Traumatic Brain Injury With Loss of ConsciousnessCAPCOG-TBINCT06480838
Cerebral Autoregulation, Brain Perfusion, and Neurocognitive Outcomes After Traumatic Brain Injury
An observational study of Traumatic Brain Injury With Loss of Consciousness and Brain Injury Traumatic Severe, run by University of Texas Southwestern Medical Center at 3 sites in United States.
Trial summary
Cognitive impairment after moderate to severe traumatic brain injury (msTBI) not only significantly affects the quality of life in individuals with msTBI, but also increases the possibility of late-life dementia. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Traumatic Brain Injury With Loss of Consciousness, Brain Injury Traumatic Severe, Brain Injury Traumatic Moderate
- How many people
- 130 participants
- Where
- 3 sitesUnited States
- Study dates
- 1 Sep 2023to 31 May 2029
- 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 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with either moderate to severe traumatic brain injury within one week of injury, or plain orthopedic trauma within one week of injury.
Who may be able to join
- Documented/Verified TBI (ACRM Criteria) (eg, motor vehicle (MV) occupant, MV pedestrian/cyclist, fall, other non-intentional, violence/assault)
- A documented moderate to severe TBI defined as: Glasgow Coma Scale (GCS) < 13, or loss of consciousness (LOC) > 30 minutes, or posttraumatic amnesia (PTA) > 24 hours or intracranial neuroimaging abnormalities
- Between the age 18 - 80 year-old
- ≤ 1 week postinjury
- Acute brain CT for clinical care
- Admitted to the hospital for TBI
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- Visual acuity/hearing adequate for testing
- Fluent in English or Spanish
- Patient or LAR ability to provide informed consent
Who cannot join
- Age greater or less than the range 18-80 years
- Significant polytrauma that would interfere with follow-up and outcome assessment
- Major debilitating baseline mental health disorders (e.g., schizophrenia, bipolar disorder, severe depression with active suicidal thoughts at the time of evaluation) that would interfere with follow-up and the validity of outcome assessment.
- Major debilitating neurological disease (e.g., stroke, CVA, dementia, tumor) impairing baseline awareness, cognition, or validity of follow-up and outcome assessment.
- Significant history of pre-existing conditions that would interfere with follow-up and outcome assessment (e.g., active substance abuse, alcoholism, HIV/AIDs, end-stage cancers, learning disabilities, developmental disorders)
- Patients on psychiatric hold
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- Prisoners or patients in custody
- Pregnancy in female subjects
- Low likelihood of follow-up (e.g., participants or family indicating low interest, residence in another state or country, homeless or lack of reliable contacts)
- Current participant in an interventional trial (e.g., drug, device, behavioral)
- Penetrating TBI
- Spinal cord injury with ASIA score of C or worse
- Contraindications to MRI
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States3 sites, 3 recruiting
- Recruiting
Texas Health Presbyterian Hospital
Dallas, Texas, 75231
Philip Edmundson, MD, philipedmundson@texashealth.org
Jill Morales, BA, jill.morales@utsouthwestern.edu
- Recruiting
Parkland Health and Hospital System
Dallas, Texas, 75235
Alex Valadka, MD, alex.valadka@utsouthwestern.edu
Alex Valadka
- Recruiting
UT Southwestern Medical Center
Dallas, Texas, 75390
Kan Ding, MD, kan.ding@utsouthwestern.edu
Jill Morales, BA, jill.morales@utsouthwestern.edu
About this study
Cognitive impairment after moderate to severe traumatic brain injury (msTBI) not only significantly affects the quality of life in individuals with msTBI, but also increases the possibility of late-life dementia. The goal of this study is to determine whether acute (< 1 week) cerebrovascular injury and its recovery within the first year postinjury measured by cerebral autoregulation and brain perfusion are associated with cognitive outcome at 12 months after msTBI. The results from this study will improve our understanding of cerebrovascular contributions to cognitive decline related to TBI and provide critical data to inform the development of strategies based on vascular mechanisms to improve cognition and prevent neurodegeneration after msTBI.
Read the detailed description
Nonfatal traumatic brain injury (TBI) is a leading cause of disability in adults, with an estimated economic cost of approximately $40.6 billion for the US population. The quality of life of TBI survivors is highly dependent on the extent of cognitive recovery after injury. Of note, about 65% of moderate to severe traumatic brain injury (msTBI) survivors continue to experience cognitive symptoms including impaired memory, slow processing speed, and poor attention span years after injury, with broad individual variability. Epidemiological studies also suggest that TBI is a risk factor for Alzheimer's Disease (AD) and AD-related dementias (ADRD). Further understanding of the pathophysiological mechanisms by which TBI contributes to progressive cognitive decline/dementia is a prominent research priority for the NIH.
Although TBI and ADRD have different etiologies, mounting evidence indicates that cerebrovascular dysfunction occurs in both TBI and ADRD. Impaired cerebral autoregulation (CA) and brain hypoperfusion are well documented after acute TBI which are associated with unfavorable functional outcomes at 6 months. Our recent studies and others using multimodal hemodynamic and imaging approaches have shown that impaired CA and brain hypoperfusion also occur in chronic TBI years after injury and are associated with poor cognitive performance. The 2019 ADRD Summit called for further studies to understand the vascular contributions to progressive cognitive impairment/dementia after TBI and develop non-invasive diagnostic approaches. The following important questions remain to be addressed: 1) What is the impact of cerebrovascular dysfunction after acute TBI on short- and long-term cognitive outcomes? 2) What is the temporal relationship between the recovery of cerebrovascular function and cognitive outcome after TBI? and 3) Is there a relationship between changes in cerebrovascular function and post-TBI neurodegeneration as assessed through changes in brain volume and axonal integrity?
The overarching goal of this proposal is to determine whether acute, subacute, and chronic cerebrovascular dysfunction measured by CA and brain perfusion after msTBI are associated with cognitive outcomes and neurodegeneration after 12 months. We hypothesize that the degree of cerebrovascular dysfunction assessed during the acute stage (<1 week postinjury) and its poor recovery during the first year are associated with poor cognitive outcomes, brain volume loss, and axonal damage at 12 months postinjury. We propose a longitudinal study with 100 adults who sustained a single msTBI19 and 30 controls with orthopedic trauma only. The primary cognitive outcome is the NIH Toolbox Cognitive Battery (NIH_TB) fluid composite score at 12 months postinjury. Secondary clinical outcomes include the Glasgow Outcome Score-Extended (GOSE) and Traumatic Brain Injury Quality of Life (TBI-QOL). Brain volume loss and axonal integrity will be assessed using MRI. Our team has complementary expertise and research experience in TBI clinical care, cognitive outcomes after TBI, aging/dementia, cerebrovascular physiology, and neuroimaging to successfully conduct this project.
Aim 1: To determine the associations of cerebrovascular dysfunction assessed during the acute stage of msTBI (< 1 week postinjury) with cognitive outcome at 1 year. We will measure dynamic CA and brain perfusion using non-invasive multimodality approaches, including 2D duplex ultrasonography for cerebral blood flow (CBF), transcranial Doppler (TCD) for CBF velocity (CBFV), near-infrared spectroscopy (NIRS) for regional brain tissue oxygenation, and finger arterial photoplethysmography for beat-to-beat arterial blood pressure (ABP). CA will be quantified by dynamic changes in ABP and CBFV and brain tissue oxygenation. We hypothesize that the degree of cerebrovascular dysfunction during the acute stage of brain injury is inversely associated with 1) cognitive performance and 2) the GOSE and TBI-QOL score at 1 year postinjury.
Aim 2: To determine the temporal associations between the recovery of cerebrovascular function and cognitive outcomes after msTBI. Dynamic CA and brain perfusion will be measured at 3, 6 and 12 months postinjury. We hypothesize that the extent of cerebrovascular function recovery after TBI is associated temporally with 1) cognitive outcomes and 2) the GOSE and TBI-QOL score at 1 year postinjury.
Aim 3: To determine the temporal associations of acute cerebrovascular dysfunction and its recovery with the imaging biomarkers of neurodegeneration after msTBI. We will perform state-of-the-art MRI studies of brain structure and function at 3 months and 12 months postinjury. Brain imaging biomarkers will include whole and regional brain volumes and white matter axonal integrity. We hypothesize that the severity of acute cerebrovascular dysfunction and its poor recovery are associated with brain volume loss and axonal damage, and the associations between cerebrovascular dysfunction and cognitive outcome after TBI are mediated by the brain structural changes.
The findings from this study will improve our understanding of cerebrovascular contributions to cognitive and functional outcomes after TBI. This study will also provide the urgently needed knowledge of potential pharmacological and non-pharmacological therapies targeting cerebrovascular function to improve cognition and slow neurodegeneration after TBI.
- Conditions
- Traumatic Brain Injury With Loss of Consciousness, Brain Injury Traumatic Severe, Brain Injury Traumatic Moderate, TBI (Traumatic Brain Injury), TBI
- Medical subject headings
- Brain Injuries, Traumatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| msTBI | Subjects with moderate to severe TBI within the first week after initial injury | |
| Orthopedic control | Orthopedic trauma controls within the first week after initial injury |
What is being measured
The primary outcome is the main question the study is designed to answer.
NIH Toolbox Cognitive Battery
NIH Toolbox is a set of brief, comprehensive assessment tools. This study protocol will use the Cognitive battery of the Toolbox consisting of 7 subtests designed to measure executive function and attention (Flanker and Dimensional Change Card Sort), episodic memory (Picture Sequence Memory Test), working memory (List Sorting Working Memory Test), processing speed (Pattern Comparison Processing Speed and Flanker), and language (Picture Vocabulary Test). Assessments will be administered on an iPad (5th generation).
Measured: September 1, 2023 - May 31, 2028
Secondary outcomes (10)
Hopkins Verbal Learning Test-Revised (HVLT-R)
A word-list learning and episodic memory test. Each form consists of a list of 12 nouns (targets) with four words drawn from each of three semantic categories.
Measured: September 1, 2023 - May 31, 2028
Trail Making Test A &B (TMT A & B)
The TMT is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled consecutive numbers distributed on a page. Part A tests visual scanning, numeric sequencing, and visuomotor speed. Part B is similar except the person must alternate between ascending numbers and letters. Part B tests cognitive demands
including visuomotor, visual scanning, and mental flexibility. Both sections are timed and the score represents the amount of time required to complete the task.
Measured: September 1, 2023 - May 31, 2028
Wechsler Adult Intelligence Scale (WAIS) IV Processing Speed Index (Coding and Symbol Search subtests)
The Processing Speed Index consists of two subtests: Symbol Search and Coding.
Measured: September 1, 2023 - May 31, 2028
Revised-Glasgow Outcome Scale-Extended (R-GOSE)
The Revised Glasgow Outcome Scale Extended (R-GOSE) is a measure of disability and handicap intended for use following head injury. It was developed specifically to meet the aims of the TRACK-TBI study and is based on the GOSE structured interview (Wilson et al. 1998). Unlike the GOSE, which does not distinguish between disability related to the brain injury and disability related to peripheral injuries sustained in the same incident, the R-GOSE assesses the impact of both non-CNS injuries (i.e. peripheral injuries) and the brain injury separately. As a result, two scores are obtained: an 'All' rating which reflects the participant's change in level of dependence as a function of peripheral and brain injuries combined, and a 'TBI' rating that removes the impact of the peripheral injuries leaving a disability rating that reflects only the TBI.
Measured: September 1, 2023 - May 31, 2028
Expanded Disability Rating Scale Post-Acute Interview (E-DRS-PI)
The E-DRS-PI measures the degree of disability experienced by an individual with a history of TBI using a structured interview. The answers to the interview questions are designed to guide the ratings of the items represented on the E-DRS-PI. The higher the total score, the greater the degree of disability. The interview is comprised of a series of multiple-choice questions that pertain to neurologic function, self-care and vocational activities. Depending on the answers to earlier questions relevant to a particular item, later questions are skipped. The total score will be added on the paper form. This form and the total will be uploaded into the database.
Measured: September 1, 2023 - May 31, 2028
Pittsburgh Sleep Quality Index (PSQI)
The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. Nineteen individual items generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yields one global score.
Measured: September 1, 2023 - May 31, 2028
NINDS Epilepsy Screening Questionnaire
NINDS-ESQ was first used and validated in the TRACK-TBI cohort as an Epilepsy screening tool. The questionnaire consisted of screening items in which the participant has to answer if they had experienced (or were told they experienced) any of the following: item 1a, "Uncontrolled movements of part or all of your body such as twitching, jerking, shaking, or going limp, lasting about 5 minutes or less?"; item 1b, "An unexplained change in mental state or level of awareness; or an episode of "spacing out" which you could not control, lasting about 5 minutes or less?"; and item 1c, "Any other type of repeated unusual attacks or convulsions lasting about 5 minutes or less?" In addition, the patient was asked item 1d, "Has anyone ever told you that you have seizure(s) or epilepsy?"
Measured: September 1, 2023 - May 31, 2028
Rivermead Post-concussion Questionnaire (RPQ)
The Rivermead PCS Questionnaire (RPQ) was originally developed as a measure of severity of symptoms following MTBI. It consists of 16 post-concussion symptoms including headaches, dizziness, nausea/vomiting, noise sensitivity, sleep disturbance, fatigue, irritability, feeling depressed/tearful, feeling frustrated/ impatient, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision and restlessness. In the original version of the RPQ, participants are asked to rate the degree (on a scale of 0 to 4) to which a particular symptom has been absent or a mild, moderate or severe problem over the previous 24 hours compared with premorbid levels. Note that the five-point rating scale asks the respondent to compare his/her current symptoms (if any) to symptoms experienced prior to the current injury. Thus, a score of 0 (i.e., "not experienced) means the symptom was not previously experienced and is currently not a problem.
Measured: September 1, 2023 - May 31, 2028
Participant Health Questionnaire (PHQ)-9
The Participant Health Questionnaire 9 is a standardized assessment instrument designed to screen, diagnose, monitor, and measure the severity of depression.
Measured: September 1, 2023 - May 31, 2028
Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia Suicide Severity Rating Scale is a standardized assessment instrument designed to assess the presence and severity of suicidal ideation and behavior, identify those at risk and track response to treatment. Four constructs are measured. The first is the severity of ideation (hereafter referred to as the "severity subscale"), which is rated on a 5-point ordinal scale. The second is the intensity of ideation subscale (hereafter referred to as the "intensity subscale"), which comprises 5 items, each rated on a 5-point ordinal scale. The third is the behavior subscale, which is rated on a nominal scale that includes actual, aborted, and interrupted attempts; preparatory behavior; and non-suicidal self-injurious behavior. And the fourth is the lethality subscale, which assesses actual attempts.
Measured: September 1, 2023 - May 31, 2028
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jun 2024
- Study start1 Sep 2023
- Primary completion31 Mar 2028 (estimated)
- Study completion31 May 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for Traumatic Brain Injury With Loss of ConsciousnessStudies of the same condition, open and under way.
- More trials run by University of Texas Southwestern Medical CenterThe sponsor's other registered studies.
- 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
- Prospective
- Enrolment
- 130 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Texas Southwestern Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Albert Einstein College of Medicine, Texas Health Resources, Institute for Exercise and Environmental Medicine, National Institute of Neurological Disorders and Stroke (NINDS)
- Responsible party
- Principal investigator, Kan Ding, University of Texas Southwestern Medical Center
- Investigators
- Kan Ding, MD, Principal investigator, University of Texas Southwestern Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06480838
- Sponsor's protocol ID
- STU-2023-0254
- Other IDs
- 1R01NS129934-01A1
- Acronym
- CAPCOG-TBI
- Status last verified
- Jun 2026
- First submitted
- 24 Jun 2024
- Last updated
- 2 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: IPD will be upload to FITBIR. The protocols including statistic analysis plan will be published. CSR will be shared through FITBIR.
Publications
Miller GF, DePadilla L, Xu L. Costs of Nonfatal Traumatic Brain Injury in the United States, 2016. Med Care. 2021 May 1;59(5):451-455. doi: 10.1097/MLR.0000000000001511.
PubMed 33528230Wilson L, Stewart W, Dams-O'Connor K, Diaz-Arrastia R, Horton L, Menon DK, Polinder S. The chronic and evolving neurological consequences of traumatic brain injury. Lancet Neurol. 2017 Oct;16(10):813-825. doi: 10.1016/S1474-4422(17)30279-X. Epub 2017 Sep 12.
PubMed 28920887Dikmen SS, Corrigan JD, Levin HS, Machamer J, Stiers W, Weisskopf MG. Cognitive outcome following traumatic brain injury. J Head Trauma Rehabil. 2009 Nov-Dec;24(6):430-8. doi: 10.1097/HTR.0b013e3181c133e9.
PubMed 19940676Ponsford JL, Olver JH, Curran C. A profile of outcome: 2 years after traumatic brain injury. Brain Inj. 1995 Jan;9(1):1-10. doi: 10.3109/02699059509004565.
PubMed 7874089Julie Schneider SJ, Jordan T. Gladman, Roderick A. Corriveau. ADRD Summit 2019 Report to the National Advisory Neurological Disorders and Stroke Council. 2019;
Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbaek G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet. 2017 Dec 16;390(10113):2673-2734. doi: 10.1016/S0140-6736(17)31363-6. Epub 2017 Jul 20. No abstract available.
PubMed 28735855Nordstrom P, Michaelsson K, Gustafson Y, Nordstrom A. Traumatic brain injury and young onset dementia: a nationwide cohort study. Ann Neurol. 2014 Mar;75(3):374-81. doi: 10.1002/ana.24101.
PubMed 24812697Gardner RC, Burke JF, Nettiksimmons J, Kaup A, Barnes DE, Yaffe K. Dementia risk after traumatic brain injury vs nonbrain trauma: the role of age and severity. JAMA Neurol. 2014 Dec;71(12):1490-7. doi: 10.1001/jamaneurol.2014.2668.
PubMed 25347255Ramos-Cejudo J, Wisniewski T, Marmar C, Zetterberg H, Blennow K, de Leon MJ, Fossati S. Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link. EBioMedicine. 2018 Feb;28:21-30. doi: 10.1016/j.ebiom.2018.01.021. Epub 2018 Jan 31.
PubMed 29396300Preiksaitis A, Krakauskaite S, Petkus V, Rocka S, Chomskis R, Dagi TF, Ragauskas A. Association of Severe Traumatic Brain Injury Patient Outcomes With Duration of Cerebrovascular Autoregulation Impairment Events. Neurosurgery. 2016 Jul;79(1):75-82. doi: 10.1227/NEU.0000000000001192.
PubMed 26695090Vavilala MS, Muangman S, Tontisirin N, Fisk D, Roscigno C, Mitchell P, Kirkness C, Zimmerman JJ, Chesnut R, Lam AM. Impaired cerebral autoregulation and 6-month outcome in children with severe traumatic brain injury: preliminary findings. Dev Neurosci. 2006;28(4-5):348-53. doi: 10.1159/000094161.
PubMed 16943658Sviri GE, Aaslid R, Douville CM, Moore A, Newell DW. Time course for autoregulation recovery following severe traumatic brain injury. J Neurosurg. 2009 Oct;111(4):695-700. doi: 10.3171/2008.10.17686.
PubMed 19392589Thomas BP, Tarumi T, Wang C, Zhu DC, Tomoto T, Munro Cullum C, Dieppa M, Diaz-Arrastia R, Bell K, Madden C, Zhang R, Ding K. Hippocampal and rostral anterior cingulate blood flow is associated with affective symptoms in chronic traumatic brain injury. Brain Res. 2021 Nov 15;1771:147631. doi: 10.1016/j.brainres.2021.147631. Epub 2021 Aug 28.
PubMed 34464600Amyot F, Kenney K, Spessert E, Moore C, Haber M, Silverman E, Gandjbakhche A, Diaz-Arrastia R. Assessment of cerebrovascular dysfunction after traumatic brain injury with fMRI and fNIRS. Neuroimage Clin. 2020;25:102086. doi: 10.1016/j.nicl.2019.102086. Epub 2019 Nov 11.
PubMed 31790877Bonne O, Gilboa A, Louzoun Y, Kempf-Sherf O, Katz M, Fishman Y, Ben-Nahum Z, Krausz Y, Bocher M, Lester H, Chisin R, Lerer B. Cerebral blood flow in chronic symptomatic mild traumatic brain injury. Psychiatry Res. 2003 Nov 30;124(3):141-52. doi: 10.1016/s0925-4927(03)00109-4.
PubMed 14623066
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cerebral Autoregulation, Brain Perfusion, and Neurocognitive Outcomes After Traumatic Brain Injury
- ClinicalTrials.gov ID
- NCT06480838
- Acronym / sponsor ID
- CAPCOG-TBI / STU-2023-0254
- Conditions
- Traumatic Brain Injury With Loss of Consciousness, Brain Injury Traumatic Severe, Brain Injury Traumatic Moderate, TBI (Traumatic Brain Injury), TBI
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 130 participants (estimated)
- Lead sponsor
- University of Texas Southwestern Medical CenterUniversity, hospital or other
- Collaborators
- Albert Einstein College of Medicine, Texas Health Resources, Institute for Exercise and Environmental Medicine, National Institute of Neurological Disorders and Stroke (NINDS)
- Study start
- 1 Sep 2023 (actual)
- Primary completion
- 31 Mar 2028 (estimated)
- Study completion
- 31 May 2029 (estimated)
- First posted
- 28 Jun 2024 (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.
Cognitive impairment after moderate to severe traumatic brain injury (msTBI) not only significantly affects the quality of life in individuals with msTBI, but also increases the possibility of late-life dementia. The goal of this study is to determine whether acute (< 1 week) cerebrovascular injury and its recovery within the first year postinjury measured by cerebral autoregulation and brain perfusion are associated with cognitive outcome at 12 months after msTBI. The results from this study will improve our understanding of cerebrovascular contributions to cognitive decline related to TBI and provide critical data to inform the development of strategies based on vascular mechanisms to improve cognition and prevent neurodegeneration after msTBI.
Detailed description
Nonfatal traumatic brain injury (TBI) is a leading cause of disability in adults, with an estimated economic cost of approximately $40.6 billion for the US population. The quality of life of TBI survivors is highly dependent on the extent of cognitive recovery after injury. Of note, about 65% of moderate to severe traumatic brain injury (msTBI) survivors continue to experience cognitive symptoms including impaired memory, slow processing speed, and poor attention span years after injury, with broad individual variability. Epidemiological studies also suggest that TBI is a risk factor for Alzheimer's Disease (AD) and AD-related dementias (ADRD). Further understanding of the pathophysiological mechanisms by which TBI contributes to progressive cognitive decline/dementia is a prominent research priority for the NIH.
Although TBI and ADRD have different etiologies, mounting evidence indicates that cerebrovascular dysfunction occurs in both TBI and ADRD. Impaired cerebral autoregulation (CA) and brain hypoperfusion are well documented after acute TBI which are associated with unfavorable functional outcomes at 6 months. Our recent studies and others using multimodal hemodynamic and imaging approaches have shown that impaired CA and brain hypoperfusion also occur in chronic TBI years after injury and are associated with poor cognitive performance. The 2019 ADRD Summit called for further studies to understand the vascular contributions to progressive cognitive impairment/dementia after TBI and develop non-invasive diagnostic approaches. The following important questions remain to be addressed: 1) What is the impact of cerebrovascular dysfunction after acute TBI on short- and long-term cognitive outcomes? 2) What is the temporal relationship between the recovery of cerebrovascular function and cognitive outcome after TBI? and 3) Is there a relationship between changes in cerebrovascular function and post-TBI neurodegeneration as assessed through changes in brain volume and axonal integrity?
The overarching goal of this proposal is to determine whether acute, subacute, and chronic cerebrovascular dysfunction measured by CA and brain perfusion after msTBI are associated with cognitive outcomes and neurodegeneration after 12 months. We hypothesize that the degree of cerebrovascular dysfunction assessed during the acute stage (<1 week postinjury) and its poor recovery during the first year are associated with poor cognitive outcomes, brain volume loss, and axonal damage at 12 months postinjury. We propose a longitudinal study with 100 adults who sustained a single msTBI19 and 30 controls with orthopedic trauma only. The primary cognitive outcome is the NIH Toolbox Cognitive Battery (NIH_TB) fluid composite score at 12 months postinjury. Secondary clinical outcomes include the Glasgow Outcome Score-Extended (GOSE) and Traumatic Brain Injury Quality of Life (TBI-QOL). Brain volume loss and axonal integrity will be assessed using MRI. Our team has complementary expertise and research experience in TBI clinical care, cognitive outcomes after TBI, aging/dementia, cerebrovascular physiology, and neuroimaging to successfully conduct this project.
Aim 1: To determine the associations of cerebrovascular dysfunction assessed during the acute stage of msTBI (< 1 week postinjury) with cognitive outcome at 1 year. We will measure dynamic CA and brain perfusion using non-invasive multimodality approaches, including 2D duplex ultrasonography for cerebral blood flow (CBF), transcranial Doppler (TCD) for CBF velocity (CBFV), near-infrared spectroscopy (NIRS) for regional brain tissue oxygenation, and finger arterial photoplethysmography for beat-to-beat arterial blood pressure (ABP). CA will be quantified by dynamic changes in ABP and CBFV and brain tissue oxygenation. We hypothesize that the degree of cerebrovascular dysfunction during the acute stage of brain injury is inversely associated with 1) cognitive performance and 2) the GOSE and TBI-QOL score at 1 year postinjury.
Aim 2: To determine the temporal associations between the recovery of cerebrovascular function and cognitive outcomes after msTBI. Dynamic CA and brain perfusion will be measured at 3, 6 and 12 months postinjury. We hypothesize that the extent of cerebrovascular function recovery after TBI is associated temporally with 1) cognitive outcomes and 2) the GOSE and TBI-QOL score at 1 year postinjury.
Aim 3: To determine the temporal associations of acute cerebrovascular dysfunction and its recovery with the imaging biomarkers of neurodegeneration after msTBI. We will perform state-of-the-art MRI studies of brain structure and function at 3 months and 12 months postinjury. Brain imaging biomarkers will include whole and regional brain volumes and white matter axonal integrity. We hypothesize that the severity of acute cerebrovascular dysfunction and its poor recovery are associated with brain volume loss and axonal damage, and the associations between cerebrovascular dysfunction and cognitive outcome after TBI are mediated by the brain structural changes.
The findings from this study will improve our understanding of cerebrovascular contributions to cognitive and functional outcomes after TBI. This study will also provide the urgently needed knowledge of potential pharmacological and non-pharmacological therapies targeting cerebrovascular function to improve cognition and slow neurodegeneration after TBI.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| msTBI | – | –Subjects with moderate to severe TBI within the first week after initial injury |
| Orthopedic control | – | –Orthopedic trauma controls within the first week after initial injury |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with either moderate to severe traumatic brain injury within one week of injury, or plain orthopedic trauma within one week of injury.
Key inclusion criteria (9 listed)
- Documented/Verified TBI (ACRM Criteria) (eg, motor vehicle (MV) occupant, MV pedestrian/cyclist, fall, other non-intentional, violence/assault)
- A documented moderate to severe TBI defined as: Glasgow Coma Scale (GCS) < 13, or loss of consciousness (LOC) > 30 minutes, or posttraumatic amnesia (PTA) > 24 hours or intracranial neuroimaging abnormalities
- Between the age 18 - 80 year-old
- ≤ 1 week postinjury
- Acute brain CT for clinical care
Key exclusion criteria (13 listed)
- Age greater or less than the range 18-80 years
- Significant polytrauma that would interfere with follow-up and outcome assessment
- Major debilitating baseline mental health disorders (e.g., schizophrenia, bipolar disorder, severe depression with active suicidal thoughts at the time of evaluation) that would interfere with follow-up and the validity of outcome assessment.
- Major debilitating neurological disease (e.g., stroke, CVA, dementia, tumor) impairing baseline awareness, cognition, or validity of follow-up and outcome assessment.
- Significant history of pre-existing conditions that would interfere with follow-up and outcome assessment (e.g., active substance abuse, alcoholism, HIV/AIDs, end-stage cancers, learning disabilities, developmental disorders)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
NIH Toolbox Cognitive Battery
Time frame: September 1, 2023 - May 31, 2028
NIH Toolbox is a set of brief, comprehensive assessment tools. This study protocol will use the Cognitive battery of the Toolbox consisting of 7 subtests designed to measure executive function and attention (Flanker and Dimensional Change Card Sort), episodic memory (Picture Sequence Memory Test), working memory (List Sorting Working Memory Test), processing speed (Pattern Comparison Processing Speed and Flanker), and language (Picture Vocabulary Test). Assessments will be administered on an iPad (5th generation).
10 secondary outcomes
Hopkins Verbal Learning Test-Revised (HVLT-R)
Time frame: September 1, 2023 - May 31, 2028
Trail Making Test A &B (TMT A & B)
Time frame: September 1, 2023 - May 31, 2028
Wechsler Adult Intelligence Scale (WAIS) IV Processing Speed Index (Coding and Symbol Search subtests)
Time frame: September 1, 2023 - May 31, 2028
Revised-Glasgow Outcome Scale-Extended (R-GOSE)
Time frame: September 1, 2023 - May 31, 2028
Expanded Disability Rating Scale Post-Acute Interview (E-DRS-PI)
Time frame: September 1, 2023 - May 31, 2028
Pittsburgh Sleep Quality Index (PSQI)
Time frame: September 1, 2023 - May 31, 2028
NINDS Epilepsy Screening Questionnaire
Time frame: September 1, 2023 - May 31, 2028
Rivermead Post-concussion Questionnaire (RPQ)
Time frame: September 1, 2023 - May 31, 2028
Participant Health Questionnaire (PHQ)-9
Time frame: September 1, 2023 - May 31, 2028
Columbia Suicide Severity Rating Scale (C-SSRS)
Time frame: September 1, 2023 - May 31, 2028
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 2 Jul 2026.
- Background: PubMed 33528230Miller GF, DePadilla L, Xu L. Costs of Nonfatal Traumatic Brain Injury in the United States, 2016. Med Care. 2021 May 1;59(5):451-455. doi: 10.1097/MLR.0000000000001511.
- Background: PubMed 28920887Wilson L, Stewart W, Dams-O'Connor K, Diaz-Arrastia R, Horton L, Menon DK, Polinder S. The chronic and evolving neurological consequences of traumatic brain injury. Lancet Neurol. 2017 Oct;16(10):813-825. doi: 10.1016/S1474-4422(17)30279-X. Epub 2017 Sep 12.
- Background: PubMed 19940676Dikmen SS, Corrigan JD, Levin HS, Machamer J, Stiers W, Weisskopf MG. Cognitive outcome following traumatic brain injury. J Head Trauma Rehabil. 2009 Nov-Dec;24(6):430-8. doi: 10.1097/HTR.0b013e3181c133e9.
- Background: PubMed 7874089Ponsford JL, Olver JH, Curran C. A profile of outcome: 2 years after traumatic brain injury. Brain Inj. 1995 Jan;9(1):1-10. doi: 10.3109/02699059509004565.
- BackgroundJulie Schneider SJ, Jordan T. Gladman, Roderick A. Corriveau. ADRD Summit 2019 Report to the National Advisory Neurological Disorders and Stroke Council. 2019;
- Background: PubMed 28735855Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbaek G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet. 2017 Dec 16;390(10113):2673-2734. doi: 10.1016/S0140-6736(17)31363-6. Epub 2017 Jul 20. No abstract available.
- Background: PubMed 24812697Nordstrom P, Michaelsson K, Gustafson Y, Nordstrom A. Traumatic brain injury and young onset dementia: a nationwide cohort study. Ann Neurol. 2014 Mar;75(3):374-81. doi: 10.1002/ana.24101.
- Background: PubMed 25347255Gardner RC, Burke JF, Nettiksimmons J, Kaup A, Barnes DE, Yaffe K. Dementia risk after traumatic brain injury vs nonbrain trauma: the role of age and severity. JAMA Neurol. 2014 Dec;71(12):1490-7. doi: 10.1001/jamaneurol.2014.2668.
- Background: PubMed 29396300Ramos-Cejudo J, Wisniewski T, Marmar C, Zetterberg H, Blennow K, de Leon MJ, Fossati S. Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link. EBioMedicine. 2018 Feb;28:21-30. doi: 10.1016/j.ebiom.2018.01.021. Epub 2018 Jan 31.
- Background: PubMed 26695090Preiksaitis A, Krakauskaite S, Petkus V, Rocka S, Chomskis R, Dagi TF, Ragauskas A. Association of Severe Traumatic Brain Injury Patient Outcomes With Duration of Cerebrovascular Autoregulation Impairment Events. Neurosurgery. 2016 Jul;79(1):75-82. doi: 10.1227/NEU.0000000000001192.
- Background: PubMed 16943658Vavilala MS, Muangman S, Tontisirin N, Fisk D, Roscigno C, Mitchell P, Kirkness C, Zimmerman JJ, Chesnut R, Lam AM. Impaired cerebral autoregulation and 6-month outcome in children with severe traumatic brain injury: preliminary findings. Dev Neurosci. 2006;28(4-5):348-53. doi: 10.1159/000094161.
- Background: PubMed 19392589Sviri GE, Aaslid R, Douville CM, Moore A, Newell DW. Time course for autoregulation recovery following severe traumatic brain injury. J Neurosurg. 2009 Oct;111(4):695-700. doi: 10.3171/2008.10.17686.
- Individual participant dataSharing planned: Yes. IPD will be upload to FITBIR. The protocols including statistic analysis plan will be published. CSR will be shared through FITBIR.
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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.
Kan Ding, MD principal investigator
University of Texas Southwestern Medical Center
3 sites 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 With Loss of Consciousness and Brain Injury Traumatic Severe, run by University of Texas Southwestern Medical Center at 3 sites 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 9 inclusion and 13 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 2 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites 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 Kan Ding, MD (214-648-3571, kan.ding@utsouthwestern.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
NIH Toolbox Cognitive Battery (time frame: September 1, 2023 - May 31, 2028). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06480838, which also lists 26 linked publications.
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 2 Jul 2026.