Conditional Deletion of CC2D1A Reduces Hippocampal Synaptic Plasticity and Impairs Cognitive Function through Rac1 Hyperactivation.

Coiled-coil and C2 domain containing 1A (CC2D1A) is an evolutionarily conserved protein, originally identified as a nuclear factor-κB activator through a large-scale screen of human genes. Mutations in the human Cc2d1a gene result in autosomal recessive nonsyndromic intellectual disability. It remains unclear, however, how Cc2d1a mutation leads to alterations in brain function. Here, we have taken advantage of Cre/loxP recombinase-based strategy to conditionally delete Cc2d1a exclusively from excitatory neurons of male mouse forebrain to examine its role in hippocampal synaptic plasticity and cognitive function. We confirmed the expression of CC2D1A protein and mRNA in the mouse hippocampus. Double immunofluorescence staining showed that CC2D1A is expressed in both excitatory and inhibitory neurons of the adult hippocampus. Conditional deletion of Cc2d1a (cKO) from excitatory neurons leads to impaired performance in object location memory test and altered anxiety-like behavior. Consistently, cKO mice displayed a deficit in the maintenance of LTP in the CA1 region of hippocampal slices. Cc2d1a deletion also resulted in decreased complexity of apical and basal dendritic arbors of CA1 pyramidal neurons. An enhanced basal Rac1 activity was observed following Cc2d1a deletion, and this enhancement was mediated by reduced SUMO-specific protease 1 (SENP1) and SENP3 expression, thus increasing the amount of Rac1 SUMOylation. Furthermore, partial blockade of Rac1 activity rescued impairments in LTP and object location memory performance in cKO mice. Together, our results implicate Rac1 hyperactivity in synaptic plasticity and cognitive deficits observed in Cc2d1a cKO mice and reveal a novel role for CC2D1A in regulating hippocampal synaptic function.SIGNIFICANCE STATEMENT CC2D1A is abundantly expressed in the brain, but there is little known about its physiological function. Taking advantage of Cc2d1a cKO mice, the present study highlights the importance of CC2D1A in the maintenance of LTP at Schaffer collateral-CA1 synapses and the formation of hippocampus-dependent long-term object location memory. Our findings establish a critical link between elevated Rac1 activity, structural and synaptic plasticity alterations, and cognitive impairment caused by Cc2d1a deletion. Moreover, partial blockade of Rac1 activity rescues synaptic plasticity and memory deficits in Cc2d1a cKO mice. Such insights may have implications for the utility of Rac1 inhibitors in the treatment of intellectual disability caused by Cc2d1a mutations in human patients.

Stepwise stent deployment technique for tandem intracranial aneurysms: a review of 21 cases.

OBJECTIVES: We performed this study to report our experience using a stepwise stent deployment technique for the treatment of tandem intracranial aneurysms. METHODS: Patients with intracranial tandem aneurysms that were treated with a stepwise stent deployment technique between May 2009 and June 2013 were retrospectively reviewed. RESULTS: Twenty-one patients with 42 tandem aneurysms were identified (11 men, 10 women), with a mean age of 53.7 years (range, 17-82 years). Subarachnoid haemorrhage was confirmed in 12 patients using computed tomography at onset. Complete occlusion was achieved in 20 of the aneurysms (47.6%) after the procedure, neck remnant in 9 (21.4%), and aneurysm remnant in 13 (31.0%). The perioperative complications included in-stent thrombosis in one case and vasospasm in two cases, none of which left a permanent neurological deficit. The modified Rankin Scale (mRS) score at discharge was 0-2 in 20 cases and 3 in one case. The follow-up angiograms available for 17 patients showed complete occlusion in 26 aneurysms, improved in 4, and stable in 4. All of the patients had mRS scores of 0-1 during the clinical follow-up period. CONCLUSIONS: The stepwise stent deployment technique is feasible and helpful in the treatment of intracranial tandem aneurysms. KEY POINTS: • Treating wide-necked intracranial aneurysms with stent-assisted coiling is preferable. • Tandem wide-necked intracranial aneurysms can be treated with a single stent. • Stepwise stent deployment is technically feasible for embolizing tandem intracranial aneurysms.

Effect of Baseline Characteristics on the Outcome of Stent Retriever-Based Thrombectomy in Acute Basilar Artery Occlusions: A Single-Center Experience and Pooled Data Analysis.

OBJECTIVES: To explore the association of baseline characteristics and the outcome of patients with acute basilar artery occlusion (BAO) after stent retriever-based thrombectomy (SRT). METHODS: Clinical and imaging information of consecutive SRT-treated patients with BAO from a comprehensive stroke center and up-to-date literature were reviewed respectively. The impact of baseline variables toward favorable outcome was evaluated using subgroup analysis and odds ratio (OR) extracted from published data together with single-center records using pooled analysis. RESULTS: Nineteen cases from our center and 15 published studies involving 487 cases were included. Estimated pooled favorable outcome rate was 0.3746 (95% confidence interval [CI], 0.3165-0.4327), mortality was 0.2950 (95% CI, 0.2390-0.3510). Pooled estimates showed that successful reperfusion (modified thrombolysis in cerebral ischemia scale 2b or 3) gained by SRT alone was 0.7317 (95% CI, 0.6532-0.8102) and final successful reperfusion rate with or without additional reperfusion procedures was 0.8834 (95% CI, 0.8279-0.9390). Univariate analysis indicated that patients with successful reperfusion (OR, 2.05; P = 0.05), distal segment occlusion (OR, 2.03; P = 0.03), and cardioembolus origin (OR, 2.13; P = 0.01) were more likely to have favorable outcome (modified Rankin Scale score ≤2 at 3 months). Study series that applied intra-arterial thrombolysis, angioplasty, or stenting as rescuing therapy had higher successful reperfusion rate but they did not show a higher rate of favorable outcome. CONCLUSIONS: SRT with or without additional treatment appeared to be effective for the treatment of BAO. Successful reperfusion, distal segment occlusion, and cardiac embolism were associated with favorable outcome. The overall benefit of lesions requiring additional reperfusion therapy was unclear.

Endovascular Treatment of 48 Early Branch Aneurysms of the Middle Cerebral Artery.

OBJECTIVE: To evaluate the feasibility of endovascular treatment (EVT) for early branch aneurysms (EBAs) of the middle cerebral artery (MCA). METHODS: We reviewed 211 MCA aneurysms that received EVT between January 2012 and December 2014. The EBAs were identified according to their special patterns on cerebral angiography. The angiographic features, clinical outcomes, and angiographic results were investigated. RESULTS: Forty-eight EBAs (22.7%) in 47 patients were identified among the MCA aneurysms. The treatments were successful in all EBAs, including coiling in 23 aneurysms, balloon-assisted coiling in 4, and stent-assisted coiling in 21. Immediate angiograms showed complete occlusion in 15 aneurysms, residual neck in 18, and residual aneurysm in 15. A procedure-related complication occurred in 1 patient (2.1%) who experienced rebleeding during treatment, and no neurologic function was insulted. Thirty-nine patients underwent angiographic follow-up (mean, 8.2 months), which showed 36 aneurysms were not aggravated, 3 had minor recanalization, and none showed major recanalization. The clinical follow-up (mean, 22.8 months) of all patients demonstrated no neurologic deterioration or rebleeding; however, 1 patient died of unexplained cerebral hemorrhage. CONCLUSIONS: Preliminary experience demonstrates that EVT for EBAs is feasible and safe. Direct comparison of clipping and coiling is warranted.

Endovascular Embolization of Intracranial Aneurysms: To Use Stent(s) or Not? Systematic Review and Meta-analysis.

OBJECTIVES: We sought to review the literature concerning stent-assisted coiling (SAC) in comparison with coiling without stents for treating intracranial aneurysms and to evaluate the safety and effectiveness of SAC by conducting a meta-analysis of published studies. METHODS: According to the methods and guidelines for meta-analysis, PubMed, Embase, and Cochrane Database were searched. All articles that compared SAC and coiling without stent were reviewed. The data extracted were the rates of immediate occlusion, progressive thrombosis, angiographic occlusion, angiographic recurrence, overall complications, ischemic stroke, and hemorrhagic stroke. RESULTS: Sixteen studies with 4294 aneurysms were analyzed. SAC was performed for 1466 aneurysms; and coiling without stent was performed for 2828 aneurysms. No significant difference in immediate occlusion rate was found between the 2 groups (odds ratio [OR] = 1.01; 95% confidence interval [CI], 0.73-1.39, P = 0.96). However, SAC had an advantage in terms of angiographic occlusion rate during follow-up (OR = 1.62, 95% CI: 1.16-2.26, P < 0.01), progressive thrombosis rate (OR = 2.54, 95% CI: 2.00-3.24, P < 0.01), and reduction in recurrence rate (OR = 0.46; 95% CI, 0.35-0.59, P < 0.01). No significant differences were shown in overall complication rate (OR = 1.30, 95% CI: 086-1.96, P = 0.21) and hemorrhagic stroke rate (OR = 0.72, 95% CI: 0.43-1.20, P = 0.21). Ischemic strokes were more common in the SAC patients than in the non-stent-assisted patients (OR = 1.66; 95% CI: 1.05-2.63, P = 0.03). CONCLUSION: Compared with coiling without stent, stent-assisted coiling of intracranial aneurysms achieved satisfactory results, with higher long-term angiographic occlusion rate and lower recurrence rate. However, ischemic stroke remains a problem that cannot be ignored.

Parametric Digital Subtraction Angiography Imaging for the Objective Grading of Collateral Flow in Acute Middle Cerebral Artery Occlusion.

PURPOSE: To report the feasibility of parametric color-coded digital subtraction angiography (DSA) in complementing the traditional, subjective way of leptomeningeal collateral assessment in acute middle cerebral artery (MCA) occlusions. METHODS: Thirty-three consecutive patients with acute MCA occlusion who received endovascular treatment were recruited for investigation. Eighteen of 33 consecutive patients were included. The target downstream territory (TDT) of MCA and reference point at terminal internal carotid artery of each patient was contoured by 5 raters independently on the basis of anteroposterior 2-dimensional DSA. Two parameters of relative maximum density of TDT (rDensitymax) and peak time interval (ΔPT) between reference and TDT were extracted by the use of parametric DSA analysis software. Interrater reliability was tested with intraclass correlation coefficients. Parameters with sufficient interrater reliability entered validity evaluation. Then, the correlation test with the American Society of Interventional and Therapeutic Neuroradiology collateral grading system and efficacy in predicting favorable clinical outcome was evaluated. RESULTS: The intraclass correlation coefficient of rDensitymax and ΔPT were 0.983, 95% confidence interval 0.968-0.993 and 0.831, 95% confidence interval 0.705-0.923, respectively. The parameter rDensitymax showed a strong correlation with the American Society of Interventional and Therapeutic Neuroradiology collateral grading system score (r of Spearman correlation test = 0.869, P < 0.001) and mRS at 3 months (partial correlation coefficient = 0.616, P = 0.009), whereas ΔPT_average did not. A cut-off point of 0.224 in rDensitymax predicted a favorable clinical outcome with high sensitivity and specificity. CONCLUSIONS: The relative maximum contrast density of MCA territory on 2-dimensional DSA measured by parametric imaging technique appears to be a simple and reliable metric for the assessment of leptomeningeal collaterals in cases of acute MCA occlusion.