Cerebral Autoregulation, Brain Perfusion, and Neurocognitive Outcomes After Traumatic Brain Injury

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.

Eligibility Criteria:
Inclusion Criteria:

* 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
* Visual acuity/hearing adequate for testing
* Fluent in English or Spanish
* Patient or LAR ability to provide informed consent

Exclusion Criteria:

* 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
* 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