Vascular Abnormalities within Normal Appearing Tissue in Chronic Traumatic Brain Injury

Abstract

Magnetic resonance imaging (MRI) is a powerful tool for visualizing traumatic brain injury(TBI)-related lesions. Trauma-induced encephalomalacia is frequently identified by its hyperintense appearance on fluid-attenuated inversion recovery (FLAIR) sequences. In addition to parenchymal lesions, TBI commonly results in cerebral microvascular injury, but its anatomical relationship to parenchymal encephalomalacia is not well characterized. The current study utilized a multi-modal MRI protocol to assess microstructural tissue integrity (by mean diffusivity [MD] and fractional aniosotropy [FA]) and altered vascular function (by cerebral blood flow [CBF] and cerebral vascular reactivity [CVR]) within regions of visible encephalomalacia and normal appearing tissue in 27 chronic TBI (minimum 6 months post-injury) subjects. Fifteen subjects had visible encephalomalacias whereas 12 did not have evident lesions on MRI. Imaging from 14 age-matched healthy volunteers were used as controls. CBF was assessed by arterial spin labeling (ASL) and CVR by measuring the change in blood-oxygen-level-dependent (BOLD) MRI during a hypercapnia challenge. There was a significant reduction in FA, CBF, and CVR with a complementary increase in MD within regions of FLAIR-visible encephalomalacia (p < 0.05 for all comparisons). In normal-appearing brain regions, only CVR was significantly reduced relative to controls (p < 0.05). These findings indicate that vascular dysfunction represents a TBI endophenotype that is distinct from structural injury detected using conventional MRI, may be present even in the absence of visible structural injury, and persists long after trauma. CVR may serve as a useful diagnostic and pharmacodynamic imaging biomarker of traumatic microvascular injury.

Changes in Plasma von Willebrand Factor and Cellular Fibronectin in MRI-Defined Traumatic Microvascular Injury

“…Taken together, these data suggest a model wherein TH and TVI are distinct injury patterns, and not simply a continuum of bleeding diathesis, with TVI representing a more “mild” bleeding injury than TH. This is consistent with data from our group showing that, in the chronic state, there can be cerebral vascular dysfunction even in the absence of frank injury from a TBI-related hemorrhage (33, 46).…”

Impairment of cerebrovascular reactivity in response to hypercapnic challenge in a mouse model of repetitive mild traumatic brain injury

“…Although CVR deficit is a symptom of many neurodegenerative diseases, 23,54,55 recent work by Diaz-Arrastia et al 7,17,56,57 has demonstrated global, Figure 7. ELISA measurement of aSMA concentration in cortical vascular-enriched fractions at three months and nine months post-injury.…”

Repetitive mTBI is associated with age-related reductions in cerebral blood flow but not cortical thickness

“…For example, altered cerebral blood flow (CBF), cerebrovascular reactivity, and blood–brain barrier permeability have been observed in both the acute and chronic phases of injury following all severities of TBI. 13–16 Importantly, this prolonged cerebrovascular dysfunction not only directly negatively influences cognitive and behavioral functioning, but independently initiates degenerative processes within the brain. 10,11 Indeed, we recently showed that lower CBF is associated with reduced axonal integrity in middle-aged Veterans with history of mild or moderate TBI.…”