Elucidating and Pharmacologically Targeting Secondary Injury Cascades following Neural Injury

3.4 million concussions occur each year in the United States. Recent evidence suggests that some of these individuals are susceptible to neurodegenerative disease development following traumatic brain injury. The unknown factor is how acute injury contributes to this degenerative process. A prominent neurotrauma related neurodegenerative disease is chronic traumatic encephalopathy (CTE). CTE is defined by neurofibrillary tau tangles with a perivascular distribution and mood disturbances. In order to elucidate the pathologic changes associated with CTE, it is imperative to utilize adequate preclinical models. We have strategically developed and tested a clinically relevant rodent blast model. The model reliably produces a CTE phenotype including tauopathy, cell death, impulsivity, and cognitive decline. Using this validated model, we investigated several important secondary injury cascades that link acute brain injury to chronic neurodegenerative changes. More importantly, we pharmacologically targeted these pathways and found improved pathologic and behavioral outcomes. In chapter 1, we discuss the potential mechanisms linking acute injury to CTE in athletes and soldiers. In chapter 2, we highlight the physics behind the compression wave produced by our model and how this wave produces injury. In chapter 3, data is presented regarding the CTE phenotype generated by our model following repetitive blast exposure in rodents. Chapter 4 focuses on the role of blood brain barrier disruption and how targeting protein kinase C activity with bryostatin reduces this disruption. In chapter 5, we look at the role endoplasmic reticulum stress plays in human pathologic specimens from patients diagnosed with CTE and in rodents following repeat blast. We found that docosahexaenoic acid successfully targeted endoplasmic reticulum stress, reduced tauopathy, and improved cognitive performance. In chapter 6, we looked at lipoic acid and its role in reducing NADPH oxidative stress following repetitive neurotrauma. We found that lipoic acid reduces impulsive-like behavior and decreased cell death. Finally, in chapter 7 we discuss important strategies for improving preclinical models going forward and what needs to be investigated to improve our understanding of CTE. In this dissertation, we highlight important secondary injury cascades including blood brain barrier disruption, protein kinase C activity, endoplasmic reticulum stress, and oxidative stress that warrant further investigation for the development of novel treatment approaches for CTE

Lung Cancer Metastasis Presenting as a Solitary Skull Mass

Lung cancer has been well documented to spread to bone and the axial skeleton after metastasis to adjacent organs. Bony metastasis is not, however, the typical presenting manifestation. The differential diagnosis for a tissue mass on the skull should warrant a workup for metastatic disease. Bony metastasis plays an important role in treatment and disease management. We report an exceptionally rare case of stage IV lung adenocarcinoma that presented with a solitary skull metastasis and a significant soft-tissue component. The lesion was treated by excision via craniotomy and subsequent medical management of the adenocarcinoma. This case illustrates a very rare presentation of lung adenocarcinoma and also represents what the authors believe to be the first report of a solitary skull mass originating from a lung primary. We also present a review of the literature surrounding bony metastasis to the skull and implications for patient care

Endoscopic Endonasal Transclival Approach versus Dual Transorbital Port Technique for Clip Application to the Posterior Circulation: A Cadaveric Anatomical and Cerebral Circulation Simulation Study

Purpose  Simulation training offers a useful opportunity to appreciate vascular anatomy and develop the technical expertise required to clip intracranial aneurysms of the posterior circulation. Materials and Methods  In cadavers, a comparison was made between the endoscopic transclival approach (ETA) alone and a combined multiportal approach using the ETA and a transorbital precaruncular approach (TOPA) to evaluate degrees of freedom, angles of visualization, and ergonomics of aneurysm clip application to the posterior circulation depending on basilar apex position relative to the posterior clinoids. Results  ETA alone provided improved access to the posterior circulation when the basilar apex was high riding compared with the posterior clinoids. ETA + TOPA provided a significantly improved functional working area for instruments and visualization of the posterior circulation for a midlevel basilar apex. A single-shaft clip applier provided improved visualization and space for instruments. Proximal and distal vascular control and feasibility of aneurysmal clipping were demonstrated. Conclusions  TOPA is a medial orbital approach to the central skull base; a transorbital neuroendoscopic surgery approach. This anatomical simulation provides surgical teams an alternative to the ETA approach alone to address posterior circulation aneurysms, and a means to preoperatively prepare for intraoperative anatomical and surgical instrumentation challenges

Tension pneumocephalus as a complication of surgical evacuation of chronic subdural hematoma: case report and literature review

The management of symptomatic chronic subdural hematoma (CSDH) is surgical evacuation and prognosis in most cases is good. Tension pneumocephalus is the presence of air under pressure in the intracranial cavity. A case of tension pneumocephalus developing as a complication of burr hole evacuation of CSDH is illustrated. In this case, tension pneumocephalus was managed by reopening the wound and saline irrigation with a subdural drain placement. Considering this case report and after a careful review of the literature, the physiopathology, diagnosis, and treatment of this complication are highlighted in the article

Endoscopic Management of Cavernous Carotid Surgical Complications: Evaluation of a Simulated Perfusion Model

Objective—Endoscopic surgical treatment of pituitary tumors, lateral invading tumors, or aneurysms requires surgeons to operate adjacent to the cavernous sinus. During these endoscopic endonasal procedures, the carotid artery is vulnerable to surgical injury at its genu. The objective of this simulation model was to evaluate trainees regarding management of a potentially lifethreatening vascular injury. Methods—Cadaveric heads were prepared in accordance with the Oregon Health & Science University body donation program. An endoscopic endonasal approach was used, and a perfusion pump with a catheter was placed in the ipsilateral common carotid artery at its origin in the neck. Learners used a muscle graft to establish vascular control and were evaluated over 3 training sessions. Simulation assessment, blood loss during sessions, and performance metric data were collected for learners. Results—Vascular control was obtained at a mean arterial pressure of 65 mm Hg using a muscle graft correctly positioned at the arteriotomy site. Learners improved over the course of training, with senior residents (n = 4) performing better across all simulation categories (situation awareness, decision making, communications and teamwork, and leadership); the largest mean difference was in communication and teamwork. Additionally, learner performance concerning blood loss improved between sessions (t = 3.667, P \u3c 0.01). Conclusions—In this pilot endoscopic endonasal simulation study, we successfully demonstrate a vascular complication perfusion model. Learners were able to gain direct applicable expertise in endoscopic endonasal techniques, instrumentation use, and teamwork required to optimize the technique. Learners gained skills of vascular complication management that transcend this model

An introductory review of post-resection chemotherapeutics for primary brain tumors

The treatment of central nervous system (CNS) tumors is complicated by high rates of recurrence and treatment resistance that contribute to high morbidity and mortality (Nat Rev Neurol. 2022;18:221–36. doi: 10.1038/s41582-022-00621-0). One of the challenges of treating these tumors is the limited permeability of the blood brain barrier (BBB). Early pharmacologic treatments worked to overcome the BBB by targeting vulnerabilities in the tumor cell replication process directly through alkylating agents like temozolomide. However, as advancements have been made options have expanded to include immunologic targets through the use of monoclonal antibodies. In the future, treatment will likely continue to focus on the use of immunotherapies, as well as emerging technology like the use of low-intensity focused ultrasound (LIFU). Ultimately, this paper serves as an introductory overview of current therapeutic options for post-resection primary brain tumors, as well as a look towards future work and emerging treatment options

Glioblastoma Survival Outcomes at a Tertiary Hospital in Appalachia: Factors Impacting the Survival of Patients Following Implementation of the Stupp Protocol

Glioblastoma is a fatal brain cancer with low median and yearly survival rates. The standard of care for treating glioblastoma is gross total resection (GTR) coupled with the Stupp protocol, but various factors influence the interventions undertaken and survival achieved. As health disparities exist in rural areas, survival in these areas need to be assessed in order to understand which factors detract from the successes of these standard medical interventions. We retrospectively determined the impact of age of diagnosis, number of lesions, the molecular marker O6-methylguanine methyltransferase (MGMT), extent of surgery, and completion of the Stupp protocol on survival among patients treated at West Virginia University Hospitals. We found that an age of diagnosis under 60 years, having the MGMT gene methylated, having a unifocal tumor, receiving GTR, adhering to the Stupp protocol, and undergoing a treatment course of GTR followed by the Stupp protocol significantly increased survival. Lastly, we compared our findings to a pre-Stupp study done in West Virginia in 1996. This comparison showed that although overall median survival has not increased, all interventions involving GTR have resulted in a significantly higher survival. We conclude that we can serve our patient population by offering GTR to all adult glioblastoma patients when no contraindications exist and ensuring that patients follow the Stupp protocol. After discharge, the Stupp protocol may not be followed/completed for a variety of reasons. In the future, we aim to assess these reasons and analyze other significant interventional and socioeconomic factors which influence survival

The Effect of Adherence to Dietary Tracking on Weight Loss: Using HLM to Model Weight Loss over Time

The role of dietary tracking on weight loss remains unexplored despite being part of multiple diabetes and weight management programs. Hence, participants of the Diabetes Prevention and Management (DPM) program (12 months, 22 sessions) tracked their food intake for the duration of the study. A scatterplot of days tracked versus total weight loss revealed a nonlinear relationship. Hence, the number of possible tracking days was divided to create the 3 groups of participants: rare trackers (66% total days tracked). After controlling for initial body mass index, hemoglobin A1c, and gender, only consistent trackers had significant weight loss (−9.99 pounds), following a linear relationship with consistent loss throughout the year. In addition, the weight loss trend for the rare and inconsistent trackers followed a nonlinear path, with the holidays slowing weight loss and the onset of summer increasing weight loss. These results show the importance of frequent dietary tracking for consistent long-term weight loss success

Role of Sigma-1 Receptors in Neurodegenerative Diseases

Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders