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

Abstract

Chronic 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.

Repetitive head impacts induce neuronal loss and neuroinflammation in young athletes

“…Next, due to the key involvement of vascular dysfunction in CTE, we characterized the vascular response to RHI exposure 8,9 (Extended Data Fig. 4a, b).…”

“…Taken together, capillary cells undergo significant upregulation of angiogenesis and inflammation associated genes along with an increase in basement membrane components, identifying pathways that may underlie the known microvascular dysfunction in CTE 8,9 . Consistent with the changes observed in astrocytes and microglia following RHI, endothelial cell alterations are observed in individuals with RHI exposure without p-tau pathology, suggesting that microvascular alterations occur before the onset of neurodegeneration in CTE.…”

“…Our previous research suggests that microglia-mediated neuroinflammation occurs prior to the deposition of p-tau 5 . Additionally, other work has demonstrated RHI exposure is associated with astrocytic activation, white matter inflammation and damage, blood-brain barrier (BBB) breakdown, serum protein leakage, and increases in vascular density in the CTE brain [5][6][7][8][9] . These cellular changes occur prior to overt neurodegeneration and are likely driving many of the early clinical impairments not explained by the occurrence and extent of p-tau pathology.…”