Traumatic cerebrovascular injury (TCVI) is a common pathologic mechanism of traumatic brain injury (TBI) and presents an attractive target for intervention. The aims of this study were to assess cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) using magnetic resonance imaging (MRI) to assess their value as biomarkers of TCVI in chronic TBI, characterize the spatial distribution of TCVI, and assess the relationships between each biomarker and neuropsychological and clinical assessments. Forty-two subjects (27 chronic TBI, 15 age- and gender-matched healthy volunteers) were studied cross-sectionally. CBF was measured by arterial spin labeling and CVR by assessing the MRI-blood oxygen level-dependent signal with hypercapnia challenge. A focused neuropsychological battery adapted from the TBI Common Data Elements and neurobehavioral symptom questionnaires were administered at the time of the imaging session. Chronic TBI subjects showed a significant reduction in mean global, gray matter (GM), and white matter (WM) CVR, compared with healthy volunteers (p < 0.001). Mean GM CVR had the greatest effect size (Cohen's d = 0.9). CVR maps in chronic TBI subjects showed patchy, multifocal CVR deficits. CBF discriminated poorly between TBI subjects and healthy volunteers and did not correlate with CVR. Mean global CVR correlated best with chronic neurobehavioral symptoms among TBI subjects. Global, GM, and WM CVR are reliable and potentially useful biomarkers of TCVI in the chronic stage after moderate-to-severe TBI. CBF is less useful as biomarker of TCVI. CVR correlates best with chronic TBI symptoms. CVR has potential as a predictive and pharmacodynamic biomarker for interventions targeting TCVI.

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.

Traumatic cerebral vascular injury (TCVI) is a frequent, but under-recognized, endophenotype of traumatic brain injury (TBI).  It likely contributes to functional deficits after TBI and TBI-related chronic disability, and represents an attractive target for targeted therapeutic interventions. The aim of this prospective study is to assess microvascular injury/dysfunction in chronic TBI by measuring cerebral vascular reactivity (CVR) by 2 methods, functional magnetic resonance imaging (fMRI) and functional Near InfraRed Spectroscopy (fNIRS) imaging, as each has attractive features relevant to clinical utility.42 subjects (27 chronic TBI, 15 age- and gender-matched non-TBI volunteers) were enrolled and underwent outpatient CVR testing by 2 methods, MRI-BOLD and fNIRS, each with hypercapnia challenge, a neuropsychological testing battery, and symptom survey questionnaires.Chronic TBI subjects showed a significant reduction in global CVR compared to HC (p < 0.0001). Mean CVR measures by fMRI were 0.225 ± 0.014 and 0.183 ± 0.026 %BOLD/mmHg for non-TBI and TBI subjects respectively and 12.3 ± 1.8 and 9.2 ± 1.7 mM/mmHg by fNIRS for non-TBI versus TBI subjects respectively. Global CVR measured by fNIRS imaging correlates with results by MRI-BOLD (R = 0.5). Focal CVR deficits seen on CVR maps by fMRI are also observed in the same areas by fNIRS in the frontal regions.Global CVR is significantly lower in chronic TBI patients and is reliably measured by both fMRI and fNIRS, the former with better spatial and the latter with better temporal resolution.  Both methods show promise as non-invasive measures of CVR function and microvascular integrity after TBI.

BackgroundTraumatic cerebrovascular injury (TCVI), a common consequence of traumatic brain injury (TBI), presents an attractive therapeutic target. Because phosphodiesterase‐5 (PDE5) inhibitors potentiate the action of nitric oxide (NO) produced by endothelial cells, they are candidate therapies for TCVI. This study aims to: (1) measure cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and change in CVR after a single dose of sildenafil (ΔCVR) in chronic TBI compared to uninjured controls; (2) examine the safety and tolerability of 8‐week sildenafil administration in chronic symptomatic moderate/severe TBI patients; and as an exploratory aim, (3) assess the effect of an 8‐week course of sildenafil on chronic TBI symptoms.MethodsForty‐six subjects (31 chronic TBI, 15 matched healthy volunteers) were enrolled. Baseline CBF and CVR before and after administration of sildenafil were measured. Symptomatic TBI subjects then completed an 8‐week double‐blind, placebo‐controlled, crossover trial of sildenafil. A neuropsychological battery and neurobehavioral symptom questionnaires were administered at each study visit.ResultsAfter a single dose of sildenafil, TBI subjects showed a significant increase in global CVR compared to healthy controls (P < 0.001, d = 0.9). Post‐sildenafil CVR maps showed near‐normalization of CVR in many regions where baseline CVR was low, predominantly within areas without structural abnormalities. Sildenafil was well tolerated. Clinical Global Impression (CGI) scale showed a trend toward clinical improvement while on sildenafil treatment.FindingsSingle‐dose sildenafil improves regional CVR deficits in chronic TBI patients. CVR and ΔCVR are potential predictive and pharmacodynamic biomarkers of PDE5 inhibitor therapy for TCVI. Sildenafil is a potential therapy for TCVI.

Traumatic brain injury (TBI) results in short and long-term disability neurodegeneration. Mild traumatic brain injury (mTBI) represents up to 85% of head injuries; diagnosis and early management is based on computed tomography (CT) or in-hospital observation, which are time-and cost-intensive. CT involves exposure to potentially harmful ionizing radiation and >90% of the scans are negative. Blood-brain barrier (BBB) damage is suspected pathological event post-TBI contributing to long-term sequelae and a reliable and rapid point-of-care test to screen those who can safely forego acute head CT would be of great help in evaluating patients with an acute mTBI. In this pilot study, 15 adult patients with suspected TBI (mean age = 47 years, range 18-79) and 15 control subjects (mean age = 33 years, range 23-53) were enrolled. We found that the average salivary S100B level was 3.9 fold higher than blood S100B, regardless of the presence of pathology. [S100B] saliva positively correlated with [S100B] serum (Pearson' coefficient = 0.79; p < 0.01). Salivary S100B levels were as effective in differentiating TBI patients from control subjects as serum levels (Control vs. TBI: p < 0.01; Serum ROC AUC = 0.94 and Saliva ROC AUC = 0.75). I These initial results suggest that measuring salivary S100B could represent an alternative to serum S100B in the diagnosis of TBI. Larger and confirmatory trials are needed to define salivary biomarker kinetics in relation to TBI severity and the possible roles of gender, ethnicity and age in influencing salivary S100B levels.