Mild Traumatic Brain Injury Results in Significant and Lasting Cortical Demyelination

Do we have demyelination in stroke and what is the solution to that?

Mild Traumatic Brain Injury Results in Significant and Lasting Cortical Demyelination

Sean O. Mahoney^1†, Nahian F. Chowdhury^1†, Van Ngo¹, Phoebe Imms¹ and Andrei Irimia^1,2* for the Alzheimer's Disease Neuroimaging Initiative^‡

• ¹Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States
• ²Corwin D. Denney Research Center, Department of Biomedical Engineering, Andrew and Edna Viterbi School of Engineering, University of Southern California, Los Angeles, CA, United States

Despite contributing to neurocognitive deficits, intracortical demyelination after traumatic brain injury (TBI) is understudied. This study uses magnetic resonance imaging (MRI) to map intracortical myelin and its change in healthy controls and after mild TBI (mTBI). Acute mTBI involves reductions in relative myelin content primarily in lateral occipital regions. Demyelination mapped ~6 months post-injury is significantly more severe than that observed in typical aging (p < 0.05), with temporal, cingulate, and insular regions losing more myelin (30%, 20%, and 16%, respectively) than most other areas, although occipital regions experience 22% less demyelination. Thus, occipital regions may be more susceptible to primary injury, whereas temporal, cingulate and insular regions may be more susceptible to later manifestations of injury sequelae. The spatial profiles of aging- and mTBI-related chronic demyelination overlap substantially; exceptions include primary motor and somatosensory cortices, where myelin is relatively spared post-mTBI. These features resemble those of white matter demyelination and cortical thinning during Alzheimer's disease, whose risk increases after mTBI.

Introduction

Approximately 1.7 million Americans sustain traumatic brain injuries (TBIs) every year (1), ~75% of which are mild TBIs (mTBIs). TBI can cause cerebral demyelination, mechanical damage to axons, and impairment of remyelination mechanisms resulting in either insufficient or excessive remyelination (2). These phenomena can contribute to secondary traumatic axonal injury, oligodendrocyte dysfunction, and/or brain cell death (3). Together, such events can lead to macroscale brain structure changes associated with cognitive deficits (4), mild cognitive impairment (MCI) (5, 6), Alzheimer's disease (AD) (7) and other neurological disorders (8).

Whereas both acute and chronic post-traumatic demyelination of the cerebral cortex have been studied extensively in animals (9–11), hardly any human studies have quantified the spatial profiles and extent of these phenomena. This is due partly to the challenges of measuring human cortical myelin content in vivo. The gold standard for measuring human cortical myelin content is post-mortem histopathological examination. However, as Glasser & Van Essen (12) showed, the ratio R of T₁- to T₂-weighted magnetic resonance images (MRIs) provides an accurate measure of brain myelin content because T₁-weighted MRI intensity and the reciprocal of T₂-weighted MRI intensity are both proportional to myelin content. Computing R offers improved myelin estimates because this measure implicitly adjusts for nuisance effects that can contribute to the intensities of each distinct MRI modality (13, 14).

Studies have confirmed the reliability of the T₁/T₂-weighted MRI intensity ratio R as a trustworthy measure reflecting relative intracortical myelin content after TBI (15). Specifically, in TBI subjects, cortical maps of R are not only consistent with maps of myelin content inferred from histopathology, but also confirmatory of the fact that TBI is associated with relatively lower cortical myelin content in cross-section (15). To our knowledge, no detailed longitudinal study of post-traumatic cortical myelin change has been published.

Due to the potential to stimulate remyelination before axonal injury occurs, myelination-related therapies are being investigated to improve mTBI outcomes (16). Furthermore, better understanding of the effects of mTBI on brain architecture can improve surgical intervention (17, 18). For these and other potential reasons, the study of post-traumatic demyelination is clinically relevant. This study quantifies how the T₁/T₂ MRI intensity ratio R of the gray matter (GM) changes across the first ~6 months after mTBI relative to age- and sex- matched healthy controls (HCs). Whereas other studies have mapped R after TBI, this is the first study that leverages MRI to quantify post-traumatic cortical myelin changes and to map the spatial patterns of these changes.

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