Annually in the United States, at least 3.5 million people seek medical attention for traumatic brain injury (TBI). The development of therapies for TBI is limited by the absence of diagnostic and ...prognostic biomarkers. Microtubule-associated protein tau is an axonal phosphoprotein. To date, the presence of the hypophosphorylated tau protein (P-tau) in plasma from patients with acute TBI and chronic TBI has not been investigated.
To examine the associations between plasma P-tau and total-tau (T-tau) levels and injury presence, severity, type of pathoanatomic lesion (neuroimaging), and patient outcomes in acute and chronic TBI.
In the TRACK-TBI Pilot study, plasma was collected at a single time point from 196 patients with acute TBI admitted to 3 level I trauma centers (<24 hours after injury) and 21 patients with TBI admitted to inpatient rehabilitation units (mean SD, 176.4 44.5 days after injury). Control samples were purchased from a commercial vendor. The TRACK-TBI Pilot study was conducted from April 1, 2010, to June 30, 2012. Data analysis for the current investigation was performed from August 1, 2015, to March 13, 2017.
Plasma samples were assayed for P-tau (using an antibody that specifically recognizes phosphothreonine-231) and T-tau using ultra-high sensitivity laser-based immunoassay multi-arrayed fiberoptics conjugated with rolling circle amplification.
In the 217 patients with TBI, 161 (74.2%) were men; mean (SD) age was 42.5 (18.1) years. The P-tau and T-tau levels and P-tau-T-tau ratio in patients with acute TBI were higher than those in healthy controls. Receiver operating characteristic analysis for the 3 tau indices demonstrated accuracy with area under the curve (AUC) of 1.000, 0.916, and 1.000, respectively, for discriminating mild TBI (Glasgow Coma Scale GCS score, 13-15, n = 162) from healthy controls. The P-tau level and P-tau-T-tau ratio were higher in individuals with more severe TBI (GCS, ≤12 vs 13-15). The P-tau level and P-tau-T-tau ratio outperformed the T-tau level in distinguishing cranial computed tomography-positive from -negative cases (AUC = 0.921, 0.923, and 0.646, respectively). Acute P-tau levels and P-tau-T-tau ratio weakly distinguished patients with TBI who had good outcomes (Glasgow Outcome Scale-Extended GOS-E, 7-8) (AUC = 0.663 and 0.658, respectively) and identified those with poor outcomes (GOS-E, ≤4 vs >4) (AUC = 0.771 and 0.777, respectively). Plasma samples from patients with chronic TBI also showed elevated P-tau levels and a P-tau-T-tau ratio significantly higher than that of healthy controls, with both P-tau indices strongly discriminating patients with chronic TBI from healthy controls (AUC = 1.000 and 0.963, respectively).
Plasma P-tau levels and P-tau-T-tau ratio outperformed T-tau level as diagnostic and prognostic biomarkers for acute TBI. Compared with T-tau levels alone, P-tau levels and P-tau-T-tau ratios show more robust and sustained elevations among patients with chronic TBI.
Cervical spinal cord injury (SCI) is a devastating condition with very few treatment options. It remains unclear if early surgery correlated with conversion of American Spinal Injury Association ...Impairment Scale (AIS) grade A injuries to higher grades.
To determine the optimal time to surgery after cervical SCI through retrospective analysis.
We collected data from 48 patients with cervical SCI. Based on the time from Emergency Department (ED) presentation to surgical decompression, we grouped patients into ultra-early (decompression within 12 h of presentation), early (within 12-24 h), and late groups (>24 h). We compared the improvement in AIS grade from admission to discharge, controlling for confounding factors such as AIS grade on admission, injury severity, and age. The mean time from injury to ED for this group of patients was 17 min.
Patients who received surgery within 12 h after presentation had a relative improvement in AIS grade from admission to discharge: the ultra-early group improved on average 1.3. AIS grades compared to 0.5 in the early group (P = .02). In addition, 88.8% of patients with an AIS grade A converted to a higher grade (AIS B or better) in the ultra-early group, compared to 38.4% in the early and late groups (P = .054).
These data suggest that surgical decompression after SCI that takes place within 12 h may lead to a relative improved neurological recovery compared to surgery that takes place after 12 h.
The superficial temporal artery to middle cerebral artery (STA-MCA) bypass is the most common bypass for augmenting or restoring cerebral blood flow. Although the single-barrel (SB) STA-MCA bypass is ...sufficient in most cases, the double-barrel (DB) STA-MCA bypass can supply the demands of different vascular territories or multiple efferent arteries. We present a comparative analysis of SB and DB STA-MCA bypass in a large, consecutive series to examine indications, surgical results, and patient outcomes.
A retrospective review of a prospectively maintained database identified all STA-MCA bypasses performed by a single surgeon over 21 years.
In total, 261 patients received 378 STA-MCA bypasses in 351 surgeries. SB STA-MCA bypasses were performed in 234 patients (90%), whereas DB STA-MCA bypasses were performed in 27 patients (10%). Patients with DB STA-MCA bypasses were more likely to undergo bilateral bypass procedures than those receiving SB STA-MCA bypass (P < 0.0001). In patients with bilateral STA-MCA bypasses (n = 91, 35%), 69 patients received bilateral SB STA-MCA bypasses (76%), whereas 22 patients received a DB STA-MCA bypass on 1 hemisphere (24%). There was no difference in bypass patency or clinical outcome in patients with SB and DB STA-MCA bypasses.
DB STA-MCA bypasses are reserved for patients requiring revascularization of multiple vascular territories or efferent arteries. DB STA-MCA bypasses have patency rates and patient outcomes comparable to SB STA-MCA, with the advantages of a single incision and reduced operative complexity compared to high-flow bypasses. DB STA-MCA bypass is an important element in the vascular neurosurgeon's bypass armamentarium.
The neurovascular unit is composed of endothelial cells, vascular smooth muscle cells, pericytes, astrocytes and neurons. Through tightly regulated multi-directional cell signaling, the neurovascular ...unit is responsible for the numerous functionalities of the cerebrovasculature – including the regulation of molecular and cellular transport across the blood-brain barrier, angiogenesis, blood flow responses to brain activation and neuroinflammation. Historically, the study of the brain vasculature focused on endothelial cells; however, recent work has demonstrated that pericytes and vascular smooth muscle cells – collectively known as mural cells – play critical roles in many of these functions. Given this emerging data, a more complete mechanistic understanding of the cellular basis of brain vascular malformations is needed. In this review, we examine the integrated functions and signaling within the neurovascular unit necessary for normal cerebrovascular structure and function. We then describe the role of aberrant cell signaling within the neurovascular unit in brain arteriovenous malformations and identify how these pathways may be targeted therapeutically to eradicate or stabilize these lesions.
•Normal cerebrovascular function requires coordination of multiple cell types.•Brain AVMs are high flow arterial-venous shunts which may rupture.•Brain AVMs arise from abnormalities in TGF-β, VEGF, NOTCH or other signaling pathways.•New therapies are being developed to target disrupted signaling pathways in brain AVMs.
Civilian firearm injury is an important public health concern in the United States. Gunshot wounds to the head (GSWH) remain in need of update and systematic characterization. We identify predictors ...of prolonged hospital length of stay (HLOS), intensive care unit length of stay (ICU LOS), medical complications, mortality, and discharge disposition from a population-based sample using the National Sample Program (NSP) of the National Trauma Data Bank (NTDB), years 2003-2012. Statistical significance was assessed at α < 0.001 to correct for multiple comparisons. In total, 8148 adult GSWH patients were included extrapolating to 32,439 national incidents. Age was 36.6 ± 16.4 years and 64.4% were severe traumatic brain injury (TBI; Glasgow Coma Scale GCS score 3-8). Assault (49.2%), handgun (50.3%), and residential injury (43.2%) were of highest incidence. HLOS and ICU LOS were 7.7 ± 14.2 and 5.7 ± 13.4 days, respectively. Overall mortality was 54.6%; suicide/self-injury was associated with the highest mortality rate (71.6%). GCS, Injury Severity Score, and hypotension were significant predictors for outcomes overall. Medicare/Medicaid patients had longer HLOS compared to private/commercial insured (mean increase, 4.4 days; 95% confidence interval 2.6-6.3). Compared to the Midwest, the South had longer HLOS (mean increase, 3.7 days; 2.0-5.4) and higher odds of complications (odds ratio OR, 1.7 1.4-2.0); the West had lower odds of complications (OR, 0.6; 0.5-0.7). Versus handgun, shotgun (OR, 0.3; 0.2-0.4) and hunting rifle (OR, 0.5; 0.4-0.8) resulted in lower mortality. Patients with government/other insurance had higher odds of discharging home compared to private/commercially insured (OR, 1.7; 1.3-2.3). In comparison to level I trauma centers, level II trauma centers had lower odds of discharge to home (OR, 0.7; 0.5-0.8). Our results support hypotension, injury severity, injury intent, firearm type, and U.S. geographical location as important prognostic variables in firearm-related TBI. Improved understanding of civilian GSWH is critical to promoting increased awareness of firearm injuries as a public health concern and reducing its debilitating injury burden to patients, families, and healthcare systems.
Despite the high incidence and burden of stroke, biological biomarkers are not used routinely in clinical practice to diagnose, determine progression, or prognosticate outcomes of acute ischemic ...stroke (AIS). Because of its direct interface with neural tissue, cerebrospinal fluid (CSF) is a potentially valuable source for biomarker development. This systematic review was conducted using three databases. All trials investigating clinical and preclinical models for CSF biomarkers for AIS diagnosis, prognostication, and severity grading were included, yielding 22 human trials and five animal studies for analysis. In total, 21 biomarkers and other multiomic proteomic markers were identified. S100B, inflammatory markers (including tumor necrosis factor-alpha and interleukin 6), and free fatty acids were the most frequently studied biomarkers. The review showed that CSF is an effective medium for biomarker acquisition for AIS. Although CSF is not routinely clinically obtained, a potential benefit of CSF studies is identifying valuable biomarkers from the pathophysiologic microenvironment that ultimately inform optimization of targeted low-abundance assays from peripheral biofluid samples (e.g., plasma). Several important catabolic and anabolic markers can serve as effective measures of diagnosis, etiology identification, prognostication, and severity grading. Trials with large cohorts studying the efficacy of biomarkers in altering clinical management are still needed.
Background
Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression ...and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs.
Methods
Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26
CreER
;
Alk1
2f/2f
(
Alk1
-iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization.
Results
Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions,
Alk1
-iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3−9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion.
Conclusions
We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model’s longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.
Background
Optimal definitive treatment timing for patients with aneurysmal subarachnoid hemorrhage (aSAH) remains controversial. We compared outcomes for aSAH patients with ultra-early treatment ...versus later treatment at a single large center.
Method
Patients who received definitive open surgical or endovascular treatment for aSAH between January 1, 2014, and July 31, 2019, were included. Ultra-early treatment was defined as occurring within 24 h from aneurysm rupture. The primary outcome was poor neurologic outcome (modified Rankin Scale score > 2). Propensity adjustment was performed for age, sex, Charlson Comorbidity Index, Hunt and Hess grade, Fisher grade, aneurysm treatment type, aneurysm type, size, and anterior location.
Results
Of the 1013 patients (mean SD age, 56 14 years; 702 69% women, 311 31% men) included, 94 (9%) had ultra-early treatment. Compared with the non-ultra-early cohort, the ultra-early treatment cohort had a significantly lower percentage of saccular aneurysms (53 of 94 56% vs 746 of 919 81%,
P
<0 .001), greater frequency of open surgical treatment (72 of 94 77% vs 523 of 919 57%,
P
<0 .001), and greater percentage of men (38 of 94 40% vs 273 of 919 30%,
P
= .04). After adjustment, ultra-early treatment was not associated with neurologic outcome in those with at least 180-day follow-up (OR = 0.86), the occurrence of delayed cerebral ischemia (OR = 0.87), or length of stay (exp(β), 0.13) (
P
≥ 0.60).
Conclusions
In a large, single-center cohort of aSAH patients, ultra-early treatment was not associated with better neurologic outcome, fewer cases of delayed cerebral ischemia, or shorter length of stay.
PDF
