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Neurometabolites Alteration in the Acute Phase of Mild Traumatic Brain Injury (mTBI)

Posted Aug 31, 2018 Updated Apr 10, 2023
By Vigneswaran Veeramuthu PhD , Pohchoo Seow MSc , Vairavan Narayanan FRCS , Jeannie Hsiu Ding Wong PhD , Li Kuo Tan MEng , Aditya Tri Hernowo PhD , Norlisah Ramli FRCR MBBS
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Rationale and Objectives

Magnetic resonance spectroscopy is a noninvasive imaging technique that allows for reliable assessment of microscopic changes in brain cytoarchitecture, neuronal injuries, and neurochemical changes resultant from traumatic insults. We aimed to evaluate the acute alteration of neurometabolites in complicated and uncomplicated mild traumatic brain injury (mTBI) patients in comparison to control subjects using proton magnetic resonance spectroscopy (1H magnetic resonance spectroscopy).

Material and Methods

Forty-eight subjects (23 complicated mTBI [cmTBI] patients, 12 uncomplicated mTBI [umTBI] patients, and 13 controls) underwent magnetic resonance imaging scan with additional single voxel spectroscopy sequence. Magnetic resonance imaging scans for patients were done at an average of 10 hours (standard deviation 4.26) post injury. The single voxel spectroscopy adjacent to side of injury and noninjury regions were analysed to obtain absolute concentrations and ratio relative to creatine of the neurometabolites. One-way analysis of variance was performed to compare neurometabolite concentrations of the three groups, and a correlation study was done between the neurometabolite concentration and Glasgow Coma Scale.

Results

Significant difference was found in ratio of N -acetylaspartate to creatine (NAA/Cr + PCr) (χ 2 (2) = 0.22, P < .05) between the groups. The sum of NAA and N -acetylaspartylglutamate (NAAG) also shows significant differences in both the absolute concentration (NAA + NAAG) and ratio to creatine (NAA + NAAG/Cr + PCr) between groups (χ 2 (2) = 4.03, P < .05and (χ 2 (2) = 0.79, P < .05)). NAA values were lower in cmTBI and umTBI compared to control group. A moderate weak positive correlation were found between Glasgow Coma Scale with NAA/Cr + PCr ( ρ = 0.36, P < .05 and NAA + NAAG/Cr + PCr ( ρ = 0.45, P < .05)), whereas a moderate correlation was seen with NAA + NAAG ( ρ = 0.38, P < .05).

Conclusion

Neurometabolite alterations were already apparent at onset of both complicated and uncomplicated traumatic brain injury. The ratio of NAA and NAAG has potential to serve as a biomarker reflecting injury severity in a quantifiable manner as it discriminates between the complicated and uncomplicated cases of mTBI.

Introduction

Deranged metabolites-induced cellular energy crisis is a common occurrence in traumatic head injury . The cascading events post trauma may lead to terminal membrane depolarization with excessive release of excitatory neurotransmitters , lysis of the cell membranes and apoptosis, disrupting various neural connectivity networks and consequentially affecting neurocognitive function or performance . Injury severity in mild traumatic brain injury (mTBI) could be categorized into complicated or uncomplicated. A complicated mTBI is differentiated from an uncomplicated mTBI by the presence of a closed depressed skull fracture or trauma-related intracranial abnormality or lesion .

The advent of advanced magnetic resonance imaging (MRI) techniques in recent years have enabled reliable assessment of microscopic changes in brain cytoarchitecture, neuronal injuries, and neurochemical changes resultant from traumatic insults. While conventional computed tomography scans and structural magnetic resonance sequences are usually unable to detect such physiological and biochemical changes occurring at cellular level , magnetic resonance spectroscopy (MRS) is capable of evaluating metabolic perturbation associated with mTBI in vivo.

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Methods

Participant Recruitment

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Figure 1, The inclusion and exclusion criteria of the study. CNS, central nervous system; GCS, Glasgow Coma Scale; mTBI, mild traumatic brain injury.

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Magnetic Resonance Imaging Acquisition

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Figure 2, Example of MRI images and spectra of a cmTBI patient with a Lt temporal-extradural hematoma (arrow) (a) axial T1-weighted FSPGR, (b) axial T2-weighted, (c) voxel placed at Lt temporal lobe of white matter (indicated by blue box) with voxel size 19 × 19 × 19 mm, and (d) corresponding neurometabolite profiles after preprocessing using LCModel. 10 The red line is the LCModel fit to spectral data. NAA are labeled at the corresponding peaks. The upper plot is the residuals for indication of LCModel fit. cmTBI, complicated mild traumatic brain injury; FSPGR, fast spoiled gradient-recalled echo; MRI; magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA, N -acetylaspartate; SVS, single voxel spectroscopy. (Color version of figure is available online.)

Figure 3, Example of MRI images and spectra of an umTBI patient's (a) axial T1-weighted FSPGR, (b) axial T2-weighted, (c) voxel placed at Lt occipital lobe of white matter (indicated by blue box) with voxel size 19 × 19 × 19 mm, and (d) corresponding neurometabolite profiles after preprocessing using LCModel. 10 The red line is the LCModel fit to spectral data. NAA are labeled at the corresponding peaks. The upper plot is the residuals for indication of LCModel fit. FSPGR, fast spoiled gradient-recalled echo; MRI; magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA, N -acetylaspartate; umTBI, uncomplicated mild traumatic brain injury; SVS, single voxel spectroscopy. (Color version of figure is available online.)

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Brain Spectra Analysis

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Spectra Inclusion Criteria

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Statistical Analysis

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Results

Patient Demography and Clinical Variables

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Table 1

Demographic Information According to Study Groups (cmTBI, umTBI, and Control)

Type of Injury Demographic/Clinical Presentation cmTBI umTBI Control (n = 23) (n = 12) (n = 13) Age (year) 28.96 (SD 10.2) 28.25 (SD 7.34) 27.15 (SD 4.88) Education (years) 10.96 (SD 1.97) 12.25 (SD 2.70) 16.31 (SD 3.28)

% % % Gender Male 87 83.3 61.5 Female 13 16.7 38.5 GCS on admission GCS 13 21.7 0 n/a GCS 14 39.1 0 n/a GCS 15 39.1 100 n/a Loss of consciousness Yes 95.7 83.3 n/a No 4.3 16.7 n/a Post traumatic amnesia None 21.7 33.3 n/a <1 h 52.2 33.3 n/a >1 h <24 h 26.1 33.3 n/a Voxel placement Frontal lobe 8 2 1 Parietal lobe 10 8 12 Temporal lobe 4 0 0 Occipital lobe 1 2 0

cmTBI, complicated mild traumatic brain injury; GCS, Glasgow Coma Scale; umTBI, uncomplicated mild traumatic brain injury; SD, standard deviation.

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Spectra Analysis

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Table 2

Descriptive Summary for Absolute Metabolite Concentrations

Metabolites cmTBI (n = 23)

(ppm) umTBI (n = 12)

(ppm) Control (n = 13)

(ppm)P Values Mean SD Mean SD Mean SD Glu 2.817 0.387 2.988 0.371 2.736 0.272 .313 GPC 0.572 0.147 0.685 0.068 0.660 0.109 .166 Ins 1.633 0.347 1.759 0.147 1.576 0.271 .878 NAA 2.690 0.536 2.862 0.541 3.019 0.284 .058 GPC + PCh 0.585 0.129 0.666 0.046 0.660 0.109 .076 NAA + NAAG 3.097 0.775 3.235 0.708 3.620 0.352 .027 \* Cr + PCr 1.702 0.340 1.693 0.217 1.766 0.225 .591 Glu + Gln 4.195 0.831 4.150 0.422 3.634 0.328 .120 MM09 1.895 0.574 2.20 0.600 2.319 0.477 .173 MM20 3.105 0.826 3.206 0.448 3.614 0.546 .174 MM09 + Lip09 1.98 0.553 2.440 0.354 2.554 0.692 .144 MM20 + Lip20 3.162 0.8 3.215 0.434 3.736 0.608 .264

cmTBI, complicated mild traumatic brain injury; Cr, creatine; Gln, glutamine; Glu, glutamate; GPC, glycerophosphocholine; Ins, inositol; MM09 + Lip09, sum mixture of macromolecules and lipids signals at around 0.9 ppm; MM09, macromolecules at signals around 0.9 ppm; MM20 + Lip20, 2.0 ppm; MM20, macromolecules at signals around 2.0 ppm; NAA, N -acetylasparte; NAAG, N -acetylaspartylglutamate; PCh, phosphocholine; PCr, phosphocreatine; ppm, parts per million; SD, standard deviation; umTBI, uncomplicated mild traumatic brain injury.

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Table 3

Descriptive Summary for Relative Metabolite Concentrations Over Total Creatine

Metabolites (/Cr + PCr) cmTBI (n = 23)

(ppm) umTBI (n = 12)

(ppm) Control (n = 13)

(ppm)P Values Mean SD Mean SD Mean SD Glu 1.699 0.293 1.782 0.250 1.567 0.215 .222 GPC 0.343 0.1 0.395 0.035 0.374 0.049 .705 Ins 0.978 0.219 1.050 0.101 0.894 0.129 .291 NAA 1.593 0.202 1.68 0.163 1.72 0.125 .025 \* GPC + PCh 0.354 0.097 0.397 0.035 0.374 0.049 .771 NAA + NAAG 1.82 0.282 1.895 0.287 2.059 0.11 .004 \* Glu + Gln 2.464 0.435 2.352 0.376 2.051 0.336 .139 MM09 1.098 0.249 1.278 0.253 1.289 0.216 .402 MM20 1.796 0.332 1.882 0.096 2.028 0.361 .282 MM09 + Lip09 1.149 0.229 1.367 0.191 1.418 0.330 .400 MM20 + Lip20 1.831 0.307 1.889 0.099 2.097 0.399 .619

cmTBI, complicated mild traumatic brain injury; Cr, creatine; Gln, glutamine; Glu, glutamate; GPC, glycerophosphocholine; Ins, inositol; MM09 + Lip09, sum mixture of macromolecules and lipids signals at around 0.9 ppm; MM09, macromolecules at signals around 0.9 ppm; MM20 + Lip20, 2.0 ppm; MM20, macromolecules at signals around 2.0 ppm; NAA, N -acetylasparte; NAAG, N -acetylaspartylglutamate; PCh, phosphocholine; PCr, phosphocreatine; ppm, parts per million; SD, standard deviation; umTBI, uncomplicated mild traumatic brain injury.

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Figure 4, Example of MRI images and spectra of a control patient's (a) axial T1-weighted FSPGR, (b) axial T2-weighted, (c) voxel placed at Rt occipital lobe of white matter (indicated by blue box) with voxel size 19 × 19 × 19 mm, and (d) corresponding neurometabolite profiles after preprocessing using LCModel. 10 The red line is the LCModel fit to spectral data. NAA are labeled at the corresponding peaks. The upper plot is the residuals for indication of LCModel fit. FSPGR, fast spoiled gradient-recalled echo; MRI; magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA, N -acetylaspartate; SVS, single voxel spectroscopy. (Color version of figure is available online.)

Table 4

The Post Hoc Test for Absolute Metabolite Concentration NAA + NAAG

I Group J Group Mean Difference (I-J) Std Error Sig 95% CI Lower Bound Upper Bound cmTBI umTBI −0.502 0.255 0.132 −1.12 0.116 Control −0.636 0.248 0.036 \* −1.238 −0.339 umTBI cmTBI 0.502 0.255 0.259 −0.095 0.459 Control −0.134 0.287 0.132 −0.116 1.12

CI, confidence interval; cmTBI, complicated mild traumatic brain injury; NAA, N -acetylasparte; NAAG, N -acetylaspartylglutamate; umTBI, uncomplicated mild traumatic brain injury.

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Table 5

The Post Hoc Test for Metabolite Ratio NAA + NAAG/Cr + PCr

I Group J Group Mean Difference (I-J) Std Error Sig 95% CI Lower Bound Upper Bound cmTBI umTBI −0.227 0.899 0.039 \* −0.445 0.009 Control −0.279 0.088 0.007 \* −0.491 −0.066 umTBI cmTBI 0.227 0.090 0.039 \* 0.009 0.445 Control −0.052 0.101 0.866 −0.297 0.193

CI, confidence interval; cmTBI, complicated mild traumatic brain injury; NAA + NAAG/Cr + PCr, N -acetylasparte and N -acetylaspartylglutamate/creatine and phosphocreatine; umTBI, uncomplicated mild traumatic brain injury.

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Associations Between Neurometabolites With Injury Complexity and GCS

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Figure 5, The box plots of neurometabolites distributions (a) NAA/Cr + PCr, (b) NAA + NAAG, and (c) NAA + NAAG/Cr + PCr across the groups, and (d) NAA/Cr + PCr, (e) NAA + NAAG, and (f) NAA + NAAG/Cr + PCr across the GCS scores. The values beside the boxplots describe the median value of the neurometabolites. GCS, Glasgow Coma Scale; NAA/Cr + PCr, N -acetylaspartate to creatine and phosphocreatine; NAA + NAAG, N -acetylasparte and N -acetylaspartylglutamate; NAA + NAAG/Cr + PCr, N -acetylasparte and N -acetylaspartylglutamate/creatine and phosphocreatine.

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Discussion

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Conclusion

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Acknowledgments

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Academic Radiology, Volume 25, Issue 9
Journals General Radiology
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