Measurement of cerebrovascular reserve by multimodal imaging for cerebral arterial occlusion or stenosis patients: protocol of a prospective, randomized, controlled clinical study.

BACKGROUND: Cerebrovascular reactivity (CVR) is the change in cerebral blood flow in response to a vaso-active stimulus, and may assist the treatment strategy of ischemic stroke. However, previous studies reported that a therapeutic strategy for stroke mainly depends on the degree of vascular stenosis with steady-state vascular parameters (e.g., cerebral blood flow and CVR). Hence, measurement of CVR by multimodal imaging techniques may improve the treatment of ischemic stroke. METHODS/DESIGN: This is a prospective, randomized, controlled clinical trial that aimed to examine the capability of multimodal imaging techniques for the evaluation of CVR to improve treatment of patients with ischemic stroke. A total of 66 eligible patients will be recruited from Renji Hospital, Shanghai Jiaotong University School of Medicine. The patients will be categorized based on CVR into two subgroups as follows: CVR > 10% group and CVR < 10% group. The patients will be randomly assigned to medical management, percutaneous transluminal angioplasty and stenting, and intracranial and extra-cranial bypass groups in a 1:1:1 ratio. The primary endpoint is all adverse events and ipsilateral stroke recurrence at 6, 12, and 24 months after management. The secondary outcomes include the CVR, the National Institute of Health stroke scale and the Modified Rankin Scale at 6, 12, and 24 months. DISCUSSION: Measurement of cerebrovascular reserve by multimodal image is recommended by most recent studies to guide the treatment of ischemic stroke, and thus its efficacy and evaluation accuracy need to be established in randomized controlled settings. This prospective, parallel, randomized, controlled registry study, together with other ongoing studies, should present more evidence for optimal individualized accurate treatment of ischemic stroke. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-IOR-16009635; Registered on 16 October 2016. All items are from the World Health Organization Trial Registration Data Set and registration in the Chinese Clinical Trial Registry: ChiCTR-IOR-16009635.

Expression of nerve growth factor carried by pseudotyped lentivirus improves neuron survival and cognitive functional recovery of post-ischemia in rats.

AIMS: Nerve growth factor (NGF) has been reported to prevent neuronal damage and contributes to the functional recovery in animal brain injury models and human ischemic disease as well. We aimed to investigate a potential therapeutic effect of NGF gene treatment in ischemic stroke and to estimate the functional recovery both at the cellular and cognitive levels in an ischemia rat model. METHODS: After microinjection of pseudolentivirus-delivered ß-NGF into an established ischemic stroke model in rats (tMCAO), we estimated neuronal cell apoptosis with TUNEL labeling and neurogenesis by cell proliferation marker Ki67 staining in both ischemic core and penumbra of striatum. Furthermore, we used behavioral functional tests, Morris water maze performance, to evaluate cognitive functional recovery in vivo and propose a potential underlying mechanism. RESULTS: We found that pseudolentivirus-mediated delivery of ß-NGF gene into the brain induced high expression in striatum of the infarct core area after ischemia in rats. The ß-NGF overexpression in the striatal infarction core after ischemia not only improved neuronal survival by reducing cell apoptosis and increasing cell proliferation, but also rescued cognitive functional impairment through upregulation of GAP-43 protein expression in tMCAO rat model of ischemia. CONCLUSION: This study demonstrates a potential ß-NGF gene therapy by utilization of pseudolentivirus in ischemia and indicates future applications of NGF gene treatment in ischemic patients.

Potassium channel dysfunction in neurons and astrocytes in Huntington's disease.

Huntington's disease (HD) is a late-onset fatal neurodegenerative disease, characterized by progressive movement disorders, psychiatric symptoms, and cognitive impairment. The cytosine-adenine-guanine (CAG) triplet expansion encoding glutamine present in the protein huntingtin (Htt), produces widespread neuronal and glial pathology. Mutant huntingtin (mHtt) nuclear aggregates are the primary cause of cortical and striatal neuron degeneration, neuronal inflammation, apoptosis and eventual cell loss. The precise mechanisms underlying the pathogenesis of neurodegeneration in HD remain poorly understood and HD patients have no current cure. Potassium channels are widely expressed in most cell types. In neurons, they play a crucial role in setting the resting membrane potential, mediating the rapid repolarization phase of the action potential and controlling sub-threshold oscillations of membrane potentials. In glial cells, their major contributions are maintaining the resting membrane potential and buffering extracellular K+ . Thus, potassium channels have an essential function in both physiological and pathological brain conditions. This review summarizes recent progress on potassium channels involved in the pathology of HD by using different HD mouse models. Exploring the dysfunction of potassium channels in the brain illustrates new approaches for targeting this channel for the treatment of HD.

Global transcriptomic study of atherosclerosis development in rats.

Atherosclerosis is a chronic disease of the arterial wall and a leading cause of death worldwide. Though the pathophysiology of atherosclerotic lesion formation has been studied, we still lack evidence of the global changes in the artery during atherosclerosis. In this report, we induced atherosclerosis in rats and conducted GeneChip analysis on carotid arteries with or without plaque formation. We found that molecular pathways underlying plaque formation in atherosclerosis were related to immune response, angiogenesis, cell proliferation, apoptosis and hypoxic microenvironments, suggesting that the pathophysiology of atherosclerosis is varied. In addition, we showed that three lncRNAs, GAS5, SNHG6 and Zfas1, were significantly increased in the plaque of atherosclerosis patients compared to normal people. A complex interaction of mRNA and lncRNA was identified in atherosclerosis. Our results provide a global transcriptomic network of atherosclerosis development in rats and possible targets that could lead to new clinical applications in the future.

Inter-hemispheric functional and anatomical connectivity abnormalities in traffic accident-induced PTSD: a study combining fMRI and DTI.

BACKGROUND: Aberrant brain functional and structural changes are considered to be one of the important mechanisms underlying post-traumatic stress disorder (PTSD). However, it remains unclear whether inter-hemispheric connection is changed. The current study aimed to identify the inter-hemispheric functional and anatomical connectivity changes in patients who consequently develop PTSD using the voxel-mirrored homotopic connectivity (VMHC) analysis and diffusion tractography techniques. METHODS: Resting-state fMRI and DTI data were acquired on victims who had experienced traffic accidents within 2 days after the traumatic event. The diagnosis was made using the Clinician-Administered PTSD Scale at 1 or 6 months later. Fifteen trauma-exposed victims met the criteria for diagnosis of PTSD and 14 trauma-exposed victims who did not develop PTSD at 6 months after trauma were selected as the control group. RESULTS: Compared with the victims without PTSD, the victims with PTSD exhibited an abnormal homotopic pattern with decreased VMHC in the superior/middle frontal gyrus before diagnosis. The regions showing abnormal functional connectivity were then chosen as regions of interest for an analysis of DTI tractography. Decreased fractional anisotropy values in the genu of the corpus callosum were found in the victims with PTSD. Greater WM disruptions within 2 days predicted greater symptom severity at diagnosis. LIMITATIONS: The study was lack of comparison with controls who did not experience a traumatic event. CONCLUSION: Our results suggest that the inter-hemispheric functional and structural connectivity is impaired in PTSD within 2 days, which may be the potential marker showing predisposition towards developing PTSD.

Direct hippocampal injection of pseudo lentivirus-delivered nerve growth factor gene rescues the damaged cognitive function after traumatic brain injury in the rat.

Traumatic brain injury (TBI) treatment is a long-term process and requires repeated medicine administration, which, however, can cause high expense, infection, and hemorrhage to patients. To investigate how a long-term expression of nerve growth factor (Ngf) gene affects the injured hippocampus function post-TBI, in this study, a pseudo lentivirus carrying the ß-Ngf fusion gene, with green fluorescence protein (GFP) gene, was constructed to show the gene expression and its ability of protecting cells from oxidative damage in vitro. Then, the pseudo lentivirus-carried ß-Ngf fusion gene was directly injected into the injured brain to evaluate its influence on the injured hippocampus function post-TBI in vivo. We found that the expression of the pseudo lentivirus-delivered ß-Ngf fusion gene lasted more than four-week after the cell transduction and the encoded ß-NGF fusion protein could induce the neuron-like PC12 cell differentiation. Moreover, the hippocampal injection of the pseudo lentivirus-carried ß-Ngf fusion gene sped the injured cognitive function recovery of the rat subjected to TBI. Together, our findings indicate that the long-term expression of the ß-Ngf fusion gene, delivered by the pseudo lentivirus, can promote the neurite outgrowth of the neuron-like cells and protect the cells from the oxidative damage in vitro, and that the direct and single dose hippocampal injection of the pseudo lentivirus-carried ß-Ngf fusion gene is able to rescue the hippocampus function after the TBI in the rat.

Neurocognitive improvement after carotid artery stenting in patients with chronic internal carotid artery occlusion: a prospective, controlled, single-center study.

Symptomatic internal carotid artery (ICA) occlusion with hemodynamic impairment remains a dismal disease when untreated. In this prospective, single-center, controlled study, we investigated the feasibility, safety, and long-term outcome of stenting by endovascular recanalization for patients with chronic ICA occlusion. Forty patients with symptomatic chronically occluded ICA were assigned to receive endovascular recanalization (group A, n = 18) or conservative management (group B, n = 22). The primary end point was 100% complete recanalization of the primary occlusion at 60 minutes, and secondary end points were improvement in neurologic function and cognitive function. Patients in the 2 groups were comparable in demographic and baseline characteristics. Successful recanalization was achieved in 88.9% (16 of 18) of patients with the restoration of Thrombolysis in Myocardial Ischemia/Thrombolysis in Cerebral Ischemia 2 or 3 flow. There was no procedural or new cerebral ischemic event. Improvement in brain perfusion was observed in 12 (12 of 18, 75%) patients on single-photon emission computed tomography. Improvement in neurologic function defined as a reduction of ≥4 points on the National Institutes of Health Stroke Scale (NIHSS) at 6 months was observed in group A (baseline, 6.83 ± 3.01 vs 6 months, 2.61 ± 1.20; P < .01) and group B (baseline, 6.05 ± 2.75 vs 6 months, 4.77 ± 1.69; P < .05). A significant difference in NIHSS scores was noted between group A and B at 1, 3, and 6 months (P < .05 or .001). Improvement in cognitive function defined as an increase of ≥8 on the Montreal Cognitive Assessment (MoCA) was observed in group A at 3 and 6 months (baseline, 14.67 ± 3.56 vs 3 months, 24.17 ± 3.55 and 6 months, 24.72 ± 2.85; P < .01). Significant improvement in MoCA was also observed in group B (P < .01). Furthermore, a significant difference in MoCA scores was noted between group A and B at 1, 3, and 6 months (P < .05 or .001). Endovascular recanalization is feasible and safe for patients with symptomatic chronic carotid artery occlusion. Successful carotid artery stenting can improve neurological function and global cognitive function than nonrevascularization.

Over expression of PPP2R2C inhibits human glioma cells growth through the suppression of mTOR pathway.

PPP2R2C encodes a gamma isoform of the subunit B55 subfamily, which is a regulatory subunit of Protein phosphatase type 2A (PP2A). Our study shows that PPP2R2C is downregulated in glioma cells and human brain cancer patient samples. Overexpression of PPP2R2C inhibited cancer cell proliferation both in vitro and in vivo through the suppression of the activity of S6K in the mTOR pathway. Moreover, exogenous expression of PPP2R2C promoted the formation of a complex with the PP2A-C subunit to further enhance the binding of PP2A-C with S6K. Our results suggest that PPP2R2C is a potential tumor suppressor gene in human brain cancers. This study will provide novel insight into the development of therapeutic strategies in the treatment of human brain tumors.

Early altered resting-state functional connectivity predicts the severity of post-traumatic stress disorder symptoms in acutely traumatized subjects.

The goal of this study was to investigate the relationship between resting-state functional connectivity and the severity of post-traumatic stress disorder (PTSD) symptoms in 15 people who developed PTSD following recent trauma. Fifteen participants who experienced acute traumatic events underwent a 7.3-min resting functional magnetic resonance imaging scan within 2 days post-event. All the patients were diagnosed with PTSD within 1 to 6 months after trauma. Brain areas in which activity was correlated with that of the posterior cingulate cortex (PCC) were assessed. To assess the relationship between the severity of PTSD symptoms and PCC connectivity, contrast images representing areas positively correlated with the PCC were correlated with the subject's Clinician-Administered PTSD Scale scores (CAPS) when they were diagnosed. Furthermore, the PCC, medial prefrontal cortex and bilateral amygdala were selected to assess the correlation of the strength of functional connectivity with the CAPS. Resting state connectivity with the PCC was negatively correlated with CAPS scores in the left superior temporal gyrus and right hippocampus/amygdala. Furthermore, the strength of connectivity between the PCC and bilateral amygdala, and even between the bilateral amygdala could predict the severity of PTSD symptoms later. These results suggest that early altered resting-state functional connectivity of the PCC with the left superior temporal gyrus, right hippocampus and amygdala could predict the severity of the disease and may be a major risk factor that predisposes patients to develop PTSD.

A preliminary study of alterations in default network connectivity in post-traumatic stress disorder patients following recent trauma.

This study used resting-state functional magnetic resonance imaging (fMRI) to investigate whether functional connectivity is altered in people developing post-traumatic stress disorder (PTSD) following recent trauma. Sixty-two participants who had experienced recent acute traumatic events underwent a 7.3 min resting fMRI scan within 2 days post accident. Of these, 22 participants were diagnosed with PTSD within 1 to 6 months. Nineteen age- and sex-matched subjects without PTSD were selected as the trauma-exposed control group. Posterior cingulate cortex connectivity was determined from 17 PTSD patients and 15 control subjects by investigating synchronic low-frequency fMRI signal fluctuations using a temporal correlation method. To assess the relationship between PTSD symptom severity and PCC connectivity, the contrast image representing areas correlated with the PCC was correlated with the 17 PTSD subjects' Clinician Administered PTSD Scale (CAPS) scores at diagnosis. Compared with the control group, PTSD patients exhibited decreased functional connectivity in the right lingual and right middle temporal gyri, and left lingual/posterior cingulate cortex. The left inferior temporal gyrus, right middle temporal gyrus, left middle temporal gyrus/insula, left medial frontal lobe/anterior cingulate cortex, and right medial frontal gyrus also showed increased connectivity within two days post accident. A negative correlation was found between PCC connectivity and CAPS scores in the left medial prefrontal cortex (mPFC). These results suggest that patients who develop PTSD exhibit different resting-state patterns of neuronal activity following recent trauma. Abnormal FC of mPFC may be a major risk factor predisposing patients to the development of PTSD.

Surgical management of large solid hemangioblastomas of the posterior fossa.

From January 2000 to January 2009, 15 patients presented with large solid hemangioblastomas of the posterior fossa; eight of these patients were also diagnosed with von Hippel-Lindau (VHL) disease. Diagnostic imaging showed large vascular lesions. All 15 patients underwent surgery through a suboccipital ipsilateral, modified far-lateral, suboccipital midline or suboccipital supracerebellar approach. Preoperative embolization was attempted in seven patients. Complete removal of the tumor was performed in all patients. An overall neurological improvement was observed in 11 of the 15 patients, corresponding to 61.5%. During follow-up, six patients, all with VHL disease, developed recurrence. Two patients died of renal cell carcinoma after 1 year. Our favorable outcomes suggest that surgical resection is the optimal treatment for patients with large solid hemangioblastomas of the posterior fossa. With improved microsurgical techniques and a better understanding of the vascular pattern of this type of tumor, total microsurgical removal can be performed with low mortality.