Brain Injury-Mediated Neuroinflammatory Response and Alzheimer's Disease.

Traumatic brain injury (TBI) is a major health problem in the United States, which affects about 1.7 million people each year. Glial cells, T-cells, and mast cells perform specific protective functions in different regions of the brain for the recovery of cognitive and motor functions after central nervous system (CNS) injuries including TBI. Chronic neuroinflammatory responses resulting in neuronal death and the accompanying stress following brain injury predisposes or accelerates the onset and progression of Alzheimer's disease (AD) in high-risk individuals. About 5.7 million Americans are currently living with AD. Immediately following brain injury, mast cells respond by releasing prestored and preactivated mediators and recruit immune cells to the CNS. Blood-brain barrier (BBB), tight junction and adherens junction proteins, neurovascular and gliovascular microstructural rearrangements, and dysfunction associated with increased trafficking of inflammatory mediators and inflammatory cells from the periphery across the BBB leads to increase in the chronic neuroinflammatory reactions following brain injury. In this review, we advance the hypothesis that neuroinflammatory responses resulting from mast cell activation along with the accompanying risk factors such as age, gender, food habits, emotional status, stress, allergic tendency, chronic inflammatory diseases, and certain drugs can accelerate brain injury-associated neuroinflammation, neurodegeneration, and AD pathogenesis.

Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders.

Despite significant advancements in the field of molecular neurobiology especially neuroinflammation and neurodegeneration, the highly complex molecular mechanisms underlying neurodegenerative diseases remain elusive. As a result, the development of the next generation neurotherapeutics has experienced a considerable lag phase. Recent advancements in the field of genome editing offer a new template for dissecting the precise molecular pathways underlying the complex neurodegenerative disorders. We believe that the innovative genome and transcriptome editing strategies offer an excellent opportunity to decipher novel therapeutic targets, develop novel neurodegenerative disease models, develop neuroimaging modalities, develop next-generation diagnostics as well as develop patient-specific precision-targeted personalized therapies to effectively treat neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia etc. Here, we review the latest developments in the field of CRISPR-mediated genome editing and provide unbiased futuristic insights regarding its translational potential to improve the treatment outcomes and minimize financial burden. However, despite significant advancements, we would caution the scientific community that since the CRISPR field is still evolving, currently we do not know the full spectrum of CRISPR-mediated side effects. In the wake of the recent news regarding CRISPR-edited human babies being born in China, we urge the scientific community to maintain high scientific and ethical standards and utilize CRISPR for developing in vitro disease in a dish model, in vivo testing in nonhuman primates and lower vertebrates and for the development of neurotherapeutics for the currently incurable neurodegenerative disorders. Graphical Abstract.

CRISPR/Cas9 Editing of Glia Maturation Factor Regulates Mitochondrial Dynamics by Attenuation of the NRF2/HO-1 Dependent Ferritin Activation in Glial Cells.

Microglial cells are brain specific professional phagocytic immune cells that play a crucial role in the inflammation- mediated neurodegeneration especially in Parkinson's disease (PD) and Alzheimer's disease. Glia maturation factor (GMF) is a neuroinflammatory protein abundantly expressed in the brain. We have previously shown that GMF expression is significantly upregulated in the substantia nigra (SN) of PD brains. However, its possible role in PD progression is still not fully understood. The Clustered-Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR Associated (Cas) protein9 (CRISPR/Cas9) system is a simple, rapid and often extremely efficient gene editing tool at desired loci, enabling complete gene knockout or homology directed repair. In this study, we examined the effect of GMF editing by using the CRISPR/Cas9 technique in BV2 microglial cells (hereafter referred to as BV2-G) on oxidative stress and nuclear factor erythroid 2-related factor 2 (NRF2)/Hemeoxygenase1 (HO-1)-dependent ferritin activation after treatment with (1-methyl-4-phenylpyridinium) MPP+. Knockout of GMF in BV2-G cells significantly attenuated oxidative stress via reduced ROS production and calcium flux. Furthermore, deficiency of GMF significantly reduced nuclear translocation of NRF2, which modulates HO-1 and ferritin activation, cyclooxygenase 2 (COX2) and nitric oxide synthase 2 (NOS2) expression in BV2 microglial cells. Lack of GMF significantly improved CD11b and CD68 positive microglial cells as compared with untreated cells. Our results also suggest that pharmacological and genetic intervention targeting GMF may represent a promising and a novel therapeutic strategy in controlling Parkinsonism by regulating microglial functions. Targeted regulation of GMF possibly mediates protein aggregation in microglial homeostasis associated with PD progression through regulation of iron metabolism by modulating NRF2-HO1 and ferritin expression.

Seizure prophylaxis in the neuroscience intensive care unit.

BACKGROUND: Seizures are a considerable complication in critically ill patients. Their incidence is significantly high in neurosciences intensive care unit patients. Seizure prophylaxis with anti-epileptic drugs is a common practice in neurosciences intensive care unit. However, its utility in patients without clinical seizure, with an underlying neurological injury, is somewhat controversial. BODY: In this article, we have reviewed the evidence for seizure prophylaxis in commonly encountered neurological conditions in neurosciences intensive care unit and discussed the possible prognostic role of continuous electroencephalography monitoring in detecting early seizures in critically ill patients. CONCLUSION: Based on the current evidence and guidelines, we have proposed a presumptive protocol for seizure prophylaxis in neurosciences intensive care unit. Patients with severe traumatic brain injury and possible subarachnoid hemorrhage seem to benefit with a short course of anti-epileptic drug. In patients with other neurological illnesses, the use of continuous electroencephalography would make sense rather than indiscriminately administering anti-epileptic drug.

Primary Intraventricular Hemorrhage Isolated in Cerebral Aqueduct Secondary to Dural Arteriovenous Fistula.

OBJECTIVE: We report a case of dural arteriovenous fistula (dAVF) presenting as isolated cerebral aqueduct hemorrhage. RESULT: A 73-year-old man with a history of hypertension and chronic alcoholism presented with altered mental status and gait difficulties, bilateral fronto-occipital headaches, and intermittent dizziness. He had bilateral upward gaze restriction. Computerized tomography scan showed hyperdensity in the cerebral aqueduct and dilation of the lateral and third ventricles. The diagnostic angiogram demonstrated dAVF with arterial feeders from the cavernous segment of the left internal carotid artery and venous drainage into left transverse and sigmoid venous sinus. CONCLUSION: Underlying dAVF should be considered in patients with isolated cerebral aqueduct hemorrhage.

Improvement in Quality Metrics Outcomes and Patient and Family Satisfaction in a Neurosciences Intensive Care Unit after Creation of a Dedicated Neurocritical Care Team.

INTRODUCTION: Dedicated neurointensivists have been shown to improve outcome measurements in the neurosciences intensive care unit (NSICU). Quality outcome data in relation to patient and family satisfaction is lacking. This study evaluated the impact of newly appointed neurointensivists and creation of a neurocritical care team on quality outcome measures including patient satisfaction in a NSICU. METHODS: This is a retrospective study of data over 36 months from a 14-bed NSICU evaluating quality outcome measures and anonymous patient satisfaction questionnaires before and after neurointensivists appointment. RESULTS: After appointment of neurointensivists, patient acuity of the NSICU increased by 33.4% while LOS decreased by 3.5%. There was a decrease in neurosciences mortality (35.8%), catheter-associated urinary tract infection (50%), central line associated bloodstream infection (100%), and ventilator-associated pneumonia (50%). During the same time, patient satisfaction increased by 28.3% on physicians/nurses consistency (p = 0.025), by 69.5% in confidence/trust in physicians (p < 0.0001), by 78.3% on physicians treated me with courtesy/respect (p < 0.0001), and by 46.4% on physicians' attentiveness (p < 0.0001). Ultimately, patients recommending the hospital to others increased by 67.5% (p < 0.0001). CONCLUSION: Dedicated neurointensivists and the subsequent development of a neurocritical care team positively impacted quality outcome metrics, particularly significantly improving patient satisfaction.

Prolonged duration of apnea test during brain death examination in a case of intraparenchymal hemorrhage.

OBJECTIVE: Apnea test is required as part of the brain death examination. The duration of the apnea test is variable but typically requires 8-10 min. Prolonged apnea tests have been reported in the setting of hypothermia. Here, we describe a case of prolonged duration of apnea test secondary to a phenomenon called cardiac ventilation. METHODS: The patient presented in coma with brainstem areflexia after having an intracerebral hemorrhage resulting in subfalcine, central, uncal, and tonsillar herniations. Confounding variables were excluded. Brain death testing was performed, and she was found to have brainstem areflexia. Pre-requisites for apnea test were then met. RESULTS: Apnea testing, however, was prolonged at 110 min. When reconnected to ventilator, it was noted that she had small (30-35 cc) tidal volumes at a rate of her heart rate without respiratory effort. Ancillary testing with four-vessel cerebral angiogram confirmed cerebral circulatory arrest. CONCLUSIONS: To our knowledge, this is the longest reported case of apnea testing during brain death testing. Variables known to cause a delay in the rise of carbon dioxide (PaCO2) levels were excluded. We suspect the hyperdynamic cardiac state caused cardiac ventilations resulting in slow increase in carbon dioxide levels.

Comparison of Two Surface Cooling Devices for Temperature Management in a Neurocritical Care Unit.

Fever increases mortality and morbidity and length of stay in neurocritically ill patients. Various methods are used in the neuroscience intensive care unit (NSICU) to control fever. Two such methods involve the Arctic Sun hydrogel wraps and the Gaymar cooling wraps. The purpose of our study was to compare these two methods in neurocritical care patients who had temperature >37.5°C for more than three consecutive hours and that was refractory to standard treatments. Data of patients requiring cooling wraps for treatment of hyperthermia at an NSICU at an academic, tertiary referral center were retrospectively reviewed. The average temperature before cooling was 38.5°C ± 0.38°C and 38.4°C ± 0.99°C for the Gaymar and Arctic Sun groups, respectively (p = 0.89). The Gaymar group took on average 16 ± 21.9 hours to reach goal temperature, whereas the Arctic Sun group took 2.22 ± 1.39 hours (p = 0.08). The average time outside of the target temperature was 57.0 ± 58.0 hours in the Gaymar group compared with 13.7 ± 17.1 hours in the Arctic Sun group (p = 0.04). Average duration of using the cooling wraps was similar between the two groups; 81.8% of patients had rebound hyperthermia in the Gaymar group compared with 20% in the Arctic Sun group (p = 0.0089). The Arctic Sun group had a nonsignificant increased incidence of shivering compared with the Gaymar group (40% vs. 18.18%, p = 0.36). We found that Arctic Sun surface cooling device was more efficient in attaining the target temperature, had less incidence of rebound hyperthermia, and was able to maintain normothermia better than Gaymar cooling wraps. The incidence of shivering tended to be more common in the Arctic Sun group.