Charles L. Rosen

Early disruptions of the blood-brain barrier may contribute to exacerbated neuronal damage and prolonged functional recovery following stroke in aged rats

We examined the effects of age on stroke progression and outcome in order to explore the association between blood-brain barrier (BBB) disruption, neuronal damage, and functional recovery. Using middle cerebral artery occlusion (MCAO), young (3 months) and aged (18 months) rats were assessed for BBB disruption at 20min post-MCAO, and 24h post-MCAO with tissue plasminogen activator induced reperfusion at 120min. Results showed that BBB disruptions in aged rats occurred early and increased nearly two-fold at both the 20min and 24h time points when compared to young animals. Neuronal damage in aged rats was increased two-fold as compared to young rats at 24h, while no neuronal damage was observed at 20min. Young and aged rats exhibited neurological deficits when compared to sham-controls out to 14 days following MCAO and reperfusion; however, aged rats exhibited more severe onset of deficits and prolonged recovery. Results indicate that aged rats suffer larger infarctions, reduced functional recovery and increased BBB disruption preceding observable neuronal injury.

Age exaggerates proinflammatory cytokine signaling and truncates signal transducers and activators of transcription 3 signaling following ischemic stroke in the rat.

Neuroinflammation is associated with glial activation following a variety of brain injuries, including stroke. While activation of perilesional astrocytes and microglia following ischemic brain injury is well documented, the influence of age on these cellular responses after stroke is unclear. This study investigated the influence of advanced age on neuronal degeneration, neuroinflammation, and glial activation in female Sprague-Dawley rats after reversible embolic occlusion of the middle cerebral artery (MCAO). Results indicate that in comparison to young adult rats (3 months), aged rats (18 months) showed enhanced neuronal degeneration, altered microglial response, and a markedly increased expression of proinflammatory cytokines/chemokines following MCAO. In addition, the time-course for activation of signal transducers and activators of transcription 3 (STAT3), the signaling mechanism that regulates astrocyte reactivity, was truncated in the aged rats after MCAO. Moreover, the expression of suppressor of cytokine signaling 3 (SOCS3), which is associated with termination of astrogliosis, was enhanced as a function of age after MCAO. These findings are suggestive of an enhanced proinflammatory response and a truncated astroglial response as a function of advanced age following MCAO. These data provide further evidence of the prominent role played by age in the molecular and cellular responses to ischemic stroke and suggest that astrocytes may represent targets for future therapies aimed at improving stroke outcome.

Primary angiitis of the central nervous system as a first presentation in Hodgkin's disease : a case report and review of the literature

OBJECTIVE AND IMPORTANCE Granulomatous angiitis of the central nervous system is a rare cause of neurological deterioration. It is often diagnosed posthumously, and a high index of suspicion is necessary to make the correct diagnosis on a timely basis. CLINICAL PRESENTATION A 27-year-old woman presented to the emergency room with complaints of worsening headache, nausea, and vomiting for 10 days, which were preceded by swelling of her tongue. At the examination, she had mild ocular tenderness, but no cranial nerve abnormalities. Radiographic examination revealed a right temporal lobe area with edema, and mild contrast enhancement was noted on computed tomography and magnetic resonance imaging. A similar but smaller region was present in the left frontal lobe. INTERVENTION Stereotactic biopsy of the left temporal lobe revealed granulomatous angiitis. Further workup revealed Hodgkins disease in the mediastinum. Dexamethasone as well as chemotherapy for Hodgkins disease was initiated. The patients symptoms resolved, and she returned to work with her disease in remission. CONCLUSION Previous reports of central nervous system angiitis have shown an association with Sjogrens syndrome, herpes zoster infection, human immunodeficiency virus, and Hodgkins disease. A review of the literature revealed a total of 12 patients with central nervous system angiitis and Hodgkins disease. As a group, these patients had very poor outcomes. However, of six patients who presented with central nervous system angiitis and concurrent Hodgkins disease and who underwent aggressive treatment for both conditions, three had a full recovery, two had a partial recovery, and one died.

The science of cerebral ischemia and the quest for neuroprotection: navigating past failure to future success

Ischemic stroke remains a leading cause of morbidity and death for which few therapeutic options are available. The development of neuroprotective agents, a once promising field of investigation, has failed to translate from bench to bedside successfully. This work reviews the ischemic cascade, agents targeting steps within the cascade, and potential reasons for lack of translation. Additional therapeutic targets are highlighted and areas requiring further investigation are discussed. It is clear that alternative targets need to be pursued, such as the role glia play in neurological injury and recovery, particularly the interactions between neurons, astrocytes, microglia, and the vasculature. Similarly, the biphasic nature of many signaling molecules such as matrix metalloproteinases and high-mobility group box 1 protein must be further investigated to elucidate periods of detrimental versus beneficial activity.

Selective MCA occlusion: a precise embolic stroke model.

The present study describes a method for improving the precision and accuracy of clot placement within the middle cerebral artery (MCA) of rats, utilizing a micro-catheter and laser Doppler flowmetry. This technique reduces the size of clot needed to achieve stable occlusion with no failed embolizations and a low percentage of early recanalizations. Infarctions were consistent in both size and distribution within the MCA perfusion territory. Selective embolization in aged animals (n = 10) resulted in substantially larger infarctions than those seen in aged animals (n = 10) following non-selective embolization (P < 0.05), or young animals (n = 10) subjected to filamentous occlusion (P < 0.001). Clots were localized to the MCA by direct examination at 0, 60 and 120 min post-embolization (n = 14). All aged animals surviving 24h exhibited moderate to severe functional deficits, with selectively occluded animals having a higher mean score on the modified neurologic severity scale (P = 0.002). This model provides a highly reproducible method for embolization of the MCA and reliable reperfusion with rt-PA.

Linking Traumatic Brain Injury to Chronic Traumatic Encephalopathy: Identification of Potential Mechanisms Leading to Neurofibrillary Tangle Development

Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sports-related concussions in athletes and blast-induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and, occasionally, transactive response DNA binding protein 43 (TDP43) oligomers, both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed postmortem by neuropathological identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for premortem diagnosis, to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders.

Targeting the neurovascular unit for treatment of neurological disorders

Drug discovery for CNS disorders has been restricted by the inability for therapeutic agents to cross the blood-brain barrier (BBB). Moreover, current drugs aim to correct neuron cell signaling, thereby neglecting pathophysiological changes affecting other cell types of the neurovascular unit (NVU). Components of the NVU (pericytes, microglia, astrocytes, and neurons, and basal lamina) act as an intricate network to maintain the neuronal homeostatic microenvironment. Consequently, disruptions to this intricate cell network lead to neuron malfunction and symptoms characteristic of CNS diseases. A lack of understanding in NVU signaling cascades may explain why current treatments for CNS diseases are not curative. Current therapies treat symptoms by maintaining neuron function. Refocusing drug discovery to sustain NVU function may provide a better method of treatment by promoting neuron survival. In this review, we will examine current therapeutics for common CNS diseases, describe the importance of the NVU in cerebral homeostasis and discuss new possible drug targets and technologies that aim to improve treatment and drug delivery to the diseased brain.

Modeling clinically relevant blast parameters based on scaling principles produces functional & histological deficits in rats

Blast-induced traumatic brain injury represents a leading cause of injury in modern warfare with injury pathogenesis poorly understood. Preclinical models of blast injury remain poorly standardized across laboratories and the clinical relevance unclear based upon pulmonary injury scaling laws. Models capable of high peak overpressures and of short duration may better replicate clinical exposure when scaling principles are considered. In this work we demonstrate a tabletop shock tube model capable of high peak overpressures and of short duration. By varying the thickness of the polyester membrane, peak overpressure can be controlled. We used membranes with a thickness of 0.003, 0.005, 0.007, and 0.010 in to generate peak reflected overpressures of 31.47, 50.72, 72.05, and 90.10 PSI, respectively. Blast exposure was shown to decrease total activity and produce neural degeneration as indicated by fluoro-jade B staining. Similarly, blast exposure resulted in increased glial activation as indicated by an increase in the number of glial fibrillary acidic protein expressing astrocytes compared to control within the corpus callosum, the region of greatest apparent injury following blast exposure. Similar findings were observed with regard to activated microglia, some of which displayed phagocytic-like morphology within the corpus callosum following blast exposure, particularly with higher peak overpressures. Furthermore, hematoxylin and eosin staining showed the presence of red blood cells within the parenchyma and red, swollen neurons following blast injury. Exposure to blast with 90.10 PSI peak reflected overpressure resulted in immediate mortality associated with extensive intracranial bleeding. This work demonstrates one of the first examples of blast-induced brain injury in the rodent when exposed to a blast wave scaled from human exposure based on scaling principles derived from pulmonary injury lethality curves.

NEUROLOGICAL INJURY AND DEATH IN ALL-TERRAIN VEHICLE CRASHES IN WEST VIRGINIA: A 10-YEAR RETROSPECTIVE REVIEW

OBJECTIVEThe purpose of this study was to profile all-terrain vehicle crash victims with neurological injuries who were treated at a Level I trauma center. METHODSWe retrospectively reviewed trauma registry data for 238 patients who were admitted to the Jon Michael Moore Trauma Center at the West Virginia University School of Medicine after all-terrain vehicle crashes, between January 1991 and December 2000. Age, helmet status, alcohol and drug use, head injuries, length of stay, disposition, and hospital costs were studied. Death rates, head injuries, age, helmet use, and safety legislation in all 50 states were compared. RESULTSEighty percent of victims were male, with an average age of 27.3 years. Only 22% of all patients were wearing helmets. Alcohol and/or drugs were involved in almost one-half of all incidents. Fifty-five of 238 patients sustained spinal axis injuries; only 5 were wearing helmets. One-third of victims (75 of 238 victims) were in the pediatric population, and only 21% were wearing helmets. Only 15% of victims less than 16 years of age were wearing helmets. There were a total of eight deaths; only one patient was wearing a helmet. CONCLUSIONIn the United States, all-terrain vehicles caused an estimated 240 deaths/yr between 1990 and 1994, which increased to 357 deaths/yr between 1995 and 2000. Brain and spine injuries occurred in 80% of fatal crashes. West Virginia has a fatality rate approximately eight times the national rate. Helmets reduce the risk of head injury by 64%, but only 21 states have helmet laws. Juvenile passengers on adult-driven vehicles are infrequently helmeted (<20%) and frequently injured (>65%). We conclude that safety legislation would save lives.

NOX2 inhibition with apocynin worsens stroke outcome in aged rats

This study utilized middle cerebral artery occlusion (MCAO) with tissue plasminogen activator (tPA) to assess inhibition of the NOX2 isoform of NADPH oxidase on brain injury and functional recovery in aged rats. Effects of NOX2 on the degree of brain injury and functional recovery following MCAO and tPA reperfusion was assessed in young adult and aged rats. Rats received apocynin (NOX2 inhibitor; 5 mg/kg) or saline 30 min prior to MCAO. At 24 h following MCAO, blood-brain barrier permeability (BBB), stroke infarct volume, edema formation, and oxidative damage were measured. Apocynin treatment in aged rats increased mortality rate and failed to improve functional outcome, total infarct volume, edema formation, and BBB permeability. Aged rats displayed increased BBB permeability to sucrose in the contralateral hemisphere following MCAO and diminished antioxidant capacity in the brain as compared to young adult rats. We conclude that inhibition of NOX2 in the aged rat exacerbates stroke injury and diminishes functional outcome. These results suggest age is an important factor in stroke damage and more rigorous examination of apocynin as a therapeutic agent for treatment of stroke must be done.