From Chronic Traumatic Encephalopathy Biomarkers to Therapeutics: What We Need to Know to Design Clinical Trials

The failure of multiple clinical trials in traumatic brain injury (TBI) has forced a rethinking of clinical research in this area. Several National Institutes of Health and Department of Defense consensus conferences concluded that precision medicine tools must be developed to (1) identify injury mechanisms active in individual patients, so they can be selected for targeted therapies, and (2) allow individualized tuning of the dose, timing, and duration of therapy by monitoring the physiological response to treatment. Although a detailed molecular understanding of chronic traumatic encephalopathy (CTE) is still emerging, it is not too early to start thinking of how the initial clinical trials of CTE will look. This contribution focuses on recent studies of diffuse vascular injury (DVI) as an endophenotype of TBI. Our approach has been to identify biomarkers that can be used as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers of DVI, to rationally design clinical trials targeting this endophenotype. We have adapted neuroimaging methods to measure cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) noninvasively in humans. We find robust deficits in CVR, and to a lesser extent in CBF, during the chronic stage after TBI, often in areas of normal-looking brain parenchyma. We also find that inhibition of phosphodiesterase 5 by administration of sildenafil citrate improves CVR in patients with TBI. These results suggest that CBF and particularly CVR show promise as biomarkers of DVI. Because DVI is prominent in CTE, such strategies may point toward therapeutic interventions to ameliorate progressive neurodegeneration after repetitive TBI.