Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sport- and military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “cistauosis”, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis p-tau is a major early driver after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.

backgroundHyponatremia has emerged as an important cause of race-related death and life-threatening illness among marathon runners. We studied a cohort of marathon runners to estimate the incidence of hyponatremia and to identify the principal risk factors. methods Participants in the 2002 Boston Marathon were recruited one or two days before the race. Subjects completed a survey describing demographic information and training history. After the race, runners provided a blood sample and completed a questionnaire detailing their fluid consumption and urine output during the race. Prerace and postrace weights were recorded. Multivariate regression analyses were performed to identify risk factors associated with hyponatremia. resultsOf 766 runners enrolled, 488 runners (64 percent) provided a usable blood sample at the finish line. Thirteen percent had hyponatremia (a serum sodium concentration of 135 mmol per liter or less); 0.6 percent had critical hyponatremia (120 mmol per liter or less). On univariate analyses, hyponatremia was associated with substantial weight gain, consumption of more than 3 liters of fluids during the race, consumption of fluids every mile, a racing time of >4:00 hours, female sex, and low body-mass index. On multivariate analysis, hyponatremia was associated with weight gain (odds ratio, 4.2; 95 percent confidence interval, 2.2 to 8.2), a racing time of >4:00 hours (odds ratio for the comparison with a time of <3:30 hours, 7.4; 95 percent confidence interval, 2.9 to 23.1), and body-mass-index extremes.conclusions Hyponatremia occurs in a substantial fraction of nonelite marathon runners and can be severe. Considerable weight gain while running, a long racing time, and bodymass-index extremes were associated with hyponatremia, whereas female sex, composition of fluids ingested, and use of nonsteroidal antiinflammatory drugs were not.

IMPORTANCE Sport-related concussion (SRC) is a significant public health problem without an effective treatment. OBJECTIVE To assess the effectiveness of subsymptom threshold aerobic exercise vs a placebo-like stretching program prescribed to adolescents in the acute phase of recovery from SRC. DESIGN, SETTING, AND PARTICIPANTS This multicenter prospective randomized clinical trial was conducted at university concussion centers. Male and female adolescent athletes (age 13-18 years) presenting within 10 days of SRC were randomly assigned to aerobic exercise or a placebo-like stretching regimen. INTERVENTIONS After systematic determination of treadmill exercise tolerance on the first visit, participants were randomly assigned to a progressive subsymptom threshold aerobic exercise or a progressive placebo-like stretching program (that would not substantially elevate heart rate). Both forms of exercise were performed approximately 20 minutes per day, and participants reported daily symptoms and compliance with exercise prescription via a website. MAIN OUTCOMES AND MEASURES Days from injury to recovery; recovery was defined as being asymptomatic, having recovery confirmed through an assessment by a physician blinded to treatment group, and returning to normal exercise tolerance on treadmill testing. Participants were also classified as having normal (<30 days) or delayed (Ն30 days) recovery. RESULTS A total of 103 participants were included (aerobic exercise: n = 52; 24 female [46%]; stretching, n = 51; 24 female [47%]). Participants in the aerobic exercise group were seen a mean (SD) of 4.9 (2.2) days after the SRC, and those in the stretching group were seen a mean (SD) of 4.8 (2.4) days after the SRC. There were no differences in age, sex, previous concussions, time from injury, initial symptom severity score, or initial exercise treadmill test and physical examination results. Aerobic exercise participants recovered in a median of 13 (interquartile range [IQR], 10-18.5) days, whereas stretching participants recovered in 17 (IQR, 13-23) days (P = .009 by Mann-Whitney test). There was a nonsignificant lower incidence of delayed recovery in the aerobic exercise group (2 participants [4%] in the aerobic group vs 7 [14%] in the placebo group; P = .08). CONCLUSIONS AND RELEVANCE This is, to our knowledge, the first RCT to show that individualized subsymptom threshold aerobic exercise treatment prescribed to adolescents with concussion symptoms during the first week after SRC speeds recovery and may reduce the incidence of delayed recovery.