Axonal disruption in white matter underlying cortical sulcus tau pathology in chronic traumatic encephalopathy

Abstract

Chronic traumatic encephalopathy (CTE) is a progressive degenerative disorder associated with repetitive traumatic brain injury. One of the primary defining neuropathological lesions in CTE, based on the first consensus conference, is the accumulation of hyperphosphorylated tau in gray matter sulcal depths. Post-mortem CTE studies have also reported myelin loss, axonal injury and white matter degeneration. Currently, the diagnosis of CTE is restricted to post-mortem neuropathological analysis. We hypothesized that high spatial resolution advanced diffusion MRI might be useful for detecting white matter microstructural changes directly adjacent to gray matter tau pathology. To test this hypothesis, formalin-fixed post-mortem tissue blocks from the superior frontal cortex of ten individuals with an established diagnosis of CTE were obtained from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank. Advanced diffusion MRI data was acquired using an 11.74 T MRI scanner at Washington University with 250 × 250 × 500 µm spatial resolution. Diffusion tensor imaging, diffusion kurtosis imaging and generalized q-sampling imaging analyses were performed in a blinded fashion. Following MRI acquisition, tissue sections were tested for phosphorylated tau immunoreactivity in gray matter sulcal depths. Axonal disruption in underlying white matter was assessed using two-dimensional Fourier transform analysis of myelin black gold staining. A robust image co-registration method was applied to accurately quantify the relationship between diffusion MRI parameters and histopathology. We found that white matter underlying sulci with high levels of tau pathology had substantially impaired myelin black gold Fourier transform power coherence, indicating axonal microstructural disruption (r = -0.55, p = 0.0015). Using diffusion tensor MRI, we found that fractional anisotropy (FA) was modestly (r = 0.53) but significantly (p = 0.0012) correlated with axonal disruption, where lower FA was associated with greater axonal disruption in white matter directly adjacent to hyperphosphorylated tau positive sulci. In summary, our findings indicate that axonal disruption and tau pathology are closely associated, and high spatial resolution ex vivo diffusion MRI has the potential to detect microstructural alterations observed in CTE tissue. Future studies will be required to determine whether this approach can be applied to living people.

Systematic review on the characterization of chronic traumatic encephalopathy by MRI and MRS

“…Ten studies based on chronic TBI individuals examined a mixed gender experimental group and one did not provide information on the sex of study participants . All studies focusing on contact sports athletes investigated solely male experimental groups, and the two ex vivo studies did not provide any information on gender . Contact sports athletes included soccer players, boxers, American football players, baseball players, and wrestlers.…”

“…The systematic search resulted in only two articles using ex vivo samples of patients with confirmed CTE (for more details, refer to Table ).…”

“…Twenty‐one studies applied structural MRI, including T 1 ‐weighted (T 1 ‐w), T 2 ‐weighted (T 2 ‐w), fluid attenuated inversion recovery (FLAIR), susceptibility weighted imaging (SWI), and proton‐density weighted (PD‐w) imaging . Thirteen studies used diffusion MRI, specifically diffusion tensor imaging (DTI), generalized q‐sampling imaging (GQI), diffusion kurtosis imaging (DKI), and diffusion weighted imaging (DWI) . Six studies acquired functional MRI (fMRI) with either blood oxygenation level‐dependent (BOLD) or arterial spin labeling (ASL) sequences .…”

“…Furthermore, the scan coverage varied between studies. All in vivo MRI studies applied whole‐brain coverage, the MRS study analyzed the posterior cingulate gyrus, and the ex vivo studies analyzed BA 8/9 . In addition, the analysis methods varied considerably between the studies and not all used an age‐matched control group, which limits the possibility of direct comparison.…”

Tau in Oligodendrocytes Takes Neurons in Sickness and in Health

“…It is unknown how an acute variation of tau phosphorylation in OLGs might impact CNS health. However, studies of post-traumatic brain injury patients reveal that physical trauma causes long-term consequences, including increased tau phosphorylation as well as myelin and CNS degeneration [70]. Although the consequences of oxidative stress on tau phosphorylation and cellular process outgrowth have been investigated in OLG cultures, future work is required to address short- and long-term consequences of OLG tau post-translation modifications on neurons.…”