Does white matter and vascular injury from repetitive head impacts lead to a novel pattern on T2 FLAIR MRI? A hypothesis proposal and call for research

Abstract

The goal of this paper is to introduce the hypothesis that white matter (WM) and vascular injury are long-term consequences of repetitive head impacts (RHI) that result in a novel T2 fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging pattern. A non-systematic literature review of autopsy and FLAIR studies of RHI-exposed adults was first conducted as a foundation for our hypothesis. A case series of RHI-exposed participants is presented to illustrate the unique FLAIR WM hyperintensities (WMH) pattern. Current literature shows a direct link between RHI and later-life WM/vascular neuropathologies, and that FLAIR WMH are associated with RHI, independent of modifiable vascular risk factors. Initial observations suggest a distinctive pattern of WMH in RHI-exposed participants, termed RHI-associated WMH (RHI-WMH). RHI-WMH defining features are as follows: (1) small, punctate, non-confluent, (2) spherical, and (3) proximal to the gray matter. Our hypothesis serves as a call for research to empirically validate RHI-WMH and clarify their biological and clinical correlates. HIGHLIGHTS: Repetitive head impacts (RHI) have been associated with later-life white matter (WM) and vascular neuropathologies. T2 FLAIR MRI of RHI-exposed participants reveals a potentially unique WM hyperintensity (WMH) pattern that is termed RHI-associated WMH (RHI-WMH). RHI-WMH are characterized as (1) small, punctate, and non-confluent, (2) spherical, and (3) proximal to the gray matter at an area anatomically susceptible to impact injury, such as the depths of the cortical sulci.

Keywords: FLAIR MRI; RHI‐WMH; chronic traumatic encephalopathy; contact and collision sports; fluid attenuated inversion recovery neuroimaging biomarkers; head trauma; neurodegenerative disease; repetitive head impacts; repetitive head impact‐associated white matter hyperintensities; traumatic brain injury; traumatic encephalopathy syndrome; white matter hyperintensities.

FIGURE 1

Conceptual framework of the associations between repetitive head impacts (RHI), neuropathologies, clinical outcomes, and modifiers. The lists of pathologies, clinical outcomes, and modifiers are not exhaustive. Neuropathologies not included in this figure but that are still associated with RHI include, but are not limited to, presence of Lewy bodies, alpha synuclein, amyloid beta (Aβ), and transactive response DNA‐binding protein with 43 kDa (TDP‐43) deposits.

FIGURE 2

Pathognomonic lesion of chronic traumatic encephalopathy (CTE). This figure, taken from McKee et al., shows microscopic findings in stage II CTE. A, Whole mount coronal sections in stage II CTE show multiple foci of phosphorylated tau (p‐tau) pathology primarily located at the depths of the cortical sulci of the frontal and temporal lobes (free floating 50 μ sections, AT8 immunostain). B–H, The p‐tau pathology consists of neurofibrillary tangles and dot‐like and thread‐like dystrophic neurites and is characteristically found around small blood vessels (B–F, free floating 50 μ sections, AT8 immunostain, G, H, 10 μ paraffin embedded sections, AT8 immunostain). I, Subpial astrocytic tangles are also found at the cortical depths (free floating 50 μ sections, AT8 immunostain). Other pathologies include pretangles (J), dystrophic neurites in the white matter (K), and occasional p‐tau astrocytes (L; free floating 50 μ sections, AT8 immunostain). There may be marked astrocytosis of the white matter (M, N; free floating 50 μ sections, glial fibrillary acidic protein immunostain). Hemosiderin‐laden macrophages (O; 10 μ paraffin section, Luxol fast blue hematoxylin and eosin stain) and multiple perivascular foci of reactive microglia (P) are found around small vessels in the cerebral white matter (free floating 50 μ sections, LN3 immunostain). Text taken from McKee et al.

FIGURE 3

White matter rarefaction in a participant with chronic traumatic encephalopathy. Figure from Alosco et al. A, Luxol fast blue with hematoxylin–eosin histochemical staining shows robust myelin staining (blue) in a former US football college player in his early 40s who was neuropathologically diagnosed with chronic traumatic encephalopathy (CTE; stage I/II) who was not determined to have had antemortem dementia. B, A man who had played professional US football, was in his mid‐80s, had been neuropathologically diagnosed with CTE (stage III/IV), and was determined by consensus to have dementia, there was severe loss (3+) of myelinated fibers. Text adapted from Alosco et al.

FIGURE 4

Cross‐sectional model on the contributions of white matter rarefaction, arteriolosclerosis, and phosphorylated tau to dementia in chronic traumatic encephalopathy (CTE). Figure from Alosco et al. Simultaneous equations regression models tested the association of pathological markers of cerebrovascular disease with dementia in older deceased individuals who had played football and had CTE. Not all variables or pathways are displayed for ease of presentation. The β values shown are standardized estimates, and each path shown is significant at an α < 0.05. Standardized estimates permit direct comparison of the effect sizes across pathways. The dashed line between years of football play and dementia denotes a significant indirect effect in which the association of years of football play with dementia was mediated by dorsolateral frontal cortex neurofibrillary tangles and severity of white matter rarefaction. Text adapted from Alosco et al. ^.

FIGURE 5

Pathology in brain areas susceptible to damage by repetitive head impact (RHI). A, Figure taken from Holleran et al. Phosphorylated tau (p‐tau), myelin black gold II, and high‐resolution ex vivo diffusion tensor imaging in chronic traumatic encephalopathy (CTE) tissue. a, Low magnification immunohistochemistry using AT8 p‐tau antibody demonstrating high tau pathology in the depth of one sulcus and lower tau pathology in another sulcus. c, Myelin black gold II staining in an adjacent slice from the same CTE brain tissue sample. The overlayed grid demonstrates the individual regions of interest analyzed for power coherence measurements. The arrows indicate the tau‐negative and tau‐positive sulcal depths. e, Diffusion tensor imaging fractional anisotrophy map from the corresponding region of the same CTE brain tissue sample. The yellow outlines indicate 0.5 mm white matter regions of interest immediately adjacent to the sulcal depths. B, Figure taken from McKee et al. Whole mount coronal sections in stage II CTE show multiple foci of p‐tau pathology primarily located at the depths of the cortical sulci of the frontal and temporal lobes (free floating 50 μ sections, AT8 immunostain). C, Coronal slices of fluid attenuated inversion recovery magnetic resonance imaging (FLAIR MRI) of two RHI‐exposed participants demonstrating round white matter hyperintensities (WMH) scattered throughout the cerebrum at the base of the cerebral sulci. D, Axial slice of FLAIR MRI of an RHI‐exposed participant exhibiting the RHI‐WMH pattern. Text adapted from Holleran et al. and McKee et al.

FIGURE 6

RHI‐WMH: T2 FLAIR MRI images of eight RHI‐exposed cases. Axial images demonstrate the pattern of RHI‐WMH scattered throughout the cerebrum at the depths of the cerebral sulci. Includes images from participants A to H.

FIGURE 7

RHI‐WMH: T2 FLAIR MRI slices from illustrative case participant D. A series of axial images taken from one participant demonstrate the pattern of WMH throughout the cerebrum. These RHI‐WMH are consistently located at the depths of the cerebral sulci and demonstrate the same small, punctate, non‐confluent, and spherical morphometry. Images taken from participant D's FLAIR MRI.