References

2016

Calcagnile, O; Anell, A; Unden, J

The addition of S100B to guidelines for management of mild head injury is potentially cost saving Journal Article

In: BMC Neurology, vol. 16, no. 1, pp. 200, 2016.

Abstract | BibTeX | Tags: *Brain Concussion/bl [Blood], *Brain Concussion/ec [Economics], *Cost Savings, *Practice Guidelines as Topic, *S100 Calcium Binding Protein beta Subunit/bl [Blo, 0 (Biomarkers), 0 (S100 Calcium Binding Protein beta Subunit), 80 and over, Adolescent, adult, aged, Biomarkers/bl [Blood], Female, Humans, Male, middle aged, SWEDEN, Young Adult

@article{Calcagnile2016,

title = {The addition of S100B to guidelines for management of mild head injury is potentially cost saving},

author = {Calcagnile, O and Anell, A and Unden, J},

year  = {2016},

date = {2016-01-01},

journal = {BMC Neurology},

volume = {16},

number = {1},

pages = {200},

abstract = {BACKGROUND: Mild traumatic brain injury (TBI) is associated with substantial costs due to over-triage of patients to computed tomography (CT) scanning, despite validated decision rules. Serum biomarker S100B has shown promise for safely omitting CT scans but the economic impact from clinical use has never been reported. In 2007, S100B was adapted into the existing Scandinavian management guidelines in Halmstad, Sweden, in an attempt to reduce CT scans and save costs. METHODS: Consecutive adult patients with mild TBI (GCS 14-15, loss of consciousness and/or amnesia), managed with the aid of S100B, were prospectively included in this study. Patients were followed up after 3 months with a standardized questionnaire. Theoretical and actual cost differences were calculated. RESULTS: Seven hundred twenty-six patients were included and 29 (4.7 %) showed traumatic abnormalities on CT. No further significant intracranial complications were discovered on follow-up. Two hundred twenty-nine patients (27 %) had normal S100B levels and 497 patients (73 %) showed elevated S100B levels. Over-triage occurred in 73 patients (32 %) and under-triage occurred in 39 patients (7 %). No significant intracranial complications were missed. The introduction of S100B could save 71 per patient if guidelines were strictly followed. As compliance to the guidelines was not perfect, the actual cost saving was 39 per patient. CONCLUSION: Adding S100B to existing guidelines for mild TBI seems to reduce CT usage and costs, especially if guideline compliance could be increased.},

keywords = {*Brain Concussion/bl [Blood], *Brain Concussion/ec [Economics], *Cost Savings, *Practice Guidelines as Topic, *S100 Calcium Binding Protein beta Subunit/bl [Blo, 0 (Biomarkers), 0 (S100 Calcium Binding Protein beta Subunit), 80 and over, Adolescent, adult, aged, Biomarkers/bl [Blood], Female, Humans, Male, middle aged, SWEDEN, Young Adult},

pubstate = {published},

tppubtype = {article}

}

Stergiou-Kita, M; Mansfield, E; Sokoloff, S; Colantonio, A

Gender Influences on Return to Work After Mild Traumatic Brain Injury Journal Article

In: Archives of Physical Medicine & Rehabilitation, vol. 97, no. 2 Suppl, pp. S40–5, 2016.

Abstract | BibTeX | Tags: *Brain Injuries/rh [Rehabilitation], *Return to Work/px [Psychology], *Sex Factors, adult, aged, Brain Injuries/px [Psychology], Female, Humans, Male, middle aged, Patient Acceptance of Health Care/px [Psychology], Qualitative Research, Rehabilitation, Social Environment, Vocational/px [Psychology], Workplace/px [Psychology], Young Adult

Puvenna, V; Engeler, M; Banjara, M; Brennan, C; Schreiber, P; Dadas, A; Bahrami, A; Solanki, J; Bandyopadhyay, A; Morris, J K; Bernick, C; Ghosh, C; Rapp, E; Bazarian, J J; Janigro, D

Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy Journal Article

In: Brain Research, vol. 1630, pp. 225–240, 2016.

Abstract | BibTeX | Tags: *Brain Injury, *Brain/me [Metabolism], *Epilepsy/me [Metabolism], *tau Proteins/me [Metabolism], 0 (MAPT protein, 0 (tau Proteins), 80 and over, Adolescent, adult, aged, Brain Injury, Brain/pa [Pathology], Brain/su [Surgery], Child, Chronic/me [Metabolism], Chronic/pa [Pathology], ENZYME-linked immunosorbent assay, Epilepsy/pa [Pathology], Epilepsy/su [Surgery], Female, human), Humans, immunohistochemistry, Infant, Male, middle aged, Phosphorylation, Preschool, Young Adult

@article{Puvenna2016,

title = {Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy},

author = {Puvenna, V and Engeler, M and Banjara, M and Brennan, C and Schreiber, P and Dadas, A and Bahrami, A and Solanki, J and Bandyopadhyay, A and Morris, J K and Bernick, C and Ghosh, C and Rapp, E and Bazarian, J J and Janigro, D},

year  = {2016},

date = {2016-01-01},

journal = {Brain Research},

volume = {1630},

pages = {225--240},

abstract = {Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six postmortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P\<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE. Copyright © 2015 Elsevier B.V. All rights reserved.},

keywords = {*Brain Injury, *Brain/me [Metabolism], *Epilepsy/me [Metabolism], *tau Proteins/me [Metabolism], 0 (MAPT protein, 0 (tau Proteins), 80 and over, Adolescent, adult, aged, Brain Injury, Brain/pa [Pathology], Brain/su [Surgery], Child, Chronic/me [Metabolism], Chronic/pa [Pathology], ENZYME-linked immunosorbent assay, Epilepsy/pa [Pathology], Epilepsy/su [Surgery], Female, human), Humans, immunohistochemistry, Infant, Male, middle aged, Phosphorylation, Preschool, Young Adult},

pubstate = {published},

tppubtype = {article}

}

Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six postmortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE. Copyright © 2015 Elsevier B.V. All rights reserved.

Leung, A; Shukla, S; Fallah, A; Song, D; Lin, L; Golshan, S; Tsai, A; Jak, A; Polston, G; Lee, R

Repetitive Transcranial Magnetic Stimulation in Managing Mild Traumatic Brain Injury-Related Headaches Journal Article

In: Neuromodulation, vol. 19, no. 2, pp. 133–141, 2016.

Abstract | BibTeX | Tags: *Brain Concussion/co [Complications], *Headache/et [Etiology], *Headache/th [Therapy], *Transcranial Magnetic Stimulation/mt [Methods], adult, aged, Female, Humans, Male, middle aged, Neuronavigation, Neuropsychological Tests, treatment outcome

@article{Leung2016,

title = {Repetitive Transcranial Magnetic Stimulation in Managing Mild Traumatic Brain Injury-Related Headaches},

author = {Leung, A and Shukla, S and Fallah, A and Song, D and Lin, L and Golshan, S and Tsai, A and Jak, A and Polston, G and Lee, R},

year  = {2016},

date = {2016-01-01},

journal = {Neuromodulation},

volume = {19},

number = {2},

pages = {133--141},

abstract = {OBJECTIVE: Headache is one of the most common debilitating chronic pain conditions in either active or retired military personnel with mild traumatic brain injury (MTBI). This study assessed the effect of repetitive transcranial magnetic stimulation (rTMS) in alleviating MTBI-related headache (MTBI-HA). MATERIALS AND METHOD: Veterans with MTBI-HA were randomized to receive either real rTMS (REAL group) at 10 hz for a total of 2000 pulses divided into 20 trains with one-sec inter-train interval or sham rTMS (SHAM group) at the left motor cortex (LMC) with brain magnetic resonance imaging neuronavigation guidance. Pretreatment, posttreatment one-week and four-week headache and neuropsychological assessments were conducted. RESULT: Thirty veterans were screened and twenty four (21 men and 3 women with average year-old +/- SD at 14.3 +/- 12.6) subjects' data were analyzed. A two-factor (visit x treatment) repeated measures analysis of variance (RM-ANOVA) indicated a close to significant (p = 0.06) trend of interaction between pretreatment and posttreatment one-week assessment with the intensity of the persistent daily headache decreasing from 5.7 +/- 1.9 to 2.2 +/- 2.7 and 4.6 +/- 1.3 to 3.5 +/- 2.0 for the REAL and SHAM groups, respectively. Subsequent analyses indicated REAL group demonstrated a significantly (p = 0.041) higher % of reduction in persistent headache intensity than the SHAM group (56.3 +/- 48.2% vs.15.4 +/- 43.6%) at the posttreatment one-week assessment and the trend continued to the four-week assessment. Overall, a significantly (p = 0.035) higher percentage of the subjects in the REAL group (58.3%) demonstrated at least a 50% headache intensity reduction at posttreatment one-week assessment compared with the SHAM group (16.6%). The overall composite score of functionally debilitating headache exacerbation is significantly (p = 0.017) reduced in REAL group at the posttreatment four-week assessment in comparison with the SHAM group. No major sustained change in neuropsychological assessments was noted. CONCLUSION: The studied rTMS protocol appears to be a clinically feasible and effective treatment option in managing MTBI-HA.Copyright © 2015 International Neuromodulation Society.},

keywords = {*Brain Concussion/co [Complications], *Headache/et [Etiology], *Headache/th [Therapy], *Transcranial Magnetic Stimulation/mt [Methods], adult, aged, Female, Humans, Male, middle aged, Neuronavigation, Neuropsychological Tests, treatment outcome},

pubstate = {published},

tppubtype = {article}

}

OBJECTIVE: Headache is one of the most common debilitating chronic pain conditions in either active or retired military personnel with mild traumatic brain injury (MTBI). This study assessed the effect of repetitive transcranial magnetic stimulation (rTMS) in alleviating MTBI-related headache (MTBI-HA). MATERIALS AND METHOD: Veterans with MTBI-HA were randomized to receive either real rTMS (REAL group) at 10 hz for a total of 2000 pulses divided into 20 trains with one-sec inter-train interval or sham rTMS (SHAM group) at the left motor cortex (LMC) with brain magnetic resonance imaging neuronavigation guidance. Pretreatment, posttreatment one-week and four-week headache and neuropsychological assessments were conducted. RESULT: Thirty veterans were screened and twenty four (21 men and 3 women with average year-old +/- SD at 14.3 +/- 12.6) subjects' data were analyzed. A two-factor (visit x treatment) repeated measures analysis of variance (RM-ANOVA) indicated a close to significant (p = 0.06) trend of interaction between pretreatment and posttreatment one-week assessment with the intensity of the persistent daily headache decreasing from 5.7 +/- 1.9 to 2.2 +/- 2.7 and 4.6 +/- 1.3 to 3.5 +/- 2.0 for the REAL and SHAM groups, respectively. Subsequent analyses indicated REAL group demonstrated a significantly (p = 0.041) higher % of reduction in persistent headache intensity than the SHAM group (56.3 +/- 48.2% vs.15.4 +/- 43.6%) at the posttreatment one-week assessment and the trend continued to the four-week assessment. Overall, a significantly (p = 0.035) higher percentage of the subjects in the REAL group (58.3%) demonstrated at least a 50% headache intensity reduction at posttreatment one-week assessment compared with the SHAM group (16.6%). The overall composite score of functionally debilitating headache exacerbation is significantly (p = 0.017) reduced in REAL group at the posttreatment four-week assessment in comparison with the SHAM group. No major sustained change in neuropsychological assessments was noted. CONCLUSION: The studied rTMS protocol appears to be a clinically feasible and effective treatment option in managing MTBI-HA.Copyright © 2015 International Neuromodulation Society.

Stern, R A; Tripodis, Y; Baugh, C M; Fritts, N G; Martin, B M; Chaisson, C; Cantu, R C; Joyce, J A; Shah, S; Ikezu, T; Zhang, J; Gercel-Taylor, C; Taylor, D D

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy Journal Article

In: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1099–1109, 2016.

Abstract | BibTeX | Tags: *Chronic Traumatic Encephalopathy/bl [Blood], *Extracellular Vesicles/me [Metabolism], *Plasma/cy [Cytology], *tau Proteins/me [Metabolism], 0 (tau Proteins), adult, aged, ANALYSIS of variance, Case-Control Studies, Humans, Male, middle aged

@article{Stern2016,

title = {Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy},

author = {Stern, R A and Tripodis, Y and Baugh, C M and Fritts, N G and Martin, B M and Chaisson, C and Cantu, R C and Joyce, J A and Shah, S and Ikezu, T and Zhang, J and Gercel-Taylor, C and Taylor, D D},

year  = {2016},

date = {2016-01-01},

journal = {Journal of Alzheimer's Disease},

volume = {51},

number = {4},

pages = {1099--1109},

abstract = {BACKGROUND: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers. OBJECTIVE: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. METHODS: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. RESULTS: The NFL group had higher exosomal tau than the control group (p \< 0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). CONCLUSION: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.},

keywords = {*Chronic Traumatic Encephalopathy/bl [Blood], *Extracellular Vesicles/me [Metabolism], *Plasma/cy [Cytology], *tau Proteins/me [Metabolism], 0 (tau Proteins), adult, aged, ANALYSIS of variance, Case-Control Studies, Humans, Male, middle aged},

pubstate = {published},

tppubtype = {article}

}

Koerte, I K; Hufschmidt, J; Muehlmann, M; Tripodis, Y; Stamm, J M; Pasternak, O; Giwerc, M Y; Coleman, M J; Baugh, C M; Fritts, N G; Heinen, F; Lin, A; Stern, R A; Shenton, M E

Cavum Septi Pellucidi in Symptomatic Former Professional Football Players Journal Article

In: Journal of Neurotrauma, vol. 33, no. 4, pp. 346–353, 2016.

Abstract | BibTeX | Tags: *Athletes, *Football/in [Injuries], *Septum Pellucidum/pa [Pathology], adult, aged, Brain Concussion/di [Diagnosis], Brain Concussion/ep [Epidemiology], Humans, Male, middle aged

@article{Koerte2016,

title = {Cavum Septi Pellucidi in Symptomatic Former Professional Football Players},

author = {Koerte, I K and Hufschmidt, J and Muehlmann, M and Tripodis, Y and Stamm, J M and Pasternak, O and Giwerc, M Y and Coleman, M J and Baugh, C M and Fritts, N G and Heinen, F and Lin, A and Stern, R A and Shenton, M E},

year  = {2016},

date = {2016-01-01},

journal = {Journal of Neurotrauma},

volume = {33},

number = {4},

pages = {346--353},

abstract = {Post-mortem studies reveal a high rate of cavum septi pellucidi (CSP) in chronic traumatic encephalopathy (CTE). It remains, however, to be determined whether or not the presence of CSP may be a potential in vivo imaging marker in populations at high risk to develop CTE. The aim of this study was to evaluate CSP in former professional American football players presenting with cognitive and behavioral symptoms compared with noncontact sports athletes. Seventy-two symptomatic former professional football players (mean age 54.53 years, standard deviation [SD] 7.97) as well as 14 former professional noncontact sports athletes (mean age 57.14 years, SD 7.35) underwent high-resolution structural 3T magnetic resonance imaging. Two raters independently evaluated the CSP, and interrater reliability was calculated. Within National Football League players, an association of CSP measures with cognitive and behavioral functioning was evaluated using a multivariate mixed effects model. The measurements of the two raters were highly correlated (CSP length: rho = 0.98; Intraclass Correlation Coefficient [ICC] 0.99; p \< 0.0001; septum length: rho = 0.93; ICC 0.96; p \< 0.0001). For presence versus absence of CSP, there was high agreement (Cohen kappa = 0.83, p \< 0.0001). A higher rate of CSP, a greater length of CSP, as well as a greater ratio of CSP length to septum length was found in symptomatic former professional football players compared with athlete controls. In addition, a greater length of CSP was associated with decreased performance on a list learning task (Neuropsychological Assessment Battery List A Immediate Recall},

keywords = {*Athletes, *Football/in [Injuries], *Septum Pellucidum/pa [Pathology], adult, aged, Brain Concussion/di [Diagnosis], Brain Concussion/ep [Epidemiology], Humans, Male, middle aged},

pubstate = {published},

tppubtype = {article}

}

Papa, L; Brophy, G M; Welch, R D; Lewis, L M; Braga, C F; Tan, C N; Ameli, N J; Lopez, M A; Haeussler, C A; Mendez Giordano, D I; Silvestri, S; Giordano, P; Weber, K D; Hill-Pryor, C; Hack, D C

Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury Journal Article

In: JAMA Neurology, vol. 73, no. 5, pp. 551–560, 2016.

Abstract | Links | BibTeX | Tags: adult, aged, American Indian, amnesia, area under the curve, Article, Asian, assault, bicycle, Black person, blood sampling, blunt trauma, brain concussion, Caucasian, cohort analysis, computer assisted tomography, controlled study, diagnostic accuracy, diagnostic test accuracy study, disorientation, emergency ward, falling, Female, Glasgow Coma Scale, glial fibrillary acidic protein, Hispanic, human, limit of detection, limit of quantitation, major clinical study, Male, mild to moderate traumatic brain injury, neurosurgery, pedestrian, priority journal, prospective study, sport injury, traffic accident, traumatic brain injury, traumatic intracranial lesion, ubiquitin, ubiquitin carboxy terminal hydrolase L1, unclassified drug, unconsciousness, very elderly

@article{Papa2016a,

title = {Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury},

author = {Papa, L and Brophy, G M and Welch, R D and Lewis, L M and Braga, C F and Tan, C N and Ameli, N J and Lopez, M A and Haeussler, C A and {Mendez Giordano}, D I and Silvestri, S and Giordano, P and Weber, K D and Hill-Pryor, C and Hack, D C},

doi = {10.1001/jamaneurol.2016.0039},

year  = {2016},

date = {2016-01-01},

journal = {JAMA Neurology},

volume = {73},

number = {5},

pages = {551--560},

abstract = {Importance: Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have been widely studied and show promise for clinical usefulness in suspected traumatic brain injury (TBI) and concussion. Understanding their diagnostic accuracy over time will help translate them into clinical practice. Objectives: To evaluate the temporal profiles of GFAP and UCH-L1 in a large cohort of trauma patients seen at the emergency department and to assess their diagnostic accuracy over time, both individually and in combination, for detecting mild to moderate TBI (MMTBI), traumatic intracranial lesions on head computed tomography (CT), and neurosurgical intervention. Design, Setting, and Participants: This prospective cohort study enrolled adult trauma patients seen at a level I trauma center from March 1, 2010, to March 5, 2014. All patients underwent rigorous screening to determine whether they had experienced an MMTBI (blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale score of 9-15). Of 3025 trauma patients assessed, 1030 met eligibility criteria for enrollment, and 446 declined participation. Initial blood samples were obtained in 584 patients enrolled within 4 hours of injury. Repeated blood sampling was conducted at 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 hours after injury. Main Outcomes and Measures: Diagnosis of MMTBI, presence of traumatic intracranial lesions on head CT scan, and neurosurgical intervention. Results: A total of 1831 blood samples were drawn from 584 patients (mean [SD] age, 40 [16] years; 62.0%[362 of 584] male) over 7 days. Both GFAP and UCH-L1 were detectible within 1 hour of injury. GFAP peaked at 20 hours after injury and slowly declined over 72 hours. UCH-L1 rose rapidly and peaked at 8 hours after injury and declined rapidly over 48 hours. Over the course of 1 week, GFAP demonstrated a diagnostic range of areas under the curve for detecting MMTBI of 0.73 (95%CI, 0.69-0.77) to 0.94 (95%CI, 0.78-1.00), and UCH-L1 demonstrated a diagnostic range of 0.30 (95%CI, 0.02-0.50) to 0.67 (95%CI, 0.53-0.81). For detecting intracranial lesions on CT, the diagnostic ranges of areas under the curve were 0.80 (95%CI, 0.67-0.92) to 0.97 (95%CI, 0.93-1.00)for GFAP and 0.31 (95%CI, 0-0.63) to 0.77 (95%CI, 0.68-0.85) for UCH-L1. For distinguishing patients with and without a neurosurgical intervention, the range for GFAP was 0.91 (95%CI, 0.79-1.00) to 1.00 (95% CI, 1.00-1.00), and the range for UCH-L1 was 0.50 (95%CI, 0-1.00) to 0.92 (95%CI, 0.83-1.00). Conclusions and Relevance: GFAP performed consistently in detecting MMTBI, CT lesions, and neurosurgical intervention across 7 days. UCH-L1 performed best in the early postinjury period. © Copyright 2016 American Medical Association. All rights reserved.},

keywords = {adult, aged, American Indian, amnesia, area under the curve, Article, Asian, assault, bicycle, Black person, blood sampling, blunt trauma, brain concussion, Caucasian, cohort analysis, computer assisted tomography, controlled study, diagnostic accuracy, diagnostic test accuracy study, disorientation, emergency ward, falling, Female, Glasgow Coma Scale, glial fibrillary acidic protein, Hispanic, human, limit of detection, limit of quantitation, major clinical study, Male, mild to moderate traumatic brain injury, neurosurgery, pedestrian, priority journal, prospective study, sport injury, traffic accident, traumatic brain injury, traumatic intracranial lesion, ubiquitin, ubiquitin carboxy terminal hydrolase L1, unclassified drug, unconsciousness, very elderly},

pubstate = {published},

tppubtype = {article}

}

Importance: Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have been widely studied and show promise for clinical usefulness in suspected traumatic brain injury (TBI) and concussion. Understanding their diagnostic accuracy over time will help translate them into clinical practice. Objectives: To evaluate the temporal profiles of GFAP and UCH-L1 in a large cohort of trauma patients seen at the emergency department and to assess their diagnostic accuracy over time, both individually and in combination, for detecting mild to moderate TBI (MMTBI), traumatic intracranial lesions on head computed tomography (CT), and neurosurgical intervention. Design, Setting, and Participants: This prospective cohort study enrolled adult trauma patients seen at a level I trauma center from March 1, 2010, to March 5, 2014. All patients underwent rigorous screening to determine whether they had experienced an MMTBI (blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale score of 9-15). Of 3025 trauma patients assessed, 1030 met eligibility criteria for enrollment, and 446 declined participation. Initial blood samples were obtained in 584 patients enrolled within 4 hours of injury. Repeated blood sampling was conducted at 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 hours after injury. Main Outcomes and Measures: Diagnosis of MMTBI, presence of traumatic intracranial lesions on head CT scan, and neurosurgical intervention. Results: A total of 1831 blood samples were drawn from 584 patients (mean [SD] age, 40 [16] years; 62.0%[362 of 584] male) over 7 days. Both GFAP and UCH-L1 were detectible within 1 hour of injury. GFAP peaked at 20 hours after injury and slowly declined over 72 hours. UCH-L1 rose rapidly and peaked at 8 hours after injury and declined rapidly over 48 hours. Over the course of 1 week, GFAP demonstrated a diagnostic range of areas under the curve for detecting MMTBI of 0.73 (95%CI, 0.69-0.77) to 0.94 (95%CI, 0.78-1.00), and UCH-L1 demonstrated a diagnostic range of 0.30 (95%CI, 0.02-0.50) to 0.67 (95%CI, 0.53-0.81). For detecting intracranial lesions on CT, the diagnostic ranges of areas under the curve were 0.80 (95%CI, 0.67-0.92) to 0.97 (95%CI, 0.93-1.00)for GFAP and 0.31 (95%CI, 0-0.63) to 0.77 (95%CI, 0.68-0.85) for UCH-L1. For distinguishing patients with and without a neurosurgical intervention, the range for GFAP was 0.91 (95%CI, 0.79-1.00) to 1.00 (95% CI, 1.00-1.00), and the range for UCH-L1 was 0.50 (95%CI, 0-1.00) to 0.92 (95%CI, 0.83-1.00). Conclusions and Relevance: GFAP performed consistently in detecting MMTBI, CT lesions, and neurosurgical intervention across 7 days. UCH-L1 performed best in the early postinjury period. © Copyright 2016 American Medical Association. All rights reserved.

2015

Lefebvre, G; Tremblay, S; Théoret, H

Probing the effects of mild traumatic brain injury with transcranial magnetic stimulation of the primary motor cortex Journal Article

In: Brain Injury, vol. 29, no. 9, pp. 1032–1043, 2015.

Abstract | Links | BibTeX | Tags: 4 aminobutyric acid B receptor, adult, aged, Article, brain concussion, brain cortex, Brain Injuries, central motor conduction time, clinical assessment, Concussion, cortical excitability, electrostimulation, evoked muscle response, Evoked Potentials, Female, human, Humans, Inhibition, latent inhibition, latent period, long interval intracortical inhibition, magnetic stimulation, Male, Medline, middle aged, Motor, motor cortex, motor evoked potential, motor nerve conduction, muscle contraction, nerve cell excitability, nerve cell plasticity, neuromuscular facilitation, Neuronal Plasticity, outcome assessment, paired associative stimulation, Pathophysiology, PHYSIOLOGY, postsynaptic inhibition, primary motor cortex, procedures, short interval intracortical inhibition, short latency afferent inhibition, sport injury, stimulus response, Systematic Review, therapy effect, theta burst stimulation, TRANSCRANIAL magnetic stimulation, traumatic brain injury, Young Adult

@article{Lefebvre2015,

title = {Probing the effects of mild traumatic brain injury with transcranial magnetic stimulation of the primary motor cortex},

author = {Lefebvre, G and Tremblay, S and Th\'{e}oret, H},

doi = {10.3109/02699052.2015.1028447},

year  = {2015},

date = {2015-01-01},

journal = {Brain Injury},

volume = {29},

number = {9},

pages = {1032--1043},

abstract = {Primary objective: The present paper systematically reviews studies using transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) to assess cortical excitability, intra-cortical inhibition/facilitation and synaptic plasticity following mild traumatic brain injury (mTBI).Methods: Articles using TMS over M1 in patients with mTBI or sport-related concussion indexed in PubMed and published between 1998 and September 2014 were included in the present review.Main outcomes and results: From the 17 articles that matched search criteria, results from various TMS paradigms were summarized and divided in three main areas of interest: motor cortical excitability/facilitation, motor cortical inhibition and cortical plasticity. Although studies suggest a trend of abnormal intra-cortical inhibition following mTBI, no clear and specific pattern emerges from the surveyed data.Conclusions: At this time and with the possible exception of intra-cortical inhibitory measures, TMS cannot reliably detect changes in M1 excitability in individuals with mTBI or a concussion at both the acute and chronic stages of injury. This may be explained by the small number of studies and large variety of stimulation parameters. Additional longitudinal and multimodal studies are needed to better understand the nature of the excitability changes that may occur within M1 following mTBI. © 2015 Taylor \& Francis Group, LLC.},

keywords = {4 aminobutyric acid B receptor, adult, aged, Article, brain concussion, brain cortex, Brain Injuries, central motor conduction time, clinical assessment, Concussion, cortical excitability, electrostimulation, evoked muscle response, Evoked Potentials, Female, human, Humans, Inhibition, latent inhibition, latent period, long interval intracortical inhibition, magnetic stimulation, Male, Medline, middle aged, Motor, motor cortex, motor evoked potential, motor nerve conduction, muscle contraction, nerve cell excitability, nerve cell plasticity, neuromuscular facilitation, Neuronal Plasticity, outcome assessment, paired associative stimulation, Pathophysiology, PHYSIOLOGY, postsynaptic inhibition, primary motor cortex, procedures, short interval intracortical inhibition, short latency afferent inhibition, sport injury, stimulus response, Systematic Review, therapy effect, theta burst stimulation, TRANSCRANIAL magnetic stimulation, traumatic brain injury, Young Adult},

pubstate = {published},

tppubtype = {article}

}

Lawrence, D W; Comper, P; Hutchison, M G; Sharma, B

The role of apolipoprotein E episilon ($epsilon$)-4 allele on outcome following traumatic brain injury: A systematic review Journal Article

In: Brain Injury, vol. 29, no. 9, pp. 1018–1031, 2015.

Abstract | Links | BibTeX | Tags: 80 and over, aged, allele, Alleles, Alzheimer disease, amyloid beta protein, APOE, apolipoprotein E, apolipoprotein E4, Article, athlete, brain concussion, Brain Injuries, clinical evaluation, cognition, cognitive defect, disease severity, Female, follow up, genetic association, genetic risk, genetics, GENOTYPE, Glasgow Outcome Scale, heterozygote, histopathology, homozygote, human, Humans, Incidence, injury severity, Male, Memory, nerve cell necrosis, neuropathology, Neuroprotection, outcome assessment, pediatrics, Prevalence, Prognosis, prognostic assessment, protein function, psychologic test, psychology, Recovery, scoring system, Systematic Review, tau protein, traumatic brain injury, treatment outcome, very elderly, Wechsler Intelligence Scale

@article{Lawrence2015,

title = {The role of apolipoprotein E episilon ($epsilon$)-4 allele on outcome following traumatic brain injury: A systematic review},

author = {Lawrence, D W and Comper, P and Hutchison, M G and Sharma, B},

doi = {10.3109/02699052.2015.1005131},

year  = {2015},

date = {2015-01-01},

journal = {Brain Injury},

volume = {29},

number = {9},

pages = {1018--1031},

abstract = {Background: The apolipoprotein E gene (APOE) has emerged as a candidate for prognosticating traumatic brain injury (TBI) recovery, with APOE$epsilon$4 identified as a susceptibility marker for poor outcome, despite large discrepancy in its reported influence post-TBI.Methods: A systematic review was conducted, including all primary articles investigating the role of APOE$epsilon$4 on TBI outcome. A total of 65 studies were included, including 24 predominantly investigating mild (mTBI), seven moderate (modTBI) and 33 severe (sTBI); severity was not reported in one study.Results: In mTBI studies, the association between APOE$epsilon$4 and post-TBI outcome was concluded as non-contributory in 14 studies (58.3%), hazardous in nine (37.5%) and protective in one (4.2%). In sTBI studies, the role of APOE$epsilon$4 was hazardous in 21 (63.6%), non-contributory in nine (27.3%) and protective in three (9.1%). Of the seven studies investigating dementia outcomes, four observed a hazardous association with APOE$epsilon$4, while three reported no association. Six studies examined Alzheimers dementia pathology, of which three reported a hazardous influence of APOE$epsilon$4.Conclusions: The influence of APOE$epsilon$4 on neuropsychological testing, functional outcome and in paediatric populations was incongruous. This review supports the majority of research indicating APOE$epsilon$4 adversely influences recovery following TBI, particularly with respect to dementia-related outcomes and outcomes following sTBI. © 2015 Taylor \& Francis Group, LLC.},

keywords = {80 and over, aged, allele, Alleles, Alzheimer disease, amyloid beta protein, APOE, apolipoprotein E, apolipoprotein E4, Article, athlete, brain concussion, Brain Injuries, clinical evaluation, cognition, cognitive defect, disease severity, Female, follow up, genetic association, genetic risk, genetics, GENOTYPE, Glasgow Outcome Scale, heterozygote, histopathology, homozygote, human, Humans, Incidence, injury severity, Male, Memory, nerve cell necrosis, neuropathology, Neuroprotection, outcome assessment, pediatrics, Prevalence, Prognosis, prognostic assessment, protein function, psychologic test, psychology, Recovery, scoring system, Systematic Review, tau protein, traumatic brain injury, treatment outcome, very elderly, Wechsler Intelligence Scale},

pubstate = {published},

tppubtype = {article}

}

Barrio, J R; Small, G W; Wong, K P; Huang, S C; Liu, J; Merrill, D A; Giza, C C; Fitzsimmons, R P; Omalu, B; Bailes, J; Kepe, V

In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.[Erratum appears in Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):E2981; PMID: 25964344] Journal Article

In: Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 16, pp. E2039–47, 2015.

Abstract | BibTeX | Tags: *Brain Injury, *Brain/pa [Pathology], *Brain/ri [Radionuclide Imaging], *Nitriles, *Positron-Emission Tomography, 0 (2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphth, 0 (Nitriles), 80 and over, adult, aged, Alzheimer Disease/ri [Radionuclide Imaging], Amygdala/mi [Microbiology], Amygdala/pa [Pathology], autopsy, Case-Control Studies, Chronic/ri [Radionuclide Imaging], Demography, Humans, Male, Mesencephalon/mi [Microbiology], Mesencephalon/pa [Pathology], middle aged

@article{Barrio2015,

title = {In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.[Erratum appears in Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):E2981; PMID: 25964344]},

author = {Barrio, J R and Small, G W and Wong, K P and Huang, S C and Liu, J and Merrill, D A and Giza, C C and Fitzsimmons, R P and Omalu, B and Bailes, J and Kepe, V},

year  = {2015},

date = {2015-01-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {112},

number = {16},

pages = {E2039--47},

abstract = {Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-beta] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.},

keywords = {*Brain Injury, *Brain/pa [Pathology], *Brain/ri [Radionuclide Imaging], *Nitriles, *Positron-Emission Tomography, 0 (2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphth, 0 (Nitriles), 80 and over, adult, aged, Alzheimer Disease/ri [Radionuclide Imaging], Amygdala/mi [Microbiology], Amygdala/pa [Pathology], autopsy, Case-Control Studies, Chronic/ri [Radionuclide Imaging], Demography, Humans, Male, Mesencephalon/mi [Microbiology], Mesencephalon/pa [Pathology], middle aged},

pubstate = {published},

tppubtype = {article}

}

Bieniek, K F; Ross, O A; Cormier, K A; Walton, R L; Soto-Ortolaza, A; Johnston, A E; DeSaro, P; Boylan, K B; Graff-Radford, N R; Wszolek, Z K; Rademakers, R; Boeve, B F; McKee, A C; Dickson, D W

Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank Journal Article

In: Acta Neuropathologica, vol. 130, no. 6, pp. 877–889, 2015.

Abstract | BibTeX | Tags: *Brain Injury, *Brain/pa [Pathology], *Neurodegenerative Diseases/et [Etiology], *Neurodegenerative Diseases/pa [Pathology], 0 (Apolipoproteins E), 0 (MAPT protein, 0 (Membrane Proteins), 0 (Nerve Tissue Proteins), 0 (tau Proteins), 0 (TMEM106B protein, aged, Apolipoproteins E/ge [Genetics], Athletic Injuries/co [Complications], Athletic Injuries/ge [Genetics], Athletic Injuries/me [Metabolism], Athletic Injuries/pa [Pathology], Brain Injury, Brain/me [Metabolism], Chronic/et [Etiology], Chronic/ge [Genetics], Chronic/me [Metabolism], Chronic/pa [Pathology], Female, human), Humans, immunohistochemistry, Male, Membrane Proteins/ge [Genetics], Nerve Tissue Proteins/ge [Genetics], Neurodegenerative Diseases/ge [Genetics], Neurodegenerative Diseases/me [Metabolism], Retrospective Studies, tau Proteins/ge [Genetics], tau Proteins/me [Metabolism], Tissue Banks

@article{Bieniek2015,

title = {Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank},

author = {Bieniek, K F and Ross, O A and Cormier, K A and Walton, R L and Soto-Ortolaza, A and Johnston, A E and DeSaro, P and Boylan, K B and Graff-Radford, N R and Wszolek, Z K and Rademakers, R and Boeve, B F and McKee, A C and Dickson, D W},

year  = {2015},

date = {2015-01-01},

journal = {Acta Neuropathologica},

volume = {130},

number = {6},

pages = {877--889},

abstract = {Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed.},

keywords = {*Brain Injury, *Brain/pa [Pathology], *Neurodegenerative Diseases/et [Etiology], *Neurodegenerative Diseases/pa [Pathology], 0 (Apolipoproteins E), 0 (MAPT protein, 0 (Membrane Proteins), 0 (Nerve Tissue Proteins), 0 (tau Proteins), 0 (TMEM106B protein, aged, Apolipoproteins E/ge [Genetics], Athletic Injuries/co [Complications], Athletic Injuries/ge [Genetics], Athletic Injuries/me [Metabolism], Athletic Injuries/pa [Pathology], Brain Injury, Brain/me [Metabolism], Chronic/et [Etiology], Chronic/ge [Genetics], Chronic/me [Metabolism], Chronic/pa [Pathology], Female, human), Humans, immunohistochemistry, Male, Membrane Proteins/ge [Genetics], Nerve Tissue Proteins/ge [Genetics], Neurodegenerative Diseases/ge [Genetics], Neurodegenerative Diseases/me [Metabolism], Retrospective Studies, tau Proteins/ge [Genetics], tau Proteins/me [Metabolism], Tissue Banks},

pubstate = {published},

tppubtype = {article}

}

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed.

Stone Jr., M E; Safadjou, S; Farber, B; Velazco, N; Man, J; Reddy, S H; Todor, R; Teperman, S

Utility of the Military Acute Concussion Evaluation as a screening tool for mild traumatic brain injury in a civilian trauma population Journal Article

In: Journal of Trauma and Acute Care Surgery, vol. 79, no. 1, pp. 147–151, 2015.

Abstract | Links | BibTeX | Tags: Adolescent, adult, aged, Alcoholic Intoxication, amnesia, Article, assessment of humans, brain concussion, Brain Injuries, clinical assessment tool, computer assisted tomography, Concussion screening, Confounding Factors (Epidemiology), controlled study, DATA analysis, Demography, diagnostic test accuracy study, Dizziness, emergency health service, Female, Head, headache, hospital admission, human, Humans, injury severity, irritability, major clinical study, Male, middle aged, mild traumatic brain injury, Military Acute Concussion Evaluation, military medicine, nausea and vomiting, predictive value, priority journal, quality control, receiver operating characteristic, ROC Curve, screening test, Sensitivity and Specificity, traumatic brain injury, unconsciousness, Urban Population, visual disorder, Young Adult

@article{StoneJr.2015,

title = {Utility of the Military Acute Concussion Evaluation as a screening tool for mild traumatic brain injury in a civilian trauma population},

author = {{Stone Jr.}, M E and Safadjou, S and Farber, B and Velazco, N and Man, J and Reddy, S H and Todor, R and Teperman, S},

doi = {10.1097/TA.0000000000000679},

year  = {2015},

date = {2015-01-01},

journal = {Journal of Trauma and Acute Care Surgery},

volume = {79},

number = {1},

pages = {147--151},

abstract = {BACKGROUND: Mild traumatic brain injury (mTBI) constitutes 75% of more than 1.5 million traumatic brain injuries annually. There exists no consensus on point-of-care screening for mTBI. The Military Acute Concussion Evaluation (MACE) is a quick and easy test used by the US Army to screen for mTBI; however, its utility in civilian trauma is unclear. It has two parts: a history section and the Standardized Assessment of Concussion (SAC) score (0-30) previously validated in sports injury. As a performance improvement project, our institution sought to evaluate the MACE as a concussion screening tool that could be used by housestaff in a general civilian trauma population. METHODS: From June 2013 to May 2014, patients 18 years to 65 years old with suspected concussion were given the MACE within 72 hours of admission to our urban Level I trauma center. Patients with a positive head computed tomography were excluded. Demographic data and MACE scores were recorded in prospect. Concussion was defined as loss of consciousness and/or posttraumatic amnesia; concussed patients were compared with those nonconcussed. Sensitivity and specificity for each respective MACE score were used to plot a receiver operating characteristic (ROC) curve. An ROC curve area of 0.8 was set as the benchmark for a good screening test to distinguish concussion from nonconcussion. RESULTS: There were 84 concussions and 30 nonconcussed patients. Both groups were similar; however, the concussion group had a lower mean MACE score than the nonconcussed patients. Data analysis demonstrated the sensitivity and specificity of a range of MACE scores used to generate an ROC curve area of only 0.65. CONCLUSION: The MACE showed a lower mean score for individuals with concussion, defined by loss of consciousness and/or posttraumatic amnesia. However, the ROC curve area of 0.65 highly suggests that MACE alone would be a poor screening test for mTBI in a general civilian trauma population. LEVEL OF EVIDENCE: Diagnostic study, level II. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.},

keywords = {Adolescent, adult, aged, Alcoholic Intoxication, amnesia, Article, assessment of humans, brain concussion, Brain Injuries, clinical assessment tool, computer assisted tomography, Concussion screening, Confounding Factors (Epidemiology), controlled study, DATA analysis, Demography, diagnostic test accuracy study, Dizziness, emergency health service, Female, Head, headache, hospital admission, human, Humans, injury severity, irritability, major clinical study, Male, middle aged, mild traumatic brain injury, Military Acute Concussion Evaluation, military medicine, nausea and vomiting, predictive value, priority journal, quality control, receiver operating characteristic, ROC Curve, screening test, Sensitivity and Specificity, traumatic brain injury, unconsciousness, Urban Population, visual disorder, Young Adult},

pubstate = {published},

tppubtype = {article}

}

BACKGROUND: Mild traumatic brain injury (mTBI) constitutes 75% of more than 1.5 million traumatic brain injuries annually. There exists no consensus on point-of-care screening for mTBI. The Military Acute Concussion Evaluation (MACE) is a quick and easy test used by the US Army to screen for mTBI; however, its utility in civilian trauma is unclear. It has two parts: a history section and the Standardized Assessment of Concussion (SAC) score (0-30) previously validated in sports injury. As a performance improvement project, our institution sought to evaluate the MACE as a concussion screening tool that could be used by housestaff in a general civilian trauma population. METHODS: From June 2013 to May 2014, patients 18 years to 65 years old with suspected concussion were given the MACE within 72 hours of admission to our urban Level I trauma center. Patients with a positive head computed tomography were excluded. Demographic data and MACE scores were recorded in prospect. Concussion was defined as loss of consciousness and/or posttraumatic amnesia; concussed patients were compared with those nonconcussed. Sensitivity and specificity for each respective MACE score were used to plot a receiver operating characteristic (ROC) curve. An ROC curve area of 0.8 was set as the benchmark for a good screening test to distinguish concussion from nonconcussion. RESULTS: There were 84 concussions and 30 nonconcussed patients. Both groups were similar; however, the concussion group had a lower mean MACE score than the nonconcussed patients. Data analysis demonstrated the sensitivity and specificity of a range of MACE scores used to generate an ROC curve area of only 0.65. CONCLUSION: The MACE showed a lower mean score for individuals with concussion, defined by loss of consciousness and/or posttraumatic amnesia. However, the ROC curve area of 0.65 highly suggests that MACE alone would be a poor screening test for mTBI in a general civilian trauma population. LEVEL OF EVIDENCE: Diagnostic study, level II. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Stein, T D; Montenigro, P H; Alvarez, V E; Xia, W; Crary, J F; Tripodis, Y; Daneshvar, D H; Mez, J; Solomon, T; Meng, G; Kubilus, C A; Cormier, K A; Meng, S; Babcock, K; Kiernan, P; Murphy, L; Nowinski, C J; Martin, B; Dixon, D; Stern, R A; Cantu, R C; Kowall, N W; McKee, A C

Beta-amyloid deposition in chronic traumatic encephalopathy Journal Article

In: Acta Neuropathologica, vol. 130, no. 1, pp. 21–34, 2015.

Abstract | BibTeX | Tags: *Amyloid beta-Peptides/me [Metabolism], *Brain Injury, *Brain/pa [Pathology], *Neurodegenerative Diseases/pa [Pathology], *tau Proteins/me [Metabolism], 0 (Amyloid beta-Peptides), 0 (Apolipoprotein E4), 0 (MAPT protein, 0 (tau Proteins), 80 and over, adult, Age Factors, aged, Amyloid/et [Etiology], Amyloid/me [Metabolism], Amyloid/pa [Pathology], Apolipoprotein E4/ge [Genetics], Athletes, Athletic Injuries/ep [Epidemiology], Athletic Injuries/ge [Genetics], Athletic Injuries/me [Metabolism], Athletic Injuries/pa [Pathology], Brain Injury, Brain/me [Metabolism], Chronic/ep [Epidemiology], Chronic/ge [Genetics], Chronic/me [Metabolism], Chronic/pa [Pathology], Cohort Studies, comorbidity, human), Humans, middle aged, Neurodegenerative Diseases/ep [Epidemiology], Neurodegenerative Diseases/ge [Genetics], Neurodegenerative Diseases/me [Metabolism], Plaque, SEVERITY of illness index, veterans, War-Related Injuries/ep [Epidemiology], War-Related Injuries/ge [Genetics], War-Related Injuries/me [Metabolism], War-Related Injuries/pa [Pathology]

@article{Stein2015b,

title = {Beta-amyloid deposition in chronic traumatic encephalopathy},

author = {Stein, T D and Montenigro, P H and Alvarez, V E and Xia, W and Crary, J F and Tripodis, Y and Daneshvar, D H and Mez, J and Solomon, T and Meng, G and Kubilus, C A and Cormier, K A and Meng, S and Babcock, K and Kiernan, P and Murphy, L and Nowinski, C J and Martin, B and Dixon, D and Stern, R A and Cantu, R C and Kowall, N W and McKee, A C},

year  = {2015},

date = {2015-01-01},

journal = {Acta Neuropathologica},

volume = {130},

number = {1},

pages = {21--34},

abstract = {Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer's disease (AD). Although trauma has been suggested to increase amyloid beta peptide (Abeta) levels, the extent of Abeta deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that Abeta deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that Abeta deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, Abeta deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p \< 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with Abeta plaques and those without. Abeta deposition was significantly associated with the presence of the APOE epsilon4 allele (p = 0.035), older age at symptom onset (p \< 0.001), and older age at death (p \< 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (beta = 2.43},

keywords = {*Amyloid beta-Peptides/me [Metabolism], *Brain Injury, *Brain/pa [Pathology], *Neurodegenerative Diseases/pa [Pathology], *tau Proteins/me [Metabolism], 0 (Amyloid beta-Peptides), 0 (Apolipoprotein E4), 0 (MAPT protein, 0 (tau Proteins), 80 and over, adult, Age Factors, aged, Amyloid/et [Etiology], Amyloid/me [Metabolism], Amyloid/pa [Pathology], Apolipoprotein E4/ge [Genetics], Athletes, Athletic Injuries/ep [Epidemiology], Athletic Injuries/ge [Genetics], Athletic Injuries/me [Metabolism], Athletic Injuries/pa [Pathology], Brain Injury, Brain/me [Metabolism], Chronic/ep [Epidemiology], Chronic/ge [Genetics], Chronic/me [Metabolism], Chronic/pa [Pathology], Cohort Studies, comorbidity, human), Humans, middle aged, Neurodegenerative Diseases/ep [Epidemiology], Neurodegenerative Diseases/ge [Genetics], Neurodegenerative Diseases/me [Metabolism], Plaque, SEVERITY of illness index, veterans, War-Related Injuries/ep [Epidemiology], War-Related Injuries/ge [Genetics], War-Related Injuries/me [Metabolism], War-Related Injuries/pa [Pathology]},

pubstate = {published},

tppubtype = {article}

}

2014

Mitsis, E M; Riggio, S; Kostakoglu, L; Dickstein, D L; Machac, J; Delman, B; Goldstein, M; Jennings, D; D'Antonio, E; Martin, J; Naidich, T P; Aloysi, A; Fernandez, C; Seibyl, J; DeKosky, S T; Elder, G A; Marek, K; Gordon, W; Hof, P R; Sano, M; Gandy, S

Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: Studies of a retired NFL player and of a man with FTD and a severe head injury Journal Article

In: Translational Psychiatry, vol. 4, no. 9, 2014.

Abstract | Links | BibTeX | Tags: adult, aged, amyloid plaque, arachnoid cyst, Article, case report, Chronic Traumatic Encephalopathy florbetapir f 18, Concussion, diagnostic accuracy, eye movement, football, frontotemporal dementia, head injury, human, injury severity, ligand binding, Male, memory disorder, middle aged, molecular imaging, motor dysfunction, muscle tone, personality disorder, positron emission tomography, short term memory, subdural hematoma, tauopathy, traumatic brain injury

@article{Mitsis2014,

title = {Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: Studies of a retired NFL player and of a man with FTD and a severe head injury},

author = {Mitsis, E M and Riggio, S and Kostakoglu, L and Dickstein, D L and Machac, J and Delman, B and Goldstein, M and Jennings, D and D'Antonio, E and Martin, J and Naidich, T P and Aloysi, A and Fernandez, C and Seibyl, J and DeKosky, S T and Elder, G A and Marek, K and Gordon, W and Hof, P R and Sano, M and Gandy, S},

url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-84918535750\&partnerID=40\&md5=704b918a7429432cbd631e703c44eb63},

doi = {10.1038/tp.2014.91},

year  = {2014},

date = {2014-01-01},

journal = {Translational Psychiatry},

volume = {4},

number = {9},

abstract = {Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [18F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [18F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [18F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [18F]-T807 PET imaging revealed striatal and nigral [18F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56- year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [18F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [18F]- Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [18F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [18F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [18F]-fluorodeoxyglucose, [18F]-Florbetapir and/or [18F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions. © 2014 Macmillan Publishers Limited.},

keywords = {adult, aged, amyloid plaque, arachnoid cyst, Article, case report, Chronic Traumatic Encephalopathy florbetapir f 18, Concussion, diagnostic accuracy, eye movement, football, frontotemporal dementia, head injury, human, injury severity, ligand binding, Male, memory disorder, middle aged, molecular imaging, motor dysfunction, muscle tone, personality disorder, positron emission tomography, short term memory, subdural hematoma, tauopathy, traumatic brain injury},

pubstate = {published},

tppubtype = {article}

}

Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [18F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [18F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [18F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [18F]-T807 PET imaging revealed striatal and nigral [18F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56- year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [18F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [18F]- Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [18F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [18F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [18F]-fluorodeoxyglucose, [18F]-Florbetapir and/or [18F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions. © 2014 Macmillan Publishers Limited.

Ling, H; Kara, E; Revesz, T; Lees, A J; Plant, G T; Martino, D; Houlden, H; Hardy, J; Holton, J L

Concomitant progressive supranuclear palsy and chronic traumatic encephalopathy in a boxer Journal Article

In: Acta neuropathologica communications, vol. 2, pp. 24, 2014.

Abstract | Links | BibTeX | Tags: aged, Brain Injury, case report, Chronic, Chronic Traumatic Encephalopathy GRN protein, complication, genetics, huma, human, Humans, Intercellular Signaling Peptides and Proteins, LRRK2 protein, Male, MAPT protein, pathology, Progressive, progressive supranuclear palsy, protein serine threonine kinase, Protein-Serine-Threonine Kinases, signal peptide, Supranuclear Palsy, tau protein, tau Proteins

2008

Thornton, A E; Cox, D N; Whitfield, K; Fouladi, R T

Cumulative concussion exposure in rugby players: neurocognitive and symptomatic outcomes Journal Article

In: Journal of Clinical & Experimental Neuropsychology, vol. 30, no. 4, pp. 398–409, 2008.

Abstract | BibTeX | Tags: *Brain Concussion/co [Complications], *COGNITION, *Cognition Disorders/et [Etiology], *Football/in [Injuries], adult, Age Factors, aged, Brain Concussion/di [Diagnosis], Female, Humans, Male, middle aged, Neuropsychological Tests, Predictive Value of Tests, REGRESSION analysis, Surveys and Questionnaires, Trauma Severity Indices

2007

Chiu, W T; Huang, S J; Tsai, S H; Lin, J W; Tsai, M D; Lin, T J; Huang, W C

The impact of time, legislation, and geography on the epidemiology of traumatic brain injury Journal Article

In: Journal of Clinical Neuroscience, vol. 14, no. 10, pp. 930–935, 2007.

Abstract | BibTeX | Tags: *Accidents, *Brain Injuries/ep [Epidemiology], *Legislation as Topic/sn [Statistics & Numerical D, *Rural Population/sn [Statistics & Numerical Data], *Urban Population/sn [Statistics & Numerical Data], Accidents, adult, age distribution, aged, Cohort Studies, Female, Head Protective Devices/sn [Statistics & Numerical, Head Protective Devices/st [Standards], Humans, Incidence, Legislation as Topic/td [Trends], Male, middle aged, Motorcycles/lj [Legislation & Jurisprudence], Motorcycles/sn [Statistics & Numerical Data], Motorcycles/st [Standards], Prospective Studies, Rural Population/td [Trends], Sex Distribution, Taiwan/ep [Epidemiology], Time Factors, Traffic/lj [Legislation & Jurisprudence, Traffic/pc [Prevention & Control], Traffic/sn [Statistics & Numerical Dat, Trauma Severity Indices, Urban Population/td [Trends]

@article{Chiu2007,

title = {The impact of time, legislation, and geography on the epidemiology of traumatic brain injury},

author = {Chiu, W T and Huang, S J and Tsai, S H and Lin, J W and Tsai, M D and Lin, T J and Huang, W C},

year  = {2007},

date = {2007-01-01},

journal = {Journal of Clinical Neuroscience},

volume = {14},

number = {10},

pages = {930--935},

abstract = {In 1991, a population-based epidemiologic traumatic brain injury (TBI) study was done in urban and rural areas of Taiwan; this was 5 years before the helmet use law was passed and 8 years before the drink driving law was passed. In order to evaluate the impact of three major determinants (time, geography, and legislation) on the epidemiology of TBI, we conducted a prospective study in 2001 and used the 1991 data to examine the differences in TBI distribution in urban and rural Taiwan a decade after these laws were passed. In 2001, 5754 TBI cases were collected from the urban area of Taipei City, and 1474 TBI cases were collected from the rural area of Hualien County. The TBI incidence rate in Taipei City in 2001 was estimated to be 218/100,000 population (285/100,000 for males and 152/100,000 for females). When compared to the 1991 data, the incidence rate in 2001 had increased by 20%. The TBI incidence rate in Hualien County in 2001 was estimated to be 417/100,000 population (516/100,000 for males and 306/100,000 for females); this was a 37% increase over the 1991 data. Our study found that the distribution of causes and age distribution had shifted significantly over the 10-year period. In 2001, the age group with the highest incidence was 20-29 years, while in 1991 it had been the over 70 years age group. While traffic-related TBI had decreased, falls and assaults had increased in 2001. We also found that legislation, such as the helmet law, affects TBI distribution by decreasing the traffic-related TBI rate, decreasing the admission severity of TBI, and reducing TBI-related mortality. Finally, geography plays a crucial role in the outcome of TBI; over the 10 year period, Taipei had an increase in moderately severe outcomes, while Hualien had an increase in more severe outcomes. Comparative studies of TBI in urban and rural areas have shown that time, legislation, and geography are crucial determinants of TBI epidemiology. Although time and legal interventions seem to have more of an impact, geography does affect TBI outcomes.},

keywords = {*Accidents, *Brain Injuries/ep [Epidemiology], *Legislation as Topic/sn [Statistics \&amp; Numerical D, *Rural Population/sn [Statistics \&amp; Numerical Data], *Urban Population/sn [Statistics \&amp; Numerical Data], Accidents, adult, age distribution, aged, Cohort Studies, Female, Head Protective Devices/sn [Statistics \&amp; Numerical, Head Protective Devices/st [Standards], Humans, Incidence, Legislation as Topic/td [Trends], Male, middle aged, Motorcycles/lj [Legislation \&amp; Jurisprudence], Motorcycles/sn [Statistics \&amp; Numerical Data], Motorcycles/st [Standards], Prospective Studies, Rural Population/td [Trends], Sex Distribution, Taiwan/ep [Epidemiology], Time Factors, Traffic/lj [Legislation \&amp; Jurisprudence, Traffic/pc [Prevention \&amp; Control], Traffic/sn [Statistics \&amp; Numerical Dat, Trauma Severity Indices, Urban Population/td [Trends]},

pubstate = {published},

tppubtype = {article}

}

In 1991, a population-based epidemiologic traumatic brain injury (TBI) study was done in urban and rural areas of Taiwan; this was 5 years before the helmet use law was passed and 8 years before the drink driving law was passed. In order to evaluate the impact of three major determinants (time, geography, and legislation) on the epidemiology of TBI, we conducted a prospective study in 2001 and used the 1991 data to examine the differences in TBI distribution in urban and rural Taiwan a decade after these laws were passed. In 2001, 5754 TBI cases were collected from the urban area of Taipei City, and 1474 TBI cases were collected from the rural area of Hualien County. The TBI incidence rate in Taipei City in 2001 was estimated to be 218/100,000 population (285/100,000 for males and 152/100,000 for females). When compared to the 1991 data, the incidence rate in 2001 had increased by 20%. The TBI incidence rate in Hualien County in 2001 was estimated to be 417/100,000 population (516/100,000 for males and 306/100,000 for females); this was a 37% increase over the 1991 data. Our study found that the distribution of causes and age distribution had shifted significantly over the 10-year period. In 2001, the age group with the highest incidence was 20-29 years, while in 1991 it had been the over 70 years age group. While traffic-related TBI had decreased, falls and assaults had increased in 2001. We also found that legislation, such as the helmet law, affects TBI distribution by decreasing the traffic-related TBI rate, decreasing the admission severity of TBI, and reducing TBI-related mortality. Finally, geography plays a crucial role in the outcome of TBI; over the 10 year period, Taipei had an increase in moderately severe outcomes, while Hualien had an increase in more severe outcomes. Comparative studies of TBI in urban and rural areas have shown that time, legislation, and geography are crucial determinants of TBI epidemiology. Although time and legal interventions seem to have more of an impact, geography does affect TBI outcomes.

2005

Chetelat, G; Eustache, F; Viader, F; De La Sayette, V; Pelerin, A; Mezenge, F; Hannequin, D; Dupuy, B; Baron, J C; Desgranges, B

FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment Journal Article

In: Neurocase, vol. 11, no. 1, pp. 14–25, 2005.

Abstract | BibTeX | Tags: *Cognition Disorders/dg [Diagnostic Imaging], *Fluorodeoxyglucose F18, *Neuropsychological Tests, *Positron-Emission Tomography, 0Z5B2CJX4D (Fluorodeoxyglucose F18), 80 and over, aged, ANALYSIS of variance, Brain Concussion/dg [Diagnostic Imaging], Brain Concussion/pa [Pathology], BRAIN mapping, Cognition Disorders/di [Diagnosis], Dementia/dg [Diagnostic Imaging], Dementia/di [Diagnosis], Dementia/pp [Physiopathology], Female, Follow-Up Studies, Humans, Male, Memory/ph [Physiology], Mental Status Schedule, middle aged, Predictive Value of Tests, Regression (Psychology), Reproducibility of Results, Time Factors

@article{Chetelat2005,

title = {FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment},

author = {Chetelat, G and Eustache, F and Viader, F and {De La Sayette}, V and Pelerin, A and Mezenge, F and Hannequin, D and Dupuy, B and Baron, J C and Desgranges, B},

year  = {2005},

date = {2005-01-01},

journal = {Neurocase},

volume = {11},

number = {1},

pages = {14--25},

abstract = {The accurate prediction, at a pre-dementia stage of Alzheimer's disease (AD), of the subsequent clinical evolution of patients would be a major breakthrough from both therapeutic and research standpoints. Amnestic mild cognitive impairment (MCI) is presently the most common reference to address the pre-dementia stage of AD. However, previous longitudinal studies on patients with MCI assessing neuropsychological and PET markers of future conversion to AD are sparse and yield discrepant findings, while a comprehensive comparison of the relative accuracy of these two categories of measure is still lacking. In the present study, we assessed the global cognitive decline as measured by the Mattis scale in 18 patients with amnestic MCI over an 18-month follow-up period, studying which subtest of this scale showed significant deterioration over time. Using baseline measurements from neuropsychological evaluation of memory and PET, we then assessed significant markers of global cognitive change, that is, percent annual change in the Mattis scale total score, and searched for the best predictor of this global cognitive decline. Altogether, our results revealed significant decline over the 18-month follow-up period in the total score and the verbal initiation and memory-recall subscores of the Mattis scale. The percent annual change in the total Mattis score significantly correlated with age and baseline performances in delayed episodic memory recall as well as semantic autobiographical and category word fluencies. Regarding functional imaging, significant correlations were also found with baseline PET values in the right temporo-parietal and medial frontal areas. Age and right temporo-parietal PET values were the most significant predictors of subsequent global cognitive decline, and the only ones to survive stepwise regression analyses. Our findings are consistent with previous works showing predominant delayed recall and semantic memory impairment at a pre-dementia stage of AD, as well as early metabolic defects in the temporo-parietal associative cortex. However, they suggest that only the latter predictor is specifically and accurately associated with subsequent cognitive decline in patients with MCI within 18 months of first assessment.},

keywords = {*Cognition Disorders/dg [Diagnostic Imaging], *Fluorodeoxyglucose F18, *Neuropsychological Tests, *Positron-Emission Tomography, 0Z5B2CJX4D (Fluorodeoxyglucose F18), 80 and over, aged, ANALYSIS of variance, Brain Concussion/dg [Diagnostic Imaging], Brain Concussion/pa [Pathology], BRAIN mapping, Cognition Disorders/di [Diagnosis], Dementia/dg [Diagnostic Imaging], Dementia/di [Diagnosis], Dementia/pp [Physiopathology], Female, Follow-Up Studies, Humans, Male, Memory/ph [Physiology], Mental Status Schedule, middle aged, Predictive Value of Tests, Regression (Psychology), Reproducibility of Results, Time Factors},

pubstate = {published},

tppubtype = {article}

}

The accurate prediction, at a pre-dementia stage of Alzheimer's disease (AD), of the subsequent clinical evolution of patients would be a major breakthrough from both therapeutic and research standpoints. Amnestic mild cognitive impairment (MCI) is presently the most common reference to address the pre-dementia stage of AD. However, previous longitudinal studies on patients with MCI assessing neuropsychological and PET markers of future conversion to AD are sparse and yield discrepant findings, while a comprehensive comparison of the relative accuracy of these two categories of measure is still lacking. In the present study, we assessed the global cognitive decline as measured by the Mattis scale in 18 patients with amnestic MCI over an 18-month follow-up period, studying which subtest of this scale showed significant deterioration over time. Using baseline measurements from neuropsychological evaluation of memory and PET, we then assessed significant markers of global cognitive change, that is, percent annual change in the Mattis scale total score, and searched for the best predictor of this global cognitive decline. Altogether, our results revealed significant decline over the 18-month follow-up period in the total score and the verbal initiation and memory-recall subscores of the Mattis scale. The percent annual change in the total Mattis score significantly correlated with age and baseline performances in delayed episodic memory recall as well as semantic autobiographical and category word fluencies. Regarding functional imaging, significant correlations were also found with baseline PET values in the right temporo-parietal and medial frontal areas. Age and right temporo-parietal PET values were the most significant predictors of subsequent global cognitive decline, and the only ones to survive stepwise regression analyses. Our findings are consistent with previous works showing predominant delayed recall and semantic memory impairment at a pre-dementia stage of AD, as well as early metabolic defects in the temporo-parietal associative cortex. However, they suggest that only the latter predictor is specifically and accurately associated with subsequent cognitive decline in patients with MCI within 18 months of first assessment.

2002

Horner, A; VanDemark, M; Jensen, G A

The challenge of assessing a patient with dementia and head injury Journal Article

In: AACN Clinical Issues, vol. 13, no. 1, pp. 73–83, 2002.

Abstract | BibTeX | Tags: *Craniocerebral Trauma/co [Complications], *Dementia/co [Complications], Accidental Falls, Accidents, aged, Alzheimer Disease/di [Diagnosis], Brain Concussion/di [Diagnosis], Brain Concussion/et [Etiology], Brain Concussion/pp [Physiopathology], Craniocerebral Trauma/di [Diagnosis], Craniocerebral Trauma/pp [Physiopathology], Delirium/di [Diagnosis], Delirium/et [Etiology], Home, Humans

1989

Bigler, E D; Rosa, L; Schultz, F; Hall, S; Harris, J

Rey-Auditory Verbal Learning and Rey-Osterrieth Complex Figure Design performance in Alzheimer's disease and closed head injury.[Erratum appears in J Clin Psychol 1989 Nov;45(6):1013] Journal Article

In: Journal of Clinical Psychology, vol. 45, no. 2, pp. 277–280, 1989.

Abstract | BibTeX | Tags: *Alzheimer Disease/px [Psychology], *Brain Concussion/px [Psychology], *Form Perception, *MEMORY, *Mental Recall, *Neurocognitive Disorders/px [Psychology], *Neuropsychological Tests, *Pattern Recognition, *Verbal Learning, 80 and over, adult, aged, attention, Female, Humans, Male, middle aged, Psychometrics, SPEECH perception, Visual

Reference Search

Calcagnile, O; Anell, A; Unden, J

The addition of S100B to guidelines for management of mild head injury is potentially cost saving Journal Article

In: BMC Neurology, vol. 16, no. 1, pp. 200, 2016.

Abstract | BibTeX

Stergiou-Kita, M; Mansfield, E; Sokoloff, S; Colantonio, A

Gender Influences on Return to Work After Mild Traumatic Brain Injury Journal Article

In: Archives of Physical Medicine & Rehabilitation, vol. 97, no. 2 Suppl, pp. S40–5, 2016.

Abstract | BibTeX

Puvenna, V; Engeler, M; Banjara, M; Brennan, C; Schreiber, P; Dadas, A; Bahrami, A; Solanki, J; Bandyopadhyay, A; Morris, J K; Bernick, C; Ghosh, C; Rapp, E; Bazarian, J J; Janigro, D

Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy Journal Article

In: Brain Research, vol. 1630, pp. 225–240, 2016.

Abstract | BibTeX

@article{Puvenna2016,

title = {Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy},

author = {Puvenna, V and Engeler, M and Banjara, M and Brennan, C and Schreiber, P and Dadas, A and Bahrami, A and Solanki, J and Bandyopadhyay, A and Morris, J K and Bernick, C and Ghosh, C and Rapp, E and Bazarian, J J and Janigro, D},

year  = {2016},

date = {2016-01-01},

journal = {Brain Research},

volume = {1630},

pages = {225--240},

abstract = {Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six postmortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P\<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE. Copyright © 2015 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

Leung, A; Shukla, S; Fallah, A; Song, D; Lin, L; Golshan, S; Tsai, A; Jak, A; Polston, G; Lee, R

Repetitive Transcranial Magnetic Stimulation in Managing Mild Traumatic Brain Injury-Related Headaches Journal Article

In: Neuromodulation, vol. 19, no. 2, pp. 133–141, 2016.

Abstract | BibTeX

@article{Leung2016,

title = {Repetitive Transcranial Magnetic Stimulation in Managing Mild Traumatic Brain Injury-Related Headaches},

author = {Leung, A and Shukla, S and Fallah, A and Song, D and Lin, L and Golshan, S and Tsai, A and Jak, A and Polston, G and Lee, R},

year  = {2016},

date = {2016-01-01},

journal = {Neuromodulation},

volume = {19},

number = {2},

pages = {133--141},

abstract = {OBJECTIVE: Headache is one of the most common debilitating chronic pain conditions in either active or retired military personnel with mild traumatic brain injury (MTBI). This study assessed the effect of repetitive transcranial magnetic stimulation (rTMS) in alleviating MTBI-related headache (MTBI-HA). MATERIALS AND METHOD: Veterans with MTBI-HA were randomized to receive either real rTMS (REAL group) at 10 hz for a total of 2000 pulses divided into 20 trains with one-sec inter-train interval or sham rTMS (SHAM group) at the left motor cortex (LMC) with brain magnetic resonance imaging neuronavigation guidance. Pretreatment, posttreatment one-week and four-week headache and neuropsychological assessments were conducted. RESULT: Thirty veterans were screened and twenty four (21 men and 3 women with average year-old +/- SD at 14.3 +/- 12.6) subjects' data were analyzed. A two-factor (visit x treatment) repeated measures analysis of variance (RM-ANOVA) indicated a close to significant (p = 0.06) trend of interaction between pretreatment and posttreatment one-week assessment with the intensity of the persistent daily headache decreasing from 5.7 +/- 1.9 to 2.2 +/- 2.7 and 4.6 +/- 1.3 to 3.5 +/- 2.0 for the REAL and SHAM groups, respectively. Subsequent analyses indicated REAL group demonstrated a significantly (p = 0.041) higher % of reduction in persistent headache intensity than the SHAM group (56.3 +/- 48.2% vs.15.4 +/- 43.6%) at the posttreatment one-week assessment and the trend continued to the four-week assessment. Overall, a significantly (p = 0.035) higher percentage of the subjects in the REAL group (58.3%) demonstrated at least a 50% headache intensity reduction at posttreatment one-week assessment compared with the SHAM group (16.6%). The overall composite score of functionally debilitating headache exacerbation is significantly (p = 0.017) reduced in REAL group at the posttreatment four-week assessment in comparison with the SHAM group. No major sustained change in neuropsychological assessments was noted. CONCLUSION: The studied rTMS protocol appears to be a clinically feasible and effective treatment option in managing MTBI-HA.Copyright © 2015 International Neuromodulation Society.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

Stern, R A; Tripodis, Y; Baugh, C M; Fritts, N G; Martin, B M; Chaisson, C; Cantu, R C; Joyce, J A; Shah, S; Ikezu, T; Zhang, J; Gercel-Taylor, C; Taylor, D D

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy Journal Article

In: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1099–1109, 2016.

Abstract | BibTeX

@article{Stern2016,

title = {Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy},

author = {Stern, R A and Tripodis, Y and Baugh, C M and Fritts, N G and Martin, B M and Chaisson, C and Cantu, R C and Joyce, J A and Shah, S and Ikezu, T and Zhang, J and Gercel-Taylor, C and Taylor, D D},

year  = {2016},

date = {2016-01-01},

journal = {Journal of Alzheimer's Disease},

volume = {51},

number = {4},

pages = {1099--1109},

abstract = {BACKGROUND: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers. OBJECTIVE: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. METHODS: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. RESULTS: The NFL group had higher exosomal tau than the control group (p \< 0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). CONCLUSION: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

Koerte, I K; Hufschmidt, J; Muehlmann, M; Tripodis, Y; Stamm, J M; Pasternak, O; Giwerc, M Y; Coleman, M J; Baugh, C M; Fritts, N G; Heinen, F; Lin, A; Stern, R A; Shenton, M E

Cavum Septi Pellucidi in Symptomatic Former Professional Football Players Journal Article

In: Journal of Neurotrauma, vol. 33, no. 4, pp. 346–353, 2016.

Abstract | BibTeX

@article{Koerte2016,

title = {Cavum Septi Pellucidi in Symptomatic Former Professional Football Players},

author = {Koerte, I K and Hufschmidt, J and Muehlmann, M and Tripodis, Y and Stamm, J M and Pasternak, O and Giwerc, M Y and Coleman, M J and Baugh, C M and Fritts, N G and Heinen, F and Lin, A and Stern, R A and Shenton, M E},

year  = {2016},

date = {2016-01-01},

journal = {Journal of Neurotrauma},

volume = {33},

number = {4},

pages = {346--353},

abstract = {Post-mortem studies reveal a high rate of cavum septi pellucidi (CSP) in chronic traumatic encephalopathy (CTE). It remains, however, to be determined whether or not the presence of CSP may be a potential in vivo imaging marker in populations at high risk to develop CTE. The aim of this study was to evaluate CSP in former professional American football players presenting with cognitive and behavioral symptoms compared with noncontact sports athletes. Seventy-two symptomatic former professional football players (mean age 54.53 years, standard deviation [SD] 7.97) as well as 14 former professional noncontact sports athletes (mean age 57.14 years, SD 7.35) underwent high-resolution structural 3T magnetic resonance imaging. Two raters independently evaluated the CSP, and interrater reliability was calculated. Within National Football League players, an association of CSP measures with cognitive and behavioral functioning was evaluated using a multivariate mixed effects model. The measurements of the two raters were highly correlated (CSP length: rho = 0.98; Intraclass Correlation Coefficient [ICC] 0.99; p \< 0.0001; septum length: rho = 0.93; ICC 0.96; p \< 0.0001). For presence versus absence of CSP, there was high agreement (Cohen kappa = 0.83, p \< 0.0001). A higher rate of CSP, a greater length of CSP, as well as a greater ratio of CSP length to septum length was found in symptomatic former professional football players compared with athlete controls. In addition, a greater length of CSP was associated with decreased performance on a list learning task (Neuropsychological Assessment Battery List A Immediate Recall},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

Papa, L; Brophy, G M; Welch, R D; Lewis, L M; Braga, C F; Tan, C N; Ameli, N J; Lopez, M A; Haeussler, C A; Mendez Giordano, D I; Silvestri, S; Giordano, P; Weber, K D; Hill-Pryor, C; Hack, D C

Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury Journal Article

In: JAMA Neurology, vol. 73, no. 5, pp. 551–560, 2016.

Abstract | Links | BibTeX

@article{Papa2016a,

title = {Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury},

author = {Papa, L and Brophy, G M and Welch, R D and Lewis, L M and Braga, C F and Tan, C N and Ameli, N J and Lopez, M A and Haeussler, C A and {Mendez Giordano}, D I and Silvestri, S and Giordano, P and Weber, K D and Hill-Pryor, C and Hack, D C},

doi = {10.1001/jamaneurol.2016.0039},

year  = {2016},

date = {2016-01-01},

journal = {JAMA Neurology},

volume = {73},

number = {5},

pages = {551--560},

abstract = {Importance: Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have been widely studied and show promise for clinical usefulness in suspected traumatic brain injury (TBI) and concussion. Understanding their diagnostic accuracy over time will help translate them into clinical practice. Objectives: To evaluate the temporal profiles of GFAP and UCH-L1 in a large cohort of trauma patients seen at the emergency department and to assess their diagnostic accuracy over time, both individually and in combination, for detecting mild to moderate TBI (MMTBI), traumatic intracranial lesions on head computed tomography (CT), and neurosurgical intervention. Design, Setting, and Participants: This prospective cohort study enrolled adult trauma patients seen at a level I trauma center from March 1, 2010, to March 5, 2014. All patients underwent rigorous screening to determine whether they had experienced an MMTBI (blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale score of 9-15). Of 3025 trauma patients assessed, 1030 met eligibility criteria for enrollment, and 446 declined participation. Initial blood samples were obtained in 584 patients enrolled within 4 hours of injury. Repeated blood sampling was conducted at 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 hours after injury. Main Outcomes and Measures: Diagnosis of MMTBI, presence of traumatic intracranial lesions on head CT scan, and neurosurgical intervention. Results: A total of 1831 blood samples were drawn from 584 patients (mean [SD] age, 40 [16] years; 62.0%[362 of 584] male) over 7 days. Both GFAP and UCH-L1 were detectible within 1 hour of injury. GFAP peaked at 20 hours after injury and slowly declined over 72 hours. UCH-L1 rose rapidly and peaked at 8 hours after injury and declined rapidly over 48 hours. Over the course of 1 week, GFAP demonstrated a diagnostic range of areas under the curve for detecting MMTBI of 0.73 (95%CI, 0.69-0.77) to 0.94 (95%CI, 0.78-1.00), and UCH-L1 demonstrated a diagnostic range of 0.30 (95%CI, 0.02-0.50) to 0.67 (95%CI, 0.53-0.81). For detecting intracranial lesions on CT, the diagnostic ranges of areas under the curve were 0.80 (95%CI, 0.67-0.92) to 0.97 (95%CI, 0.93-1.00)for GFAP and 0.31 (95%CI, 0-0.63) to 0.77 (95%CI, 0.68-0.85) for UCH-L1. For distinguishing patients with and without a neurosurgical intervention, the range for GFAP was 0.91 (95%CI, 0.79-1.00) to 1.00 (95% CI, 1.00-1.00), and the range for UCH-L1 was 0.50 (95%CI, 0-1.00) to 0.92 (95%CI, 0.83-1.00). Conclusions and Relevance: GFAP performed consistently in detecting MMTBI, CT lesions, and neurosurgical intervention across 7 days. UCH-L1 performed best in the early postinjury period. © Copyright 2016 American Medical Association. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

Lefebvre, G; Tremblay, S; Théoret, H

Probing the effects of mild traumatic brain injury with transcranial magnetic stimulation of the primary motor cortex Journal Article

In: Brain Injury, vol. 29, no. 9, pp. 1032–1043, 2015.

Abstract | Links | BibTeX

Lawrence, D W; Comper, P; Hutchison, M G; Sharma, B

The role of apolipoprotein E episilon ($epsilon$)-4 allele on outcome following traumatic brain injury: A systematic review Journal Article

In: Brain Injury, vol. 29, no. 9, pp. 1018–1031, 2015.

Abstract | Links | BibTeX

@article{Lawrence2015,

title = {The role of apolipoprotein E episilon ($epsilon$)-4 allele on outcome following traumatic brain injury: A systematic review},

author = {Lawrence, D W and Comper, P and Hutchison, M G and Sharma, B},

doi = {10.3109/02699052.2015.1005131},

year  = {2015},

date = {2015-01-01},

journal = {Brain Injury},

volume = {29},

number = {9},

pages = {1018--1031},

abstract = {Background: The apolipoprotein E gene (APOE) has emerged as a candidate for prognosticating traumatic brain injury (TBI) recovery, with APOE$epsilon$4 identified as a susceptibility marker for poor outcome, despite large discrepancy in its reported influence post-TBI.Methods: A systematic review was conducted, including all primary articles investigating the role of APOE$epsilon$4 on TBI outcome. A total of 65 studies were included, including 24 predominantly investigating mild (mTBI), seven moderate (modTBI) and 33 severe (sTBI); severity was not reported in one study.Results: In mTBI studies, the association between APOE$epsilon$4 and post-TBI outcome was concluded as non-contributory in 14 studies (58.3%), hazardous in nine (37.5%) and protective in one (4.2%). In sTBI studies, the role of APOE$epsilon$4 was hazardous in 21 (63.6%), non-contributory in nine (27.3%) and protective in three (9.1%). Of the seven studies investigating dementia outcomes, four observed a hazardous association with APOE$epsilon$4, while three reported no association. Six studies examined Alzheimers dementia pathology, of which three reported a hazardous influence of APOE$epsilon$4.Conclusions: The influence of APOE$epsilon$4 on neuropsychological testing, functional outcome and in paediatric populations was incongruous. This review supports the majority of research indicating APOE$epsilon$4 adversely influences recovery following TBI, particularly with respect to dementia-related outcomes and outcomes following sTBI. © 2015 Taylor \& Francis Group, LLC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

10.

Barrio, J R; Small, G W; Wong, K P; Huang, S C; Liu, J; Merrill, D A; Giza, C C; Fitzsimmons, R P; Omalu, B; Bailes, J; Kepe, V

In: Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 16, pp. E2039–47, 2015.

Abstract | BibTeX

@article{Barrio2015,

title = {In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.[Erratum appears in Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):E2981; PMID: 25964344]},

author = {Barrio, J R and Small, G W and Wong, K P and Huang, S C and Liu, J and Merrill, D A and Giza, C C and Fitzsimmons, R P and Omalu, B and Bailes, J and Kepe, V},

year  = {2015},

date = {2015-01-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {112},

number = {16},

pages = {E2039--47},

abstract = {Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-beta] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

11.

Bieniek, K F; Ross, O A; Cormier, K A; Walton, R L; Soto-Ortolaza, A; Johnston, A E; DeSaro, P; Boylan, K B; Graff-Radford, N R; Wszolek, Z K; Rademakers, R; Boeve, B F; McKee, A C; Dickson, D W

Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank Journal Article

In: Acta Neuropathologica, vol. 130, no. 6, pp. 877–889, 2015.

Abstract | BibTeX

@article{Bieniek2015,

title = {Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank},

author = {Bieniek, K F and Ross, O A and Cormier, K A and Walton, R L and Soto-Ortolaza, A and Johnston, A E and DeSaro, P and Boylan, K B and Graff-Radford, N R and Wszolek, Z K and Rademakers, R and Boeve, B F and McKee, A C and Dickson, D W},

year  = {2015},

date = {2015-01-01},

journal = {Acta Neuropathologica},

volume = {130},

number = {6},

pages = {877--889},

abstract = {Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

12.

Stone Jr., M E; Safadjou, S; Farber, B; Velazco, N; Man, J; Reddy, S H; Todor, R; Teperman, S

Utility of the Military Acute Concussion Evaluation as a screening tool for mild traumatic brain injury in a civilian trauma population Journal Article

In: Journal of Trauma and Acute Care Surgery, vol. 79, no. 1, pp. 147–151, 2015.

Abstract | Links | BibTeX

@article{StoneJr.2015,

title = {Utility of the Military Acute Concussion Evaluation as a screening tool for mild traumatic brain injury in a civilian trauma population},

author = {{Stone Jr.}, M E and Safadjou, S and Farber, B and Velazco, N and Man, J and Reddy, S H and Todor, R and Teperman, S},

doi = {10.1097/TA.0000000000000679},

year  = {2015},

date = {2015-01-01},

journal = {Journal of Trauma and Acute Care Surgery},

volume = {79},

number = {1},

pages = {147--151},

abstract = {BACKGROUND: Mild traumatic brain injury (mTBI) constitutes 75% of more than 1.5 million traumatic brain injuries annually. There exists no consensus on point-of-care screening for mTBI. The Military Acute Concussion Evaluation (MACE) is a quick and easy test used by the US Army to screen for mTBI; however, its utility in civilian trauma is unclear. It has two parts: a history section and the Standardized Assessment of Concussion (SAC) score (0-30) previously validated in sports injury. As a performance improvement project, our institution sought to evaluate the MACE as a concussion screening tool that could be used by housestaff in a general civilian trauma population. METHODS: From June 2013 to May 2014, patients 18 years to 65 years old with suspected concussion were given the MACE within 72 hours of admission to our urban Level I trauma center. Patients with a positive head computed tomography were excluded. Demographic data and MACE scores were recorded in prospect. Concussion was defined as loss of consciousness and/or posttraumatic amnesia; concussed patients were compared with those nonconcussed. Sensitivity and specificity for each respective MACE score were used to plot a receiver operating characteristic (ROC) curve. An ROC curve area of 0.8 was set as the benchmark for a good screening test to distinguish concussion from nonconcussion. RESULTS: There were 84 concussions and 30 nonconcussed patients. Both groups were similar; however, the concussion group had a lower mean MACE score than the nonconcussed patients. Data analysis demonstrated the sensitivity and specificity of a range of MACE scores used to generate an ROC curve area of only 0.65. CONCLUSION: The MACE showed a lower mean score for individuals with concussion, defined by loss of consciousness and/or posttraumatic amnesia. However, the ROC curve area of 0.65 highly suggests that MACE alone would be a poor screening test for mTBI in a general civilian trauma population. LEVEL OF EVIDENCE: Diagnostic study, level II. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

13.

Beta-amyloid deposition in chronic traumatic encephalopathy Journal Article

In: Acta Neuropathologica, vol. 130, no. 1, pp. 21–34, 2015.

Abstract | BibTeX

@article{Stein2015b,

title = {Beta-amyloid deposition in chronic traumatic encephalopathy},

author = {Stein, T D and Montenigro, P H and Alvarez, V E and Xia, W and Crary, J F and Tripodis, Y and Daneshvar, D H and Mez, J and Solomon, T and Meng, G and Kubilus, C A and Cormier, K A and Meng, S and Babcock, K and Kiernan, P and Murphy, L and Nowinski, C J and Martin, B and Dixon, D and Stern, R A and Cantu, R C and Kowall, N W and McKee, A C},

year  = {2015},

date = {2015-01-01},

journal = {Acta Neuropathologica},

volume = {130},

number = {1},

pages = {21--34},

abstract = {Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer's disease (AD). Although trauma has been suggested to increase amyloid beta peptide (Abeta) levels, the extent of Abeta deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that Abeta deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that Abeta deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, Abeta deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p \< 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with Abeta plaques and those without. Abeta deposition was significantly associated with the presence of the APOE epsilon4 allele (p = 0.035), older age at symptom onset (p \< 0.001), and older age at death (p \< 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (beta = 2.43},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

14.

Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: Studies of a retired NFL player and of a man with FTD and a severe head injury Journal Article

In: Translational Psychiatry, vol. 4, no. 9, 2014.

Abstract | Links | BibTeX

@article{Mitsis2014,

title = {Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: Studies of a retired NFL player and of a man with FTD and a severe head injury},

author = {Mitsis, E M and Riggio, S and Kostakoglu, L and Dickstein, D L and Machac, J and Delman, B and Goldstein, M and Jennings, D and D'Antonio, E and Martin, J and Naidich, T P and Aloysi, A and Fernandez, C and Seibyl, J and DeKosky, S T and Elder, G A and Marek, K and Gordon, W and Hof, P R and Sano, M and Gandy, S},

url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-84918535750\&partnerID=40\&md5=704b918a7429432cbd631e703c44eb63},

doi = {10.1038/tp.2014.91},

year  = {2014},

date = {2014-01-01},

journal = {Translational Psychiatry},

volume = {4},

number = {9},

abstract = {Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [18F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [18F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [18F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [18F]-T807 PET imaging revealed striatal and nigral [18F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56- year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [18F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [18F]- Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [18F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [18F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [18F]-fluorodeoxyglucose, [18F]-Florbetapir and/or [18F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions. © 2014 Macmillan Publishers Limited.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

15.

Ling, H; Kara, E; Revesz, T; Lees, A J; Plant, G T; Martino, D; Houlden, H; Hardy, J; Holton, J L

Concomitant progressive supranuclear palsy and chronic traumatic encephalopathy in a boxer Journal Article

In: Acta neuropathologica communications, vol. 2, pp. 24, 2014.

Abstract | Links | BibTeX

16.

Thornton, A E; Cox, D N; Whitfield, K; Fouladi, R T

Cumulative concussion exposure in rugby players: neurocognitive and symptomatic outcomes Journal Article

In: Journal of Clinical & Experimental Neuropsychology, vol. 30, no. 4, pp. 398–409, 2008.

Abstract | BibTeX

17.

Chiu, W T; Huang, S J; Tsai, S H; Lin, J W; Tsai, M D; Lin, T J; Huang, W C

The impact of time, legislation, and geography on the epidemiology of traumatic brain injury Journal Article

In: Journal of Clinical Neuroscience, vol. 14, no. 10, pp. 930–935, 2007.

Abstract | BibTeX

@article{Chiu2007,

title = {The impact of time, legislation, and geography on the epidemiology of traumatic brain injury},

author = {Chiu, W T and Huang, S J and Tsai, S H and Lin, J W and Tsai, M D and Lin, T J and Huang, W C},

year  = {2007},

date = {2007-01-01},

journal = {Journal of Clinical Neuroscience},

volume = {14},

number = {10},

pages = {930--935},

abstract = {In 1991, a population-based epidemiologic traumatic brain injury (TBI) study was done in urban and rural areas of Taiwan; this was 5 years before the helmet use law was passed and 8 years before the drink driving law was passed. In order to evaluate the impact of three major determinants (time, geography, and legislation) on the epidemiology of TBI, we conducted a prospective study in 2001 and used the 1991 data to examine the differences in TBI distribution in urban and rural Taiwan a decade after these laws were passed. In 2001, 5754 TBI cases were collected from the urban area of Taipei City, and 1474 TBI cases were collected from the rural area of Hualien County. The TBI incidence rate in Taipei City in 2001 was estimated to be 218/100,000 population (285/100,000 for males and 152/100,000 for females). When compared to the 1991 data, the incidence rate in 2001 had increased by 20%. The TBI incidence rate in Hualien County in 2001 was estimated to be 417/100,000 population (516/100,000 for males and 306/100,000 for females); this was a 37% increase over the 1991 data. Our study found that the distribution of causes and age distribution had shifted significantly over the 10-year period. In 2001, the age group with the highest incidence was 20-29 years, while in 1991 it had been the over 70 years age group. While traffic-related TBI had decreased, falls and assaults had increased in 2001. We also found that legislation, such as the helmet law, affects TBI distribution by decreasing the traffic-related TBI rate, decreasing the admission severity of TBI, and reducing TBI-related mortality. Finally, geography plays a crucial role in the outcome of TBI; over the 10 year period, Taipei had an increase in moderately severe outcomes, while Hualien had an increase in more severe outcomes. Comparative studies of TBI in urban and rural areas have shown that time, legislation, and geography are crucial determinants of TBI epidemiology. Although time and legal interventions seem to have more of an impact, geography does affect TBI outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

18.

Chetelat, G; Eustache, F; Viader, F; De La Sayette, V; Pelerin, A; Mezenge, F; Hannequin, D; Dupuy, B; Baron, J C; Desgranges, B

FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment Journal Article

In: Neurocase, vol. 11, no. 1, pp. 14–25, 2005.

Abstract | BibTeX

@article{Chetelat2005,

title = {FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment},

author = {Chetelat, G and Eustache, F and Viader, F and {De La Sayette}, V and Pelerin, A and Mezenge, F and Hannequin, D and Dupuy, B and Baron, J C and Desgranges, B},

year  = {2005},

date = {2005-01-01},

journal = {Neurocase},

volume = {11},

number = {1},

pages = {14--25},

abstract = {The accurate prediction, at a pre-dementia stage of Alzheimer's disease (AD), of the subsequent clinical evolution of patients would be a major breakthrough from both therapeutic and research standpoints. Amnestic mild cognitive impairment (MCI) is presently the most common reference to address the pre-dementia stage of AD. However, previous longitudinal studies on patients with MCI assessing neuropsychological and PET markers of future conversion to AD are sparse and yield discrepant findings, while a comprehensive comparison of the relative accuracy of these two categories of measure is still lacking. In the present study, we assessed the global cognitive decline as measured by the Mattis scale in 18 patients with amnestic MCI over an 18-month follow-up period, studying which subtest of this scale showed significant deterioration over time. Using baseline measurements from neuropsychological evaluation of memory and PET, we then assessed significant markers of global cognitive change, that is, percent annual change in the Mattis scale total score, and searched for the best predictor of this global cognitive decline. Altogether, our results revealed significant decline over the 18-month follow-up period in the total score and the verbal initiation and memory-recall subscores of the Mattis scale. The percent annual change in the total Mattis score significantly correlated with age and baseline performances in delayed episodic memory recall as well as semantic autobiographical and category word fluencies. Regarding functional imaging, significant correlations were also found with baseline PET values in the right temporo-parietal and medial frontal areas. Age and right temporo-parietal PET values were the most significant predictors of subsequent global cognitive decline, and the only ones to survive stepwise regression analyses. Our findings are consistent with previous works showing predominant delayed recall and semantic memory impairment at a pre-dementia stage of AD, as well as early metabolic defects in the temporo-parietal associative cortex. However, they suggest that only the latter predictor is specifically and accurately associated with subsequent cognitive decline in patients with MCI within 18 months of first assessment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

19.

Horner, A; VanDemark, M; Jensen, G A

The challenge of assessing a patient with dementia and head injury Journal Article

In: AACN Clinical Issues, vol. 13, no. 1, pp. 73–83, 2002.

Abstract | BibTeX

20.

Bigler, E D; Rosa, L; Schultz, F; Hall, S; Harris, J

Rey-Auditory Verbal Learning and Rey-Osterrieth Complex Figure Design performance in Alzheimer's disease and closed head injury.[Erratum appears in J Clin Psychol 1989 Nov;45(6):1013] Journal Article

In: Journal of Clinical Psychology, vol. 45, no. 2, pp. 277–280, 1989.

Abstract | BibTeX

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2016

Calcagnile, O; Anell, A; Unden, J

The addition of S100B to guidelines for management of mild head injury is potentially cost saving Journal Article

In: BMC Neurology, vol. 16, no. 1, pp. 200, 2016.

@article{Calcagnile2016,

title = {The addition of S100B to guidelines for management of mild head injury is potentially cost saving},

author = {Calcagnile, O and Anell, A and Unden, J},

year  = {2016},

date = {2016-01-01},

journal = {BMC Neurology},

volume = {16},

number = {1},

pages = {200},

abstract = {BACKGROUND: Mild traumatic brain injury (TBI) is associated with substantial costs due to over-triage of patients to computed tomography (CT) scanning, despite validated decision rules. Serum biomarker S100B has shown promise for safely omitting CT scans but the economic impact from clinical use has never been reported. In 2007, S100B was adapted into the existing Scandinavian management guidelines in Halmstad, Sweden, in an attempt to reduce CT scans and save costs. METHODS: Consecutive adult patients with mild TBI (GCS 14-15, loss of consciousness and/or amnesia), managed with the aid of S100B, were prospectively included in this study. Patients were followed up after 3 months with a standardized questionnaire. Theoretical and actual cost differences were calculated. RESULTS: Seven hundred twenty-six patients were included and 29 (4.7 %) showed traumatic abnormalities on CT. No further significant intracranial complications were discovered on follow-up. Two hundred twenty-nine patients (27 %) had normal S100B levels and 497 patients (73 %) showed elevated S100B levels. Over-triage occurred in 73 patients (32 %) and under-triage occurred in 39 patients (7 %). No significant intracranial complications were missed. The introduction of S100B could save 71 per patient if guidelines were strictly followed. As compliance to the guidelines was not perfect, the actual cost saving was 39 per patient. CONCLUSION: Adding S100B to existing guidelines for mild TBI seems to reduce CT usage and costs, especially if guideline compliance could be increased.},

keywords = {*Brain Concussion/bl [Blood], *Brain Concussion/ec [Economics], *Cost Savings, *Practice Guidelines as Topic, *S100 Calcium Binding Protein beta Subunit/bl [Blo, 0 (Biomarkers), 0 (S100 Calcium Binding Protein beta Subunit), 80 and over, Adolescent, adult, aged, Biomarkers/bl [Blood], Female, Humans, Male, middle aged, SWEDEN, Young Adult},

pubstate = {published},

tppubtype = {article}

}

Stergiou-Kita, M; Mansfield, E; Sokoloff, S; Colantonio, A

Gender Influences on Return to Work After Mild Traumatic Brain Injury Journal Article

In: Archives of Physical Medicine & Rehabilitation, vol. 97, no. 2 Suppl, pp. S40–5, 2016.

Puvenna, V; Engeler, M; Banjara, M; Brennan, C; Schreiber, P; Dadas, A; Bahrami, A; Solanki, J; Bandyopadhyay, A; Morris, J K; Bernick, C; Ghosh, C; Rapp, E; Bazarian, J J; Janigro, D

Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy Journal Article

In: Brain Research, vol. 1630, pp. 225–240, 2016.

@article{Puvenna2016,

title = {Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy},

author = {Puvenna, V and Engeler, M and Banjara, M and Brennan, C and Schreiber, P and Dadas, A and Bahrami, A and Solanki, J and Bandyopadhyay, A and Morris, J K and Bernick, C and Ghosh, C and Rapp, E and Bazarian, J J and Janigro, D},

year  = {2016},

date = {2016-01-01},

journal = {Brain Research},

volume = {1630},

pages = {225--240},

abstract = {Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six postmortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P\<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE. Copyright © 2015 Elsevier B.V. All rights reserved.},

keywords = {*Brain Injury, *Brain/me [Metabolism], *Epilepsy/me [Metabolism], *tau Proteins/me [Metabolism], 0 (MAPT protein, 0 (tau Proteins), 80 and over, Adolescent, adult, aged, Brain Injury, Brain/pa [Pathology], Brain/su [Surgery], Child, Chronic/me [Metabolism], Chronic/pa [Pathology], ENZYME-linked immunosorbent assay, Epilepsy/pa [Pathology], Epilepsy/su [Surgery], Female, human), Humans, immunohistochemistry, Infant, Male, middle aged, Phosphorylation, Preschool, Young Adult},

pubstate = {published},

tppubtype = {article}

}

Leung, A; Shukla, S; Fallah, A; Song, D; Lin, L; Golshan, S; Tsai, A; Jak, A; Polston, G; Lee, R

Repetitive Transcranial Magnetic Stimulation in Managing Mild Traumatic Brain Injury-Related Headaches Journal Article

In: Neuromodulation, vol. 19, no. 2, pp. 133–141, 2016.

@article{Leung2016,

title = {Repetitive Transcranial Magnetic Stimulation in Managing Mild Traumatic Brain Injury-Related Headaches},

author = {Leung, A and Shukla, S and Fallah, A and Song, D and Lin, L and Golshan, S and Tsai, A and Jak, A and Polston, G and Lee, R},

year  = {2016},

date = {2016-01-01},

journal = {Neuromodulation},

volume = {19},

number = {2},

pages = {133--141},

abstract = {OBJECTIVE: Headache is one of the most common debilitating chronic pain conditions in either active or retired military personnel with mild traumatic brain injury (MTBI). This study assessed the effect of repetitive transcranial magnetic stimulation (rTMS) in alleviating MTBI-related headache (MTBI-HA). MATERIALS AND METHOD: Veterans with MTBI-HA were randomized to receive either real rTMS (REAL group) at 10 hz for a total of 2000 pulses divided into 20 trains with one-sec inter-train interval or sham rTMS (SHAM group) at the left motor cortex (LMC) with brain magnetic resonance imaging neuronavigation guidance. Pretreatment, posttreatment one-week and four-week headache and neuropsychological assessments were conducted. RESULT: Thirty veterans were screened and twenty four (21 men and 3 women with average year-old +/- SD at 14.3 +/- 12.6) subjects' data were analyzed. A two-factor (visit x treatment) repeated measures analysis of variance (RM-ANOVA) indicated a close to significant (p = 0.06) trend of interaction between pretreatment and posttreatment one-week assessment with the intensity of the persistent daily headache decreasing from 5.7 +/- 1.9 to 2.2 +/- 2.7 and 4.6 +/- 1.3 to 3.5 +/- 2.0 for the REAL and SHAM groups, respectively. Subsequent analyses indicated REAL group demonstrated a significantly (p = 0.041) higher % of reduction in persistent headache intensity than the SHAM group (56.3 +/- 48.2% vs.15.4 +/- 43.6%) at the posttreatment one-week assessment and the trend continued to the four-week assessment. Overall, a significantly (p = 0.035) higher percentage of the subjects in the REAL group (58.3%) demonstrated at least a 50% headache intensity reduction at posttreatment one-week assessment compared with the SHAM group (16.6%). The overall composite score of functionally debilitating headache exacerbation is significantly (p = 0.017) reduced in REAL group at the posttreatment four-week assessment in comparison with the SHAM group. No major sustained change in neuropsychological assessments was noted. CONCLUSION: The studied rTMS protocol appears to be a clinically feasible and effective treatment option in managing MTBI-HA.Copyright © 2015 International Neuromodulation Society.},

keywords = {*Brain Concussion/co [Complications], *Headache/et [Etiology], *Headache/th [Therapy], *Transcranial Magnetic Stimulation/mt [Methods], adult, aged, Female, Humans, Male, middle aged, Neuronavigation, Neuropsychological Tests, treatment outcome},

pubstate = {published},

tppubtype = {article}

}

Stern, R A; Tripodis, Y; Baugh, C M; Fritts, N G; Martin, B M; Chaisson, C; Cantu, R C; Joyce, J A; Shah, S; Ikezu, T; Zhang, J; Gercel-Taylor, C; Taylor, D D

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy Journal Article

In: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1099–1109, 2016.

@article{Stern2016,

title = {Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy},

author = {Stern, R A and Tripodis, Y and Baugh, C M and Fritts, N G and Martin, B M and Chaisson, C and Cantu, R C and Joyce, J A and Shah, S and Ikezu, T and Zhang, J and Gercel-Taylor, C and Taylor, D D},

year  = {2016},

date = {2016-01-01},

journal = {Journal of Alzheimer's Disease},

volume = {51},

number = {4},

pages = {1099--1109},

abstract = {BACKGROUND: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers. OBJECTIVE: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. METHODS: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. RESULTS: The NFL group had higher exosomal tau than the control group (p \< 0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). CONCLUSION: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.},

keywords = {*Chronic Traumatic Encephalopathy/bl [Blood], *Extracellular Vesicles/me [Metabolism], *Plasma/cy [Cytology], *tau Proteins/me [Metabolism], 0 (tau Proteins), adult, aged, ANALYSIS of variance, Case-Control Studies, Humans, Male, middle aged},

pubstate = {published},

tppubtype = {article}

}

Koerte, I K; Hufschmidt, J; Muehlmann, M; Tripodis, Y; Stamm, J M; Pasternak, O; Giwerc, M Y; Coleman, M J; Baugh, C M; Fritts, N G; Heinen, F; Lin, A; Stern, R A; Shenton, M E

Cavum Septi Pellucidi in Symptomatic Former Professional Football Players Journal Article

In: Journal of Neurotrauma, vol. 33, no. 4, pp. 346–353, 2016.

@article{Koerte2016,

title = {Cavum Septi Pellucidi in Symptomatic Former Professional Football Players},

author = {Koerte, I K and Hufschmidt, J and Muehlmann, M and Tripodis, Y and Stamm, J M and Pasternak, O and Giwerc, M Y and Coleman, M J and Baugh, C M and Fritts, N G and Heinen, F and Lin, A and Stern, R A and Shenton, M E},

year  = {2016},

date = {2016-01-01},

journal = {Journal of Neurotrauma},

volume = {33},

number = {4},

pages = {346--353},

abstract = {Post-mortem studies reveal a high rate of cavum septi pellucidi (CSP) in chronic traumatic encephalopathy (CTE). It remains, however, to be determined whether or not the presence of CSP may be a potential in vivo imaging marker in populations at high risk to develop CTE. The aim of this study was to evaluate CSP in former professional American football players presenting with cognitive and behavioral symptoms compared with noncontact sports athletes. Seventy-two symptomatic former professional football players (mean age 54.53 years, standard deviation [SD] 7.97) as well as 14 former professional noncontact sports athletes (mean age 57.14 years, SD 7.35) underwent high-resolution structural 3T magnetic resonance imaging. Two raters independently evaluated the CSP, and interrater reliability was calculated. Within National Football League players, an association of CSP measures with cognitive and behavioral functioning was evaluated using a multivariate mixed effects model. The measurements of the two raters were highly correlated (CSP length: rho = 0.98; Intraclass Correlation Coefficient [ICC] 0.99; p \< 0.0001; septum length: rho = 0.93; ICC 0.96; p \< 0.0001). For presence versus absence of CSP, there was high agreement (Cohen kappa = 0.83, p \< 0.0001). A higher rate of CSP, a greater length of CSP, as well as a greater ratio of CSP length to septum length was found in symptomatic former professional football players compared with athlete controls. In addition, a greater length of CSP was associated with decreased performance on a list learning task (Neuropsychological Assessment Battery List A Immediate Recall},

keywords = {*Athletes, *Football/in [Injuries], *Septum Pellucidum/pa [Pathology], adult, aged, Brain Concussion/di [Diagnosis], Brain Concussion/ep [Epidemiology], Humans, Male, middle aged},

pubstate = {published},

tppubtype = {article}

}

Papa, L; Brophy, G M; Welch, R D; Lewis, L M; Braga, C F; Tan, C N; Ameli, N J; Lopez, M A; Haeussler, C A; Mendez Giordano, D I; Silvestri, S; Giordano, P; Weber, K D; Hill-Pryor, C; Hack, D C

Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury Journal Article

In: JAMA Neurology, vol. 73, no. 5, pp. 551–560, 2016.

@article{Papa2016a,

title = {Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury},

author = {Papa, L and Brophy, G M and Welch, R D and Lewis, L M and Braga, C F and Tan, C N and Ameli, N J and Lopez, M A and Haeussler, C A and {Mendez Giordano}, D I and Silvestri, S and Giordano, P and Weber, K D and Hill-Pryor, C and Hack, D C},

doi = {10.1001/jamaneurol.2016.0039},

year  = {2016},

date = {2016-01-01},

journal = {JAMA Neurology},

volume = {73},

number = {5},

pages = {551--560},

abstract = {Importance: Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have been widely studied and show promise for clinical usefulness in suspected traumatic brain injury (TBI) and concussion. Understanding their diagnostic accuracy over time will help translate them into clinical practice. Objectives: To evaluate the temporal profiles of GFAP and UCH-L1 in a large cohort of trauma patients seen at the emergency department and to assess their diagnostic accuracy over time, both individually and in combination, for detecting mild to moderate TBI (MMTBI), traumatic intracranial lesions on head computed tomography (CT), and neurosurgical intervention. Design, Setting, and Participants: This prospective cohort study enrolled adult trauma patients seen at a level I trauma center from March 1, 2010, to March 5, 2014. All patients underwent rigorous screening to determine whether they had experienced an MMTBI (blunt head trauma with loss of consciousness, amnesia, or disorientation and a Glasgow Coma Scale score of 9-15). Of 3025 trauma patients assessed, 1030 met eligibility criteria for enrollment, and 446 declined participation. Initial blood samples were obtained in 584 patients enrolled within 4 hours of injury. Repeated blood sampling was conducted at 4, 8, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 hours after injury. Main Outcomes and Measures: Diagnosis of MMTBI, presence of traumatic intracranial lesions on head CT scan, and neurosurgical intervention. Results: A total of 1831 blood samples were drawn from 584 patients (mean [SD] age, 40 [16] years; 62.0%[362 of 584] male) over 7 days. Both GFAP and UCH-L1 were detectible within 1 hour of injury. GFAP peaked at 20 hours after injury and slowly declined over 72 hours. UCH-L1 rose rapidly and peaked at 8 hours after injury and declined rapidly over 48 hours. Over the course of 1 week, GFAP demonstrated a diagnostic range of areas under the curve for detecting MMTBI of 0.73 (95%CI, 0.69-0.77) to 0.94 (95%CI, 0.78-1.00), and UCH-L1 demonstrated a diagnostic range of 0.30 (95%CI, 0.02-0.50) to 0.67 (95%CI, 0.53-0.81). For detecting intracranial lesions on CT, the diagnostic ranges of areas under the curve were 0.80 (95%CI, 0.67-0.92) to 0.97 (95%CI, 0.93-1.00)for GFAP and 0.31 (95%CI, 0-0.63) to 0.77 (95%CI, 0.68-0.85) for UCH-L1. For distinguishing patients with and without a neurosurgical intervention, the range for GFAP was 0.91 (95%CI, 0.79-1.00) to 1.00 (95% CI, 1.00-1.00), and the range for UCH-L1 was 0.50 (95%CI, 0-1.00) to 0.92 (95%CI, 0.83-1.00). Conclusions and Relevance: GFAP performed consistently in detecting MMTBI, CT lesions, and neurosurgical intervention across 7 days. UCH-L1 performed best in the early postinjury period. © Copyright 2016 American Medical Association. All rights reserved.},

keywords = {adult, aged, American Indian, amnesia, area under the curve, Article, Asian, assault, bicycle, Black person, blood sampling, blunt trauma, brain concussion, Caucasian, cohort analysis, computer assisted tomography, controlled study, diagnostic accuracy, diagnostic test accuracy study, disorientation, emergency ward, falling, Female, Glasgow Coma Scale, glial fibrillary acidic protein, Hispanic, human, limit of detection, limit of quantitation, major clinical study, Male, mild to moderate traumatic brain injury, neurosurgery, pedestrian, priority journal, prospective study, sport injury, traffic accident, traumatic brain injury, traumatic intracranial lesion, ubiquitin, ubiquitin carboxy terminal hydrolase L1, unclassified drug, unconsciousness, very elderly},

pubstate = {published},

tppubtype = {article}

}

2015

Lefebvre, G; Tremblay, S; Théoret, H

Probing the effects of mild traumatic brain injury with transcranial magnetic stimulation of the primary motor cortex Journal Article

In: Brain Injury, vol. 29, no. 9, pp. 1032–1043, 2015.

@article{Lefebvre2015,

title = {Probing the effects of mild traumatic brain injury with transcranial magnetic stimulation of the primary motor cortex},

author = {Lefebvre, G and Tremblay, S and Th\'{e}oret, H},

doi = {10.3109/02699052.2015.1028447},

year  = {2015},

date = {2015-01-01},

journal = {Brain Injury},

volume = {29},

number = {9},

pages = {1032--1043},

abstract = {Primary objective: The present paper systematically reviews studies using transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) to assess cortical excitability, intra-cortical inhibition/facilitation and synaptic plasticity following mild traumatic brain injury (mTBI).Methods: Articles using TMS over M1 in patients with mTBI or sport-related concussion indexed in PubMed and published between 1998 and September 2014 were included in the present review.Main outcomes and results: From the 17 articles that matched search criteria, results from various TMS paradigms were summarized and divided in three main areas of interest: motor cortical excitability/facilitation, motor cortical inhibition and cortical plasticity. Although studies suggest a trend of abnormal intra-cortical inhibition following mTBI, no clear and specific pattern emerges from the surveyed data.Conclusions: At this time and with the possible exception of intra-cortical inhibitory measures, TMS cannot reliably detect changes in M1 excitability in individuals with mTBI or a concussion at both the acute and chronic stages of injury. This may be explained by the small number of studies and large variety of stimulation parameters. Additional longitudinal and multimodal studies are needed to better understand the nature of the excitability changes that may occur within M1 following mTBI. © 2015 Taylor \& Francis Group, LLC.},

keywords = {4 aminobutyric acid B receptor, adult, aged, Article, brain concussion, brain cortex, Brain Injuries, central motor conduction time, clinical assessment, Concussion, cortical excitability, electrostimulation, evoked muscle response, Evoked Potentials, Female, human, Humans, Inhibition, latent inhibition, latent period, long interval intracortical inhibition, magnetic stimulation, Male, Medline, middle aged, Motor, motor cortex, motor evoked potential, motor nerve conduction, muscle contraction, nerve cell excitability, nerve cell plasticity, neuromuscular facilitation, Neuronal Plasticity, outcome assessment, paired associative stimulation, Pathophysiology, PHYSIOLOGY, postsynaptic inhibition, primary motor cortex, procedures, short interval intracortical inhibition, short latency afferent inhibition, sport injury, stimulus response, Systematic Review, therapy effect, theta burst stimulation, TRANSCRANIAL magnetic stimulation, traumatic brain injury, Young Adult},

pubstate = {published},

tppubtype = {article}

}

Lawrence, D W; Comper, P; Hutchison, M G; Sharma, B

The role of apolipoprotein E episilon ($epsilon$)-4 allele on outcome following traumatic brain injury: A systematic review Journal Article

In: Brain Injury, vol. 29, no. 9, pp. 1018–1031, 2015.

@article{Lawrence2015,

title = {The role of apolipoprotein E episilon ($epsilon$)-4 allele on outcome following traumatic brain injury: A systematic review},

author = {Lawrence, D W and Comper, P and Hutchison, M G and Sharma, B},

doi = {10.3109/02699052.2015.1005131},

year  = {2015},

date = {2015-01-01},

journal = {Brain Injury},

volume = {29},

number = {9},

pages = {1018--1031},

abstract = {Background: The apolipoprotein E gene (APOE) has emerged as a candidate for prognosticating traumatic brain injury (TBI) recovery, with APOE$epsilon$4 identified as a susceptibility marker for poor outcome, despite large discrepancy in its reported influence post-TBI.Methods: A systematic review was conducted, including all primary articles investigating the role of APOE$epsilon$4 on TBI outcome. A total of 65 studies were included, including 24 predominantly investigating mild (mTBI), seven moderate (modTBI) and 33 severe (sTBI); severity was not reported in one study.Results: In mTBI studies, the association between APOE$epsilon$4 and post-TBI outcome was concluded as non-contributory in 14 studies (58.3%), hazardous in nine (37.5%) and protective in one (4.2%). In sTBI studies, the role of APOE$epsilon$4 was hazardous in 21 (63.6%), non-contributory in nine (27.3%) and protective in three (9.1%). Of the seven studies investigating dementia outcomes, four observed a hazardous association with APOE$epsilon$4, while three reported no association. Six studies examined Alzheimers dementia pathology, of which three reported a hazardous influence of APOE$epsilon$4.Conclusions: The influence of APOE$epsilon$4 on neuropsychological testing, functional outcome and in paediatric populations was incongruous. This review supports the majority of research indicating APOE$epsilon$4 adversely influences recovery following TBI, particularly with respect to dementia-related outcomes and outcomes following sTBI. © 2015 Taylor \& Francis Group, LLC.},

keywords = {80 and over, aged, allele, Alleles, Alzheimer disease, amyloid beta protein, APOE, apolipoprotein E, apolipoprotein E4, Article, athlete, brain concussion, Brain Injuries, clinical evaluation, cognition, cognitive defect, disease severity, Female, follow up, genetic association, genetic risk, genetics, GENOTYPE, Glasgow Outcome Scale, heterozygote, histopathology, homozygote, human, Humans, Incidence, injury severity, Male, Memory, nerve cell necrosis, neuropathology, Neuroprotection, outcome assessment, pediatrics, Prevalence, Prognosis, prognostic assessment, protein function, psychologic test, psychology, Recovery, scoring system, Systematic Review, tau protein, traumatic brain injury, treatment outcome, very elderly, Wechsler Intelligence Scale},

pubstate = {published},

tppubtype = {article}

}

Barrio, J R; Small, G W; Wong, K P; Huang, S C; Liu, J; Merrill, D A; Giza, C C; Fitzsimmons, R P; Omalu, B; Bailes, J; Kepe, V

In: Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 16, pp. E2039–47, 2015.

@article{Barrio2015,

title = {In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging.[Erratum appears in Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):E2981; PMID: 25964344]},

author = {Barrio, J R and Small, G W and Wong, K P and Huang, S C and Liu, J and Merrill, D A and Giza, C C and Fitzsimmons, R P and Omalu, B and Bailes, J and Kepe, V},

year  = {2015},

date = {2015-01-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {112},

number = {16},

pages = {E2039--47},

abstract = {Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used [F-18]FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE (n = 14) and compared results with those of cognitively intact controls (n = 28) and patients with Alzheimer's dementia (AD) (n = 24), a disease that has been cognitively associated with CTE. [F-18]FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology [paired helical filament (PHF)-tau and amyloid-beta] in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular [F-18]FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.},

keywords = {*Brain Injury, *Brain/pa [Pathology], *Brain/ri [Radionuclide Imaging], *Nitriles, *Positron-Emission Tomography, 0 (2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphth, 0 (Nitriles), 80 and over, adult, aged, Alzheimer Disease/ri [Radionuclide Imaging], Amygdala/mi [Microbiology], Amygdala/pa [Pathology], autopsy, Case-Control Studies, Chronic/ri [Radionuclide Imaging], Demography, Humans, Male, Mesencephalon/mi [Microbiology], Mesencephalon/pa [Pathology], middle aged},

pubstate = {published},

tppubtype = {article}

}

Bieniek, K F; Ross, O A; Cormier, K A; Walton, R L; Soto-Ortolaza, A; Johnston, A E; DeSaro, P; Boylan, K B; Graff-Radford, N R; Wszolek, Z K; Rademakers, R; Boeve, B F; McKee, A C; Dickson, D W

Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank Journal Article

In: Acta Neuropathologica, vol. 130, no. 6, pp. 877–889, 2015.

@article{Bieniek2015,

title = {Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank},

author = {Bieniek, K F and Ross, O A and Cormier, K A and Walton, R L and Soto-Ortolaza, A and Johnston, A E and DeSaro, P and Boylan, K B and Graff-Radford, N R and Wszolek, Z K and Rademakers, R and Boeve, B F and McKee, A C and Dickson, D W},

year  = {2015},

date = {2015-01-01},

journal = {Acta Neuropathologica},

volume = {130},

number = {6},

pages = {877--889},

abstract = {Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed.},

keywords = {*Brain Injury, *Brain/pa [Pathology], *Neurodegenerative Diseases/et [Etiology], *Neurodegenerative Diseases/pa [Pathology], 0 (Apolipoproteins E), 0 (MAPT protein, 0 (Membrane Proteins), 0 (Nerve Tissue Proteins), 0 (tau Proteins), 0 (TMEM106B protein, aged, Apolipoproteins E/ge [Genetics], Athletic Injuries/co [Complications], Athletic Injuries/ge [Genetics], Athletic Injuries/me [Metabolism], Athletic Injuries/pa [Pathology], Brain Injury, Brain/me [Metabolism], Chronic/et [Etiology], Chronic/ge [Genetics], Chronic/me [Metabolism], Chronic/pa [Pathology], Female, human), Humans, immunohistochemistry, Male, Membrane Proteins/ge [Genetics], Nerve Tissue Proteins/ge [Genetics], Neurodegenerative Diseases/ge [Genetics], Neurodegenerative Diseases/me [Metabolism], Retrospective Studies, tau Proteins/ge [Genetics], tau Proteins/me [Metabolism], Tissue Banks},

pubstate = {published},

tppubtype = {article}

}

Stone Jr., M E; Safadjou, S; Farber, B; Velazco, N; Man, J; Reddy, S H; Todor, R; Teperman, S

Utility of the Military Acute Concussion Evaluation as a screening tool for mild traumatic brain injury in a civilian trauma population Journal Article

In: Journal of Trauma and Acute Care Surgery, vol. 79, no. 1, pp. 147–151, 2015.

@article{StoneJr.2015,

title = {Utility of the Military Acute Concussion Evaluation as a screening tool for mild traumatic brain injury in a civilian trauma population},

author = {{Stone Jr.}, M E and Safadjou, S and Farber, B and Velazco, N and Man, J and Reddy, S H and Todor, R and Teperman, S},

doi = {10.1097/TA.0000000000000679},

year  = {2015},

date = {2015-01-01},

journal = {Journal of Trauma and Acute Care Surgery},

volume = {79},

number = {1},

pages = {147--151},

abstract = {BACKGROUND: Mild traumatic brain injury (mTBI) constitutes 75% of more than 1.5 million traumatic brain injuries annually. There exists no consensus on point-of-care screening for mTBI. The Military Acute Concussion Evaluation (MACE) is a quick and easy test used by the US Army to screen for mTBI; however, its utility in civilian trauma is unclear. It has two parts: a history section and the Standardized Assessment of Concussion (SAC) score (0-30) previously validated in sports injury. As a performance improvement project, our institution sought to evaluate the MACE as a concussion screening tool that could be used by housestaff in a general civilian trauma population. METHODS: From June 2013 to May 2014, patients 18 years to 65 years old with suspected concussion were given the MACE within 72 hours of admission to our urban Level I trauma center. Patients with a positive head computed tomography were excluded. Demographic data and MACE scores were recorded in prospect. Concussion was defined as loss of consciousness and/or posttraumatic amnesia; concussed patients were compared with those nonconcussed. Sensitivity and specificity for each respective MACE score were used to plot a receiver operating characteristic (ROC) curve. An ROC curve area of 0.8 was set as the benchmark for a good screening test to distinguish concussion from nonconcussion. RESULTS: There were 84 concussions and 30 nonconcussed patients. Both groups were similar; however, the concussion group had a lower mean MACE score than the nonconcussed patients. Data analysis demonstrated the sensitivity and specificity of a range of MACE scores used to generate an ROC curve area of only 0.65. CONCLUSION: The MACE showed a lower mean score for individuals with concussion, defined by loss of consciousness and/or posttraumatic amnesia. However, the ROC curve area of 0.65 highly suggests that MACE alone would be a poor screening test for mTBI in a general civilian trauma population. LEVEL OF EVIDENCE: Diagnostic study, level II. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.},

keywords = {Adolescent, adult, aged, Alcoholic Intoxication, amnesia, Article, assessment of humans, brain concussion, Brain Injuries, clinical assessment tool, computer assisted tomography, Concussion screening, Confounding Factors (Epidemiology), controlled study, DATA analysis, Demography, diagnostic test accuracy study, Dizziness, emergency health service, Female, Head, headache, hospital admission, human, Humans, injury severity, irritability, major clinical study, Male, middle aged, mild traumatic brain injury, Military Acute Concussion Evaluation, military medicine, nausea and vomiting, predictive value, priority journal, quality control, receiver operating characteristic, ROC Curve, screening test, Sensitivity and Specificity, traumatic brain injury, unconsciousness, Urban Population, visual disorder, Young Adult},

pubstate = {published},

tppubtype = {article}

}

Beta-amyloid deposition in chronic traumatic encephalopathy Journal Article

In: Acta Neuropathologica, vol. 130, no. 1, pp. 21–34, 2015.

@article{Stein2015b,

title = {Beta-amyloid deposition in chronic traumatic encephalopathy},

author = {Stein, T D and Montenigro, P H and Alvarez, V E and Xia, W and Crary, J F and Tripodis, Y and Daneshvar, D H and Mez, J and Solomon, T and Meng, G and Kubilus, C A and Cormier, K A and Meng, S and Babcock, K and Kiernan, P and Murphy, L and Nowinski, C J and Martin, B and Dixon, D and Stern, R A and Cantu, R C and Kowall, N W and McKee, A C},

year  = {2015},

date = {2015-01-01},

journal = {Acta Neuropathologica},

volume = {130},

number = {1},

pages = {21--34},

abstract = {Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer's disease (AD). Although trauma has been suggested to increase amyloid beta peptide (Abeta) levels, the extent of Abeta deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that Abeta deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that Abeta deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, Abeta deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p \< 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with Abeta plaques and those without. Abeta deposition was significantly associated with the presence of the APOE epsilon4 allele (p = 0.035), older age at symptom onset (p \< 0.001), and older age at death (p \< 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (beta = 2.43},

keywords = {*Amyloid beta-Peptides/me [Metabolism], *Brain Injury, *Brain/pa [Pathology], *Neurodegenerative Diseases/pa [Pathology], *tau Proteins/me [Metabolism], 0 (Amyloid beta-Peptides), 0 (Apolipoprotein E4), 0 (MAPT protein, 0 (tau Proteins), 80 and over, adult, Age Factors, aged, Amyloid/et [Etiology], Amyloid/me [Metabolism], Amyloid/pa [Pathology], Apolipoprotein E4/ge [Genetics], Athletes, Athletic Injuries/ep [Epidemiology], Athletic Injuries/ge [Genetics], Athletic Injuries/me [Metabolism], Athletic Injuries/pa [Pathology], Brain Injury, Brain/me [Metabolism], Chronic/ep [Epidemiology], Chronic/ge [Genetics], Chronic/me [Metabolism], Chronic/pa [Pathology], Cohort Studies, comorbidity, human), Humans, middle aged, Neurodegenerative Diseases/ep [Epidemiology], Neurodegenerative Diseases/ge [Genetics], Neurodegenerative Diseases/me [Metabolism], Plaque, SEVERITY of illness index, veterans, War-Related Injuries/ep [Epidemiology], War-Related Injuries/ge [Genetics], War-Related Injuries/me [Metabolism], War-Related Injuries/pa [Pathology]},

pubstate = {published},

tppubtype = {article}

}

2014

Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: Studies of a retired NFL player and of a man with FTD and a severe head injury Journal Article

In: Translational Psychiatry, vol. 4, no. 9, 2014.

@article{Mitsis2014,

title = {Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: Studies of a retired NFL player and of a man with FTD and a severe head injury},

author = {Mitsis, E M and Riggio, S and Kostakoglu, L and Dickstein, D L and Machac, J and Delman, B and Goldstein, M and Jennings, D and D'Antonio, E and Martin, J and Naidich, T P and Aloysi, A and Fernandez, C and Seibyl, J and DeKosky, S T and Elder, G A and Marek, K and Gordon, W and Hof, P R and Sano, M and Gandy, S},

url = {http://www.scopus.com/inward/record.url?eid=2-s2.0-84918535750\&partnerID=40\&md5=704b918a7429432cbd631e703c44eb63},

doi = {10.1038/tp.2014.91},

year  = {2014},

date = {2014-01-01},

journal = {Translational Psychiatry},

volume = {4},

number = {9},

abstract = {Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [18F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [18F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [18F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [18F]-T807 PET imaging revealed striatal and nigral [18F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56- year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [18F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [18F]- Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [18F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [18F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [18F]-fluorodeoxyglucose, [18F]-Florbetapir and/or [18F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions. © 2014 Macmillan Publishers Limited.},

keywords = {adult, aged, amyloid plaque, arachnoid cyst, Article, case report, Chronic Traumatic Encephalopathy florbetapir f 18, Concussion, diagnostic accuracy, eye movement, football, frontotemporal dementia, head injury, human, injury severity, ligand binding, Male, memory disorder, middle aged, molecular imaging, motor dysfunction, muscle tone, personality disorder, positron emission tomography, short term memory, subdural hematoma, tauopathy, traumatic brain injury},

pubstate = {published},

tppubtype = {article}

}

Ling, H; Kara, E; Revesz, T; Lees, A J; Plant, G T; Martino, D; Houlden, H; Hardy, J; Holton, J L

Concomitant progressive supranuclear palsy and chronic traumatic encephalopathy in a boxer Journal Article

In: Acta neuropathologica communications, vol. 2, pp. 24, 2014.

2008

Thornton, A E; Cox, D N; Whitfield, K; Fouladi, R T

Cumulative concussion exposure in rugby players: neurocognitive and symptomatic outcomes Journal Article

In: Journal of Clinical & Experimental Neuropsychology, vol. 30, no. 4, pp. 398–409, 2008.

2007

Chiu, W T; Huang, S J; Tsai, S H; Lin, J W; Tsai, M D; Lin, T J; Huang, W C

The impact of time, legislation, and geography on the epidemiology of traumatic brain injury Journal Article

In: Journal of Clinical Neuroscience, vol. 14, no. 10, pp. 930–935, 2007.

@article{Chiu2007,

title = {The impact of time, legislation, and geography on the epidemiology of traumatic brain injury},

author = {Chiu, W T and Huang, S J and Tsai, S H and Lin, J W and Tsai, M D and Lin, T J and Huang, W C},

year  = {2007},

date = {2007-01-01},

journal = {Journal of Clinical Neuroscience},

volume = {14},

number = {10},

pages = {930--935},

abstract = {In 1991, a population-based epidemiologic traumatic brain injury (TBI) study was done in urban and rural areas of Taiwan; this was 5 years before the helmet use law was passed and 8 years before the drink driving law was passed. In order to evaluate the impact of three major determinants (time, geography, and legislation) on the epidemiology of TBI, we conducted a prospective study in 2001 and used the 1991 data to examine the differences in TBI distribution in urban and rural Taiwan a decade after these laws were passed. In 2001, 5754 TBI cases were collected from the urban area of Taipei City, and 1474 TBI cases were collected from the rural area of Hualien County. The TBI incidence rate in Taipei City in 2001 was estimated to be 218/100,000 population (285/100,000 for males and 152/100,000 for females). When compared to the 1991 data, the incidence rate in 2001 had increased by 20%. The TBI incidence rate in Hualien County in 2001 was estimated to be 417/100,000 population (516/100,000 for males and 306/100,000 for females); this was a 37% increase over the 1991 data. Our study found that the distribution of causes and age distribution had shifted significantly over the 10-year period. In 2001, the age group with the highest incidence was 20-29 years, while in 1991 it had been the over 70 years age group. While traffic-related TBI had decreased, falls and assaults had increased in 2001. We also found that legislation, such as the helmet law, affects TBI distribution by decreasing the traffic-related TBI rate, decreasing the admission severity of TBI, and reducing TBI-related mortality. Finally, geography plays a crucial role in the outcome of TBI; over the 10 year period, Taipei had an increase in moderately severe outcomes, while Hualien had an increase in more severe outcomes. Comparative studies of TBI in urban and rural areas have shown that time, legislation, and geography are crucial determinants of TBI epidemiology. Although time and legal interventions seem to have more of an impact, geography does affect TBI outcomes.},

keywords = {*Accidents, *Brain Injuries/ep [Epidemiology], *Legislation as Topic/sn [Statistics \&amp; Numerical D, *Rural Population/sn [Statistics \&amp; Numerical Data], *Urban Population/sn [Statistics \&amp; Numerical Data], Accidents, adult, age distribution, aged, Cohort Studies, Female, Head Protective Devices/sn [Statistics \&amp; Numerical, Head Protective Devices/st [Standards], Humans, Incidence, Legislation as Topic/td [Trends], Male, middle aged, Motorcycles/lj [Legislation \&amp; Jurisprudence], Motorcycles/sn [Statistics \&amp; Numerical Data], Motorcycles/st [Standards], Prospective Studies, Rural Population/td [Trends], Sex Distribution, Taiwan/ep [Epidemiology], Time Factors, Traffic/lj [Legislation \&amp; Jurisprudence, Traffic/pc [Prevention \&amp; Control], Traffic/sn [Statistics \&amp; Numerical Dat, Trauma Severity Indices, Urban Population/td [Trends]},

pubstate = {published},

tppubtype = {article}

}

2005

Chetelat, G; Eustache, F; Viader, F; De La Sayette, V; Pelerin, A; Mezenge, F; Hannequin, D; Dupuy, B; Baron, J C; Desgranges, B

FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment Journal Article

In: Neurocase, vol. 11, no. 1, pp. 14–25, 2005.

@article{Chetelat2005,

title = {FDG-PET measurement is more accurate than neuropsychological assessments to predict global cognitive deterioration in patients with mild cognitive impairment},

author = {Chetelat, G and Eustache, F and Viader, F and {De La Sayette}, V and Pelerin, A and Mezenge, F and Hannequin, D and Dupuy, B and Baron, J C and Desgranges, B},

year  = {2005},

date = {2005-01-01},

journal = {Neurocase},

volume = {11},

number = {1},

pages = {14--25},

abstract = {The accurate prediction, at a pre-dementia stage of Alzheimer's disease (AD), of the subsequent clinical evolution of patients would be a major breakthrough from both therapeutic and research standpoints. Amnestic mild cognitive impairment (MCI) is presently the most common reference to address the pre-dementia stage of AD. However, previous longitudinal studies on patients with MCI assessing neuropsychological and PET markers of future conversion to AD are sparse and yield discrepant findings, while a comprehensive comparison of the relative accuracy of these two categories of measure is still lacking. In the present study, we assessed the global cognitive decline as measured by the Mattis scale in 18 patients with amnestic MCI over an 18-month follow-up period, studying which subtest of this scale showed significant deterioration over time. Using baseline measurements from neuropsychological evaluation of memory and PET, we then assessed significant markers of global cognitive change, that is, percent annual change in the Mattis scale total score, and searched for the best predictor of this global cognitive decline. Altogether, our results revealed significant decline over the 18-month follow-up period in the total score and the verbal initiation and memory-recall subscores of the Mattis scale. The percent annual change in the total Mattis score significantly correlated with age and baseline performances in delayed episodic memory recall as well as semantic autobiographical and category word fluencies. Regarding functional imaging, significant correlations were also found with baseline PET values in the right temporo-parietal and medial frontal areas. Age and right temporo-parietal PET values were the most significant predictors of subsequent global cognitive decline, and the only ones to survive stepwise regression analyses. Our findings are consistent with previous works showing predominant delayed recall and semantic memory impairment at a pre-dementia stage of AD, as well as early metabolic defects in the temporo-parietal associative cortex. However, they suggest that only the latter predictor is specifically and accurately associated with subsequent cognitive decline in patients with MCI within 18 months of first assessment.},

keywords = {*Cognition Disorders/dg [Diagnostic Imaging], *Fluorodeoxyglucose F18, *Neuropsychological Tests, *Positron-Emission Tomography, 0Z5B2CJX4D (Fluorodeoxyglucose F18), 80 and over, aged, ANALYSIS of variance, Brain Concussion/dg [Diagnostic Imaging], Brain Concussion/pa [Pathology], BRAIN mapping, Cognition Disorders/di [Diagnosis], Dementia/dg [Diagnostic Imaging], Dementia/di [Diagnosis], Dementia/pp [Physiopathology], Female, Follow-Up Studies, Humans, Male, Memory/ph [Physiology], Mental Status Schedule, middle aged, Predictive Value of Tests, Regression (Psychology), Reproducibility of Results, Time Factors},

pubstate = {published},

tppubtype = {article}

}

2002

Horner, A; VanDemark, M; Jensen, G A

The challenge of assessing a patient with dementia and head injury Journal Article

In: AACN Clinical Issues, vol. 13, no. 1, pp. 73–83, 2002.

1989

Bigler, E D; Rosa, L; Schultz, F; Hall, S; Harris, J

Rey-Auditory Verbal Learning and Rey-Osterrieth Complex Figure Design performance in Alzheimer's disease and closed head injury.[Erratum appears in J Clin Psychol 1989 Nov;45(6):1013] Journal Article

In: Journal of Clinical Psychology, vol. 45, no. 2, pp. 277–280, 1989.

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