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.
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 Type
OBSERVATIONAL
Enrollment
130
Texas Health Presbyterian Hospital
Dallas, Texas, United States
RECRUITINGParkland Health and Hospital System
Dallas, Texas, United States
RECRUITINGUT Southwestern Medical Center
Dallas, Texas, United States
RECRUITINGNIH 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).
Time frame: September 1, 2023 - May 31, 2028
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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?"
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: September 1, 2023 - May 31, 2028
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