Traumatic Brain InjuryNCT06034509
Cognitive and Vascular Functioning Following TBI
An observational study of Traumatic Brain Injury and Cognitive Decline, run by Walter Reed National Military Medical Center at 1 site in United States.
Trial summary
This observational study will examine the association of chronic traumatic cerebrovascular injury and cardiovascular risk factors with TBI-related cognitive impairment and vascular dementia. Cerebrovascular, inflammatory, and neurodegenerative blood biomarkers as well as clinical and neuroimaging data Read more about this study
- Who is it for?
- Ages 18 to 74 years
- Conditions the study is for
- Traumatic Brain Injury, Cognitive Decline, Vascular Dementia
- How many people
- 300 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Nov 2023to May 2027
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 74 years
- All sexes
- Adult, Older adult
Study population: Male and female active duty service members or DEERS-eligible veterans at least 18 years of age who have participated in the NICoE Intensive Outpatient Program or 15 Year Natural History Study will be invited to participate.
Who may be able to join
- Active duty uniformed SM or Veteran who is currently eligible for treatment at WRNMMC (i.e., Defense Enrollment Eligibility Reporting System (DEERS)-eligible).
- Ability to read, write, and speak English.
- Ability to provide informed consent.
- NICoE Intensive Outpatient Program (IOP) or NatHx Study comprehensive evaluation ≥3 years prior to current evaluation with valid neuropsychological test results.
- Consent to allow access to prior research data collected through the NICoE TBI Neuroimaging Core Project or NatHx Study and consent to allow access to at least 1 prior blood specimen previously collected through these studies or the DoD Serum Biorepository.
- Additional TBI Inclusion Criteria
Show all 15Show fewer
- 1. History of at least one mild, moderate, severe, or penetrating TBI > 3 years prior to enrollment. TBI will be diagnosed if any one of the following criteria immediately after the injury is met and attributed to the brain injury, rather than environmental/psychological/other injury factors (DoD-VA criteria246):
- Loss of consciousness (LOC) or post-traumatic amnesia (PTA)
- Alteration of consciousness (AOC)
- Evidence of neurologic dysfunction
- TBI-related abnormality on structural neuroimaging (either CT or MRI). Additional Healthy Control Criteria
- History of military deployment.
- Low history of blast exposure (i.e., <10 blasts) Additional Blast Control Criteria
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- History of significant blast exposure (i.e., exposure to ≥ 10 blasts)
Who cannot join
- Disabling neurologic or psychological disorders such as autism, cerebral palsy, developmental disorder, stroke, brain tumor, multiple sclerosis, meningitis, encephalitis, brain abscess, vascular malformation, pre-injury epilepsy, schizophrenia, bipolar disorder, personality disorder
- Diabetes mellitus requiring drug treatment
- Hypertension requiring more than 1 antihypertensive drug to control BP
- History of myocardial infarction or other systemic vasculopathies
- Dementia diagnosis at initial NICoE/NatHx Study assessment
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Walter Reed National Military Medical Center
Bethesda, Maryland, 20889
Sara Lippa, PhD
About this study
This observational study will examine the association of chronic traumatic cerebrovascular injury and cardiovascular risk factors with TBI-related cognitive impairment and vascular dementia. Cerebrovascular, inflammatory, and neurodegenerative blood biomarkers as well as clinical and neuroimaging data
Read the detailed description
The investigators will enroll 300 Service Members (SMs) and Veterans who participated in the National Intrepid Center of Excellence (NICoE) intensive outpatient program or Defense and Veterans Brain Injury Center/Traumatic Brain Injury Center of Excellence (DVBIC/TBICoE) 15-Year TBI Natural History of TBI Study (NatHx) at least three years prior to the present evaluation and provided prior blood specimens stored for analysis. Following informed consent, participants will undergo semi-structured interviews assessing posttraumatic stress disorder (PTSD) and updated lifetime TBI history, neurological examination, neuropsychological testing, structural Magnetic Resonance Imaging (MRI) T1, T2, fluid attenuated inversion recovery (FLAIR), diffuse tensor imaging (DTI), as well as novel imaging techniques to assess imaging biomarkers of traumatic cerebrovascular injury (TCVI): 1) functional MRI (fMRI)-Blood Oxygen Level Dependent (BOLD) with hypercapnia challenge to measure cerebrovascular reactivity (CVR); and 2) Dynamic Contrast Enhanced-MRI to assess blood brain barrier integrity, and an additional research blood draw [apolipoprotein E (APOE) genotype; plasma biomarkers including vascular (e.g., vascular endothelial growth factor, von Willebrand Factor, cholesterol, homocysteine), inflammatory (e.g., high sensitivity c-reactive protein, interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40)), and neuronal degeneration (e.g., neurofilament light, phosphorylated tau, brain-derived neurotrophic factor, beta amyloid proteins)]. A medical record review will be conducted specifically for current and past history of cerebrovascular risk factors (e.g., hypertension, diabetes, tobacco use) and psychological conditions (e.g., PTSD, depression). The project will also leverage previously collected data, comparing participants' symptoms, cognitive performance, imaging, and, blood biomarkers to those previously collected through the NICoE, 15-Year study and/or the DOD serum repository, with data from at least two time points on all individuals.
- Conditions
- Traumatic Brain Injury, Cognitive Decline, Vascular Dementia
- Being tested
- No intervention. This is an observational study.
- Keywords
- Traumatic Brain Injury, Cognitive Decline, Vascular Dementia, Blood Biomarkers, Cerebrovascular Reactivity, Military
- Medical subject headings
- Brain Injuries, Traumatic, Cognitive Dysfunction, Dementia, Vascular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
No intervention. This is an observational study.Other
There are no interventions being tested in the Cognitive and Vascular Functioning Following TBI study.
| Study group | Role | What they receive |
|---|---|---|
| TBI Group | Participants in this group will have been identified as sustaining a traumatic brain injury (mild, moderate, severe, or penetrating). Receives: Other: No intervention. This is an observational study. | |
| High-blast exposed control group | Participants in this group will have no history of traumatic brain injury AND will have a lifetime history of greater than 10 blast exposures. Receives: Other: No intervention. This is an observational study. | |
| Low-blast exposed control group | Participants in this group will have no history of traumatic brain injury AND will have a lifetime history of less than 10 blast exposures. Receives: Other: No intervention. This is an observational study. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Panel of blood biomarkers
A panel of blood biomarkers including vascular (e.g., vascular endothelial growth factor, von Willebrand Factor, cholesterol, lipoproteins, homocysteine, fibrinogen, hemoglobin A1C), inflammatory (e.g., high sensitivity c-reactive protein, Tumor Necrosis Factor-alpha, IL-6, IL-12p70, YKL-40), and neuronal degeneration (e.g., neurofilament light, Glial Fibrillary Acidic Protein, phosphorylated tau, Clusterin, brain-derived neurotrophic factor, beta amyloid proteins) will be compared between TBI groups. One-way ANOVAs will be run with TBI severity as the independent variable and each individual blood biomarker (measured in pg/mL) as the dependent variable. Spearman's rank order correlations will evaluate the relationship between blood biomarkers, number of TBIs, and TBI severity.
Measured: 3 years
Cognitive Performance- Overall Test Battery Mean
Neurocognitive data will be corrected for age, gender, education, and race, as available. An overall test battery mean (OTBM) T-score will be calculated as the average of seven cognitive domain T-scores (attention/processing speed, working memory, executive functioning, learning/immediate memory, delayed memory, language, perceptual reasoning). Each biomarker will be correlated with the OTBM using Spearman's rank order correlations. Cognitive domain T-scores will also be evaluated to understand which are driving changes in the OTBM. All scores will be evaluated as T-scores (mean=50, SD=10, min=0, max=100), for which higher scores indicate higher cognitive performance. Multivariable logistic regression will be used to evaluate the relationship between TBI number, TBI severity, blood biomarkers and normal cognition vs. mild cognitive impairment (MCI).
Measured: 3 years
Secondary outcomes (6)
Change in panel of blood biomarkers over time
Linear mixed effect (LME) models will be fit to the analysis dataset which use the panel of blood biomarkers as the response variables and investigate TBI severity, number of TBI events, and time. The panel of blood biomarkers will include vascular (e.g., vascular endothelial growth factor, von Willebrand Factor, cholesterol, lipoproteins, homocysteine, fibrinogen, hemoglobin A1C), inflammatory (e.g., high sensitivity c-reactive protein, Tumor Necrosis Factor-alpha, IL-6, IL-12p70, YKL-40), and neuronal degeneration (e.g., neurofilament light, Glial Fibrillary Acidic Protein, phosphorylated tau, Clusterin, brain-derived neurotrophic factor, beta amyloid proteins) biomarkers, all measured in pg/mL.
Measured: 3 years
Change in overall test battery mean over time
The investigators will fit a cross-sectional multivariable regression model to the data with the response variable being the change (Time 3 - Time 2) in the OTBM T-score (mean=50, SD=10, min=0, max=100). Individual cognitive domain composite T-scores will also be evaluated to understand the main components driving change in the OTBM.
Measured: 3 years
Change in brain volume over time
The investigators will fit a cross-sectional multivariable regression model to the data with the response variable being the change (Time 3 - Time 2) in total brain volume [milliliters (mL)].
Measured: 3 years
Change in white matter lesions over time
The investigators will fit a cross-sectional multivariable regression model to the data with the response variable being the change (Time 3 - Time 2) in total and total number of white matter lesions.
Measured: 3 years
Cerebrovascular Reactivity
Linear regression models will be run with the difference score in each vascular blood biomarker from the initial visit to the current study visit as the independent variable and global CVR (%S/mmHG) - (assessed during the current visit only) as the dependent variable.
Measured: 3 years
DCE-MRI
Linear regression models will be run with the difference score in each vascular blood biomarker from the initial visit to the current study visit as the independent variable and overall blood brain barrier function (assessed during the current visit only as the percentage of brain volume with suprathreshold voxels) as the dependent variable.
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Sep 2023
- Study start27 Nov 2023
- Primary completionJan 2027 (estimated)
- Study completionMay 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Traumatic Brain InjuryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Other
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Walter Reed National Military Medical Center
- Sponsor type
- US federal agency
- Collaborators
- Johns Hopkins University
- Responsible party
- Sponsor
- Investigators
- Sara M Lippa, PhD, Principal investigator, Walter Reed National Military Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06034509
- Sponsor's protocol ID
- WRNMMC-2022-0409
- Other IDs
- W81XWH-22-2
- Status last verified
- Jul 2025
- First submitted
- 17 Apr 2023
- Last updated
- 26 Sep 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Non-identified IPD will be made available through the Federal Interagency TBI Research (FITBIR) Database.
Study at a glance
From the registry record, last updated by the sponsor on 26 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cognitive and Vascular Functioning Following TBI
- ClinicalTrials.gov ID
- NCT06034509
- Acronym / sponsor ID
- WRNMMC-2022-0409
- Conditions
- Traumatic Brain Injury, Cognitive Decline, Vascular Dementia
- Keywords
- Traumatic Brain Injury, Cognitive Decline, Vascular Dementia, Blood Biomarkers, Cerebrovascular Reactivity, Military
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 300 participants (estimated)
- Lead sponsor
- Walter Reed National Military Medical CenterUS federal agency
- Collaborators
- Johns Hopkins University
- Study start
- 27 Nov 2023 (actual)
- Primary completion
- Jan 2027 (estimated)
- Study completion
- May 2027 (estimated)
- First posted
- 13 Sep 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This observational study will examine the association of chronic traumatic cerebrovascular injury and cardiovascular risk factors with TBI-related cognitive impairment and vascular dementia. Cerebrovascular, inflammatory, and neurodegenerative blood biomarkers as well as clinical and neuroimaging data
Detailed description
The investigators will enroll 300 Service Members (SMs) and Veterans who participated in the National Intrepid Center of Excellence (NICoE) intensive outpatient program or Defense and Veterans Brain Injury Center/Traumatic Brain Injury Center of Excellence (DVBIC/TBICoE) 15-Year TBI Natural History of TBI Study (NatHx) at least three years prior to the present evaluation and provided prior blood specimens stored for analysis. Following informed consent, participants will undergo semi-structured interviews assessing posttraumatic stress disorder (PTSD) and updated lifetime TBI history, neurological examination, neuropsychological testing, structural Magnetic Resonance Imaging (MRI) T1, T2, fluid attenuated inversion recovery (FLAIR), diffuse tensor imaging (DTI), as well as novel imaging techniques to assess imaging biomarkers of traumatic cerebrovascular injury (TCVI): 1) functional MRI (fMRI)-Blood Oxygen Level Dependent (BOLD) with hypercapnia challenge to measure cerebrovascular reactivity (CVR); and 2) Dynamic Contrast Enhanced-MRI to assess blood brain barrier integrity, and an additional research blood draw [apolipoprotein E (APOE) genotype; plasma biomarkers including vascular (e.g., vascular endothelial growth factor, von Willebrand Factor, cholesterol, homocysteine), inflammatory (e.g., high sensitivity c-reactive protein, interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40)), and neuronal degeneration (e.g., neurofilament light, phosphorylated tau, brain-derived neurotrophic factor, beta amyloid proteins)]. A medical record review will be conducted specifically for current and past history of cerebrovascular risk factors (e.g., hypertension, diabetes, tobacco use) and psychological conditions (e.g., PTSD, depression). The project will also leverage previously collected data, comparing participants' symptoms, cognitive performance, imaging, and, blood biomarkers to those previously collected through the NICoE, 15-Year study and/or the DOD serum repository, with data from at least two time points on all individuals.
Study design
- Observational model
- Case-control
- Time perspective
- Other
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| TBI Group | – | Other: No intervention. This is an observational study.Participants in this group will have been identified as sustaining a traumatic brain injury (mild, moderate, severe, or penetrating). |
| High-blast exposed control group | – | Other: No intervention. This is an observational study.Participants in this group will have no history of traumatic brain injury AND will have a lifetime history of greater than 10 blast exposures. |
| Low-blast exposed control group | – | Other: No intervention. This is an observational study.Participants in this group will have no history of traumatic brain injury AND will have a lifetime history of less than 10 blast exposures. |
Who may qualify
- Ages
- 18 to 74 years
- Sex
- All
- Age groups
- Adult, Older adult
- Study population
- Male and female active duty service members or DEERS-eligible veterans at least 18 years of age who have participated in the NICoE Intensive Outpatient Program or 15 Year Natural History Study will be invited to participate.
Key inclusion criteria (15 listed)
- Active duty uniformed SM or Veteran who is currently eligible for treatment at WRNMMC (i.e., Defense Enrollment Eligibility Reporting System (DEERS)-eligible).
- Ability to read, write, and speak English.
- Ability to provide informed consent.
- NICoE Intensive Outpatient Program (IOP) or NatHx Study comprehensive evaluation ≥3 years prior to current evaluation with valid neuropsychological test results.
- Consent to allow access to prior research data collected through the NICoE TBI Neuroimaging Core Project or NatHx Study and consent to allow access to at least 1 prior blood specimen previously collected through these studies or the DoD Serum Biorepository.
Key exclusion criteria (5 listed)
- Disabling neurologic or psychological disorders such as autism, cerebral palsy, developmental disorder, stroke, brain tumor, multiple sclerosis, meningitis, encephalitis, brain abscess, vascular malformation, pre-injury epilepsy, schizophrenia, bipolar disorder, personality disorder
- Diabetes mellitus requiring drug treatment
- Hypertension requiring more than 1 antihypertensive drug to control BP
- History of myocardial infarction or other systemic vasculopathies
- Dementia diagnosis at initial NICoE/NatHx Study assessment
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| No intervention. This is an observational study.There are no interventions being tested in the Cognitive and Vascular Functioning Following TBI study. | Other | High-blast exposed control group, Low-blast exposed control group, TBI Group |
Primary outcome
Panel of blood biomarkers
Time frame: 3 years
A panel of blood biomarkers including vascular (e.g., vascular endothelial growth factor, von Willebrand Factor, cholesterol, lipoproteins, homocysteine, fibrinogen, hemoglobin A1C), inflammatory (e.g., high sensitivity c-reactive protein, Tumor Necrosis Factor-alpha, IL-6, IL-12p70, YKL-40), and neuronal degeneration (e.g., neurofilament light, Glial Fibrillary Acidic Protein, phosphorylated tau, Clusterin, brain-derived neurotrophic factor, beta amyloid proteins) will be compared between TBI groups. One-way ANOVAs will be run with TBI severity as the independent variable and each individual blood biomarker (measured in pg/mL) as the dependent variable. Spearman's rank order correlations will evaluate the relationship between blood biomarkers, number of TBIs, and TBI severity.
Cognitive Performance- Overall Test Battery Mean
Time frame: 3 years
Neurocognitive data will be corrected for age, gender, education, and race, as available. An overall test battery mean (OTBM) T-score will be calculated as the average of seven cognitive domain T-scores (attention/processing speed, working memory, executive functioning, learning/immediate memory, delayed memory, language, perceptual reasoning). Each biomarker will be correlated with the OTBM using Spearman's rank order correlations. Cognitive domain T-scores will also be evaluated to understand which are driving changes in the OTBM. All scores will be evaluated as T-scores (mean=50, SD=10, min=0, max=100), for which higher scores indicate higher cognitive performance. Multivariable logistic regression will be used to evaluate the relationship between TBI number, TBI severity, blood biomarkers and normal cognition vs. mild cognitive impairment (MCI).
6 secondary outcomes
Change in panel of blood biomarkers over time
Time frame: 3 years
Change in overall test battery mean over time
Time frame: 3 years
Change in brain volume over time
Time frame: 3 years
Change in white matter lesions over time
Time frame: 3 years
Cerebrovascular Reactivity
Time frame: 3 years
DCE-MRI
Time frame: 3 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Sep 2025.
- Individual participant dataSharing planned: Yes. Non-identified IPD will be made available through the Federal Interagency TBI Research (FITBIR) Database.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Sara M Lippa, PhD principal investigator
Walter Reed National Military Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Traumatic Brain Injury and Cognitive Decline, run by Walter Reed National Military Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 26 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Sara M Lippa, PhD (301-319-3671, sara.m.lippa.civ@health.mil), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Panel of blood biomarkers (time frame: 3 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Sep 2025; AzTrials last refreshed its copy on 30 Oct 2026.