Alzheimer's disease phenotype based upon the carrier status of the apolipoprotein E ɛ4 allele.

The apolipoprotein E ɛ4 allele (APOE4) is universally acknowledged as the most potent genetic risk factor for Alzheimer's disease (AD). APOE4 promotes the initiation and progression of AD. Although the underlying mechanisms are unclearly understood, differences in lipid-bound affinity among the three APOE isoforms may constitute the basis. The protein APOE4 isoform has a high affinity with triglycerides and cholesterol. A distinction in lipid metabolism extensively impacts neurons, microglia, and astrocytes. APOE4 carriers exhibit phenotypic differences from non-carriers in clinical examinations and respond differently to multiple treatments. Therefore, we hypothesized that phenotypic classification of AD patients according to the status of APOE4 carrier will help specify research and promote its use in diagnosing and treating AD. Recent reviews have mainly evaluated the differences between APOE4 allele carriers and non-carriers from gene to protein structures, clinical features, neuroimaging, pathology, the neural network, and the response to various treatments, and have provided the feasibility of phenotypic group classification based on APOE4 carrier status. This review will facilitate the application of APOE phenomics concept in clinical practice and promote further medical research on AD.

Learning from magnetotactic bacteria: mms6 protects stem cells from oxidative damage.

Oxidative damage generally exists in stroke and impairs stem cells' survival; however, the problem is difficult to treat. In order to help stem cells to resist this damage, we inserted a magnetotactic bacteria (MB) gene, mms6, into the neural stem cell genome by lentiviral transfection. It was found that the transfection of mms6 significantly improved the survival rate of stem cells in the condition of iron overload but not hypoxia. The bioenergetic profile also revealed that iron overloading weakened the mitochondrial respiration and spare respiration capacity of stem cells, but that these were enhanced after the expression of mms6. Additionally, Western blotting (WB) data revealed that mms6 upregulated the expression of glutathione peroxidase (GPX4), which protected stem cells from oxidative damage and ferroptosis. In order to determine the possible mechanisms, we analyzed the interactions between the MMS6 protein, Fe2+, and GPX4 via analog computation. The predicted models found that the MMS6 protein had a direct chelating site in the region of M6A with divalent iron; it also had weak binding with GPX4. Taken together, the magnetotactic bacterial gene mms6 protected stem cells from oxidative damage via binding with Fe2+, which could help them adapt to the microenvironment of stroke.

Increase of ALCAM and VCAM-1 in the plasma predicts the Alzheimer's disease.

Cell adhesion molecules (CAM) are crucial in several pathological inflammation processes in Alzheimer's disease (AD). However, their potential for clinical diagnostics remains unknown. The present investigation evaluated the clinical significance of ALCAM, VCAM-1, NCAM, and ICAM-1 levels in the plasma of participants with cognitive impairment (44 patients with mild cognitive impairment, 71 patients with Alzheimer's dementia, and 18 patients with other dementia) and 28 controls with normal cognitive ability. We also detected plasma levels of multiple inflammatory factors (IFN-gamma, IL-18, IL-1beta, IL-13, IL-8, IL-7, CCL11, MCP-1, TSLP, IL-10, BDNF, IL-17, IL-5, TREM-1) using Multiplex liquid chip and plasma levels of Abeta1-42 and Abeta1-40 using liquid-phase flow cytometry (FCM). Our findings demonstrated a correlation of ALCAM and VCAM-1 with age, the severity of cognitive decline, and MTA, but no significant difference between groups for NCAM and ICAM-1. ALCAM and VCAM-1 both demonstrated a positive correlation with the degree of atrophy in the medial temporal lobe structure. Further analysis revealed no significant correlation in plasma between VCAM-1, ALCAM and Abeta1-40, Abeta1-42. Nevertheless, there was a significant correlation between VCAM-1, ALCAM and many inflammatory factors. Furthermore, the predictive value of ALCAM and VCAM-1 for AD was assessed using a multi-parameter regression model. ALCAM and VCAM-1 in combination with ApoE4, education, age, and MMSE could predict AD with high precision (AUC=0.891; AIC=146.9) without imaging diagnosis. ALCAM and VCAM-1 combination improved the predictive accuracy significantly. In a nutshell, these findings revealed ALCAM and VCAM-1 as reliable indicators of Alzheimer's disease.

Diffusion tensor magnetic resonance imaging for predicting the consistency of intracranial meningiomas.

BACKGROUND: The ability of preoperative MRI-sequences to predict the consistency of intracranial meningiomas has not yet been clearly defined. We aim to demonstrate that diffusion tensor imaging (DTI) improves the prediction of intracranial meningiomas consistency. METHODS: We prospectively studied 110 meningioma patients operated on in a single center from March 1st to the 25th of May 2012. Demographic data, location and size of the tumor, peritumoral edema, T1WI, T2WI, proton density weighted (PDWI), fluid-attenuated inversion recover (FLAIR) sequences, and arterial spin labeling (ASL) perfusion were studied and compared with the gray matter signal to predict meningioma consistency. Diffusion tensor imaging (DTI) with fractional anisotropy (FA) and mean diffusivity (MD) maps were included in the preoperative MRI. Meningioma consistency was evaluated by the operating surgeon who was unaware of the neuroradiological findings. RESULTS: In univariate analysis, meningioma size (diameter > 2 cm) and supratentorial or sphenoidal wing location were more frequently associated with hard-consistency meningiomas (p < 0.05). In addition, isointense signal on MD maps (p = 0.009), hyperintense signal on FA maps, and FA value > 0.3 (p = 0.00001) were associated with hard-consistency tumors. Age and sex, T1WI, T2WI, PDWI, FLAIR, or ASL perfusion sequences and peritumoral edema were not significantly associated with meningioma consistency. In logistic regression analysis, the most accurate model (AUC: 0.9459) for predicting a hard-consistency meningioma shows that an isointense signal in MD-maps, a hyperintense signal in FA-maps, and an FA value of more than 0.3 have a significant predictive value. CONCLUSIONS: FA value and MD and FA maps are useful for prediction of meningioma consistency and, therefore, may be considered in the preoperative routine MRI examination of all patients with intracranial meningiomas.

Minimal invasive trans-eyelid approach to anterior and middle skull base meningioma: a preliminary study of Shanghai Huashan hospital.

Transpalpebral or trans-eyelid approach is a modified trans-orbital access to lesions of anterior cranial fossa and sellar region. But whether this approach is also suitable for tumors extending laterally to the temporal lobe or middle cranial fossa is not clarified. We would like to share our experiences from the cadaveric anatomy study to clinical operations. We used 5 cadavers to study trans-eyelid approaches in a step-by-step fashion. And then assisted by an experienced ophthalmologist for incisions, we treated 3 female patients via this approach: One with spheno-orbital meningioma, one with sellar tuberculum meningioma, and the other with medial sphenoidal wing meningioma. After studying the cadavers, we made several revisions to the previously reported approach: 1) move the incision close to the edge of the eyelid, which resembled the double-eyelid incision. 2) A vascularized periosteum flap was dissected for repairing the opened frontal sinus and reconstruction of the skull base. 3) The dura was sutured up with a slice of temporalis muscle. Then we treated 3 patients by this approach. All tumors were totally resected as Simpson Grade I. Complications included orbital apex syndrome and transient oculomotor paralysis because of tumor invasion into orbit and cavernous sinus. No cerebrospinal fluid leakage. We find that trans-eyelid approach is suitable for lesions not only at anterior cranial base or sellar region, but also extending to middle cranial base, especially around sphenoidal wings within 2 cm range or spheno-orbital region. Thus, we propose whether it appropriate to nominate this approach as 'trans-eyelid pterional approach', since it may treat some anterior and middle cranial fossa lesions with a mini-craniotomy around pterion.

Lymphoplasmacyte-rich meningioma: our experience with 19 cases and a systematic literature review.

OBJECTIVE: To investigate the clinicopathological characteristics, prognosis, pathology, and differential diagnosis of LPM by analyzing our experience and reviewed relevant literature. We also postulated the necessity of postoperative adjuvant therapy. METHODS: 19 patients with LPM underwent surgical treatment from 2007 through 2010 in our department. The clinical charts of the patients, including surgical, histological, and follow-up records, as well as imaging studies, were analyzed retrospectively. Other 43 cases searched from the literature were also included, so that 62 LPM cases were summarized and reviewed together. RESULTS: The summarized 62 patients comprised 30 males and 31 females aged 9 years to 79 years (40.7±18.3 years). The most common locations were convexity, skull base, para-sagittal and cervical canal. Multiple or diffuse lesions were found in 8 cases. There were 13 patients had peripheral blood abnormalities (21%). One-third of the cases had moderate to severe peritumoral brain edema. Thirty-eight patients had total resection, 12 patients not specified while 12 received subtotal resection or only biopsy. MIB-1 was available in 24 cases and a third of them were higher than 3%. Follow-up more than 3 year was only completed in 19/62 cases. Seven cases suffered recurrence and two of them died after 2 years of operation. CONCLUSION: LPM is a very rare benign variant of intracranial meningioma. Both lesions and hematological abnormalities have a predilection for younger individuals. Preoperative diagnosis of this subtype of meningioma is still difficult. Surgical resection is the primary treatment option, and supportive care for those not totally removed is very important, because the recurrence rate for this subtype is rather low. However, the massive infiltration of lymphocytes and plasma cells in LPMs are still controversial and the long-term follow-ups are needed. Radiotherapy is not recommended, and hormonal or immune-inhibitor therapy might be helpful.

Prevalence, risk factors and recognition rates of depressive disorders among inpatients of tertiary general hospitals in Shanghai, China.

OBJECTIVE: To investigate the prevalence, risk factors and recognition rates of depressive disorders among inpatients of tertiary general hospitals in Shanghai, China. METHODS: A total of 784 inpatients were randomly selected from three tertiary general hospitals and evaluated with a Chinese version of the Mini International Neuropsychiatric Interview 5.0 by ten trained psychiatrists. A questionnaire, containing socio-demographic and clinical data, and a social support scale were also administered to subjects during the course of the clinical interview. Logistic regression was used to identify factors that were associated with depression. RESULTS: The current prevalence rates (95% confidence intervals) of any depressive disorder and major depressive disorder (MDD) were found to be 13.1% (10.7%-15.5%) and 6.9% (5.1%-8.7%), respectively. The risk factors for depression included poor marital status, living alone or with others, lack of medical insurance, poor or very poor self-rated physical health, hospitalization in the internal medicine department, and a subjective support score ≤23. Only 18.5% of the patients with current MDD were detected. CONCLUSION: Depression, especially MDD, has been a major mental health problem for Chinese tertiary general hospitals. There is an urgent need for the development of efficacious hospital-based consultation-liaison psychiatry programs aimed at improving Chinese physicians' recognition and ability to manage inpatient depression.

Papillary meningioma: clinical and histopathological observations.

Papillary meningioma is a rare subtype of malignant meningiomas, which is classified by the World Health Organization as Grade III. Because of lack of large sample size case studies, many of the specific characteristics of papillary meningioma are unclear. This study investigated by retrospective analysis the clinical, radiological and histopathological findings of 17 papillary meningioma patients who underwent surgical resection or biopsy, to assess the characteristics of papillary meningioma. Eight female and nine male patients were included, with a mean age of 40 (range: 6 to 55) years. Tumors were mostly located in the cerebral convexity and showed irregular margins, absence of a peritumoral rim, heterogeneous enhancement and severe peritumoral brain edema on preoperative images. Brain invasion was often confirmed during the operations, with abundant to exceedingly abundant blood supply. Intratumoral necrosis and mitosis was frequently observed on routinely stained sections. The average MIB-1 labeling index was 6.9%. Seven cases experienced tumor recurrence or progression, while seven patients died 6 to 29 months after operation. Radiation therapy was given in 52.9% of all cases. Univariate analysis showed that only the existence of intratumoral necrosis and incomplete resection correlated with tumor recurrence. The 3-year progression free survival was 66.7% after gross total resection and 63.6% for other cases. The 3-year mortality rate was 50% after gross total resection and 63.6% for other cases. Papillary meningioma has specific clinical and histopathological characteristics. Tumor recurrence (or progression) and mortality are common. Gross total tumor resection resulted in less recurrence and mortality.

Reprogramming of adult human neural stem cells into induced pluripotent stem cells.

BACKGROUND: Since an effective method for generating induced pluripotent stem cells (iPSCs) from human neural stem cells (hNSCs) can offer us a promising tool for studying brain diseases, here we reported direct reprogramming of adult hNSCs into iPSCs by retroviral transduction of four defined factors. METHODS: NSCs were successfully isolated and cultured from the hippocampus tissue of epilepsy patients. When combined with four factors (OCT3/4, SOX2, KLF4, and c-MYC), iPSCs colonies were successfully obtained. RESULTS: Morphological characterization and specific genetic expression confirmed that these hNSCs-derived iPSCs showed embryonic stem cells-like properties, which include the ability to differentiate into all three germ layers both in vitro and in vivo. CONCLUSION: Our method would be useful for generating human iPSCs from NSCs and provide an important tool for studying neurological diseases.

Secretory meningiomas: clinical, radiological and pathological findings in 70 consecutive cases at one institution.

Secretory meningioma (SM) is a rare, benign subtype of meningioma. Between January 2005 and December 2010, 70 SMs were operated on at the Department of Neurosurgery, Huashan Hospital, Fudan University. We retrospectively analyzed the clinical data, radiological and immunohistochemical findings, and patient outcome to discuss the specific features of SMs. Cranial base preference, hyper-signal in T2 weighted MR image, "xenon light" gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) enhancement were frequently observed in the 70 cases. Non-skull base SMs, which received more complete resection (p<0.01) and had better short-term and long-term outcome, were observed with more severe peritumoral brain edema (PTBE) (p<0.001). In follow-up, only 1 cranial base SM case showed tumor progression. 3 cases died after operation, all with cranial base SMs. As for the 10 cases given Simpson grade 3 or 4 resection who were available at follow-up, 3 died, 5 received gamma-knife therapy, and the other 2 cases received no treatment at all. Only one of the 2 residual SMs without postoperative radiation presented minor progression at a median of 48 months follow-up. In conclusion, cranial base preference, hyper-signal T2 weighted MR image and "xenon light" GD-DTPA enhancement are specific for SMs. Prognosis of SMs is related with operation completeness and surgical risks, rather than the extent of PTBE. Residual SM grows slowly and reacts well to gamma-knife therapy.

Histopathological classification and location of consecutively operated meningiomas at a single institution in China from 2001 to 2010.

BACKGROUND: Meningioma is one of the most common primary tumors of the central nervous system, but there are not many detailed studies on the sex, age, subtypes and locations of large series. This study was a retrospective analysis of the characteristics of meningioma cases consecutively operated on at a single institution in China from 2001 to 2010. METHODS: This study investigated the demographic background of 7084 meningioma cases, and the subtypes and locations of the tumors. Sex and age distributions were analyzed, and the pathological subtypes were classified according to the World Health Organization (WHO) classification. The location of the meningiomas was also categorized. RESULTS: The female:male ratio of the 7084 cases was 2.34:1. The mean age was 51.4 years (range, 11 months-86 years). The mean age of cases of WHO grade I meningioma was significantly older than that of grade II or III meningiomas (P < 0.001, Fisher's Least Significant Digit test). There was a significantly higher female:male ratio in WHO grade I meningiomas than in grade II or grade III meningiomas (2.57, 1.03 and 0.76, respectively; P < 0.001, χ(2) test). Meningothelial (n = 2061) and fibrous meningiomas (n = 3556) were the most common subtypes, comprising 79.3% of all meningiomas. All meningioma cases were classified into 23 locations in this study, with the cerebral convexity the most common site (38.33%, n = 2722). Cases with uncommon locations such as extra-cranial and sylvian fissure meningiomas were also present in this series. CONCLUSIONS: Female predominance was found for benign meningiomas, while malignant subtypes showed male predominance. The mean age of patients with WHO grade I meningiomas was older than that of patients with higher-grade tumors. Meningothelial and fibrous meningiomas were the most common subtypes. The cerebral convexity was the most common meningioma location.

Preoperative surgical planning for intracranial meningioma resection by virtual reality.

BACKGROUND: The Dextroscope system by Volume Interactions (Singapore) had been applied to minimally invasive neurosurgery in many units. This system enables the neurosurgeon to interact intuitively with the three-dimensional graphics in a direct manner resembling the way one communicates with the real objects. In the paper, we explored its values in pre-operation surgical planning for intracranial meningiomas resection. METHODS: Brain computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance venography (MRV) were performed on 10 patients with parasagittal and falcine meningiomas located on central groove area; brain CT, MRI and magnetic resonance angiography (MRA) were performed on 10 patients with anterior skull base meningiomas and 10 patients with sphenoid ridge meningiomas. All these data were transferred to Dextroscope virtual reality system, and reconstructed. Then meningiomas, skull base, brain tissue, drainage vein and cerebral arteries were displayed within the system, and their anatomic relationships were evaluated. Also, the simulation operations were performed. RESULTS: For parasagittal and falcine meningiomas, the relationships of tumor with drainage vein and superior sagittal sinus were clearly displayed in the Dextroscope system. For anterior skull base and sphenoid ridge meningiomas, the relationships of tumor with bilateral internal carotid arteries, anterior cerebral arteries, middle cerebral arteries and skull base were vividly displayed within the virtual reality system. Surgical planning and simulation operation of all cases were performed as well. The real operations of all patients were conducted according to the simulation with well outcomes. CONCLUSIONS: According to the virtual reality planning, neurosurgeons could get more anatomic information about meningioma and its surrounding structures, especially important vessels, and choose the best approach for tumor resection, which would lead to better prognosis for patients.

Detection of neural stem cells function in rats with traumatic brain injury by manganese-enhanced magnetic resonance imaging.

BACKGROUND: Previously we had successfully tracked adult human neural stem cells (NSCs) labeled with superparamagnetic iron oxide particles (SPIOs) in host human brain after transplantation in vivo non-invasively by magnetic resonance imaging (MRI). However, the function of the transplanted NSCs could not be evaluated by the method. In the study, we applied manganese-enhanced MRI (ME-MRI) to detect NSCs function after implantation in brain of rats with traumatic brain injury (TBI) in vivo. METHODS: Totally 40 TBI rats were randomly divided into 4 groups with 10 rats in each group. In group 1, the TBI rats did not receive NSCs transplantation. MnCl2·4H2O was intravenously injected, hyperosmolar mannitol was delivered to disrupt rightside blood brain barrier, and its contralateral forepaw was electrically stimulated. In group 2, the TBI rats received NSCs (labeled with SPIO) transplantation, and the ME-MRI procedure was same to group 1. In group 3, the TBI rats received NSCs (labeled with SPIO) transplantation, and the ME-MRI procedure was same to group 1, but diltiazem was introduced during the electrical stimulation period. In group 4, the TBI rats received phosphate buffered saline (PBS) injection, and the ME-MRI procedure was same to group 1. RESULTS: Hyperintense signals were detected by ME-MRI in the cortex areas associated with somatosensory in TBI rats of group 2. These signals, which could not be induced in TBI rats of groups 1 and 4, disappeared when diltiazem was introduced in TBI rats of group 3. CONCLUSION: In this initial study, we mapped implanted NSCs activity and its functional participation within local brain area in TBI rats by ME-MRI technique, paving the way for further pre-clinical research.

Preoperative lanreotide treatment in acromegalic patients with macroadenomas increases short-term postoperative cure rates: a prospective, randomised trial.

OBJECTIVE: To investigate whether 4-month preoperative lanreotide treatment would improve the surgical cure rate of newly diagnosed acromegalic patients with macroadenomas. DESIGN: A prospective, randomised study. METHODS: After a baseline evaluation, patients were randomly assigned to 4-month preoperative treatment with lanreotide (starting with 30 mg/2 weeks i.m. and increasing to 30 mg/week i.m. at week 8 if mean GH >2.5 microg/l on GH day curves; pretreatment group, Group 1) or to transsphenoidal surgery (direct surgery group, Group 2). Cure was evaluated 4 months postoperatively primarily by fasting IGF1 less than or equal to age-adjusted upper limit of normal. RESULTS: A pool of 108 patients was randomly divided into two groups. Five patients in each group were lost to follow-up during the study period, so 49 patients in each group were analysed. At baseline, no difference was observed between the two groups. Cure was established in 24 of 49 (49.0%, 95% confidence interval (CI), 35.0-63.0%) pretreated patients (Group 1) versus 9 of 49 (18.4%, 95% CI, 7.6-29.2%) direct surgery patients (Group 2; P=0.001). Surgical morbidity was recorded in 12 patients (12.2%) and was similar in Group 1 and 2 patients (14.3 and 10.2% respectively; P=0.538). The postoperative hospital stay was similar between groups: being 4.5+/-1.6 days in Group 1 vs 4.8+/-1.9 days in Group 2 (P=0.328). CONCLUSIONS: Pretreatment with lanreotide before transsphenoidal surgery improves surgical cure rates in patients with GH-secreting pituitary macroadenomas. Pretreatment does not affect surgical complications or duration of hospital stay (ClinicalTrials.gov number, NCT00993356).

[The value of three-dimensional 64-multi-slices helical computer tomography on the diagnosis of diseases of digestive system].

OBJECTIVE: To study the value of three-dimensional 64-slice helical computer tomography (64-MSCT) in diagnosis and surgical treatment on diseases of digestive system. METHODS: From November 2005 to August 2006, 64-MSCT was performed on 102 patients suspected of digestive diseases to display foci of infection, hepatic conduit, biliary-pancreatic duct and portal venous system, followed by three-dimensional reconstruction of those targets. The reconstructed images as well as the data obtained from the reconstruction were compared with the surgical results. RESULTS: Twenty-five of 27 patients with portal hypertension (PHT) showed blur-free imaging of main portal vein (MPV) while the other 2 cases showed congenital cavernous transformation or thrombogenesis of MPV. Compensatory circulation of portal venous system was displayed satisfactorily in 27 cases. The three-dimensionally reconstructed images of 34 cases of hepatocellular carcinoma (HCC) demonstrated no invasion of tumors into the tissues and blood vessels of 23 cases, visible invasion into portal vein and hepatic veins of 9 cases, tumor embolus in portal veins of 1 case, and arterio-venous fistula in only one case. The 3D imaging of biliary passages displayed total concretion, tumor and constrictive or dilated biliary-pancreatic duct and bile duct around amphi-obstruction, which complied with the operations research of calculus of bile duct in 25 cases, cholangiocarcinoma in 5 cases, and cancer of pancreas in 5 cases. Operations research in accordance with the 3D reconstructed imaging accorded with imaging diagnosis in respect of PHT, HCC and diseases of biliary-pancreatic system at the rates of 100%, 97% and 100%, respectively. CONCLUSIONS: Three-dimensional 64-MSCT displays foci of infection and constructions of biliary-pancreatic duct and hepatic conduit stereoscopically.

Epigenetics and neural stem cell commitment.

Neural stem cell is presently the research hotspot in neuroscience. Recent progress indicates that epigenetic modulation is closely related to the self-renewal and differentiation of neural stem cell. Epigenetics refer to the study of mitotical/meiotical heritage changes in gene function that cannot be explained by changes in the DNA sequence. Major epigenetic mechanisms include DNA methylation, histone modification, chromatin remodeling, genomic imprinting, and non-coding RNA. In this review, we focus on the new insights into the epigenetic mechanism for neural stem cells fate.