Editors' ChoiceTraumatic Brain Injury

Go with the flow: Cerebrovascular reactivity as a therapeutic target for TBI symptoms

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Science Translational Medicine  21 Mar 2018:
Vol. 10, Issue 433, eaat1643
DOI: 10.1126/scitranslmed.aat1643

Abstract

Sildenafil improves cerebrovascular reactivity in patients with chronic traumatic brain injury (TBI) and may ameliorate lingering symptoms.

Chronic motor and cognitive disabilities after traumatic brain injury (TBI) are a widespread problem, affecting over 5 million Americans. Current treatments are mostly symptomatic and do not address the underlying processes responsible for the impairments. Kenney et al. map out an approach to TBI-related disabilities that targets a potential biological mechanism underlying those symptoms: abnormal cerebrovascular reactivity (CVR).

Not all TBIs are accompanied by obvious vascular injury, but animal models show that microvascular damage is universal and correlates with symptoms. CVR is a marker of vascular health and can be measured through noninvasive techniques. Moreover, CVR is dynamic, therefore representing a potential therapeutic target. Vasoactive agents like sildenafil, currently used to treat erectile dysfunction and pulmonary hypertension, could conceivably improve abnormal CVR in patients with TBI. This might in turn ameliorate symptoms.

The authors first assessed their ability to measure changes in CVR using magnetic resonance imaging. Comparing blood flow in patients with TBI to healthy controls, they found that regional flow deficits in TBI patients normalized after sildenafil. An 8-week phase 2 study confirmed that sildenafil was safe and well tolerated. Using a series of subjective and objective outcome measures, the authors also explored the effects of sildenafil on TBI patients’ symptoms. Though their study was not powered to fully assess clinical efficacy, the authors found a trend toward improvement in neurobehavioral symptoms.

The ultimate goal of TBI-related research is—directly or indirectly—to improve functional outcome and quality of life for affected individuals. As such, even the modest clinical improvement observed after sildenafil treatment is encouraging (though will require proper validation in larger cohorts). The results showed here also demonstrate the powerful synergy of a mechanism-based pharmacologic strategy, an imaging technique that provides immediate readout of biological effect, and validated outcome measures that can quantify clinical benefit. Even if sildenafil never becomes widely prescribed as a treatment for TBI symptoms, Kenney et al.’s scientific approach provides a template for investigating underlying mechanisms while simultaneously evaluating therapies to target them.

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