Hanqiang Jiang

Molecular Analysis of RNF213 Gene for Moyamoya Disease in the Chinese Han Population

Background Moyamoya disease (MMD) is an uncommon cerebrovascular disorder characterized by progressive occlusion of the internal carotid artery causing cerebral ischemia and hemorrhage. Genetic factors in the etiology and pathogenesis of MMD are being increasingly recognized. Previous studies have shown that the RNF213 gene was related to MMD susceptibility in the Japanese population. However, there is no large scale study of the association between this gene and MMD in the Chinese Han population. Thus we designed this case-control study to validate the R4810K mutation and to define the further spectrum of RNF213 mutations in Han Chinese. Methodology/Principal Findings Genotyping of the R4810K mutation in the RNF213 gene was performed in 170 MMD cases and 507 controls from a Chinese Han population. The R4810K mutation was identified in 22 of 170 MMD cases (13%), including 21 heterozygotes and a single familial homozygote. Two of the 507 controls (0.4%) were heterozygous R4810K carriers. The R4810K mutation greatly increased the risk for MMD (OR = 36.7, 95% CI: 8.6∼156.6, P = 6.1 E-15). The allele frequency of R4810K was significantly different between patients with ischemia and hemorrhage (OR = 5.4, 95% CI: 1.8∼16.1, P = 0.001). Genomic sequencing covering RNF213 exon 40 to exon 68 also identified eight other non-R4810K variants; P4007R, Q4367L, A4399T, T4586P, L4631V, E4950D, A5021V and M5136I. Among them A4399T polymorphism was found in 28/170 cases (16.5%) and 45/507 controls (8.9%) and was associated with MMD (OR = 2.0, 95% CI: 1.2∼3.3, P = 0.004), especially with hemorrhage (OR = 2.8, 95% CI: 1.2∼6.5, P = 0.014). Conclusions RNF213 mutations are associated with MMD susceptibility in Han Chinese. The ischemic type MMD is particularly related to the R4810K mutation. However, A4399T is also a susceptible variant for MMD, primarily associated with hemorrhage. Identification of novel variants in the RNF213 gene further highlights the genetic heterogeneity of MMD.

Outcome in adult patients with hemorrhagic moyamoya disease after combined extracranial-intracranial bypass

OBJECT The outcome of patients with hemorrhagic moyamoya disease (MMD) after cerebral revascularization is uncertain. The purpose of this study was to delineate the efficacy of this surgical method in the treatment of hemorrhagic MMD. METHODS Between January 2007 and August 2011, a consecutive cohort of 113 patients with hemorrhagic MMD was enrolled into this prospective single-center cohort study. The surgical method was combined direct and indirect bypass. The cumulative probability of the primary end point (all stroke and deaths from surgery through 30 days after surgery and ipsilateral recurrent hemorrhage afterward) was analyzed. The angiographic outcome was measured by the following parameters: bypass patency, reduction of basal MMD vessels, improved degree of dilation, and branch extension of the anterior choroidal and posterior communicating arteries (AChA-PCoA). RESULTS Of the 113 enrolled cases, CT scans revealed pure intraventricular hemorrhage (IVH) in 63 cases (55.7%), pure intracranial hemorrhage (ICH) in 14 cases (12.4%), and ICH with IVH in 36 cases (31.9%). In 74 of 113 hemorrhagic hemispheres (65.5%), the AChA-PCoA was extremely dilated with extensive branches beyond the choroidal fissure. A total of 114 surgeries were performed. No patient suffered ischemic or hemorrhagic stroke through 30 days after surgery. Ipsilateral rebleeding occurred in 5 patients, 4 of whom died of the rebleeding event. The cumulative probability of the primary end point was 0% at 1 year and 1.9% at 2 years. The annual rebleeding rate was 1.87%/person/year. The improvement in AChA-PCoA extension was observed in 75 of 107 operated hemispheres (70.1%), which was higher than that in 7 of 105 unoperated hemispheres (35.2%). CONCLUSIONS Revascularization may provide a benefit over conservative therapy for hemorrhagic MMD patients. The improvement of dilation and branch extension of AChA-PCoA might be correlated with the low rebleeding rate.

Efficacy of extracranial–intracranial revascularization for non-moyamoya steno-occlusive cerebrovascular disease in a series of 66 patients

Although there is uncertainty about whether extracranial-intracranial arterial bypass is useful for the treatment of steno-occlusive cerebrovascular disease in general, there is some argument for its continued use in particular patients. In the present study, we evaluated the efficacy of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis combined with encephalo-duro-myo-synangiosis (EDMS) in the treatment of non-moyamoya steno-occlusive cerebrovascular disease by retrospectively reviewing clinical and radiological data from 66 patients treated between January 2006 and April 2011. Forty-six double STA-MCA anastomoses and 20 single anastomoses were completed, and all remained patent in the perioperative phase, as confirmed by CT angiography. Postoperative CT perfusion imaging demonstrated immediate improvement in perfusion in the revascularized hemisphere. On discharge, 50 of the 66 patients (75.8%) had an improved National Institutes of Health Stroke Scale (NIHSS) score relative to preoperative values. After at least 6 months of follow-up, 54 (88.5%) patients had improved NIHSS scores relative to discharge values. CT perfusion imaging showed significant improvement compared to post-operative images. Follow-up digital subtraction angiography confirmed that 95 of 96 (99%) anastomoses remained patent. There was no significant difference between the single and double bypasses in terms of either clinical or hemodynamic outcomes on the revascularized side. STA-MCA combined with EDMS was effective for the treatment of non-moyamoya steno-occlusive cerebrovascular disease with hemodynamic impairment. Hemodynamic evaluation before and after surgery may help identify patients in need of a bypass and may be useful for predicting outcome.

Spontaneous brain activity in adult patients with moyamoya disease: a resting-state fMRI study

Adult patients with moyamoya disease (MMD) are reported to suffer from vascular cognitive impairment (VCI), including considerable impairment of executive function/attention. The spatial pattern of functional brain activity in adult MMD patients with VCI has not been studied before and can be measured by examining the amplitude of low-frequency fluctuations (ALFF) of blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) during rest. Twenty-three adult patients with MMD were recruited to participate in this study, including 11 with VCI and 12 without VCI (NonVCI), as well as 22 healthy young adults (normal control, NC). Widespread differences in ALFF were observed between the VCI/NonVCI and NC groups in such regions as the frontal, parietal and temporal gyri, with parts of the frontal gyrus, such as the anterior cingulate cortex (ACC) and the right supplemental motor area (SMA), showing significant differences in ALFF. It is worth to note that regions such as the parietal gyrus, the right superior frontal gyrus (SFG), the right superior temporal gyrus (STG) and the left caudate nucleus (CN) exhibited significant changes in ALFF during the progressive cognitive decline of MMD. Taken together, our results demonstrate that MMD exhibits a specific intrinsic pattern of ALFF and that this pattern changes with the progression of cognitive decline, providing insight into the pathophysiological nature of this disease.

Postoperative executive function in adult moyamoya disease: a preliminary study of its functional anatomy and behavioral correlates

OBJECTIVE Chronic frontal hemodynamic disturbances are associated with executive dysfunction in adult patients with moyamoya disease (MMD). However, the impact of surgical revascularization on executive dysfunction and its underlying mechanism remains unclear. The aim of the present study was to examine the postoperative radiological correlates of cognitive improvement and thereby explore its underlying mechanism. METHODS Fourteen patients who met the inclusion criteria were identified at Huashan Hospital, were operated on, and were successfully followed up for 6 months. Postoperative changes in cortical perfusion and regional amplitude of low-frequency fluctuations (ALFF) were examined by SPECT and resting-state functional MRI, respectively. Executive function was evaluated by 2 tests (Trail Making Test Part B and the summation of executive subtests of Memory and Executive Screening [MES-EX]). Follow-up neuropsychological outcomes were then correlated with radiological changes to identify nodes functioning as leading contributors to postoperative executive outcomes. RESULTS All patients underwent successful unilateral bypass procedures, with some operations performed on the left side and some on the right side. At the 6-month follow-up, the baseline and follow-up test scores for the different sides did not differ significantly. The group with good collaterals (Matsushima Grade A, 9 patients) exhibited significantly increased postoperative perfusion (change in [△] hemodynamics) in bilateral frontal (left, p = 0.009; right, p = 0.003) and left parietal lobe (p = 0.014). The Spearmans correlation test suggested that only the right frontal lobe exhibited significant positive postoperative radiological correlates with cognitive performance (△MES-EX vs △hemodynamics, r = 0.620, p = 0.018; △MES-EX vs △ALFF, r = 0.676, p = 0.008; △hemodynamics vs △ALFF, r = 0.547, p = 0.043). Subsequent regional ALFF analysis revealed that the right dorsolateral prefrontal cortex (DLPFC) was the only node in the responsible hemisphere to exhibit significant postoperative changes. CONCLUSIONS The results not only advance our understanding of pathological interactions of postoperative executive performance in adult MMD, but also indicate that the right DLPFC amplitude might be a quantitative predictor of postoperative executive control improvement.

Aberrant regional homogeneity of resting-state executive control, default mode, and salience networks in adult patients with moyamoya disease

Aberrant local connectivity within cerebral intrinsic connectivity networks (ICNs) at rest has not been reported in adult moyamoya disease (MMD). Our aim was to examine the regional homogeneity (ReHo) of executive control (ECN), default mode (DMN), and salience networks (SN) in patients with executive dysfunction to explore the underlying mechanism. Twenty-six adult patients with MMD and 24 normal control (NC) subjects were recruited. Executive function was evaluated by Trail Making Test Part B (TMT-B) and executive subtests of Memory and Executive Screening (MES-EX). Compared with NC, the case group exhibited ReHo decrease mainly in the frontal and parietal gyrus, and increase only in the left middle temporal gyrus. Subsequent ICNs analysis indicated that compared with NC, patients with MMD exhibited significantly decreased ReHo in the dorsolateral prefrontal cortex (DLPFC) and inferior parietal gyrus (IPG) of left ECN; the IPG, superior frontal gyrus, and DLPFC of the right ECN; the right precuneus, left medial superior frontal gyrus, and right medial orbitofrontal gyrus of the DMN; as well as the left middle frontal gyrus and right supplemental motor area of SN. When referring to the Suzuki’s 6-stage classification, a trend of ReHo decrease with disease severity was observed in all of the ICNs examined, but only bilateral ECNs reached statistical significance. Finally, only bilateral ECNs exhibited a significant correlation of averaged ReHo values with executive performance. Our results provide new insight into the pathophysiology of adult MMD.

Combined extracranial-intracranial bypass surgery with stent-assisted coil embolization for moyamoya disease with a ruptured wide-necked basilar trunk aneurysm: a case report.

A ruptured wide-necked basilar trunk aneurysm is uncommon in patients with moyamoya disease. The optimal treatment is unclear. We report a safe and beneficial treatment modality for moyamoya disease with aneurysms located in the posterior circulation. A 37-year-old man presenting with subarachnoid hemorrhage was admitted to our hospital. Emergent cerebral angiography demonstrated moyamoya disease associated with a wide-necked basilar trunk aneurysm. We performed bilateral extracranial-intracranial bypass surgeries prior to stent-assisted coil embolization of the aneurysm after the acute phase. No complication occurred and the patient was discharged with no neurological deficit. Follow-up digital subtraction angiography (DSA) performed 6 months after the surgery showed that all the anastomosises were patent and bilateral collateral vascular compensation was fully established with no recanalization of the basilar trunk aneurysm post embolization.We also found that high-flow bypass did not contribute to cerebral revascularization as imagined despite the good patency. Combined extracranial-intracranial bypass surgery with endovascular treatment proved to be an efficient therapeutic modality for moyamoya disease with aneurysms located in the posterior circulation. High-flow bypass surgery was not essential due to the inefficiency and the high risk of postoperative cerebral hyperperfusion syndrome.

Preliminary experience of 256-row multidetector computed tomographic angiography for detecting cerebral aneurysms.

Object Multidetector computed tomographic angiography (MDCTA) has played an increasing role in detecting cerebral aneurysms. This study was performed to investigate the diagnostic accuracy of the upgraded 256-row MDCTA in the detection of cerebral aneurysms. Methods We identified 93 patients who had undergone both MDCTA and digital subtraction angiography (DSA) before surgery for the detection of cerebral aneurysms. Two and one independent blinded readers reviewed the MDCTA images and DSA images, respectively. The sensitivity, specificity, accuracy, and positive and negative predictive values were calculated for the image interpretation from the two CTA readers and one DSA reader using the combination of DSA and intraoperative findings as the reference standard. Results A total of 77 intracranial aneurysms were detected in 67 of the 93 patients. The overall sensitivity, specificity, and accuracy of the 256-row MDCTA in the detection of cerebral aneurysms were 96.10%, 92.31%, and 94.23%, respectively. For aneurysms larger than 5 mm, the overall sensitivity, specificity, and accuracy were 100%, 92.31%, and 96.83%, respectively. For aneurysms smaller than 5 mm, the overall sensitivity, specificity, and accuracy were 92.50%, 92.31%, and 92.42%, respectively. There was no significant difference for the sensitivity, specificity, and accuracy of 256-row MDCTA to detect cerebral aneurysm according to the conscious level of the patients. Conclusions To detect cerebral aneurysms larger than 5 mm, 256-row MDCTA is an imaging method with a satisfactory diagnostic performance equal to that of DSA. However, its diagnostic performance for aneurysms smaller than 5 mm is still inferior to that of DSA.

Long-Term Outcomes After Combined Revascularization Surgery in Adult Hemorrhagic Moyamoya Disease

OBJECTIVE Risk factors for rebleeding after revascularization surgery are unclear. We aimed to evaluate long-term outcomes after combined revascularization surgery for adult hemorrhagic moyamoya disease (MMD) and identify risk factors for initial and recurrent hemorrhage. METHODS A total of 105 adult patients with hemorrhagic MMD from January 2007 to May 2011 were prospectively enrolled in this study. All patients underwent combined revascularization surgery on unilateral hemorrhagic hemispheres and were observed for at least 5 years. RESULTS After a median follow-up time of 77 months, 12 patients were lost to follow-up. Twelve of the remaining 93 patients developed rebleeding, and 6 patients died. According to rebleeding sites, ipsilateral and contralateral rebleeding occurred in 6 and 6 patients, respectively. There was no significant difference between the 2 groups (P > 0.05). The annual risks of overall, ipsilateral, and contralateral rebleeding were 1.1%, 0.62%, and 0.51%, respectively. A significant correlation was observed between improvement of anterior choroidal artery-posterior communicating artery dilation or extension in the operated hemispheres and low risk of ipsilateral rebleeding (P < 0.05). Progression of Suzuki stage in the nonhemorrhagic hemispheres was significantly associated with contralateral rebleeding (P < 0.05). CONCLUSIONS Combined revascularization surgery may help prevent ipsilateral rebleeding in adult patients with hemorrhagic MMD by improvement of anterior choroidal artery-posterior communicating artery dilation and extension in the operated hemisphere. Progression of Suzuki stage in the nonhemorrhagic hemispheres was a strong predictor of subsequent contralateral rebleeding.

Histone Deacetylase Inhibitor Scriptaid Alleviated Neurological Dysfunction after Experimental Intracerebral Hemorrhage in Mice

Objectives To investigate the role of Scriptaid in reducing brain injury after intracerebral hemorrhage (ICH) in mice. Methods An ICH model was constructed by injecting autologous blood into the right basal ganglia in mice. The animals were administered 3.5 mg/kg of Scriptaid intraperitoneally after ICH. The hematoma volume and hemoglobin level were measured to examine hematoma resolution. A behavior test and brain edema and white matter injury examinations indicated brain injury after ICH. Results Scriptaid treatment promoted hematoma resolution and reduced the hematoma volume 7 d after ICH compared with the vehicle group (P < 0.05). Scriptaid treatment also alleviated the brain water content in the ipsilateral basal ganglia (P < 0.05) and cortex (P < 0.01) 3 d after ICH. In addition, Scriptaid improved neurological function recovery and alleviated white matter injury 35 d after ICH. Conclusions Scriptaid can protect against brain injury after ICH and may be considered a new medical therapy method for ICH.