Traumatic brain injury (TBI) is a major and serious public-health concern throughout the world [
In most mTBI cases, cognitive impairment is nonspecific and CT or MRI shows normal structure; therefore, patients might be underestimated, leading to long-term disabilities in their work and social interactions. Therefore, potential noninvasive, advanced MRI methods that can contribute to the prediction of cognitive dysfunction in patients with mTBI are demanded.
Susceptibility weighted imaging (SWI) which has the potential to provide the increased sensitivity needed to detect and characterize lesions is a high-resolution structural MRI technique. It uses a sequence that is sensitive to the presence of iron and blood products and functional blood oxygenation changes [
As the relationship between brain iron and cognitive impairment in patients in the chronic stage of mTBI remains poorly understood, this study was to examine whether the usability of SWI in assessment of brain iron could detect cognitive dysfunction in patients with chronic mild traumatic brain injury. We hypothesized that angle radian values can be associated with cognitive impairment in order to establish the clinical utility of SWI as a prognostic biomarker of patients suffering cognitive dysfunction after mTBI.
The study was approved by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and it was performed in accordance with the Declaration of Helsinki. All patients gave written informed consent.
Patients with mTBI (
The control participants (
Patients and healthy control participants who were left-handed were excluded.
Cognitive function was determined by Chinese language version of the Mini-Mental State Examination (MMSE) [
All of the participants underwent a research MRI scan at least 6 months after injury (
Comparison of the patient cohort with study population.
|
Patients ( |
Healthy controls ( |
---|---|---|
Age (yr), mean (SD) | 38.54 ± 13.15 | 38.51 ± 13.21 |
Male : female | 22 : 17 | 19 : 18 |
Initial GCS (range) | 14.08 ± 0.84 (13–15) | |
Time after injury (mo) | 19.37 ± 7.88 | |
MMSE | 25.21 ± 1.77 |
The images were acquired on a 3T MR Scanner (MAGENTOM, Verio, Siemens Healthcare, Erlangen, Germany) using a 32-channel head coil. The imaging sequences consisted of T1W, T2W, diffusion weighted imaging (DWI), and fluid-attenuated inversion recovery (FLAIR) and SWI. The scanning parameters were as follows: T2W: axial scanning TR/TE, 6000 ms/95 ms; flip angle, 150°; an image matrix,
Angle radian values were measured with the phase image. Two neuroradiologists with more than 5 years of experience were blind to patients’ clinical details that manually outlined the head of the caudate nucleus, the lenticular nucleus, hippocampus, thalamus, substantia nigra, red nucleus, the genu of corpus callosum (GCC), splenium of the corpus callosum (SCC), white matter of the frontal lobe, and the cerebellum as the regions of interest (ROIs) based on T1W and magnitude images. The ROIs were drawn in a single slice where they were best seen. Their size was adapted to the size of the structure, but the borders of the structures were excluded to avoid partial volume effects [
Representative locations of the ROIs (arrows) on axial T1W images and corresponding phase images: (a) lobe of white matter; (b) splenium of the corpus callosum (SCC); (c) hippocampus; (d) substantia nigra; (e) red nucleus; (f) head of caudate nucleus; (g) lenticular nucleus; (h) thalamus.
Analysis of covariance and correction for multiple comparisons by using Levene’s Test for Equality of Variances were performed in the study to compare differences between patients with mTBI and the controls in terms of regional angle radian values, adjusted for age. The relationship of the angle radian values with the MMSE scores was evaluated using Spearman correlations. A
The means and SDs of the angle radian values in patient and control groups are summarized in Table
Comparison of angle radian values in 15 brain regions between mTBI group and control group.
|
mTBI | Controls |
|
|
||
---|---|---|---|---|---|---|
Mean | SD | Mean | SD | |||
Brain region | ||||||
L, head of caudate nucleus |
|
0.8224 |
|
0.8223 | 480.453 | <0.001 |
R, head of caudate nucleus |
|
0.8223 |
|
0.4298 | 111.287 | <0.001 |
L, lenticular nucleus |
|
1.0171 |
|
0.4298 | 124.104 | <0.001 |
R, lenticular nucleus |
|
0.8223 |
|
0.624 | 1255.25 | <0.001 |
L, happocampus |
|
2.2719 |
|
1.721 | 4.397 | 0.039 |
R, happocampus |
|
1.0905 |
|
0.632 | 25.886 | <0.001 |
L, thalamus |
|
1.4037 |
|
1.4112 | 0.096 | 0.745 |
R, thalamus |
|
1.8679 |
|
1.9001 | 0.098 | 0.755 |
L, substantia nigra |
|
1.6514 |
|
1.5949 | 1.033 | 0.313 |
R, substantia nigra |
|
2.2027 |
|
1.6056 | 12.351 | <0.001 |
L, red nucleus |
|
2.2036 |
|
1.5068 | 5.014 | 0.028 |
R, red nucleus |
|
1.5869 |
|
1.065 | 79.547 | <0.001 |
Splenium of the corpus callosum (SCC) |
|
1.9476 |
|
1.4037 | 8.458 | 0.005 |
L, white matter of frontal lobe |
|
1.9091 |
|
1.8679 | 0.1 | 0.753 |
R, white matter of frontal lobe |
|
1.895 |
|
1.8745 | 0.095 | 0.759 |
Note: asterisk indicates statistically significant comparisons.
The cognitive scores of patients group are reported in Table
Between 10% and 20% of individuals experience persistent cognitive symptoms in the chronic stage of mTBI [
Diffusion tensor imaging (DTI) has been considered as a biomarker for mTBI, as white matter (WM) microstructural alteration can be visualized. Two reports [
Patients with mTBI who have cognitive impairment usually show decreased spontaneous brain activity on a functional MRI (fMRI) [
Recent animal and human studies have implicated abnormal iron in the pathogenesis of the neurodegenerative disorders [
A signal strength method was employed to detect brain iron, using
In the present study, increased angle radian values were observed, using SWI, in a number of regions, including the head of the caudate nucleus, the lenticular nucleus, the hippocampus, the red nucleus, the substantia nigra, and the SCC, which suggests that iron might be a source of pathology in mTBI in line with a small body of studies [
We found that angle radian values changes were most predominantly in gray matter (GM), a result that is consistent with previous reports [
Recent DTI studies of animals and humans have demonstrated that increased FA in GM is linked to prolonged symptoms [
Increased angle radian values in mTBI could indicate excessive iron deposition to some extent. In vivo iron plays an essential role in the metabolic processes as a cofactor for numerous proteins. Brain iron abnormalities belong to two categories of physiologic iron: nonheme iron and heme iron [
Abnormal iron deposition can be injurious to the brain and brain systems, as iron is a transitional metal and participates in redox reactions to form reactive oxygen species (ROS) that, in turn, can cause oxidative stress [
MMSE scores in the present study were negatively correlated with angle radian values in the right substantia nigra in the mTBI group, suggesting that cognitive impairment might be related to abnormal accumulation of iron. The substantia nigra is involved in reward and addiction. But now, there has been evidence of iron storage in the substantia nigra which is involved in cognitive impairment as well such as spatial memory performance. Meanwhile, the brain iron content is increased in the substantia nigra pars compacta (SNc) of PD patients; further, this area is known to have abnormal brain iron level in a host of pathological conditions, such as AD [
We did not find significant increases in angle values in the thalamus, the white matter of frontal lobe, and the left substantia nigra. This can be partly examined by the fact that lower accumulation of iron was revealed in the examined areas [
This is the first study to investigate the correlation between brain iron and cognitive impairment among patients in the chronic stage of mTBI using SWI. The study found that patients in the chronic stage of mTBI have multiple regions of increased angle radian values, including the head of the caudate nucleus, the lenticular nucleus, the hippocampus, the red nucleus, the substantia nigra, and the SCC. The increased angle radian values in the right substantia nigra are strongly implicated in being related to persistent cognitive impairments in patients with chronic mTBI. In conclusion, this study suggested a role of SWI for the estimation of cognitive impairment of mTBI patients in the chronic stage.
No competing financial interest exists.
Liyan Lu conceived and designed the experiments. Liyan Lu and Heli Cao performed the experiments. Xiaoer Wei and Yuehua Li analyzed the data. Wenbin Li has conducted supervision of the study.
This study is supported by the National Natural Scientific Foundation of China (NSFC; no. 81271540 and no. 81301213) and the Science and Technology Commission of Shanghai Municipality Grant (STCSM; no. 08411951200).