Rodent Traumatic Brain Injury as a Model for Human Traumatic Axonal Damage and Neurodegeneration

Traumatic brain injury (TBI) is inherently heterogeneous with a complex underlying pathophysiology. Over the past decades many attempts have been undertaken to develop novel and innovative ways to mimic human aspects of TBI in rodents. This presentation will provide a brief overview of translationally relevant rodent TBI models with special emphasis on mild-to-moderate injuries and associated pathology

Inhibiting Axon Degeneration in a Mouse Model of Acute Brain Injury Through Deletion of Sarm1

Traumatic brain injury (TBI) is a leading cause of disability worldwide. Annually, 150 to 200/1,000,000 people become disabled as a result of brain trauma. Axonal degeneration is a critical, early event following TBI of all severities but whether axon degeneration is a driver of TBI remains unclear. Molecular pathways underlying the pathology of TBI have not been defined and there is no efficacious treatment for TBI. Despite this significant societal impact, surprisingly little is known about the molecular mechanisms that actively drive axon degeneration in any context and particularly following TBI. Although severe brain injury may cause immediate disruption of axons (primary axotomy), it is now recognized that the most frequent form of traumatic axonal injury (TAI) is mediated by a cascade of events that ultimately result in secondary axonal disconnection (secondary axotomy) within hours to days. Proposed mechanisms include immediate post-traumatic cytoskeletal destabilization as a direct result of mechanical breakage of microtubules, as well as catastrophic local calcium dysregulation resulting in microtubule depolymerization, impaired axonal transport, unmitigated accumulation of cargoes, local axonal swelling, and finally disconnection. The portion of the axon that is distal to the axotomy site remains initially morphologically intact. However, it undergoes sudden rapid fragmentation along its full distal length ~72 h after the original axotomy, a process termed Wallerian degeneration. Remarkably, mice mutant for the Wallerian degeneration slow (Wlds) protein exhibit ~tenfold (for 2–3 weeks) suppressed Wallerian degeneration. Yet, pharmacological replication of the Wlds mechanism has proven difficult. Further, no one has studied whether Wlds protects from TAI. Lastly, owing to Wlds presumed gain-of-function and its absence in wild-type animals, direct evidence in support of a putative endogenous axon death signaling pathway is lacking, which is critical to identify original treatment targets and the development of viable therapeutic approaches. Novel insight into the pathophysiology of Wallerian degeneration was gained by the discovery that mutant Drosophila flies lacking dSarm (sterile a/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously recapitulated the Wlds phenotype. The pro-degenerative function of the dSarm gene (and its mouse homolog Sarm1) is widespread in mammals as shown by in vitro protection of superior cervical ganglion, dorsal root ganglion, and cortical neuron axons, as well as remarkable in-vivo long-term survival (\u3e2 weeks) of transected sciatic mouse Sarm1 null axons. Although the molecular mechanism of function remains to be clarified, its discovery provides direct evidence that Sarm1 is the first endogenous gene required for Wallerian degeneration, driving a highly conserved genetic axon death program. The central goals of this thesis were to determine (1) whether post-traumatic axonal integrity is preserved in mice lacking Sarm1, and (2) whether loss of Sarm1 is associated with improved functional outcome after TBI. I show that mice lacking the mouse Toll receptor adaptor Sarm1 gene demonstrate multiple improved TBI-associated phenotypes after injury in a closed-head mild TBI model. Sarm1-/- mice developed fewer beta amyloid precursor protein (βAPP) aggregates in axons of the corpus callosum after TBI as compared to Sarm1+/+ mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phosphorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after TBI. Strikingly, whereas wild type mice exhibited a number of behavioral deficits after TBI, I observed a strong, early preservation of neurological function in Sarm1-/- animals. Finally, using in vivo proton magnetic resonance spectroscopy, I found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1-/- mice compared to controls immediately following TBI. My results indicate that the Sarm1-mediated prodegenerative pathway promotes pathogenesis in TBI and suggest that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after TBI

Effect of Alteplase Use on Outcomes in Patients With Atrial Fibrillation: Analysis of the Initiation of Anticoagulation After Cardioembolic Stroke Study

Background Intravenous alteplase improves outcome after acute ischemic stroke without a benefit in 90-day mortality. There are limited data on whether alteplase is associated with reduced mortality in patients with atrial fibrillation (AF)-related ischemic stroke whose mortality rate is relatively high. We sought to determine the association of alteplase with hemorrhagic transformation and mortality in patients with AF. Methods and Results We retrospectively analyzed consecutive patients with acute ischemic stroke between 2015 and 2018 diagnosed with AF included in the IAC (Initiation of Anticoagulation After Cardioembolic Stroke) study, which pooled data from stroke registries at 8 comprehensive stroke centers across the United States. For our primary analysis, we included patients who did not undergo mechanical thrombectomy (MT), and secondary analyses included patients who underwent MT. We used binary logistic regression to determine whether alteplase use was associated with risk of hemorrhagic transformation and 90-day mortality. There were 1889 patients (90.6%) who had 90-day follow-up data available for analyses and were included; 1367 patients (72.4%) did not receive MT, and 522 patients (27.6%) received MT. In our primary analyses we found that alteplase use was independently associated with an increased risk for hemorrhagic transformation (odds ratio [OR], 2.23; 95% CI, 1.57-3.17) but reduced risk of 90-day mortality (OR, 0.58; 95% CI, 0.39-0.87). Among patients undergoing MT, alteplase use was not associated with a significant reduction in 90-day mortality (OR, 0.68; 95% CI, 0.45-1.04). Conclusions Alteplase reduced 90-day mortality of patients with acute ischemic stroke with AF not undergoing MT. Further study is required to assess the efficacy of alteplase in patients with AF undergoing MT

Delayed sudden coma due to artery of percheron infarction

A 52-year-old man was noted to display “unusual behavior” with transient agitation and blurry vision after otherwise uneventful diagnostic cardiac catheterization. Several hours after same-day discharge from the hospital, he suddenly became comatose, requiring intubation and admission to the intensive care unit. Two days later, he regained consciousness and was noted to have vertical gaze palsy and dysarthria without other neurologic deficits. Magnetic resonance imaging demonstrated bilateral acute medial thalamic ischemic strokes. Magnetic resonance angiography did not display extracranial or intracranial arterial stenosis (not shown). At 3 months\u27 follow-up, he had only mild residual dysarthria

Newer Oral Anticoagulants: Stroke Prevention and Pitfalls

Warfarin is very effective in preventing stroke in patients with atrial fibrillation. However, its use is limited due to fear of hemorrhagic complications, unpredictable anticoagulant effects related to multiple drug interactions and dietary restrictions, a narrow therapeutic window, frequent difficulty maintaining the anticoagulant effect within a narrow therapeutic window, and the need for inconvenient monitoring. Several newer oral anticoagulants have been approved for primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation. These agents have several advantages relative to warfarin therapy. As a group, these direct oral anticoagulants (DOAC), which include the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), are more effective than dose adjusted warfarin for prevention of all-cause stroke (including both ischemic and hemorrhagic stroke), and have an overall more favorable safety profile. Nevertheless, an increased risk of gastrointestinal bleeding (with the exception of apixaban), increased risk for thrombotic complication with sudden discontinuation, and inability to accurately assess and reverse anticoagulant effect require consideration prior to therapy initiation, and pose a challenge for decision making in acute stroke therapy

G-CSF, rt-PA and combination therapy after experimental thromboembolic stroke

BACKGROUND: Granulocyte Colony-Stimulating Factor (G-CSF) has remarkable neuroprotective properties. Due to its proven safety profile, G-CSF is currently used in clinical stroke trials. As neuroprotectants are considered to be more effective in the early phase of cerebral ischemia and during reperfusion, G-CSF should to be tested in combination with thrombolysis. Therefore, combination therapy was investigated in an experimental model of thromboembolic stroke. METHODS: Male Wistar rats (n = 72) were subjected to a model of thromboembolic occlusion (TE) of the middle cerebral artery. Different groups (n = 12 each) treated by recombinant tissue-plasminogen activator (rt-PA) or/and G-CSF: group control (control), group early G-CSF (G-CSF 60 min after TE), group rt-PA (rt-PA 60 min after TE), group com (combination rt-PA/G-CSF), group delayed rt-PA (rt-PA after 180 min), group deco (G-CSF after 60 min, rt-PA after 180 min). Animals were investigated by magnetic resonance imaging (MRI) and silver infarct staining (SIS) 24 hours after TE. RESULTS: Early G-CSF or rt-PA reduced the infarct size compared to all groups (p \u3c 0.05 to p \u3c 0.01) with the exception of group com, (p = n.s.) as measured by T2, DWI, and SIS. Late administration of rt-PA lead to high mortality and larger infarcts compared to all other groups (p \u3c 0.05 to p \u3c 0.01). Pre-treatment by G-CSF (deco) reduced infarct site compared to delayed rt-PA treatment (p \u3c 0.05). G-CSF did not significantly influence PWI when combined with rt-PA. All animals treated by rt-PA showed improved parameters in PWI indicating reperfusion. CONCLUSIONS: G-CSF was neuroprotective when given early after TE. Early combination with rt-PA showed no additional benefit compared to rt-PA or G-CSF alone, but did not lead to side effects. Pretreatment by G-CSF was able to reduce deleterious effects of late rt-PA treatment

Traumatic Brain Injury: Translation from Animal Models and Genetics to Improving Outcomes

This presentation offers background information on traumatic brain injury (TBI), a public health problem which affects approximately 1.7 million Americans each year. The presentation is part of a mini-symposium highlighting the interdisciplinary and translational nature of TBI research at the University of Massachusetts Medical School

Predictors of Outcome following Stroke due to Isolated M2 Occlusions

BACKGROUND: Factors influencing outcome after cerebral artery occlusion are not completely understood. Although it is well accepted that the site of arterial occlusion critically influences outcome, the majority of studies investigating this issue has focused on proximal large artery occlusion. To gain a better understanding of factors influencing outcome after distal large artery occlusion, we sought to assess predictors of outcome following isolated M2 middle cerebral artery occlusion infarcts. METHODS: We retrospectively analyzed patients with isolated acute M2 occlusion admitted to a single academic center from January 2010 to August 2012. Baseline clinical, laboratory imaging, and outcome data were assessed from a prospectively collected database. Factors associated with a modified Rankin Scale (mRS) score \u3c /=2 in univariable analyses (p \u3c 0.05) were entered into multivariable logistic regression analysis. The Admission National Institutes of Health Stroke Scale (aNIHSS) score, age, and infarct volume were also entered as dichotomized variables. Receiver operating characteristic curves were plotted to determine the optimal aNIHSS score, infarct volume, and age cut points predicting an mRS score \u3c /=2. Optimal thresholds were determined by maximizing the Youden index. Respective multivariable logistic regression analyses were used to identify independent predictors of a good 90-day outcome (mRS score \u3c /=2; primary analysis) as well as 90-day mortality (secondary outcome). RESULTS: 90 patients with isolated M2 occlusion were included in the final analyses. Of these, 69% had a good 90-day outcome which was associated with age \u3c 80 years (p = 0.007), aNIHSS \u3c 10 (p = 0.002), and infarct volume \u3c /=26 ml (p \u3c 0.001). Notably, 20% of patients (64% of those with a poor outcome) had died by 90 days. Secondary analysis for 90-day mortality was performed. This analysis indicated that infarct volume \u3e 28 ml (OR 11.874, 95% CI 2.630-53.604, p = 0.001), age \u3e 80 years (OR 4.953, 95% CI 1.087-22.563, p = 0.039), need for intubation (OR 7.788, 95% CI 1.072-56.604), and history of congestive heart failure (OR 5.819, 95% CI 1.140-29.695) were independent predictors of 90-day mortality (20% of all included patients). CONCLUSION: While the majority of patients with isolated M2 occlusion stroke has a good 90-day outcome, a substantial proportion of subjects dies by 90 days, as identified by a unique subset of predictors. The knowledge gained from our study may lead to an improvement in the prognostic accuracy, clinical management, and resource utilization in this patient population

Alberta Stroke Program Early CT Score Infarct Location Predicts Outcome Following M2 Occlusion

BACKGROUND: Although it is generally thought that patients with distal middle cerebral artery (M2) occlusion have a favorable outcome, it has previously been demonstrated that a substantial minority will have a poor outcome by 90 days. We sought to determine whether assessing the Alberta Stroke Program Early CT Score (ASPECTS) infarct location allows for identifying patients at risk for a poor 90-day outcome. METHODS: We retrospectively analyzed patients with isolated acute M2 occlusion admitted to a single academic center between January 2010 and August 2012. Infarct regions were defined according to ASPECTS system on the initial head computed tomography. Discriminant function analysis was used to define specific ASPECTS regions that are predictive of the 90-day functional outcome as defined as a modified Rankin Scale score of 3-6. In addition, logistic regression was used to model the relationship between each individual ASPECT region with poor outcome; for evaluation and comparison, odds ratios, c-statistics, and Akaike information criterion values were estimated for each region. RESULTS: Ninety patients with isolated M2 were included in the final analysis. ASPECTS score CONCLUSION: Infarction in ASPECTS regions M3 and M6 are key predictors of functional outcome following isolated distal M2 occlusion. These findings will be helpful in stratifying outcomes if validated in future studies