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.

Keywords: FLAIR; cerebral blood flow; cerebral vascular reactivity; diffusion tensor imaging; traumatic brain injury.

FIG. 1.

Representative images of encephalomalacia in FLAIR, CVR, MD, FA, and CBF maps. The region of encephalomalacia (red) shows imaging abnormalities in multiple MRI modalities. CBF, cerebral blood flow; CVR, cerebral vascular reactivity; FA, fractional anisotropy; FLAIR, fluid-attenuated inversion recovery; MD, mean diffusivity.

FIG. 2.

All MRI modalities are altered within the region of encephalomalacia. TBI subjects with visible encephalomalacias were assessed. (A) MD was altered in the region of encephalomalacia for all subjects with an overall positive mean z-score within the abnormal region across subjects. (B–D) FA, CVR, and CBF showed negative z-score values within the region of encephalomalacia for several subjects, with an overall negative mean z-score across all 15 subjects. CBF, cerebral blood flow; CVR, cerebral vascular reactivity; FA, fractional anisotropy; MD, mean diffusivity; MRI, magnetic resonance imaging.

FIG. 3.

The region of encephalomalacia is significantly different than normal appearing tissue for all MRI modalities. Within the region of encephalomalacia, there is a significant increase in MD (A) and a significant decrease in FA (B), CBF (C), and CVR (D) as compared to normal-appearing tissue (p < 0.05). (D) When compared to healthy controls, only CVR shows a significant alteration in normal-appearing tissue. ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05. CBF, cerebral blood flow; CVR, cerebral vascular reactivity; FA, fractional anisotropy; MD, mean diffusivity; MRI, magnetic resonance imaging.

FIG. 4.

CVR is significantly altered in TBI subjects without structural MRI abnormalities. (A) Comparison of TBI subjects with visible encephalomalacias on conventional MRI (TBI/MRI⁺) to TBI subjects without visible encephalomalacias (TBI/MRI⁻) showed no significant difference in whole-brain CBF (p > 0.05). (B) Both TBI/MRI⁺ and TBI/MRI⁻ showed a significant decrease in CVR relative to controls (p < 0.05). (C) Representative images indicate decreased CBF and CVR in the region of encephalomalacia (arrows). No apparent decrease in CBF is observed in the subject without encephalomalacia, whereas a large decrease in CVR can be observed in structurally normal-appearing tissue (arrow). **p < 0.01; *p < 0.05. CBF, cerebral blood flow; CVR, cerebral vascular reactivity.