Topically applied adipose-derived mesenchymal stem cell treatment in experimental focal cerebral ischemia.

In this study, the neuro-modulation effect of topical mesenchymal stem cells (MSCs) was tested in a rodent middle carotid artery occlusion (MCAO) model. Twenty-four hours after MCAO, craniotomy was made and 0.8 × 106 GFP-MSCs were topically applied to the exposed parietal cortex. The MSCs were fixed in position by a thin layer of fibrin glue (N = 30). In the control group, saline were topically applied to the ipsilateral parietal cortex (N = 30). Three days after topical application, few GFP-positive cells were found in the ischemic penumbra. They expressed GFAP and NeuN. Topical MSCs triggered microglial activation, astrocytosis and cellular proliferation at day 3. The recovery of neurological functions were significantly enhanced as determined in Rotarod test and Morris Water Maze test with smaller infarct volume. PCR array showed that expressions of ten genes of neurogenesis were altered in the penumbra region (fold change > 1.25, p < 0.05) in MSCs group: Apoe, Ascl1, Efnb1, Mef2c, Nog, A100a6 and B2m were up-regulated; Pax2, Pax3 and Th were down-regulated. In conclusion, topical application provided a direct and effective transplant method for the delivery of MSCs to the surface of ipsilateral cerebral cortex and the topical MSCs could improve the neurological function from cerebral ischemia resulting from a major cerebral artery occlusion in a rodent experimental model.

Cognitive Outcomes of Patients with Traumatic Bifrontal Contusions.

OBJECTIVES: We aimed to investigate the prevalence and pattern of cognitive dysfunction in patients with traumatic bifrontal contusions and their association with functional outcome. MATERIALS AND METHODS: We prospectively recruited patients with bifrontal contusions in a regional neurosurgical center in Hong Kong over a 2-year period. Functional outcome was assessed by modified Rankin Scale (mRS), and cognitive outcomes were assessed by Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and a comprehensive neuropsychological battery. RESULTS: We recruited 34 patients with traumatic bifrontal contusions over a 2-year period. Nine (26%) patients had craniotomy for evacuation of left or right frontal contusions. Functional outcome using mRS was significantly correlated with cognitive outcomes using MMSE or MoCA. The effect of cognitive outcome using MMSE or MoCA persisted after adjustments of age, sex, admission Glasgow Coma Scale, and surgery. In patients who completed the comprehensive neuropsychological assessments, cognitive impairment in at least one of the neuropsychological tests was noted in 73% of them. CONCLUSIONS: Cognitive dysfunction had a significant impact on functional outcome, and treatment strategy should be developed to minimize them.

Minimum Clinically Important Difference of Montreal Cognitive Assessment in aneurysmal subarachnoid hemorrhage patients.

Cognitive impairment is a major factor contributing to poor functional outcome after subarachnoid hemorrhage caused by a ruptured cerebral aneurysm (aSAH). Montreal Cognitive Assessment (MoCA) has been shown to be superior to the Mini-Mental State Examination in screening for cognitive domain deficit and correlating to functional outcome in aSAH patients. The aim of the current study was to determine the Montreal Cognitive Assessment (MoCA) score change that was associated with change of health in general in an aSAH patient cohort. We recruited aSAH patients from a regional neurosurgical center over a 3-year period. Patient assessments including MoCA and global rating of change (GRoC) were carried out at at 3 and 12months after aSAH. Anchor-based and distribution-based approaches were adopted to calculate the Minimum Clinically Important Difference (MID). One hundred and seventy-five aSAH patients completed both 3-month and 1-year assessments and consented for participation. Employing the distribution-based approach for the 3-month and 1-year MoCA scores, the MID estimates equated to a change of 2.0 and 1.1 respectively. Employing the anchor-based approach (with GRoC), the MID estimate of MoCA (median, IQR) was 2, 1-4. In conclusion, we found that the MID of MoCA score associated with change of health in general in aSAH patients was 2. The MID provides guidance for future clinical trial design targeting on cognitive dysfunction after aSAH.

Circulating MicroRNAs in Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral infarction (DCI) is a major cause of morbidities after aneurysmal subarachnoid hemorrhage (SAH) and typically starts at day 4 to 7 after initial hemorrhage. MicroRNAs (miRNAs) play an important role in posttranscriptional gene expression control, and distinctive patterns of circulating miRNA changes have been identified for some diseases. We aimed to investigate miRNAs that characterize SAH patients with DCI compared with those without DCI. METHODS AND RESULTS: Circulating miRNAs were collected on day 7 after SAH in healthy, SAH-free controls (n=20), SAH patients with DCI (n=20), and SAH patients without DCI (n=20). We used the LASSO (least absolute shrinkage and selection operator) method of regression analysis to characterize miRNAs associated with SAH patients with DCI compared with those without DCI. In the 28 dysregulated miRNAs associated with DCI and SAH, we found that a combination of 4 miRNAs (miR-4532, miR-4463, miR-1290, and miR-4793) could differentiate SAH patients with DCI from those without DCI with an area under the curve of 100% (95% CI 1.000-1.000, P<0.001). This 4-miRNA combination could also distinguish SAH patients with or without DCI from healthy controls with areas under the curve of 99.3% (95% CI 0.977-1.000, P<0.001) and 82.0% (95% CI 0.685-0.955, P<0.001), respectively. CONCLUSIONS: We found a 4-miRNA combination that characterized SAH patients with DCI. The findings could guide future mechanistic study to develop therapeutic targets.

Circulating microRNA 132-3p and 324-3p Profiles in Patients after Acute Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is a highly morbid and fatal condition with high rate of cognitive impairment and negative impact in quality of life among survivors. Delayed cerebral infarction (DCI) is one the major factors for these negative outcomes. In this study we compared the circulating microRNA profiles of SAH patients and healthy individuals, and the circulating microRNA profiles of SAH patients with and without DCI. METHODS: Peripheral blood samples on Day 7 after the onset of SAH were subjected to microarray analysis with Affymetrix miRNA 3.0 array and quantitative PCR analysis. SAH patients with (N = 20) and without DCI (N = 20) and Healthy controls (N = 20) were included for analyses. RESULTS: We demonstrated that 99 miRNAs were found to be dysregulated in the SAH patient group with DCI. 81 miRNAs were upregulated and 18 were downregulated. Findings from KEGG pathway analysis showed that miRNAs and target genes for axon guidance and TGF-beta signaling were involved, implying that the resulted differential miRNA expression pattern reflect the results of SAH instead of etiology of the disease. miR-132-3p and miR-324-3p showed distinctive upregulations in qPCR [miR-132: 9.5 fold (95%CI: 2.3 to 16.7) in DCI group and 3.4 fold (95%CI: 1.0 to 5.8) in Non-DCI group; miR-324: 4924 fold (95%CI: 2620 to 7228) in DCI group and 4545 fold (95%CI: 2408 to 6683) in non-DCI group]. However, there were no significant differences in fold changes between SAH patients with and without DCI [fold change ratios (mean+/-SD): 2.7+/-4.2 and 1.1+/-1.1 for miRNA-132 and miRNA-324]. CONCLUSION: Our study demonstrated that as compared to healthy control, miR-132 and miR-324 showed a upregulation in both SAH DCI and Non-DCI groups. However, the differences between the SAH DCI and non-DCI groups were not statistically significant.