Identification of LDLR mutation in cerebral venous sinus thrombosis co-existing with dural arteriovenous fistulas: a case report.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is typically associated with a prothrombotic state of the blood, with its causative factors varying widely. Prior research has not reported the simultaneous occurrence of CVST and dural arteriovenous fistulas (DAVFs) as potentially resulting from genetic mutations. In this case report, we introduce a unique occurrence wherein a patient with a heterozygous mutation of the low-density lipoprotein receptor (LDLR) gene presented with CVST in conjunction with DAVFs. CASE: Presentation: A male patient, aged 51, sought treatment at our facility due to a consistent decline in cognitive functions accompanied by recurrent headaches. Comprehensive evaluations were administered, including neurological examinations, laboratory tests, magnetic resonance imaging, digital subtraction angiography, and whole exome sequencing. Digital subtraction angiography identified DAVFs in the patient's right sigmoid sinus and an occlusion within the left transverse sinus. The whole exome sequencing of blood samples pinpointed a heterozygous mutation in the LDLR gene (NM_000527:exon12:c.C1747T:p.H583Y). Following the confirmed diagnosis of CVST and DAVFs, the patient underwent anticoagulant therapy combined with endovascular procedures - these comprised embolization of the arteriovenous fistula in the right sigmoid sinus and balloon dilation with stent implantation in the left transverse sinus. A six-month follow-up indicated a significant abatement in the patient's symptoms. CONCLUSIONS: This report marks the first documented case of an LDLR gene mutation that could be associated with the onset of CVST and DAVFs. The mutation in the LDLR gene might foster a prothrombotic environment, facilitating the gradual emergence of CVST and the subsequent genesis of DAVFs.

Connexin 43 Promotes Neurogenesis via Regulating Aquaporin-4 after Cerebral Ischemia.

We aimed to test the effects of connexin43 (Cx43) on ischemic neurogenesis and examined whether it was dependent on aquaporin-4 (AQP4). We detected the expression of Cx43 and AQP4 in the ipsilateral subventricular zone (SVZ) and peri-infarct cortex after middle cerebral artery occlusion (MCAO). Also, we examined neurogenesis in the above regions via co-labeling of 5-bromo-2-deoxyuridine (BrdU)/neuronal nuclear antigen (NeuN) and BrdU/doublecortin (DCX). The effects of Cx43 and AQP4 were investigated by using two transgenic animals: heterozygous Cx43 (Cx43±) mice and AQP4 knockout (AQP4-/-) mice, and connexin mimetic peptide (CMP), a selective Cx43 blocker. We demonstrated AQP4 and Cx43 were co-expressed in the astrocytes after MCAO and the expression was highly increased in ipsilateral SVZ and peri-infarct cortex. Cx43± mice had larger infarction volumes and worse neurological function. Both BrdU/NeuN and BrdU/DCX co-labeled cells in the two regions were reduced in Cx43± and AQP4-/- mice compared to wild-type (WT) mice, suggesting Cx43 and AQP4 participated in neurogenesis of neural stem cells. Moreover, CMP decreased AQP4 expression and inhibited neurogenesis in WT mice, while the latter failed to be observed in AQP4-/- mice. Besides, higher levels of IL-1ß and TNF-α were detected in the SVZ and peri-infarct cortex of AQP4-/- and Cx43± mice than those in WT mice. In conclusion, our data suggest that Cx43 elicits neuroprotective effects after cerebral ischemia through promoting neurogenesis in the SVZ to regenerate the injured neurons, which is AQP4 dependent and associated with down-regulation of inflammatory cytokines IL-1ß and TNF-α.

Inflammatory score predicts early hematoma expansion and poor outcomes in patients with intracerebral hemorrhage.

BACKGROUND: This study aimed to develop a prediction score named inflammatory score based on proper integration of several inflammatory markers and investigate whether it was associated with hematoma expansion and poor outcomes in patients with intracerebral hemorrhage (ICH). METHODS: This study involved a consecutive series of spontaneous ICH patients of two cohorts admitted within 24 hours after symptom onset. Inflammatory score (0-9) was developed with the combination of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, systemic immune-inflammation index, lactate dehydrogenase, and C-reactive protein. The authors investigated the association between inflammatory score and hematoma expansion and poor outcomes by using univariate and multivariate logistic regression analyses. The optimal cutoff point of inflammatory score was determined by receiver operating characteristic analysis in the development cohort and then validated. RESULTS: A total of 301 and 154 ICH patients were enrolled in the development and validation cohorts. Inflammatory score was significantly higher in patients with hematoma expansion and poor outcomes. The multivariate logistic regression analysis revealed inflammatory score was independently associated with hematoma expansion, secondary neurological deterioration within 48 hours, 30-day mortality, and 3-month poor modified Rankin scale (4-6). The diagnostic accuracy of inflammatory score exhibited by area under the curve showed numerically or statistically higher than most of the individual indicators. Moreover, inflammatory score greater than or equal to 5 was selected as the optimal cutoff point, which was further prospectively validated with high diagnostic accuracy. CONCLUSIONS: The inflammatory score is a reliable predictor for early hematoma expansion and short-term and long-term poor outcomes with good diagnostic accuracies in ICH patients.

The association of subjective sleep characteristics and plasma biomarkers of Alzheimer's disease pathology in older cognitively unimpaired adults with higher amyloid-ß burden.

We aimed to investigate the association of subjective sleep characteristics and plasma Alzheimer's disease (AD) biomarkers in older cognitively unimpaired adults with higher amyloid-ß (Aß) burden. Unimpaired cognition was determined by education-adjusted performance for the Mini-Mental State Examination and exclusion of dementia and mild cognitive impairment via standardized neuropsychological tests. We used Pittsburgh Sleep Quality Index (PSQI) to assess subjective sleep quality. The participants also underwent examination of plasma AD biomarkers and 18F-florbetapir PET scan. Correlation and multiple linear regression analyses were used to investigate the association between subjective sleep characteristics and AD biomarkers. A total of 335 participants were included and 114 were Aß-PET positive. Multivariable regression analysis showed sleep duration > 8 h and sleep disturbance were associated with Aß deposition in total participants. Two multiple linear regression models were applied and the results revealed in participants with Aß-PET (+), falling asleep at ≥ 22:00 to ≤ 23:00 was associated with higher levels of Aß42 and Aß42/40. Other associations with higher Aß42/40 and standard uptake value ratio contained sleep efficiency value, sleep efficiency ≥ 75%, no/mild daytime dysfunction and PSQI score ≤ 5. Higher p-Tau-181 level was associated with sleep latency > 30 min in Aß-PET (+) group and moderate/severe sleep disturbance in Aß-PET (-) group. Our data suggests sleep duration ≤ 8 h and no/mild sleep disturbance may be related to less Aß burden. In participants with Aß deposition, falling asleep at 22:00 to 23:00, higher sleep efficiency (at least ≥ 75%), no/mild daytime dysfunction, sleep latency ≤ 30 min, and good sleep quality may help improve AD pathology.

Optimal time window for minimally invasive surgery in treating spontaneous intracerebral hemorrhage in the basal ganglia region: a multicenter and retrospective study.

BACKGROUND: The current treatment spontaneous intracerebral hemorrhage (sICH) is limited. AIM: To determine the optimal time window for minimally invasive surgery in patients with sICH. MATERIALS AND METHODS: sICH patients with a hematoma volume of 30-80 mL in the basal ganglia region were included in our study. A total of 357 patients were divided into groups according to different operative times from ICH onset (group 1: 0-6 h, group 2: 6-12 h, group 3: >12 h) and hematoma volumes (30-50 mL and >50 mL). All patients were followed-up for three months' post-operation, and their clinical outcomes were compared. RESULTS: In the three groups of patients with hematoma volumes of 30-50 mL, the rebleeding and mortality rate were higher in group 1 than groups 2 and 3 (p < .05). The activities of daily living evaluated by Barthel Index (BI) three months' post-operation was significantly lower in group 3 than other groups (p < .05) and group 2 had the highest proportion of good outcomes. Among the patients with the hematoma volumes of 50-80 mL, the rebleeding risk was higher in group 1 than groups 2 and 3 (p < .05). However, there were no significant differences in mortality rates among these three groups. Moreover, group 1 had significantly higher BI than groups 2 and 3 (p < .05). CONCLUSIONS: Minimally invasive surgery is safe and effective in patients with sICH. 6-12 h after sICH onset is the optimal surgical window for patients with hematoma volumes of 30-50 mL, while ultra-early (≤6 h) may achieve better results in patients with hematoma volumes of >50 mL.

Reduction of Midline Shift and Short-Term Mortality Following Minimal Invasive Surgery for Spontaneous Supratentorial Intracerebral Hemorrhage: A Retrospective and Case-Control Series.

OBJECTIVE: Currently, the treatment of spontaneous intracerebral hemorrhage (sICH) is limiting, especially in patients with midline shift and supratentorial hemorrhage. Here, we investigated the clinical value of minimally invasive surgery (MIS) in patients with midline shift and supratentorial sICH by observing the consciousness state, midline shift, and short-term mortality. METHODS: A total of 124 supratentorial sICH patients with midline shift, hematoma volume >30 mL and <150 mL were included in this study. Based on treatment methods, the enrolled patients were divided into minimally invasive surgical (MIS) (group 1, n = 61) and conservative (group 2, n = 63) treatment groups. Measurements of midline shift and state of consciousness using the Glasgow Coma Scale (GCS) score were performed on day 2 following treatment. Additionally, mortality, adverse events, and neurologic recovery (modified Rankin Scale score) in each group were observed after 1 month. RESULTS: On postoperative day 2, the recovery rates of midline shift and consciousness state in group 1 patients were 59.02% and 50.82%, respectively, significantly higher than group 2, 26.98% and 25.40% (P < 0.01). By comparing death, adverse events, and neurologic function recovery of the 2 groups within 1 month postoperative, we observed a significantly lower fatality rate in group 1 (16.39%; 10 cases) than group 2 (33.33%; 21 cases) (P < 0.05). No significant difference of the adverse event rates was observed between groups 1 and 2 (19.67% [12 cases] vs. 19.05% [12 cases]). In addition, neurologic function recovery also had no significant difference between the 2 groups (P > 0.05). CONCLUSIONS: MIS could reduce early-stage midline shift, improve consciousness state and reduce short-term mortality in patients with supratentorial sICH.

Aquaporin-4 and Cognitive Disorders.

Aquaporin-4 (AQP4) is the most abundantly expressed aquaporin in the central nervous system (CNS) and is an integral part of the glymphatic system that cannot be ignored. The CNS has the glymphatic system instead of the conventional lymphatic system. The glymphatic system plays an essential role in the pathophysiological processes of many cognitive disorders. AQP4 shows noteworthy changes in various cognitive disorders and is part of the pathogenesis of these diseases. For this reason, AQP4 has attracted attention as a potential and promising target for regulating and even reversing cognitive dysfunction. This review will summarize the role of AQP4 in the pathophysiological processes of several cognitive disorders as reported in recent studies.

The stress hyperglycemia ratio predicts early hematoma expansion and poor outcomes in patients with spontaneous intracerebral hemorrhage.

BACKGROUND: Different from diabetic hyperglycemia, stress-induced hyperglycemia (SIH) can better reflect elevated blood glucose owing to intracerebral hemorrhage (ICH). However, studies about the outcome of ICH patients with SIH are still very limited. AIMS: This study aimed to investigate whether SIH measured by stress-induced hyperglycemia ratio (SHR) was associated with hematoma expansion and poor outcomes in patients with ICH. METHODS: A consecutive series of patients with spontaneous ICH from two clinical centers admitted within 24 h after symptom onset were enrolled for prospective analysis. SHR was defined as admission fasting blood glucose divided by estimated average glucose [1.59 × Hemoglobin A1c (%) - 2.59]. This study investigated the association between SHR and hematoma expansion, and short-term and long-term poor outcomes using univariate and multivariate logistic regression analyses. RESULTS: A total of 313 ICH patients were enrolled in the study. SHR was markedly higher in patients with hematoma expansion and poor outcomes (p < 0.001). The multivariate logistic regression analysis demonstrated SHR independently associated with hematoma expansion (p < 0.001) and poor outcomes, including secondary neurological deterioration within 48 h, 30-day mortality, and 3-month poor modified Rankin Scale (mRS 4-6) (p < 0.001), while the blood glucose only predicted 30-day mortality. Meanwhile, the diagnostic accuracy of SHR exhibited by area under the curve in receiver operating characteristic analysis was statistically equal to or higher than the well-known predictors. CONCLUSION: SHR is a reliable predictor for early hematoma expansion and poor outcomes in patients with ICH.

Peptide5 Attenuates rtPA Related Brain Microvascular Endothelial Cells Reperfusion Injury via the Wnt/ß-Catenin Signalling Pathway.

AIMS: Brain vascular endothelial cell dysfunction after rtPA treatment is a significant factor associated with poor prognosis, suggesting that alleviation of rtPA-related endothelial cell injury may represent a potential beneficial strategy along with rtPA thrombolysis. BACKGROUND: Thrombolysis with recombinant tissue plasminogen activator (rtPA) is beneficial for acute ischemic stroke but may increase the risk of Hemorrhagic Transformation (HT), which is considered ischemia-reperfusion injury. The underlying reason may contribute to brain endothelial injury and dysfunction related to rtPA against ischemic stroke. As previous studies have demonstrated that transiently blocked Cx43 using peptide5 (Cx43 mimetic peptide) during retinal ischemia reduced vascular leakage, it is necessary to know whether this might help decrease side effect of rtPA within the therapeutic time window. OBJECTIVE: This study aims to investigate the effects of peptide5 on rtPA-related cell injury during hypoxia/reoxygenation (H/R) within the therapeutic time window. METHODS: In this study, we established a cell hypoxia/reoxygenation H/R model in cultured primary Rat Brain Microvascular Endothelial Cells (RBMECs) and evaluated endothelial cell death and permeability after rtPA treatment with or without transient peptide5. In addition, we also investigated the potential signaling pathway to explore the underlying mechanisms preliminarily. RESULTS: The results showed that peptide5 inhibited rtPA-related endothelial cell death and permeability. It also slightly increased tight junction (ZO-1, occluding, claudin-5) and ß-catenin mRNA expression, demonstrating that peptide5 might attenuate endothelial cell injury by regulating the Wnt/ ß-catenin pathway. The following bioinformatic exploration from the GEO dataset GSE37239 was also consistent with our findings. CONCLUSION: This study showed that the application of peptide5 maintained cell viability and permeability associated with rtPA treatment, revealing a possible pathway that could be exploited to limit rtPA-related endothelial cell injury during ischemic stroke. Furthermore, the altered Wnt/ß- catenin signaling pathway demonstrated that signaling pathways associated with Cx43 might have potential applications in the future. This study may provide a new way to attenuate HT and assist the application of rtPA in ischemic stroke.

Relationship Between Hematoma Expansion Induced by Hypertension and Hyperglycemia and Blood-brain Barrier Disruption in Mice and Its Possible Mechanism: Role of Aquaporin-4 and Connexin43.

We aimed to select an optimized hematoma expansion (HE) model and investigate the possible mechanism of blood-brain barrier (BBB) damage in mice. The results showed that HE occurred in the group with hypertension combined with hyperglycemia (HH-HE) from 3 to 72 h after intracerebral hemorrhage; this was accompanied by neurological deficits and hardly influenced the survival rate. The receiver operating characteristic curve suggested the criterion for this model was hematoma volume expansion ≥ 45.0%. Meanwhile, HH-HE aggravated BBB disruption. A protector of the BBB reduced HH-HE, while a BBB disruptor induced a further HH-HE. Aquaporin-4 (AQP4) knock-out led to larger hematoma volume and more severe BBB disruption. Furthermore, hematoma volume and BBB disruption were reduced by multiple connexin43 (Cx43) inhibitors in the wild-type group but not in the AQP4 knock-out group. In conclusion, the optimized HE model is induced by hypertension and hyperglycemia with the criterion of hematoma volume expanding ≥ 45.0%. HH-HE leads to BBB disruption, which is dependent on AQP4 and Cx43.

Minimal Computed Tomography Attenuation Value Within the Hematoma is Associated with Hematoma Expansion and Poor Outcome in Intracerebral Hemorrhage Patients.

BACKGROUND: Early hematoma expansion in intracerebral hemorrhage (ICH) patients is associated with poor outcome. We aimed to investigate whether the minimal computed tomography (CT) attenuation value predicted hematoma expansion and poor outcome. METHODS: This study involved spontaneous ICH patients of two cohorts who underwent baseline CT scan within 6 h after ICH onset and follow-up CT scan within 24 h after initial CT scan. We determined the critical value of the minimal CT attenuation value via retrospective analysis of the data from a derivation cohort. Then, a prospective study on the validation cohort of three clinical centers was performed for determining the association between the minimal CT attenuation value and hematoma expansion as well as poor outcome (modified Rankin Scale scores > 3) at 90 days by using univariate and multivariate logistic regression analyses. RESULTS: One hundred and forty eight ICH patients were included in the derivation cohort. Minimal CT attenuation value ≤ 31 Hounsfield units (HU) was demonstrated as the critical value to predict hematoma expansion by using receiver operating characteristic analysis. A total of 311 ICH patients were enrolled in the validation cohort, 86 (27.7%) and 133 (42.8%) of which were found hematoma expansion and poor outcome. Minimal CT attenuation value ≤ 31 HU was positive in 73 patients (23.5%). The multivariate logistic regression analysis demonstrated minimal CT attenuation value and minimal CT attenuation value ≤ 31 HU independently predicted hematoma expansion (p < 0.001) and poor outcome (p < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of minimal CT attenuation value ≤ 31 HU for hematoma expansion and poor outcome prediction were 64.0, 92.0, 75.3, 87.0, 84.2 and 45.1%, 92.7%, 82.2%, 69.3%, 72.3%, respectively. CONCLUSIONS: The minimal CT attenuation value independently predicts early hematoma expansion and poor outcome in patients with ICH.

Lactate Dehydrogenase Predicts Early Hematoma Expansion and Poor Outcomes in Intracerebral Hemorrhage Patients.

This study aimed to investigate whether serum lactate dehydrogenase (LDH) levels predicted hematoma expansion and poor outcomes in intracerebral hemorrhage (ICH) patients. The differentially expressed proteins between patients with and without hematoma expansion were screened using proteomic analysis. Then the critical value of the target protein was determined by retrospectively analyzing the data from a derivation cohort. A prospective study on the validation cohort of three clinical centers was performed to investigate the association between the target protein and hematoma expansion and poor outcomes (modified Rankin Scale > 3) at 90 days by using univariate and multivariate logistic regression analyses. Among the 41 differentially expressed proteins, LDH A chain was upregulated, which is one of the two main subunits of LDH protein. Considering that it was easy to determine serum LDH levels, LDH was selected as the target protein. In the derivation cohort, LDH ≥ 220 U/L was selected as the critical value to predict hematoma expansion by using receiver operating characteristic analysis. A total of 366 ICH patients were enrolled in the validation cohort and LDH ≥ 220 U/L was positive in 127 patients (34.7%). The multivariate logistic regression analysis demonstrated LDH levels and LDH ≥ 220 U/L independently predicted hematoma expansion (p < 0.001) and poor outcomes (p < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of LDH ≥ 220 U/L for hematoma expansion and poor outcome prediction were 79.1%, 80.0%, 56.7%, 92.1%, and 79.8% and 53.3%, 78.2%, 63.0%, 70.7%, and 68.0%, respectively. In conclusion, LDH is a reliable predictor for early hematoma expansion and poor outcomes in patients with ICH.

The neuroprotective effect of deep brain stimulation at nucleus basalis of Meynert in transgenic mice with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia and mainly treated by drugs, while the therapeutic outcomes are very limited. This study aimed to determine the optimized parameters of deep brain stimulation (DBS) which was applied to the treatment of AD and propose the involved mechanisms. METHODS: Amyloid-ß precursor protein/Presenilin1 (APP/PS1) transgenic mice were used and received DBS at nucleus basalis of Meynert (NBM). The optimized parameters of DBS were determined by using different stimulation frequencies, durations and ages of mice under Morris water maze test. The involved mechanisms and the possible signal pathways were also investigated. RESULTS: The optimized parameters for DBS were high frequency (100 Hz) for 21 days starting from early age (4 months old). Under the above parameters, the soluble Aß40 and Aß42 in the hippocampus and cortex were down-regulated significantly. DBS increased survival neurons and reduced apoptotic cells in the hippocampus and cortex. Meanwhile, the apoptosis-related proteins caspase-3, caspase-8 and Bid were down-regulated. Moreover, DBS caused a significant increase of superoxide dismutase, glutathione peroxidase and choline acetyltransferase activity as well as a decrease of methane dicarboxylic aldehyde content and acetylcholine esterase activity. Phosphorylation of Akt (p-Akt)/total Akt (t-Akt) was up-regulated while p-extracellular signal-regulated kinase 1/2 (ERK1/2)/t-ERK1/2 was down-regulated. The neuroprotective effect of DBS was attenuated by their inhibitors. CONCLUSIONS: NBM-DBS starting from 4 months of age for 21 days at a high frequency (100 Hz) has therapeutic effects on AD through activating phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and inhibiting ERK1/2 pathway.

Hypodensities detected at 1.5-3 h after intracerebral hemorrhage better predicts secondary neurological deterioration.

BACKGROUND: Secondary neurological deterioration in patients with spontaneous intracerebral hemorrhage (sICH) develops within the first 24 or 48 h after ICH onset and appears to portend a poor prognosis. We aimed to verify whether hypodensities within an acute ICH detected by noncontrast computed tomography (NCCT) were able to predict secondary neurological deterioration and investigate which monitoring window was of the highest predictive value. MATERIALS/METHODS: This study involved sICH patients from three clinical centers of Fudan University between October 1, 2016 and March 31, 2018. Logistic regression analysis was used to assess the association between hypodensities and secondary neurological deterioration. The receiver operating characteristic curve of the subjects was performed to evaluate the critical value of the detection time window of hypodensities that best predicted the secondary neurological injury. Then, we divided the detection time window of hypodensities into 0-1.5 h, 1.5-3 h, 3-4.5 h and 4.5-6 h, and calculated the sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV) and accuracy respectively. RESULTS: A total of 240 ICH patients met the inclusion criteria, 97 (40.42%) of whom were observed secondary neurological deterioration. Hypodensities were positive in 113 patients (47.08%), and more common in patients with secondary neurological deterioration (76.25%). The multivariate logistic regression analysis demonstrated that infratentorial hemorrhage (P < .001), the baseline hematoma volume (P = .015), and the presence of hypodensities on admission CT scan (P < .001) were independent predictors of secondary neurological deterioration. The sensitivity, specificity, PPV, and NPV of hypodensities in predicting secondary neurological deterioration were 76.3%, 72.7%, 65.5%, and 81.9%, respectively. When the time to the baseline NCCT was 114.5 min, the hypodensities were of the highest predictive value. Besides, the risk of secondary neurological deterioration predicted by hypodensities detected during 1.5-3.0 h was higher than other time periods. CONCLUSIONS: Hypodensities within hematoma detected by an NCCT scan may predict secondary neurological deterioration, independent of other clinical and imaging predictors. Hypodensities detected at 1.5-3.0 h after ICH onset have better predictive efficacy.

Deep Brain Stimulation to Alleviate Freezing of Gait and Cognitive Dysfunction in Parkinson's Disease: Update on Current Research and Future Perspectives.

Freezing of gait (FOG) is a gait disorder featured by recurrent episodes of temporary gait halting and mainly found in advanced Parkinson's disease (PD). FOG has a severe impact on the quality of life of patients with PD. The pathogenesis of FOG is unclear and considered to be related to several brain areas and neural circuits. Its close connection with cognitive disorder has been proposed and some researchers explain the pathogenesis using the cognitive model theory. FOG occurs concurrently with cognitive disorder in some PD patients, who are poorly responsive to medication therapy. Deep brain stimulation (DBS) proves effective for FOG in PD patients. Cognitive impairment plays a role in the formation of FOG. Therefore, if DBS works by improving the cognitive function, both two challenging conditions can be ameliorated by DBS. We reviewed the clinical studies related to DBS for FOG in PD patients over the past decade. In spite of the varying stimulation parameters used in different studies, DBS of either subthalamic nucleus (STN) or pedunculopontine nucleus (PPN) alone or in combination can improve the symptoms of FOG. Moreover, the treatment efficacy can last for 1-2 years and DBS is generally safe. Although few studies have been conducted concerning the use of DBS for cognitive disorder in FOG patients, the existing studies seem to indicate that PPN is a potential therapeutic target to both FOG and cognitive disorder. However, most of the studies have a small sample size and involve sporadic cases, so it remains uncertain which nucleus is the optimal target of stimulation. Prospective clinical trials with a larger sample size are needed to systematically assess the efficacy of DBS for FOG and cognitive disorder.

Reduction of Ischemic Brain Edema by Combined use of Paeoniflorin and Astragaloside IV via Down-Regulating Connexin 43.

Paeoniflorin (PF) and astragaloside IV (AS-IV) have protective effects on cerebral ischemia. We aimed to test the effects of combined use of PF and AS-IV on ischemic brain edema and investigate whether the effects were dependent on connexin43 (Cx43). We detected the expression of Cx43 induced by PF and AS-IV after cerebral ischemia. We also examined the effects of combined use of PF and AS-IV on ischemic edema and further investigated the related pathways. We demonstrated PF and AS-IV decreased Cx43 and aquaporin4 (AQP4) associating with reduction of brain edema by dry-wet weight and brain-specific gravity methods after cerebral ischemia. Administration of PF and AS-IV displayed a further attenuation of brain edema with lower Cx43 levels. Meanwhile, Cx43 blockade inhibited AQP4 down-regulation by the two drugs. Moreover, phosphorylation of C-Jun amino-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) were increased by PF and AS-IV, respectively. The effects of PF and AS-IV to down-regulate Cx43 were suppressed by JNK and ERK inhibitors, respectively. Our data indicate that PF and AS-IV alleviate ischemic brain edema, which has close relation to Cx43 down-regulation causing decrease of AQP4 via JNK and ERK pathways activation, respectively. Combined administration elicits synergistic effects on brain edema reduction. Copyright © 2017 John Wiley & Sons, Ltd.

Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4.

BACKGROUND: Apelin-13 has been found to have protective effects on many neurological diseases, including cerebral ischemia. However, whether Apelin-13 acts on blood-brain barrier (BBB) disruption following cerebral ischemia is largely unknown. Aquaporin-4 (AQP4) has a close link with BBB due to the high concentration in astrocyte foot processes and regulation of astrocytes function. Here, we aimed to test Apelin-13's effects on ischemic BBB injury and examine whether the effects were dependent on AQP4. METHODS: We detected the expression of AQP4 induced by Apelin-13 injection at 1, 3, and 7 days after middle cerebral artery occlusion. Meanwhile, we examined the effects of Apelin-13 on neurological function, infarct volume, and BBB disruption owing to cerebral ischemia in wild type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the possible signal transduction pathways activated by Apelin-13 to regulate AQP4 expression via astrocyte cultures. RESULTS: It was found that Apelin-13 highly increased AQP4 expression as well as reduced neurological scores and infarct volume. Importantly, Apelin-13 played a role of BBB protection in both types of mice by reducing BBB permeability, increased vascular endothelial growth factor, upregulated endothelial nitric oxide synthase, and downregulated inducible NOS. In morphology, we demonstrated Apelin-13 suppressed tight junction opening and endothelial cell swelling via electron microscopy detection. Meanwhile, Apelin-13 also alleviated apoptosis of astrocytes and promoted angiogenesis. Interestingly, effects of AQP4 on neurological function and infarct volume varied with time course, while AQP4 elicited protective effects on BBB at all time points. Statistical analysis of 2-way analysis of variance with replication indicated that AQP4 was required for these effects. In addition, Apelin-13 upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and Akt as well as AQP4 protein in cultured astrocytes. The latter was inhibited by ERK and phosphatidylinositol 3'-kinase (PI3K) inhibitors. CONCLUSION: Our data suggest that Apelin-13 protects BBB from disruption after cerebral ischemia both morphologically and functionally, which is highly associated with the increased levels of AQP4, possibly through the activation of ERK and PI3K/Akt pathways. This study provides double targets to protection of ischemic BBB damage, which can present new insights to drugs development.