Cerebrovascular Reactivity and Oxygen Metabolism as Markers of Neurodegeneration After Traumatic Brain Injury

Study Overview
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Brief Summary
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This grant award entitled, Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury (hereafter, Neurovascular Study), aims to determine if neurovascular contributors to neurodegeneration can serve as markers of the emergence or progression of degenerative processes after traumatic brain injury in middle-aged and older adults.

Detailed Description
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This grant award entitled, Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury (hereafter, Neurovascular Study), aims to determine if neurovascular contributors to neurodegeneration can serve as markers of the emergence or progression of degenerative processes after traumatic brain injury in middle-aged and older adults. Primary outcomes are cerebrovascular reactivity (CVR), as measured by functional Magnetic Resonance Imaging (MRI) Blood Oxygen Level Dependent (BOLD) and cerebral metabolic rate of oxygen (CMRO2) as assessed by the novel MRI sequence called, T-2 Relaxation-Under-Spin-Tagging (TRUST). After the baseline primary endpoints are acquired, a single dose of sildenafil 50mg will be given to assess for the effects of a hypercapnia task on CVR and CMRO2. Other outcomes measured include additional imaging sequences (diffusion, ASL), volumetric analysis, and neuropsychological tests.

Official Title
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Cerebrovascular Reactivity and Oxygen Metabolism as Markers of Neurodegeneration After Traumatic Brain Injury

Conditions
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Neurodegenerative Diseases

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (All Participants): Ages 50-80 years Eligible for Washington, DC Veterans Affairs Medical Center (VAMC) research participation Capacity to provide consent to participate in research (assessment made by study neurologist and PI) Ability to read and write English Inclusion Criteria Case Group: • History of traumatic brain injury of sufficient severity to have resulted in medical attention ascertained via the Ohio State University TBI Identification Questionnaire (OSU TBI-ID). TBI defined by Departments of Defense/Veterans Affairs (DoD/VA) criteria. Inclusion Criteria Control Group: • No history of traumatic brain injury of sufficient severity to have resulted in medical attention ascertained via the OSU TBI-ID, and no TBI based upon DOD/VA criteria. Exclusion Criteria (All Participants): History of penetrating brain injury History or evidence of disabling neurological or psychiatric condition such as epilepsy (besides posttraumatic epilepsy), multiple sclerosis, hypoxic-ischemic encephalopathy, encephalitis, or schizophrenia History or evidence of cortical or subcortical stroke History or evidence of diabetes mellitus requiring therapy (Hemoglobin A1c > 9.0% for purposes of this study) History or evidence of uncontrolled hyperlipidemia. For the purposes of this study, hyperlipidemia will be defined as total cholesterol of 230 in the presence of either or both diabetes and hypertension and 300 in the absence of both of these conditions. Statin therapy with normal cholesterol levels is allowed. History or evidence of uncontrolled hypertension (defined as systolic pressure > 160 and/or diastolic pressure > 110 mmHg), or hypotension (systolic pressure < 110 and/or diastolic pressure < 65 mmHg). Hypertension controlled with a single anti- hypertensive medication is allowed. Untreated atrial fibrillation Active tobacco use MRI incompatibility If a participant is currently or has previously taken a phosphodiesterase inhibitor (PDESi), then a two week washout period is required immediately prior to the evaluation visit. Use of nitrates

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Case Group<br>Measurement of cerebrovascular reactivity and oxygen metabolism before and after a single dose of 50mg sildenafil citrate. Diffusion tensor imaging, other structural imaging and cognitive testing will also be completed. | |
| Control Group<br>Measurement of cerebrovascular reactivity and oxygen metabolism before and after a single dose of 50mg sildenafil citrate. Diffusion tensor imaging, other structural imaging and cognitive testing will also be completed. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebrovascular Reactivity (CVR) | Cerebrovascular reactivity is the change in cerebral blood flow in response to a vasoactive stimulus, in this case hypercapnia induced by 5% carbon dioxide as measured by MRI BOLD | Two years | 
| Cerebral Metabolic Rate of Oxygen (CMRO2) | Cerebral metabolic rate of oxygen represents the amount of oxygen consumed as measured by the MRI T2-Relaxation-Under-Spin-Tagging (TRUST) sequence. | Two years |