title: 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 µm3spatial 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.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Laurena
authors.initials: L
authors.lastname: Holleran
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Joong Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Mihika
authors.initials: M
authors.lastname: Gangolli
authors.affiliation: Center of the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Thor
authors.initials: T
authors.lastname: Stein
authors.affiliation: Center of the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Alvarez
authors.affiliation: Center of the Study of Traumatic Encephalopathy, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: McKee
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. brodyd@neuro.wustl.edu.|Hope Center for Neurological Disorders, St. Louis, MO, USA. brodyd@neuro.wustl.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Brody
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016880:Anisotropy; D001369:Axons / Q000473:pathology*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000473:pathology*; D000070627:Chronic Traumatic Encephalopathy / Q000150:complications*; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D013223:Statistics as Topic; D018709:Statistics, Nonparametric; D024801:Tauopathies / Q000150:complications* / Q000473:pathology*; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins
keywords: Chronic traumatic encephalopathy; Diffusion MRI; Diffusion tensor imaging; Fractional anisotropy; Phosphorylated tau; Radiological-pathological correlations; White matter