The sex hormone progesterone has been shown to improve outcomes in animal models of a number of neurologic diseases, including traumatic brain injury, ischemia, spinal cord injury, peripheral nerve injury, demyelinating disease, neuromuscular disorders, and seizures. Evidence suggests it exerts its neuroprotective effects through several pathways, including reducing edema, improving neuronal survival, and modulating inflammation and apoptosis. In this review, we summarize the functional outcomes and pathophysiologic mechanisms attributed to progesterone treatment in neurologic disease. We then comment on the breadth of evidence for the use of progesterone in each neurologic disease family. Finally, we provide support for further human studies using progesterone to treat several neurologic diseases.

The midbrain is biomechanically susceptible to force loading from repetitive subconcussive head impacts (RSHI), is a site of tauopathy in chronic traumatic encephalopathy (CTE), and regulates functions (e.g., eye movements) often disrupted in concussion. In a prospective longitudinal design, we demonstrate there are reductions in midbrain white matter integrity due to a single season of collegiate football, and that the amount of reduction in midbrain white matter integrity is related to the amount of rotational acceleration to which players’ brains are exposed. We then replicate the observation of reduced midbrain white matter integrity in a retrospective cohort of individuals with frank concussion, and further show that variance in white matter integrity is correlated with levels of serum-based tau, a marker of blood-brain barrier disruption. These findings mean that noninvasive structural MRI of the midbrain is a succinct index of both clinically silent white matter injury as well as frank concussion.

Mild traumatic brain injury (mTBI) remains a diagnostic challenge and therefore strategies for objective assessment of neurological function are key to limiting long-term sequelae. Current assessment methods are not optimal in austere environments such as athletic fields; therefore, we developed an immersive tool, the Display Enhanced Testing for Cognitive Impairment and mTBI (DETECT) platform, for rapid objective neuropsychological (NP) testing. The objectives of this study were to assess the ability of DETECT to accurately identify neurocognitive deficits associated with concussion and evaluate the relationship between neurocognitive measures and subconcussive head impacts. DETECT was used over a single season of two high school and two college football teams. Study participants were instrumented with Riddell Head Impact Telemetry (HIT) sensors and a subset tested with DETECT immediately after confirmed impacts for different combinations of linear and rotational acceleration. A total of 123 athletes were enrolled and completed baseline testing. Twenty-one players were pulled from play for suspected concussion and tested with DETECT. DETECT was 86.7% sensitive (95% confidence interval [CI]: 59.5%, 98.3%) and 66.7% specific (95% CI: 22.3%, 95.7%) in correctly identifying athletes with concussions (15 of 21). Weak but significant correlations were found between complex choice response time (processing speed and divided attention) and both linear (Spearman rank correlation coefficient 0.262, p = 0.02) and rotational (Spearman coefficient 0.254, p = 0.03) acceleration on a subset of 76 players (113 DETECT tests) with no concussion symptoms. This study demonstrates that DETECT confers moderate to high sensitivity in identifying acute cognitive impairment and suggests that football impacts that do not result in concussion may negatively affect cognitive performance immediately following an impact. Specificity, however, was not optimal and points to the need for additional studies across multiple neurological domains. Given the need for more objective concussion screening in triage situations, DETECT may provide a solution for mTBI assessment.

Objectives: To examine regional differences in rehabilitation outcomes among adult patients with moderate-to-severe traumatic brain injury (TBI) who received care at an inpatient rehabilitation facility (IRF). Design: We conducted a secondary analysis of a large, multi-center dataset from the Uniform Data System for Medical Rehabilitation. Setting: More than 70% of all IRFs in the United States. Participants: Adult TBI patients (N=175,358) aged 18 years or older who were admitted and discharged from an IRF in the United States between 2004 and 2014. Qualifying etiology included traumatic brain dysfunction Impairment Group codes 02.21 (traumatic, open injury) and 02.22 (traumatic, closed injury). Interventions: Not applicable. Main Outcome Measures: Discharge functional status (total, cognitive, motor), length of stay, and discharge to home. Results: Patient and clinical characteristics varied significantly by geographic location, as did median functional status, length of stay, and percentage of patients discharged home. The region where IRF care was received, race and ethnicity, age, occurrence of 1 or more falls during the IRF stay, case mix group, and insurance status were associated with discharge functional status, length of stay, and discharge to home. Conclusions: Our findings provide evidence of geographic differences in outcomes and potential disparities in care of TBI patients who received IRF care. More research is needed to identify TBI patients at risk for poor discharge outcomes to inform development and testing of interventions to reduce disparities in outcomes for these patients.