Aims The current study examined whether white matter injury occurs in the hyperacute (4 hours) phase after subarachnoid hemorrhage (SAH) and the potential role of blood‐brain barrier (BBB) disruption and an acute phase protein, lipocalin 2 (LCN2), in that injury. Methods Subarachnoid hemorrhage was induced by endovascular perforation in adult mice. First, wild‐type (WT) mice underwent MRI 4 hours after SAH to detect white matter T2 hyperintensities. Second, changes in LCN2 expression and BBB disruption associated with the MRI findings were examined. Third, SAH‐induced white matter injury at 4 hours was compared in WT and LCN2 knockout (LCN2 KO) mice. Results At 4 hours, most animals had uni‐ or bilateral white matter T2 hyperintensities after SAH in WT mice that were associated with BBB disruption and LCN2 upregulation. However, some disruption and LCN2 upregulation was also found in mice with no T2‐hyperintensity lesion. In contrast, there were no white matter T2 hyperintensities in LCN2 KO mice after SAH. LCN2 deficiency also attenuated BBB disruption, myelin damage, and oligodendrocyte loss. Conclusions Subarachnoid hemorrhage causes very early BBB disruption and LCN2 expression in white matter that is associated with and may precede T2 hyperintensities. LCN2 deletion attenuates MRI changes and pathological changes in white matter after SAH.

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Background and Purpose: The mechanisms of brain damage during ultra-early subarachnoid hemorrhage (SAH) have not been well studied. The current study examined the SAH-induced hyperacute brain damage at 4 hours using magnetic resonance imaging and brain histology in a mouse model. Methods: SAH was induced by endovascular perforation in adult mice. First, adult male wild-type mice underwent magnetic resonance imaging T2 and T2* 4 hours after an endovascular perforation or a sham operation and were euthanized to assess brain histology. Second, male and female adult lipocalin-2 knockout mice had SAH. All animals underwent magnetic resonance imaging at 4 hours, and the brains were harvested for brain histology. Results: T2* hypointensity vessels were observed in the brain 4 hours after SAH in male wild-type mice. The numbers of T2*-positive vessels were significantly higher in SAH brains than in sham-operated mice. Brain histology showed thrombosis and erythrocyte plugs in the T2*-positive cerebral vessels which may be venules. The number of T2*-positive vessels correlated with SAH grade and the presence of T2 lesions. Brain thrombosis was also accompanied by albumin leakage and neuronal injury. LCN2 deficient male mice had lower numbers of T2*-positive vessels after SAH compared with wild-type male mice. Conclusions: SAH causes ultra-early brain vessel thrombosis that can be detected by T2* gradient-echo sequence at 4 hours after SAH. LCN2 deficiency decreased the number of T2*-positive vessels.

Background3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) has been used to evaluate tumor malignancy and cell proliferation in human brain gliomas. However, 18F-FLT has several limitations in clinical use. Recently, 11C-labeled thymidine analogue, 4′-[methyl-11C]thiothymidine (11C-4DST), became available as an in vivo cell proliferation positron emission tomography (PET) tracer. The present study was conducted to evaluate the usefulness of 11C-4DST PET in the diagnosis of human brain gliomas by comparing with the images of 18F-FLT PET.MethodsTwenty patients with primary and recurrent brain gliomas underwent 18F-FLT and 11C-4DST PET scans. The uptake values in the tumors were evaluated using the maximum standardized uptake value (SUVmax), the tumor-to-normal tissue uptake (T/N) ratio, and the tumor-to-blood uptake (T/B) ratio. These values were compared among different glioma grades. Correlation between the Ki-67 labeling index and the uptake values of 11C-4DST and 18F-FLT in the tumor was evaluated using linear regression analysis. The relationship between the individual 18F-FLT and 11C-4DST uptake values in the tumors was also examined.Results11C-4DST uptake was significantly higher than that of 18F-FLT in the normal brain. The uptake values of 11C-4DST in the tumor were similar to those of 18F-FLT resulting in better visualization with 18F-FLT. No significant differences in the uptake values of 18F-FLT and 11C-4DST were noted among different glioma grades. Linear regression analysis showed a significant correlation between the Ki-67 labeling index and the T/N ratio of 11C-4DST (r = 0.50, P < 0.05) and 18F-FLT (r = 0.50, P < 0.05). Significant correlations were also found between the Ki-67 labeling index and the T/B ratio of 11C-4DST (r = 0.52, P < 0.05) and 18F-FLT (r = 0.55, P < 0.05). A highly significant correlation was observed between the individual T/N ratio of 11C-4DST and 18F-FLT in the tumor (r = 0.79, P = 0.0001).ConclusionsThe present study demonstrates that 11C-4DST is useful for the imaging of human brain gliomas with PET. A relatively higher background uptake of 11C-4DST in the normal brain compared to 18F-FLT limits the detection of low-tracer-uptake tumors. Moreover, no superiority was found in 11C-4DST over 18F-FLT in the evaluation of cell proliferation.