Defining the role of post-TBI sleep disruption in the development of CTE and alzheimer's disease-related neuropathology

Active Project Grant Awarded Last action

Award ID
R01NS128966
Recipient
Awarding agency
Obligated
$2,506,712

Award facts

Assistance listing
93.866 Aging Research
Completion date 83% complete
Funding agency
National Institute on Aging National Institutes of Health, Department of Health and Human Services
Place of performance
Washington, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $0
Amendment $1,253,356
Original award $1,253,356

Subawards

Subrecipient Amount Awarded
University Of California, San Diego Subrecipient PI will serve as project statistician. This role includes consultation with study leadership on all aspects of study statistical design and… $71,405
University Of Kansas Medical Center Research Institute, Inc. Subrecipient PI will supervise the analysis of neuroimaging data and assist in the interpretation of these data. Specifically, they will oversee the analysis of… $82,415
University Of Washington The UW site will be responsible for all non-invasive MRI imaging to study glymphatic function in this proposal. This includes performing ASL, IVIM, and fast… $89,458
Oregon Health & Science University OHSU’s role will be to configure and maintain the sleep assessment tools, and curate, analyze, and interpret these complex and multi-faceted sleep measures as… $246,763
University Of Washington The UW site will be responsible for all non-invasive MRI imaging to study glymphatic function in this proposal. This includes performing ASL, IVIM, and fast… $139,939
University Of California, San Diego Subrecipient PI will serve as project statistician. This role includes consultation with study leadership on all aspects of study statistical design and… $71,405
University Of Kansas Medical Center Research Institute, Inc. Subrecipient PI will supervise the analysis of neuroimaging data and assist in the interpretation of these data. Specifically, they will oversee the analysis of… $82,415
Oregon Health & Science University OHSU’s role will be to configure and maintain the sleep assessment tools, and curate, analyze, and interpret these complex and multi-faceted sleep measures as… $246,763

Quick answers

Who received award R01NS128966?

R01NS128966 was awarded to Seattle Institute For Biomedical And Clinical Research by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on September 20, 2022.

How much is award R01NS128966 worth?

$2,506,712 has been obligated on R01NS128966.

Which agency awarded R01NS128966?

National Institute of Neurological Disorders and Stroke (National Institutes of Health) awarded R01NS128966, with funding from National Institute on Aging (National Institutes of Health).

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