Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors

Systemic Inhibition of Tissue-Nonspecific Alkaline Phosphatase Alters the Brain-Immune Axis in Experimental Sepsis

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitous enzyme present in many cells and tissues, including the central nervous system. Yet its functions at the brain-immune axis remain unclear. The goal of this study was to use a novel small molecular inhibitor of TNAP, SBI-425, to interrogate the function of TNAP in neuroimmune disorders. Following intraperitoneal (IP) administration of SBI-425, mass spectrometry analysis revealed that the SBI-425 does not cross the blood-brain barrier (BBB) in healthy mice. To elucidate the role of TNAP at the brain-immune axis, mice were subjected to experimental sepsis and received either vehicle or SBI-425 (25 mg/kg, IP) daily for 7 days. While SBI-425 administration did not affect clinical severity outcomes, we found that SBI-425 administration suppressed CD4 + Foxp3+ CD25− and CD8 + Foxp3+ CD25− splenocyte T-cell populations compared to controls. Further evaluation of SBI-425’s effects in the brain revealed that TNAP activity was suppressed in the brain parenchyma of SBI-425-treated mice compared to controls. When primary brain endothelial cells were treated with a proinflammatory stimulus the addition of SBI-425 treatment potentiated the loss of barrier function in BBB endothelial cells. To further demonstrate a protective role for TNAP at endothelial barriers within this axis, transgenic mice with a conditional overexpression of TNAP were subjected to experimental sepsis and found to have increased survival and decreased clinical severity scores compared to controls. Taken together, these results demonstrate a novel role for TNAP activity in shaping the dynamic interactions within the brain-immune axis

Targeting the cerebrovasculature in sepsis: A focus on the brain microvascular endothelium

The blood-brain barrier (BBB) is a critical interface between the systemic circulation and the brain. It is a specialized multicellular unit composed of brain microvascular endothelial cells (BMECs), pericytes, a basement membrane, and astrocytic end foot processes. BMECs are a principal component of the BBB that provide the structural framework needed for the stringent transport of molecules into the brain. BMEC dysfunction permits the trafficking of neurotoxins from systemic circulation into the brain, which ultimately exacerbates BBB dysfunction and neuroinflammation. Studies have shown that BBB dysfunction is a key determinant of cognitive decline in sepsis. However, there are critical knowledge gaps that exist in understanding the molecular and cellular mechanisms underpinning BMEC physiology and function as it relates to the maintenance of BBB integrity. A strategy for bridging this critical knowledge gap requires an examination of proteins and enzymes localized to BMECs. Tissue-nonspecific alkaline phosphatase (TNAP) has been historically used as a brain endothelial histological marker due to its abundant expression on BMECs. Yet, the role of TNAP in BMECs remains unclear. The objective of this project was to understand the function of BMEC TNAP at the BBB in normal physiology and sepsis. Our central hypothesis is that BMEC TNAP is critical for maintenance of BBB integrity in normal physiology and in sepsis through molecular mechanisms that preserve BMEC structure and function. The studies presented in this dissertation demonstrated a novel anti-inflammatory role for TNAP in cerebral microvessels. We also demonstrated that BMEC TNAP plays an important role in maintaining paracellular barrier integrity during systemic inflammation via cytoskeletal reorganization. Importantly, our data elucidated a molecular target (Rho-associated protein kinase) through which loss of TNAP activity in cerebral microvessel in sepsis could be mitigated. Finally, we utilized the cre-lox system to generate a genetic mouse model with an endothelial VE-cadherin conditional knockout of the Alpl gene (VE-cKO). We showed that VE-cKO mice exhibited whole brain size selectively increased BBB permeability that is worsened in sepsis and stroke. Collectively, this body of work demonstrated that TNAP activity in cerebral microvessel is important for maintaining BBB integrity. These findings lay the groundwork needed to stimulate the discovery of a therapeutic target whose activity can be manipulated to mitigate long-term neurological dysfunction in sepsis. Moreover, our results will impact not only sepsis but will improve the quality of life and medical outcomes in other neurodegenerative and inflammatory diseases such as stroke and Alzheimer’s disease (AD)

Tissue-Nonspecific Alkaline Phosphatase in Central Nervous System Health and Disease: A Focus on Brain Microvascular Endothelial Cells

Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme bound to the plasma membranes of numerous cells via a glycosylphosphatidylinositol (GPI) moiety. TNAP’s function is well-recognized from earlier studies establishing its important role in bone mineralization. TNAP is also highly expressed in cerebral microvessels; however, its function in brain cerebral microvessels is poorly understood. In recent years, few studies have begun to delineate a role for TNAP in brain microvascular endothelial cells (BMECs)—a key component of cerebral microvessels. This review summarizes important information on the role of BMEC TNAP, and its implication in health and disease. Furthermore, we discuss current models and tools that may assist researchers in elucidating the function of TNAP in BMECs

Paraneoplastic Opsoclonus Myoclonus in a Patient with Pancreatic Adenocarcinoma

Opsoclonus myoclonus syndrome (OMS) is an extremely rare neurological syndrome typically affecting as few as 1 in 10,000,000 people annually. OMS is characterized by the presence of involuntary, saccadic eye movements, as well as ataxia, including gait incoordination, rigidity, and tremor. The origin of OMS is unclear, but a significant percentage of OMS cases are indicative of an underlying malignancy, most commonly neuroblastoma and small cell lung cancer. Here we describe an adult patient with OMS, who was ultimately diagnosed with a small ductal adenocarcinoma of the pancreas. To our knowledge, this is the third published report of an association between OMS and pancreatic malignancy, and the only case where the pancreatic malignancy was detected prior to metastasis or autopsy at death. This case report highlights the importance of careful, aggressive malignancy screening with OMS, as the pancreatic duct cut-off sign may be overlooked if pancreatic malignancy is not suspected

Paraneoplastic Opsoclonus Myoclonus in a Patient with Pancreatic Adenocarcinoma

Opsoclonus myoclonus syndrome (OMS) is an extremely rare neurological syndrome typically affecting as few as 1 in 10,000,000 people annually. OMS is characterized by the presence of involuntary, saccadic eye movements, as well as ataxia, including gait incoordination, rigidity, and tremor. The origin of OMS is unclear, but a significant percentage of OMS cases are indicative of an underlying malignancy, most commonly neuroblastoma and small cell lung cancer. Here we describe an adult patient with OMS, who was ultimately diagnosed with a small ductal adenocarcinoma of the pancreas. To our knowledge, this is the third published report of an association between OMS and pancreatic malignancy, and the only case where the pancreatic malignancy was detected prior to metastasis or autopsy at death. This case report highlights the importance of careful, aggressive malignancy screening with OMS, as the pancreatic duct cut-off sign may be overlooked if pancreatic malignancy is not suspected

Neurocognitive Sequelae and Rehabilitation after Subarachnoid Hemorrhage: Optimizing Outcomes

Subarachnoid hemorrhage (SAH) is a medical emergency that requires immediate intervention. The etiology varies between cases; however, rupture of an intracranial aneurysm accounts for 80% of medical emergencies. Early intervention and treatment are essential to prevent long-term complications. Over the years, treatment of SAH has drastically improved, which is responsible for the rapid rise in SAH survivors. Post-SAH, a significant number of patients exhibit impairments in memory and executive function and report high rates of depression and anxiety that ultimately affect daily living, return to work, and quality of life. Given the rise in SAH survivors, rehabilitation post-SAH to optimize patient outcomes becomes crucial. The review addresses the current rehabilitative strategies to combat the neurocognitive and behavioral issues that may arise following SAH

Myelin oligodendrocyte glycoprotein antibody-associated optic neuritis and myelitis in COVID-19: a case report and a review of the literature.

BACKGROUND: Our case explored the spectrum of autoimmune and infectious neurological complications of Coronavirus Disease 2019. In addition, we also reviewed and discussed clinical features, neuroimaging, CSF findings, and outcomes in patients with COVID-19-associated Myelin Oligodendrocyte Glycoprotein Antibody Disorder (MOGAD) CNS inflammatory disorder. CASE PRESENTATION: Here we presented a case of post-Coronavirus Disease 2019 infection Myelin Oligodendrocyte Glycoprotein Antibody Disorder in a 41-year-old male who presented with gait instability, urinary retention, and confusion. Workup done in hospital showed transverse myelitis in cervical spine region and left optic neuritis. Laboratory findings showed Myelin Oligodendrocyte Glycoprotein-IgG antibodies were positive in serum (1:100), suggestive of post-COVID Myelin Oligodendrocyte Glycoprotein Antibody Disorder. CONCLUSION: To our knowledge, this is the first comprehensive case report and the literature review that includes the clinical features, neuroimaging, CSF findings, and outcomes in COVID-19-associated Myelin Oligodendrocyte Glycoprotein Antibody Disorder

Pediatric Traumatic Brain Injury: An Update on Preclinical Models, Clinical Biomarkers, and the Implications of Cerebrovascular Dysfunction

Traumatic brain injury (TBI) is a leading cause of pediatric morbidity and mortality. Recent studies suggest that children and adolescents have worse post-TBI outcomes and take longer to recover than adults. However, the pathophysiology and progression of TBI in the pediatric population are studied to a far lesser extent compared to the adult population. Common causes of TBI in children are falls, sports/recreation-related injuries, non-accidental trauma, and motor vehicle-related injuries. A fundamental understanding of TBI pathophysiology is crucial in preventing long-term brain injury sequelae. Animal models of TBI have played an essential role in addressing the knowledge gaps relating to pTBI pathophysiology. Moreover, a better understanding of clinical biomarkers is crucial to diagnose pTBI and accurately predict long-term outcomes. This review examines the current preclinical models of pTBI, the implications of pTBI on the brain\u27s vasculature, and clinical pTBI biomarkers. Finally, we conclude the review by speculating on the emerging role of the gut-brain axis in pTBI pathophysiology

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors