Three dimensional evaluation of cerebrovascular density and branching in chronic traumatic encephalopathy

Author:

Rosen GraceORCID,Kirsch Daniel,Horowitz Sarah,Cherry Jonathan D.,Nicks Raymond,Kelley Hunter,Uretsky Madeline,Dell’Aquila Kevin,Mathias Rebecca,Cormier Kerry A.,Kubilus Caroline A.,Mez Jesse,Tripodis Yorghos,Stein Thor D.,Alvarez Victor E.,Alosco Michael L.,McKee Ann C.,Huber Bertrand R.

Abstract

AbstractChronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) and characterized by perivascular accumulations of hyperphosphorylated tau protein (p-tau) at the depths of the cortical sulci. Studies of living athletes exposed to RHI, including concussive and nonconcussive impacts, have shown increased blood–brain barrier permeability, reduced cerebral blood flow, and alterations in vasoreactivity. Blood–brain barrier abnormalities have also been reported in individuals neuropathologically diagnosed with CTE. To further investigate the three-dimensional microvascular changes in individuals diagnosed with CTE and controls, we used SHIELD tissue processing and passive delipidation to optically clear and label blocks of postmortem human dorsolateral frontal cortex. We used fluorescent confocal microscopy to quantitate vascular branch density and fraction volume. We compared the findings in 41 male brain donors, age at death 31–89 years, mean age 64 years, including 12 donors with low CTE (McKee stage I–II), 13 with high CTE (McKee stage III–IV) to 16 age- and sex-matched non-CTE controls (7 with RHI exposure and 9 with no RHI exposure). The density of vessel branches in the gray matter sulcus was significantly greater in CTE cases than in controls. The ratios of sulcus versus gyrus vessel branch density and fraction volume were also greater in CTE than in controls and significantly above one for the CTE group. Hyperphosphorylated tau pathology density correlated with gray matter sulcus fraction volume. These findings point towards increased vascular coverage and branching in the dorsolateral frontal cortex (DLF) sulci in CTE, that correlates with p-tau pathology.

Funder

NINDS/NIA

NINDS

NIA

Biomedical Laboratory Research and Development, VA Office of Research and Development

National Institute of Aging Boston University AD Research Center

Publisher

Springer Science and Business Media LLC

Subject

Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine

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