Molecular and functional alterations in the cerebral microvasculature in an optimized mouse model of sepsis-associated cognitive dysfunction.

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in systemic inflammation-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammatory response. In the acute phase, we identified novel molecular (e.g. upregulation of plasmalemma vesicle associated protein, a driver of endothelial permeability, and the pro-coagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small molecule BBB permeability, elevated levels of PAI-1, intra/perivascular fibrin/fibrinogen deposition and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor suggesting diffuse axonal injury, synapse degeneration and impaired neurotrophism. Our study serves as a standardized model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition. SIGNIFICANCE: The limited knowledge of how systemic inflammation contributes to cognitive decline is a major obstacle to the development of novel therapies for dementia and other neurodegenerative diseases. Clinical evidence supports a role for the cerebral microvasculature in sepsis-induced neurocognitive dysfunction, but the investigation of the underlying mechanisms has been limited by the lack of standardized experimental models. Herein, we optimized a mouse model that recapitulates important pathophysiological aspects of systemic inflammation-induced cognitive decline and identified key alterations in the cerebral microvasculature associated with cognitive dysfunction. Our study provides a reliable experimental model for mechanistic studies and therapeutic discovery of the impact of systemic inflammation on cerebral microvascular function and the development and progression of cognitive impairment.

Corpus Callosum Swelling after Resection of Intraventricular Central Neurocytoma.

Corpus callosum swelling has been reported to occur after ventriculoperitoneal shunting for long-standing hydrocephalus. This report presents a case of corpus callosum swelling after intraventricular tumor resection. A 34-year-old woman presented with a headache that worsened over 1 month. Magnetic resonance (MR) images revealed a mass lesion in the left lateral ventricle and obstructive hydrocephalus. She underwent subtotal resection with a transcallosal approach. After tumor resection, she had long-lasting status epilepticus followed by consciousness disturbance. T2-weighted MR images obtained 8 hr after the operation showed a hyperintense area in the corpus callosum. The patient then presented with bilateral dilated pupils 14 hr after the operation due to acute hydrocephalus and tension pneumocephalus. An emergent re-craniotomy was performed and a ventricular drain was placed. The patient recovered consciousness 3 days after the operation. However, she experienced progressive corpus callosum swelling 25 days after the operation, which improved since then. Approximately 4 months after the operation, she returned to her usual workplace with no neurocognitive functional decline. Two years later, she was doing well with no radiological abnormal findings except corpus callosum thinning. Thus, corpus callosum swelling can develop not only after shunting for chronic hydrocephalus but also after intraventricular tumor resection. It occurred relatively acutely and there was no decline in intelligence after long-term follow-up. This case suggests that corpus callosum swelling after intraventricular tumor resection is a rare but noteworthy complication that can improve without intervention.

Intravenously Transplanted Human Multilineage-Differentiating Stress-Enduring Cells Afford Brain Repair in a Mouse Lacunar Stroke Model.

Background and Purpose- Multilineage-differentiating stress-enduring cells are endogenous nontumorigenic reparative pluripotent-like stem cells found in bone marrow, peripheral blood, and connective tissues. Topically administered human multilineage-differentiating stress-enduring cells into rat/mouse stroke models differentiated into neural cells and promoted clinically relevant functional recovery. However, critical questions on the appropriate timing and dose, and safety of the less invasive intravenous administration of clinical-grade multilineage-differentiating stress-enduring cell-based product CL2020 remain unanswered. Methods- Using an immunodeficient mouse lacunar model, CL2020 was administered via the cervical vein in different doses (high dose=5×104 cells/body; medium dose=1×104 cells/body; low dose=5×103 cells/body) at subacute phase (≈9 days after onset) and chronic phase (≈30 days). Cylinder test, depletion of human cells by diphtheria toxin administration, immunohistochemistry, and human specific-genome detection were performed. Results- Tumorigenesis and adverse effects were not detected for up to 22 weeks. The high-dose group displayed significant functional recovery compared with the vehicle group in cylinder test in subacute-phase-treated and chronic-phase-treated animals after 6 weeks and 8 weeks post-injection, respectively. In the high-dose group of subacute-phase-treated animals, robust and stable recovery in cylinder test persisted up to 22 weeks compared with the vehicle group. In both groups, intraperitoneal injection of diphtheria toxin abrogated the functional recovery. Anti-human mitochondria revealed CL2020 distributed mainly in the peri-infarct area at 1, 10, and 22 weeks and expressed NeuN (neuronal nuclei)- and MAP-2 (microtubule-associated protein-2)-immunoreactivity. Conclusions- Intravenously administered CL2020 was safe, migrated to the peri-infarct area, and afforded functional recovery in experimental stroke.

[Surgical Planning for a Giant Pituitary Adenoma Based on Evaluation of the Fine Feeding System and Angioarchitecture:A Case Report].

Giant pituitary adenomas carry higher surgical risks despite recent advances in microsurgical and/or endoscopic surgery. In particular, postoperative acute catastrophic changes without major vessel disturbance are still extremely difficult to predict, and may manifest as postoperative pituitary apoplexy with very poor outcomes. These changes are associated with injuries to the capillary intratumoral feeders and/or drainers, which frequently have diameters of less than 300µm, and result in drastic hemodynamic changes. A 43-year-old woman with severe visual disturbance and a giant pituitary adenoma was referred to our institute, The tumor had extended irregularly toward the suprasellar cistern and had compressed the optic chiasm upwards, and the bilateral frontal lobes were displaced laterally. Surgery was planned based on information regarding the fine angioarchitecture and feeding systems using a C-arm cone-beam CT scanner with a flat-panel detector(GE Healthcare;IL, USA)and 50%-diluted contrast medium, which disclosed the distinct feedings from the left meningohypophyseal trunk to the left lower part of the tumor and from the left superior hypophyseal artery to the upper posterior part, and absence of pial blood supply to the lateral pole of the tumor. Extended transsphenoidal surgery was performed and achieved total tumor removal. The patient was discharged without neurological or endocrinological deficits. Detailed preoperative examination of the feeding system and hemodynamics of giant pituitary adenomas is not a priority at present. However, we would like to emphasize the need for specific individual operative strategies to prevent devastating outcomes after surgery for this formidable tumor.

Navigation-guided clipping of a de novo aneurysm associated with superficial temporal artery-middle cerebral artery bypass combined with indirect pial synangiosis in a patient with moyamoya disease.

De novo aneurysms associated with superficial temporal artery (STA)-middle cerebral artery (MCA) bypass are an extremely rare complication of direct revascularization surgery for moyamoya disease (MMD). The basic pathology of MMD includes fragility of the intracranial arterial wall characterized by medial layer thinness and waving of the internal elastic lamina. However, the incidence of newly formed aneurysms at the site of anastomosis currently remains unknown. Among 317 consecutive direct/indirect combined revascularization surgeries performed for MMD, we encountered a 52-year-old woman manifesting a de novo aneurysm adjacent to the site of anastomosis 11 years after successful STA-MCA bypass with encephalo-duro-myo-synangiosis (EDMS). Although the patient remained asymptomatic, the aneurysm gradually increased in diameter to more than 6 mm with the formation of a daughter sac, and a computational fluid dynamic study revealed low wall shear stress at the aneurysm dome. The patient underwent microsurgical clipping of the aneurysm using a neuro-navigation system that permitted the minimally invasive dissection of the temporal muscle flap used for EDMS at the site of the aneurysm without affecting pial synangiosis. The aneurysm was successfully occluded using a titanium clip without complications. The postoperative course was uneventful, and the patient was discharged without neurological deficits. De novo aneurysms associated with STA-MCA bypass for MMD may be safely treated with microsurgical clipping, even in cases initially managed by a combined revascularization procedure that includes complex pial synangiosis. We recommend the application of the neuro-navigation system for the maximum preservation of pial synangiosis during this procedure.