Measuring cognitive outcome after subarachnoid hemorrhage

Haley, E. Clarke

doi:10.1002/ana.21040

Cited by 9 publications

(5 citation statements)

References 16 publications

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“…Surviving patients are at risk for potentially severe complications, including vasospasm, cognitive dysfunction and global brain atrophy [ 1 ]. Cognitive dysfunction afflicts up to half of survivors, manifests as deficits in memory, executive function and language [ 2 , 3 , 4 , 5 ], and is responsible for the fact that only a third of previously employed SAH survivors return to work [ 6 ]. Cognitive dysfunction may be linked to global brain atrophy, which is very common in SAH, is strongly associated with poor outcome [ 7 , 8 ], and correlates with the severity of the systemic inflammatory response [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Methemoglobin Is an Endogenous Toll-Like Receptor 4 Ligand—Relevance to Subarachnoid Hemorrhage

Kwon

Woo

Kurland

et al. 2015

IJMS

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Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH), and may be responsible for important complications of SAH. Signaling by Toll-like receptor 4 (TLR4)-mediated nuclear factor κB (NFκB) in microglia plays a critical role in neuronal damage after SAH. Three molecules derived from erythrocyte breakdown have been postulated to be endogenous TLR4 ligands: methemoglobin (metHgb), heme and hemin. However, poor water solubility of heme and hemin, and lipopolysaccharide (LPS) contamination have confounded our understanding of these molecules as endogenous TLR4 ligands. We used a 5-step process to obtain highly purified LPS-free metHgb, as confirmed by Fourier Transform Ion Cyclotron Resonance mass spectrometry and by the Limulus amebocyte lysate assay. Using this preparation, we show that metHgb is a TLR4 ligand at physiologically relevant concentrations. metHgb caused time- and dose-dependent secretion of the proinflammatory cytokine, tumor necrosis factor α (TNFα), from microglial and macrophage cell lines, with secretion inhibited by siRNA directed against TLR4, by the TLR4-specific inhibitors, Rs-LPS and TAK-242, and by anti-CD14 antibodies. Injection of purified LPS-free metHgb into the rat subarachnoid space induced microglial activation and TNFα upregulation. Together, our findings support the hypothesis that, following SAH, metHgb in the subarachnoid space can promote widespread TLR4-mediated neuroinflammation.

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Section: Introductionmentioning

confidence: 99%

Methemoglobin Is an Endogenous Toll-Like Receptor 4 Ligand—Relevance to Subarachnoid Hemorrhage

Kwon

Woo

Kurland

et al. 2015

IJMS

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“…Mortality remains near 50%; 1 while relatively few SAH survivors have significant focal neurologic deficits of the sort that are common after ischemic stroke, long-term cognitive dysfunction is seen in 50% to 60%, allowing only 33% to return to their previous level of employment despite good neurologic outcome. 2 The long-term cognitive deficits after SAH cross numerous cognitive domains, including memory, executive function, and language (for review, see Al-Khindi, 3 ). Of the memory deficits, most 4–6 but not all 7 have documented visuospatial memory as being particularly affected.…”

Section: Introductionmentioning

confidence: 99%

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

Holtzman

Friess

Hartman

et al. 2014

J Cereb Blood Flow Metab

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Cognitive dysfunction is the primary driver of poor long-term outcome in aneurysmal subarachnoid hemorrhage (SAH) survivors; modeling such deficits preclinically is thus key for mechanistic and translational investigation. Although rat SAH causes long-term deficits in learning and memory, it remains unknown whether similar deficits are seen in the mouse, a species particularly amenable to powerful, targeted genetic manipulation. We thus subjected mice to endovascular perforation SAH and assessed long-term cognitive outcome via the Morris water maze (MWM), the most commonly used metric for rodent neurocognition. No significant differences in MWM performance (by either of two protocols) were seen in SAH versus sham mice. Moreover, SAH caused negligible hippocampal CA1 injury. These results undercut the potential of commonly used methods (of SAH induction and assessment of long-term neurocognitive outcome) for use in targeted molecular studies of SAH-induced cognitive deficits in the mouse.

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“…Even in patients who initially show good clinical grade, poor outcome affects as much as about 30% of cases (Germanò et al, 1997(Germanò et al, , 1998aHaley, 2006;Molyneux et al, 2005). Although several pharmacological and treatment strategies have shown positive effects in preclinical SAH models, there have been notable difficulties in their clinical translation, with a large number of late phase II and III trials failing to confirm benefits in human subjects.…”

Section: Merlo Et Almentioning

confidence: 97%

Simvastatin Administration Ameliorates Neurobehavioral Consequences of Subarachnoid Hemorrhage in the Rat

Merlo

Cimino

Scibilia

et al. 2011

Journal of Neurotrauma

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In the present study we assessed the neuroprotective effects of simvastatin in a rodent model of experimental subarachnoid hemorrhage (SAH). Based on recent data showing the role of statins not only in lowering the level of cholesterol but also in preventing cardiac and cerebrovascular damage in risk population, and in decreasing vasospasm and delayed ischemia after aneurysmal SAH, we investigated the neuroprotective effects of intraperitoneal administration of simvastatin (40 mg/kg/day for 5 consecutive days) in Sprague-Dawley rats 30 min after SAH, as compared to vehicle-treated SAH animals. We employed a battery of well-characterized tests to assess memory, learning, motivational, balance, and behavioral performances. On days 1-4 post-SAH, simvastatin-treated rats have significantly improved beam balance scores (days 1-2, p<0.001; days 3-4, p<0.01), beam balance times (days 1-4, p<0.01), and latency to traverse the beam (days 1-3, p<0.01; day 2, p<0.005; day 4, p<0.0001) in comparison with control groups that, conversely, were not protected against SAH-related body weight changes. These results demonstrate that the administration of simvastatin may represent a beneficial therapeutic approach able to reduce post-SAH cognitive dysfunction.

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Measuring cognitive outcome after subarachnoid hemorrhage

Cited by 9 publications

References 16 publications

Methemoglobin Is an Endogenous Toll-Like Receptor 4 Ligand—Relevance to Subarachnoid Hemorrhage

Methemoglobin Is an Endogenous Toll-Like Receptor 4 Ligand—Relevance to Subarachnoid Hemorrhage

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

Simvastatin Administration Ameliorates Neurobehavioral Consequences of Subarachnoid Hemorrhage in the Rat

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