Person:

Mannix, Rebekah

Recently, there has been growing interest in the association between traumatic brain injury (TBI) and Alzheimer's Disease (AD). TBI and AD share many pathologic features including chronic inflammation and the accumulation of beta amyloid (A(\beta)). Data from both AD and TBI studies suggest that microglia play a central role in A(\beta) accumulation after TBI. This paper focuses on the current research on the role of microglia response to A(\beta) after TBI.

Background: Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month. Methods: Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction. Results: Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001). Conclusions: Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.

Objectives: The purpose of this study was to evaluate the association of prior concussion on baseline computerized neurocognitive testing in a large cohort of high school athletes. Methods: This is a retrospective cohort study of student athletes from 49 Maine High Schools in 2010 who underwent baseline computerized neurocognitive evaluation with Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT®). As part of the ImPACT®, subjects reported a prior history of concussion as well as demographic information and a symptom questionnaire. We used linear regression to evaluate the association of prior concussion with baseline: (1) ImPACT® composite scores; and (2) symptom scores. Results: Six thousand seventy-five subjects were included in the study, of whom 57% were boys. The majority of student athletes (85.3%) reported no prior history of concussion while 4.6% reported having sustained two or more prior concussions. On simple linear regression, increasing number of concussions was related to worse performance in verbal memory (P = 0.039) and greater symptoms scores (P < 0.001). On multivariate modeling, only the association with baseline symptoms remained (P < 0.001). Other factors associated with baseline symptom reporting in the multivariate model included mental health history, headache/migraine history, gender, developmental and/or learning problems, and number of prior concussions. Interpretation In this large-scale, retrospective survey study, history of multiple prior concussions was associated with higher symptom burden but not baseline computerized neurocognitive testing. The association between baseline symptom reporting and clinical and demographic factors was greater than the association with a history of multiple concussions.

Objectives: To identify patient, provider, and hospital characteristics associated with the use of neuroimaging in the evaluation of head trauma in children. Methods: This was a cross-sectional study of children (≤19 years of age) with head injuries from the National Hospital Ambulatory Medical Care Survey (NHAMCS) collected by the National Center for Health Statistics. NHAMCS collects data on approximately 25,000 visits annually to 600 randomly selected hospital emergency and outpatient departments. This study examined visits to U.S. emergency departments between 2002 and 2006. Multivariable logistic regression was used to analyze characteristics associated with neuroimaging in children with head injuries. Results: There were 50,835 pediatric visits in the 5 year sample, of which 1,256 (2.5%, 95% CI = 2.2% to 2.7%) were for head injury. Among these, 39% (95% CI = 34% to 43%) underwent evaluation with neuroimaging. In multivariable analyses, factors associated with neuroimaging included white race (odds ratio [OR] 1.5, 95% CI = 1.02 to 2.1), older age (OR 1.3, 95% CI = 1.1 to 1.5), presentation to a general hospital (vs. a pediatric hospital, OR 2.4, 95% CI = 1.1 to 5.3), more emergent triage status (OR 1.4, 95% CI = 1.1 to 1.8), admission or transfer (OR 2.7, 95% CI = 1.4 to 5.3), and treatment by an attending physician (OR 2.0, 95% CI = 1.1 to 3.7). The effect of race was mitigated at the pediatric hospitals compared to at the general hospitals (p < 0.001). Conclusions: In this study, patient race, age, and hospital-specific characteristics were associated with the frequency of neuroimaging in the evaluation of children with closed head injuries. Based on these results, focusing quality improvement initiatives on physicians at general hospitals may be an effective approach to decreasing rates of neuroimaging after pediatric head trauma.

Objectives: To identify patient and hospital characteristics associated with the use of computed tomography (CT) imaging of the cervical spine (c-spine) in the evaluation of injured children and, in particular, to examine the influence of hospital setting. Methods: This was a retrospective cohort of children younger than 19 years of age from the Massachusetts Hospital Emergency Department (ED) database who were discharged from the ED with an injury diagnosis from 2005 through 2009. Multivariable logistic regression was used to analyze characteristics associated with CT imaging of the c-spine. Results: Of the 929,626 pediatric patients diagnosed with an injury in Massachusetts EDs and then discharged home, 1.3% underwent CT imaging of the c-spine. Rates of CT imaging nearly doubled over the five years. In the multivariable model, patient age (adjusted odds ratio [AOR] 2.3, 95% confidence interval [CI] = 2.0 to 2.7 for children age 12 to 18 years vs. under 1 year of age), and evaluation outside of a pediatric Level I trauma center (AOR 2.2, 95% CI = 1.1 to 4.3 for children evaluated at non Level I trauma centers vs. pediatric Level I trauma centers; AOR 2.1, 95% CI = 0.93 to 4.7 for children evaluated at adult Level I trauma centers vs. pediatric Level I trauma centers) were associated with higher rates of CT imaging of the c-spine. Conclusions: C-spine CT imaging for children discharged from the ED with trauma diagnoses increased from 2005 through 2009. Older age and evaluation outside a Level I pediatric trauma center were associated with a higher c-spine CT rate. Educational interventions focused outside pediatric trauma centers may be an effective approach to decreasing CT imaging of the c-spine of pediatric trauma patients.

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.

Traumatic brain injury (TBI) is characterized by acute neurological dysfunction and associated with the development of chronic traumatic encephalopathy (CTE) and Alzheimer’s disease. We previously showed that cis phosphorylated tau (cis P-tau), but not the trans form, contributes to tau pathology and functional impairment in an animal model of severe TBI. Here we found that in human samples obtained post TBI due to a variety of causes, cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Using mouse models of severe or repetitive TBI, we showed that cis P-tau elimination with a specific neutralizing antibody administered immediately or at delayed time points after injury, attenuates the development of neuropathology and brain dysfunction during acute and chronic phases including CTE-like pathology and dysfunction after repetitive TBI. Thus, cis P-tau contributes to short-term and long-term sequelae after TBI, but is effectively neutralized by cis antibody treatment.