Sildenafil for Microvasculopathy in Chronic TBI

Inclusion Criteria To be eligible to participate in this study, an individual must meet all of the following criteria: 1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged 18-70 4. Defense Enrollment Eligibility Reporting System (DEERS) eligible (WRNMMC only; N/A for UPenn) 5. History of TBI greater than 6 months and less than 25 years prior to enrollment, based on the 2023 American Congress of Rehabilitation Medicine Criteria92; 1. Plausible Mechanism of Injury: Criterion 1 focuses on the external force that likely disrupted brain function, including blast/explosion forces and acknowledging intentional causes. 2. Clinical Signs: Criterion 2 highlights signs observed or elicited during examination, distinguishing them from subjective symptoms. 3. Acute Symptoms: Criterion 3 considers subjective acute symptoms, requiring at least two symptoms to be present. 4. Clinical Examination/Laboratory Findings: Criterion 4 is a new addition, incorporating findings like cognitive impairment or oculomotor impairment. 5. Neuroimaging: While not required for diagnosis, neuroimaging can be used to provide further evidence of brain injury. 6. Chronic persistent post-concussive symptoms (Symptom Score \> 1 on at least 3 items from the Rivermead Post-Concussion Symptom Questionnaire; RPQ) 7. Glasgow Outcome Scale-Extended (GOSE) between 5-7 8. Ability to take oral medication and be willing to adhere to the study intervention regimen 9. Ability to participate in and complete 1 MRI including 2 CVR challenges and 4-week treatment period. 10. Adequate hearing and vision based on self-report and examiner's observation Exclusion Criteria An individual who meets any of the following criteria will be excluded from participation in this study: 1. Contraindication to sildenafil which includes the following: 1. Current/ongoing (within past month) use of organic nitrate vasodilators or riociguat 2. Current/ongoing (within past month) use of ritonavir (HIV-protease inhibitor) 3. Current/ongoing (within past month) use of erythromycin, ketoconazole, or itraconazole 4. Current/ongoing (within past month) use of cimetidine 5. Current resting hypotension (BP \< 90/50 mm Hg) 6. Current severe renal insufficiency 7. Current hepatic cirrhosis 8. Current cardiac failure or coronary artery disease causing unstable angina 9. Retinitis pigmentosa 10. Known hypersensitivity or allergy to sildenafil of any of its components 11. History of melanoma or suspicious skin lesions for melanoma on skin examination 2. Daily therapy with a PDE5 inhibitor within the month prior to consent 3. History of penetrating TBI 4. History of disabling neurological or psychiatric disorder not related to TBI 5. Active substance abuse or dependence during the past 6 months 6. Estimated preinjury intellectual level ≤70 (based on educational and vocational history) 7. Inability to understand written and spoken English, in the opinion of the investigator 8. Current inclusion in another interventional trial 9. Subjects with metal implants that would interfere with the MR imaging procedures 10. History of priapism 11. Pregnant or breast-feeding women 12. Actively suicidal (based on clinician assessment OR if patient endorses item 9 on Patient Health Questionnaire 9 (PHQ-9) and endorses suicidal ideation on Columbia Suicide Severity Rating Scale(CSSRS) 13. Hypertension requiring treatment with more than two antihypertensive drugs 14. Hyperlipidemia requiring treatment with more than one lipid lowering drug 15. Diabetes mellitus requiring medical treatment with insulin