Magnetic Resonance Spectroscopy following Mild Traumatic Brain Injury: A Systematic Review and Meta-Analysis on the Potential to Detect Posttraumatic Neurodegeneration

Abstract

<b><i>Introduction:</i></b> Traumatic brain injury (TBI) is the most relevant external risk factor for dementia and a major global health burden. Mild TBI (mTBI) contributes to up to 90% of all TBIs, and the classification “<i>mild”</i> often misrepresents the patient’s burden who suffer from neuropsychiatric long-term sequelae. Magnetic resonance spectroscopy (MRS) allows in vivo detection of compromised brain metabolism although it is not routinely used after TBI. <b><i>Objective:</i></b> Thus, we performed a systematic review and meta-analysis to elucidate if MRS has the potential to identify changes in brain metabolism in adult patients after a single mTBI with a negative routine brain scan (CCT and/or MRI scan) compared to aged- and sex-matched healthy controls (HC) during the acute or subacute postinjury phase (≤90 days after mTBI). <b><i>Methods:</i></b> A comprehensive literature search was conducted from the first edition of electronic databases until January 31, 2020. Group analyses were performed per metabolite using a random-effects model. <b><i>Results:</i></b> Four and 2 out of 5,417 articles met the inclusion criteria for the meta-analysis and systematic review, respectively. For the meta-analysis, 50 mTBI patients and 51 HC with a mean age of 31 and 30 years, respectively, were scanned using <i>N</i>-acetyl-aspartate (NAA), a marker for neuronal integrity. Glutamate (Glu), a marker for disturbed brain metabolism, choline (Cho), a marker for increased cell membrane turnover, and creatine (Cr) were used in 2 out of the 4 included articles. Regions of interests were the frontal lobe, the white matter around 1 cm above the lateral ventricles, or the whole brain. NAA was decreased in patients compared to HC with an effect size (ES) of –0.49 (95% CI –1.08 to 0.09), primarily measured in the frontal lobe. Glu was increased in the white matter in 22 mTBI patients compared to 22 HC (ES 0.79; 95% CI 0.17–1.41). Cho was decreased in 31 mTBI patients compared to 31 HC (ES –0.31; 95% CI –0.81 to 0.19). Cr was contradictory and, therefore, potentially not suitable as a reference marker after mTBI. <b><i>Conclusions:</i></b> MRS pinpoints changes in posttraumatic brain metabolism that correlate with cognitive dysfunction and, thus, might possibly help to detect mTBI patients at risk for unfavorable outcome or posttraumatic neurodegeneration early.

Dynamics of Choline-Containing Phospholipids in Traumatic Brain Injury and Associated Comorbidities

“…During the acute phase of TBI, the levels of choline-comprising metabolites tend to increase, due to shearing damage to the cellular membrane. These findings were in line with Eisele et al, who reported that the choline peak on MRS is correlated with the post-TBI myelin breakdown [ 61 ].…”

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases

“…To help identify TBI patients at risk of post-traumatic neurodegeneration, MRS has shown utility in those patients with negative routine CT and/or MRI scans, in the subacute post-injury phase (<90 days). A meta-analysis of MRS studies using N -acetyl-aspartate (NAA) as a marker of neuronal integrity and glutamate (Glu) as a marker of disturbed brain metabolism showed a reduced NAA/Glu ratio in TBI patients, primarily in the frontal lobes, indicating a possible use as a diagnostic tool [ 182 ].…”

Personalized Connectome-Based Modeling in Patients with Semi-Acute Phase TBI: Relationship to Acute Neuroimaging and 6 Month Follow-Up

“…This effect is aligned with other large-scale modeling work that showed structural disconnection associated with decreased metastability, indicating excitation–inhibition imbalance, to be related to poorer cognitive performance in TBI patients ( Hellyer et al, 2015 ). Empirical studies using MRS have also found that elevated concentrations of the neuromodulatory factor glutamate during the semiacute phase were predictive of poorer chronic outcomes ( Shutter et al, 2004 ; Eisele et al, 2020 ).…”

“…Magnetic resonance spectroscopy (MRS) is capable of detecting changes to neuromodulatory concentrations in vivo. A recent meta-analysis found evidence for elevated glutamate concentrations in adult patients after a single mild TBI (mTBI) in the acute and sub-acute phases (Eisele, Hill-Strathy, Michels, & Rauen, 2020). Furthermore, some studies have shown these elevated glutamate concentrations are predictive of long-term outcomes (Shutter, Tong, & Holshouser, 2004).…”