Page 1 of 27
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
1
Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury Running title: Association of BMX and dizziness impairment Kai-Yun Chen1,2*, Tung-Yao Tsai3*, Cheng-Fu Chang4,5,Ju-Chi Ou3, Yan-Rou Tsai1,2, Hon-Ping Ma3, Wen-Ta Chiu5, Shin-Han Tsai1,2,3,6, Kuo-Hsing Liao7, Jia-Wei Lin4,8, Chien-Min Lin4,8, John Chung-Che Wu4,5#, Yung-Hsiao Chiang1,2,4,5,9# 1
Graduate Institute of Neural Regenerative Medicine, College of Medical Science and
Technology, Taipei Medical University, Taipei, Taiwan 2
Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan
3
Department of Emergency medicine, Shuang-Ho Hospital, Taipei Medical University, New Taipei City,
Taiwan 4
Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan
5
Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan
6
College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
7
Department of Neurosurgery, Wan Fang Hospital, Taipei, Taiwan
8
Department of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, New Taipei City,
Taiwan9Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei,
Taiwan
* # These authors contributed equally.
Page 2 of 27
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
2
Corresponding author: John Chung-Che Wu Department of Neurosurgery, Taipei Medical University Hospital Department of Surgery, College of Medicine, Taipei Medical University 250 Wu-Xing Street, Taipei, Taiwan 110 Email: [email protected] Phone: 886-2-2736-1661 ext.3025 Fax :886-2-27390946
Yung-Hsiao Chiang Department of Neurosurgery, Taipei Medical University Hospital Department of Surgery, College of Medicine, Taipei Medical University Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital 250 Wu-Xing Street, Taipei, Taiwan 110 Email: [email protected] Phone: 886-2-2736-1661 ext.3025 Fax :886-2-27390946
Page 3 of 27
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
3
Abstract Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting symptoms of mTBI and the characterization of those symptoms has been challenging. Biomarkers that correlate clinical symptoms to disease outcome are desired to improve understanding of the disease and optimize patient care. BMX, a member of the TEC family of nonreceptor tyrosine kinases, is upregulated after traumatic neural injury in a rat model of mTBI. The objective of this investigation was to determine if BMX serum concentrations can effectively be used to predict outcomes after mTBI in a clinical setting. A total of 63 patients with mTBI (Glasgow Coma Score [GCS] between13-15) were included. Blood samples taken at the time of hospital admission were analyzed for BMX. Data collected included demographic and clinical variables. Outcomes were assessed using the Dizziness Handicap Inventory (DHI) questionnaire at baseline and 6 weeks post-injury. The participant was asssigned to ‘case group’ if the subject’s complaints of dizziness became worse at 6th week assessment; otherwise, the participant was assigned to ‘control group ’. A receiver operating characteristic (ROC) curve was constructed to explore BMX level. Significant associations were found between serum levels of BMX and dizziness. Areas under the curve (AUCs) for prediction of change in DHI post-injury were 0.76 for total score, 0.69 for physical score, 0.65 for emotional score and 0.66 for
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 4 of 27
4
functional score. Specificities were between 0.69 and 0.77 for total score and
emotional score, respectively. Therefore, BMX demonstrates potential as a candidate
serum biomarker of exacerbating dizziness after mTBI.
Key words: BMX, dizziness, biomarkers, traumatic brain injury
Page 5 of 27
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
5
Introduction Traumatic brain injury (TBI) constitutes a major socioeconomic and health problem, and is one of the leading causes of disability among adults worldwide. TBI can be classified using the Glasgow Coma Scale (GCS; severe
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
1
Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury Running title: Association of BMX and dizziness impairment Kai-Yun Chen1,2*, Tung-Yao Tsai3*, Cheng-Fu Chang4,5,Ju-Chi Ou3, Yan-Rou Tsai1,2, Hon-Ping Ma3, Wen-Ta Chiu5, Shin-Han Tsai1,2,3,6, Kuo-Hsing Liao7, Jia-Wei Lin4,8, Chien-Min Lin4,8, John Chung-Che Wu4,5#, Yung-Hsiao Chiang1,2,4,5,9# 1
Graduate Institute of Neural Regenerative Medicine, College of Medical Science and
Technology, Taipei Medical University, Taipei, Taiwan 2
Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan
3
Department of Emergency medicine, Shuang-Ho Hospital, Taipei Medical University, New Taipei City,
Taiwan 4
Department of Surgery, College of Medicine, Taipei Medical University, Taipei, Taiwan
5
Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan
6
College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
7
Department of Neurosurgery, Wan Fang Hospital, Taipei, Taiwan
8
Department of Neurosurgery, Shuang-Ho Hospital, Taipei Medical University, New Taipei City,
Taiwan9Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital, Taipei,
Taiwan
* # These authors contributed equally.
Page 2 of 27
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
2
Corresponding author: John Chung-Che Wu Department of Neurosurgery, Taipei Medical University Hospital Department of Surgery, College of Medicine, Taipei Medical University 250 Wu-Xing Street, Taipei, Taiwan 110 Email: [email protected] Phone: 886-2-2736-1661 ext.3025 Fax :886-2-27390946
Yung-Hsiao Chiang Department of Neurosurgery, Taipei Medical University Hospital Department of Surgery, College of Medicine, Taipei Medical University Translational Research Laboratory, Cancer Center, Taipei Medical University Hospital 250 Wu-Xing Street, Taipei, Taiwan 110 Email: [email protected] Phone: 886-2-2736-1661 ext.3025 Fax :886-2-27390946
Page 3 of 27
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
3
Abstract Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting symptoms of mTBI and the characterization of those symptoms has been challenging. Biomarkers that correlate clinical symptoms to disease outcome are desired to improve understanding of the disease and optimize patient care. BMX, a member of the TEC family of nonreceptor tyrosine kinases, is upregulated after traumatic neural injury in a rat model of mTBI. The objective of this investigation was to determine if BMX serum concentrations can effectively be used to predict outcomes after mTBI in a clinical setting. A total of 63 patients with mTBI (Glasgow Coma Score [GCS] between13-15) were included. Blood samples taken at the time of hospital admission were analyzed for BMX. Data collected included demographic and clinical variables. Outcomes were assessed using the Dizziness Handicap Inventory (DHI) questionnaire at baseline and 6 weeks post-injury. The participant was asssigned to ‘case group’ if the subject’s complaints of dizziness became worse at 6th week assessment; otherwise, the participant was assigned to ‘control group ’. A receiver operating characteristic (ROC) curve was constructed to explore BMX level. Significant associations were found between serum levels of BMX and dizziness. Areas under the curve (AUCs) for prediction of change in DHI post-injury were 0.76 for total score, 0.69 for physical score, 0.65 for emotional score and 0.66 for
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Page 4 of 27
4
functional score. Specificities were between 0.69 and 0.77 for total score and
emotional score, respectively. Therefore, BMX demonstrates potential as a candidate
serum biomarker of exacerbating dizziness after mTBI.
Key words: BMX, dizziness, biomarkers, traumatic brain injury
Page 5 of 27
Journal of Neurotrauma Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury (doi: 10.1089/neu.2014.3691) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
5
Introduction Traumatic brain injury (TBI) constitutes a major socioeconomic and health problem, and is one of the leading causes of disability among adults worldwide. TBI can be classified using the Glasgow Coma Scale (GCS; severe
