More recent clinical and translational research suggests that SWD may actually promote the development of Alzheimer’s-related pathology. Our preliminary data show that sleep disturbance is significantly associated with lower CSF Aβ42 levels (an AD-associated profile) in Veterans with mTBI >45 years of age. Based on these findings, we propose that post-TBI sleep disruption promotes the development of AD-related pathology following mTBI. This will be directly tested in Aim 1. The glymphatic system is a recently characterized brain-wide network of perivascular spaces that supports the clearance of both Aβ and tau. Glymphatic function is greatest during sleep and is impaired by TBI. Our published and preliminary data show that MRI-visible perivascular space burden (MV-PVS), a putative marker of glymphatic impairment, is increased among Veterans with blast mTBI and that these changes are associated with AD-related CSF biomarker profiles. In Aim 2, we will use novel MRI-based approaches to test whether glymphatic impairment predicts the development of AD-related pathology after blast mTBI. Sleep-wake behavior is regulated through central noradrenergic (NA) neurotransmission, with locus coeruleus (LC)-derived norepinephrine (NE) promoting arousal during waking. In our blast mTBI Veterans, CSF NE was elevated compared to controls and associated with poor sleep. However, the role that changes in central NA signaling play in promoting AD-related pathology following TBI is unknown. In Aim 3 we will test whether changes in measures of central NA tone predict the development of AD-related pathology after blast mTBI. Dr. Peskind’s 10-year longitudinal VA cohort will contribute 70 previously- and newly-enrolled Veterans >45 years of age with a history of repetitive blast mTBIs who will undergo assessment of: subjective and objective sleep; multi-domain clinical behavioral, neurological, and neurocognitive assessment; glymphatic function measured by MRI, and measurement of CSF/plasma AD/CTE-related biomarkers and NE. Aim 1. Define the role of sleep disruption in the development of post-TBI AD-related pathology. Aim 2. Define the role of glymphatic dysfunction in the development of post-TBI AD-related pathology. Aim 3. Define the role of alterations in central NA tone in the development of post-TBI AD-related pathology after TBI.


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 = $1,253,356 )
2025	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/20/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,253,356
														Subtotal = $1,253,356

Grand Total All Awards = $1,253,356

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Defining the Role of Post-TBI Sleep Disruption in the Development of CTE and Alzheimer's Disease-Related Neuropathology

Award Number: R01NS128966

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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