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 Table of Contents  
STUDY PROTOCOL
Year : 2016  |  Volume : 1  |  Issue : 4  |  Page : 170-176

Cognitive function and biomarkers after traumatic brain injury: protocol for a prospective inception cohort study


Department of Neurosurgery, the 101st Hospital of PLA, Wuxi, Jiangsu Province, China

Date of Web Publication7-Nov-2016

Correspondence Address:
Yu-hai Wang
Department of Neurosurgery, the 101st Hospital of PLA, Wuxi, Jiangsu Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2468-5577.193144

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  Abstract 

Background: Traumatic brain injury is a high-incidence condition that can cause severe cognitive impairment. At present, functional magnetic resonance imaging is used to analyze changes in brain function and network connectivity at different stages of injury. In addition, tau protein expression in nerve cells may reflect cognitive function. However, the combined use of functional magnetic resonance imaging and tau measurement to assess cognitive function following traumatic brain injury has not yet been investigated.
Methods/Design: A prospective inception cohort study will be performed at the 101 st Hospital of PLA, Wuxi, China. We will conduct a follow-up visit in 100 patients with traumatic brain injury. Cognitive function will be assessed within 24 hours of injury and 0.5, 1, and 2 years after injury. Primary outcomes will be the Montreal Cognitive Assessment score, functional magnetic resonance imaging results, and tau protein level in the cerebrospinal fluid. Secondary outcomes will include Mini-Mental State Examination Scale and Hamilton Depression Scale scores. We will assess cognitive function in patients with traumatic brain injury and analyze its correlation with functional imaging indexes and tau levels in the cerebrospinal fluid.
Discussion: This trial has been designed to determine whether functional imaging indexes and tau level in the cerebrospinal fluid can predict recovery of cognitive function in patients with traumatic brain injury. It will provide objective evidence for the clinical prevention and treatment of cognitive dysfunction following traumatic brain injury.
Trial registration: This trial was registered at Chinese Clinical Trial Registry (registration number: ChiCTR-OOC-16008574) on 31 May 2016.
Ethics: Approved by the Ethics Committee of the 101 st Hospital of PLA, China (approval number: L2016002), the study protocol will be performed in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association.
Informed consent: Written informed consent will be obtained from participants or their guardians.

Keywords: clinical trial; traumatic brain injury; cognitive function; biomarkers; functional magnetic resonance imaging; prospective inception cohort study


How to cite this article:
Lin W, Yang Lk, Cai S, Zhu J, Feng Y, Yang Lx, Feng Zz, Li Pp, Chen Jh, Wang Yh. Cognitive function and biomarkers after traumatic brain injury: protocol for a prospective inception cohort study. Asia Pac J Clin Trials Nerv Syst Dis 2016;1:170-6

How to cite this URL:
Lin W, Yang Lk, Cai S, Zhu J, Feng Y, Yang Lx, Feng Zz, Li Pp, Chen Jh, Wang Yh. Cognitive function and biomarkers after traumatic brain injury: protocol for a prospective inception cohort study. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2016 [cited 2019 May 24];1:170-6. Available from: http://www.actnjournal.com/text.asp?2016/1/4/170/193144


  Introduction Top


Traumatic brain injury (TBI) occurs when external forces, such as a blow, collision, or penetration, traumatically damage the brain, resulting in mechanical deformations in the skull, meninges, blood vessels and tissues. TBI is a major cause of death and disability worldwide, especially in children and young people, and can cause considerable suffering and financial strain to patients and those close to them (D'Ambrosio and Perucca, 2004; Maas et al., 2008; Kochanek et al., 2012; Almeida et al., 2015; Levin and Diaz-Arrastia, 2015; Lind et al., 2016). Moreover, the number of patients with TBI is increasing owing to the growing number of vehicles on the road (Maas et al., 2008).

TBI comprises primary and secondary injuries. Primary intracranial injuries mostly occur when the tissues and blood vessels are damaged directly, leading to cell death or neurological damage. Secondary injuries are varied and complex, involving damage to the blood-brain barrier, cytokine secretion, free radical overload, excessive release of neurotransmitters, calcium and sodium ion influx in neurons, mitochondrial dysfunction, cerebral blood flow changes, substantial changes in intracranial pressure and movement dysfunction, traumatic epilepsy, and personality changes (Parikh et al., 2007; Park et al., 2008; Kochanek et al., 2012; Strathmann et al., 2014; Helmick et al., 2015; Levin and Diaz-Arrastia, 2015). Patients with TBI develop long-term physiological, cognitive, social, emotional and behavioral impairments. Current tools for post-TBI cognitive function assessment are simple, real-time scales (Yang et al., 2012) that cannot provide effective evidence for prognosis or treatment (Michael et al., 2015). Therefore, there is an urgent need for an objective means of assessing TBI.

Functional magnetic resonance imaging (fMRI) is an established neuroimaging detection tool that measures hemodynamic variation caused by neuronal activity. Its spatiotemporal resolution is relatively high, and the technique is non-invasive and non-radiative. As such, fMRI has been widely used in the assessment of brain function since the 1990s (Belliveau et al., 1990), including measuring changes in brain function and network connectivity at different stages of TBI (Sharp et al., 2014; Altmeyer et al., 2016; Banks et al., 2016; Herrera et al., 2016; Li et al. , 2016).

Tau proteins are microtubule-associated proteins mainly found in neuronal axons and cytoplasm, which promote tubulin polymerization into microtubules, stabilize microtubules and maintain neurological effects (Buée et al., 2000). It was recently observed that tau was released from the neurons into the cerebrospinal fluid during nerve cell necrosis and apoptosis (Tapiola et al., 2009; Skillbäck et al., 2015). Tau protein is therefore considered a marker of nerve cell damage. Existing evidence from patients with TBI suggests that there is an excess of tau protein in the brain during long-term follow-up and at autopsy. This may be the main cause of continued cognitive, movement, behavioral and mental disorders after TBI (Mitsis et al., 2014; Laskowski et al., 2015). Combining fMRI and cerebrospinal fluid biomarker analysis will help us to understand the changes in cognitive function that occur after TBI.

Our study will determine the relationship between changes in brain imaging, level of tau in the cerebrospinal fluid, and cognitive function in patients with TBI, thereby providing a clinical basis for the early diagnosis, prevention and treatment of cognitive disorders in TBI patients.

By retrieving articles in Medline and ClinicalTrial.gov from 2014 to 2016, we found that relevant studies focused only on fMRI and cerebrospinal fluid biomarker analysis in patients with TBI ([Table 1], [Table 2]), without investigating the relationships of these measures to cognitive function.
Table 1: Studies of biomarkers and imaging analysis in patients with traumatic brain injury (TBI) published in 2014– 2016 in the MEDLINE database

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Table 2: Clinical trials registered at ClinicalTrials.gov addressing biomarker and imaging analysis in patients with traumatic brain injury (TBI)

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  Methods/Design Top


Study design

A single-group prospective inception cohort study.

Study setting

This trial will be carried out at the 101st Hospital of PLA, Wuxi, China.

Study procedures

We will recruit 100 patients admitted to the 101st Hospital of PLA with TBI, who will be screened through inclusion and exclusion criteria and baseline assessment. All patients' legal representatives will be invited to give informed consent prior to the trial. Each patient will be assessed using the Mini-Mental State Examination, Montreal Cognitive Assessment, Hamilton Depression Scale, fMRI, and tau protein measurement in the cerebrospinal fluid within 24 hours of admission and 0.5, 1, and 2 years after TBI. We will analyze the correlation between cognitive function, fMRI results, and tau levels. The flow chart of the study protocol is shown in [Figure 1].
Figure 1: Flow chart of the trial protocol.
Note: TBI: Traumatic brain injury


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Study participants

Patients with TBI will be recruited from the inpatients or outpatients admitted to the 101st Hospital of PLA.

Inclusion criteria

Patients who meet all the following criteria will be eligible for this trial:

  • Brain damage caused by external force
  • Cerebral edema/intracranial hematoma shown by brain CT or X-ray
  • Short-term (or no) decrease in consciousness, or showing cognitive, behavioral or mental impairment
  • 18-80 years of age


Exclusion criteria

Patients who meet one of the following criteria will be excluded from the trial:

  • Severe chronic diseases, such as cancer, chronic renal failure, severe respiratory insufficiency
  • Severe heart failure, central nervous system disorders and systemic infections
  • Crush syndrome
  • Other organic damages
  • Hemoglobin and albumin loss resulting from active bleeding from other body parts
  • Onset > 6 hours before admission, or death within 72 hours of admission
  • Pregnant


Withdrawal criteria

Patients will be withdrawn from the trial if one of the following conditions occurs:

  • Complications affecting efficacy and safety of judgment
  • Unable to complete a 2-year follow-up visit


Sample size

As in previous comparable studies (Vos et al., 2010; Wu et al., 2011; Lei et al., 2015), the proposed sample size of 100 patients takes into account the available research funds. The sample size will be calculated in line with the intention-to-treat principle.

Baseline data

Data collected at baseline will include demographic data (gender, age, body weight, level of education), causes of brain damage, and general medical history ([Table 3]).
Table 3: Baseline assessment of patients

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Recruitment

Ongoing recruitment of outpatients or inpatients will be carried out by neurological physicians. Patients interested in participating in the trial will contact the lead investigator by telephone, e-mail or WeChat.

Outcome measures

Recovery of neurological function after TBI usually takes more than 2 years, although it can be achieved within 6 months (Ponsford et al., 2008). All indicators will therefore be measured within 24 hours, and 0.5, 1, and 2 years after TBI.

Primary outcomes

  • Montreal Cognitive Assessment: modified from the Mini-Mental State Examination, this is a widely used scale for detecting cognitive impairment. This scale is easy to use and correlates cognitive impairment with different brain injury sites. The scale assesses the following domains: orientation, attention, naming, visuospatial and implementation capacity, memory, abstraction and language skills. The maximum score is 30; patients with scores ≤ 26 are considered to have cognitive impairment. Patients who have over 12 years of education will have 1 point subtracted to their test score to correct for the deviation of education (Julayanont et al., 2015).
  • fMRI indicators: 3T MRI scanners (GE, Boston, MA, USA) will be used for fMRI detection. The patient will lie flat on his/her back, keeping still and quiet, and T1, T2, DTI and resting state functional sequences will be collected.
  • Tau protein level in the cerebrospinal fluid: cerebrospinal fluid samples from patients with TBI will be collected during subarachnoid puncture or postoperative drainage within 24 hours of injury, and at 0.5, 1, and 2 years after injury. Tau protein level in the cerebrospinal fluid will be measured using an ELISA kit (Abcam Trading (Shanghai) Company Ltd., Shanghai, China).


Secondary outcomes

  • Mini-Mental State Examination Scale (Folstein et al., 1975): This scale is one of the most influential standardized tools for intelligence assessment, and involves orientation, memory, attention/calculation, recall, and language skills (maximum score of 30). It can be used to detect cognitive impairment.
  • Hamilton Depression Scale (Hamilton, 1960): This is the most commonly used scale for clinical assessment of depression. It has 24 domains; higher scores indicate more severe depression.


The schedule for outcome assessments is shown in [Table 4].
Table 4: Timing of outcome assessment

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Data collection, management, analysis, and open access

Data collection


Clinical researchers will be responsible for the accurate, full, and timely completion of case report forms. All data will be electronically input by two independent data entry clerks.

Data management

After database confirmation, the database will be locked by the lead investigator. The locked data will not be altered and will be preserved by the 101st Hospital of PLA.

Data analysis

All data will be analyzed by professional statisticians.

Open data

Published data will be released at http://www.figshare.com.

Statistical analysis

Measurement data will be expressed as the mean ± SD, and count data as percentages. All data will be analyzed statistically using SPSS 19.0 (IBM Corp., Armonk, NY, USA). Repeated measures analysis of variance will be used for intragroup comparisons between time points, and Spesarman correlation analysis for calculating the relationship of fMRI indicators and tau level in the cerebrospinal fluid with cognitive function in patients. A value of P < 0.05 will be considered statistically significant.

Auditing

Trial progress will be reported to the ethics committee of the 101st Hospital of PLA every 3 months, and relevant data will be updated in the Chinese Clinical Trial Registry.

Confidentiality

Electronic data will be stored on a dedicated computer, and the password will be set and managed by a data administrator. Paper reports will be preserved in a secure and locked place by the data administrator and lead investigator.


  Trial Status Top


Recruitment is ongoing at the time of submission.


  Discussion Top


Previous studies have attempted to monitor cognitive function in patients with TBI using a variety of markers for brain damage, all of which were confirmed unsuitable for clinical use because of tissue-specific issues (Strathmann et al., 2014). In the present trial, we will conduct a follow-up assessment of participants' cognitive function, and analyze the relationship between changes in brain imaging, cerebrospinal fluid biomarkers, and cognitive function after TBI.

The 101st Hospital of PLA is the military TBI treatment center, and as such is the largest center for brain trauma in Wuxi, China. The hospital sees a sufficient number of patients with TBI who will meet the inclusion criteria and whose rights will be guaranteed as written informed consent will be obtained prior to participation. The follow-up time will be up to 2 years, to cover the period of recovery from TBI (Maas et al., 2008).

A limitation of the study is that tau level in the cerebrospinal fluid will only be detected after TBI, and its baseline will not be known. This might have an impact on subsequent analysis, so future case-control studies will be warranted.

The aim of this trial is to offer an effective biomarker for predicting the development of and recovery from cognitive impairment in patients with TBI, thereby providing an objective basis for the clinical prevention and treatment of TBI.[35]

 
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Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form the patient(s) will give his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
None declared.
Author contributions
YHW is responsible for the trial; WL and LKY are the main implementers; others are project-specific operators. All authors have approved the final version of the manuscript.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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