Abnormal characteristic static and dynamic functional network connectivity in idiopathic normal pressure hydrocephalus.

AIMS: Idiopathic Normal pressure hydrocephalus (iNPH) is a neurodegenerative disease characterized by gait disturbance, dementia, and urinary dysfunction. The neural network mechanisms underlying this phenomenon is currently unknown. METHODS: To investigate the resting-state functional connectivity (rs-FC) abnormalities of iNPH-related brain connectivity from static and dynamic perspectives and the correlation of these abnormalities with clinical symptoms before and 3-month after shunt. We investigated both static and dynamic functional network connectivity (sFNC and dFNC, respectively) in 33 iNPH patients and 23 healthy controls (HCs). RESULTS: The sFNC and dFNC of networks were generally decreased in iNPH patients. The reduction in sFNC within the default mode network (DMN) and between the somatomotor network (SMN) and visual network (VN) were related to symptoms. The temporal properties of dFNC and its temporal variability in state-4 were sensitive to the identification of iNPH and were correlated with symptoms. The temporal variability in the dorsal attention network (DAN) increased, and the average instantaneous FC was altered among networks in iNPH. These features were partially associated with clinical symptoms. CONCLUSION: The dFNC may be a more sensitive biomarker for altered network function in iNPH, providing us with extra information on the mechanisms of iNPH.

Increased Cerebrospinal Fluid Levels of Soluble Triggering Receptor Expressed on Myeloid Cells 2 and Chitinase-3-Like Protein 1 in Idiopathic Normal-Pressure Hydrocephalus.

BACKGROUND: Neurodegenerative disease pathology is associated with neuroinflammation, but evidence on idiopathic normal pressure hydrocephalus (iNPH) remains limited and cerebrospinal fluid (CSF) biomarker profiles need to be elucidated. OBJECTIVE: To investigate whether iNPH pathological mechanisms are associated with greater CSF markers of core Alzheimer's disease pathology (amyloid-ß42 (Aß42), phosphorylated tau (P-tau)), neurodegeneration (total tau (T-tau)), and neuroinflammation (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40)). METHODS: The study analyzed lumbar CSF samples from 63 patients with iNPH and 20 age-matched orthopedic surgery patients who had no preoperative gait or cognitive impairment (control group). Aß42, T-tau, P-tau, sTREM2, and YKL-40 in different subgroups were investigated. RESULTS: CSF sTREM2 levels were significantly higher in the iNPH group than in the control group, but no significant between-group difference was noted in YKL-40. Moreover, YKL-40 levels were significantly higher in the tap test non-responders than in the tap test responders (p = 0.021). At the 1-year follow-up after shunt surgery, the CSF P-tau levels were significantly lower (p = 0.020) in those with gait improvement and the CSF sTREM2 levels were significantly lower (p = 0.041) in those with cognitive improvement. In subgroup analysis, CSF sTREM2 levels were strongly correlated with CSF YKL-40 in the iNPH group (r = 0.443, p < 0.001), especially in the tap test non-responders (r = 0.653, p = 0.002). CONCLUSION: YKL-40 and sTREM2 are disease-specific markers of neuroinflammation, showing higher CSF levels in iNPH. In addition, sTREM2 is positively associated with YKL-40, indicating that interactions of glial cells play an important role in iNPH pathogenesis.

White matter hyperintensity mediating gait disorders in iNPH patients via neurofilament light chain.

Purpose: This study aimed to analyze the differences in regional white matter hyperintensities (WMH) volume and cerebrospinal fluid biomarker levels between idiopathic normal pressure hydrocephalus (iNPH) patients with or without gait disorder. Methods: Forty-eight iNPH patients undergoing bypass surgery and 20 normal senile individuals were included. The LST toolkit was used to segment all MRI fluid attenuation inversion images and quantify the WMH volume in each brain region. Cerebrospinal fluid was collected from all individuals and measured for concentrations of Aß, t-tau, p-tau, and neurofilament light chain (NfL). Patients with iNPH were followed up for 1 year and divided categorized into a gait disorder improvement group and no improvement group according to the 3 m round-trip test time parameter improvement by more than 10%. Results: We found that WMH in all areas of iNPH patients was higher than that in the control group. CSF levels of Aß, t-tau, and p-tau were lower than those in the control group, while NfL levels were higher than those in the control group. The gait (+) group NfL level was higher than that in gait (-), and there were no statistical differences in Aß, t-tau, and p-tau levels. The gait (+) group of frontal and parietal lobe WMH volume PVH above the gait (-) group. The mediating effect model analysis showed that PVH might affect the gait disorder of iNPH patients through NfL. A 1-year follow-up of the patients after the bypass surgery found that 24 of the 35 patients in the gait (+) group had improvements, while 11 had no significant improvements. The comparison of CSF marker levels between the two groups showed that the CSF NfL level in the improved group was lower than that in the non-improved group. The WMH volume and PVH in the frontal-parietal lobe of the improved group were lower than those of the non-improved group. Conclusion: iNPH patients have more serious frontoparietal and periventricular white matter lesions, and WMH volume in the frontoparietal may mediate the occurrence of gait disorder in iNPH patients through the increase of NfL level.

An initial study on the predictive value using multiple MRI characteristics for Ki-67 labeling index in glioma.

BACKGROUND AND PURPOSE: Ki-67 labeling index (LI) is an important indicator of tumor cell proliferation in glioma, which can only be obtained by postoperative biopsy at present. This study aimed to explore the correlation between Ki-67 LI and apparent diffusion coefficient (ADC) parameters and to predict the level of Ki-67 LI noninvasively before surgery by multiple MRI characteristics. METHODS: Preoperative MRI data of 166 patients with pathologically confirmed glioma in our hospital from 2016 to 2020 were retrospectively analyzed. The cut-off point of Ki-67 LI for glioma grading was defined. The differences in MRI characteristics were compared between the low and high Ki-67 LI groups. The receiver operating characteristic (ROC) curve was used to estimate the accuracy of each ADC parameter in predicting the Ki-67 level, and finally a multivariate logistic regression model was constructed based on the results of ROC analysis. RESULTS: ADCmin, ADCmean, rADCmin, rADCmean and Ki-67 LI showed a negative correlation (r = - 0.478, r = - 0.369, r = - 0.488, r = - 0.388, all P < 0.001). The Ki-67 LI of low-grade gliomas (LGGs) was different from that of high-grade gliomas (HGGs), and the cut-off point of Ki-67 LI for distinguishing LGGs from HGGs was 9.5%, with an area under the ROC curve (AUROC) of 0.962 (95%CI 0.933-0.990). The ADC parameters in the high Ki-67 group were significantly lower than those in the low Ki-67 group (all P < 0.05). The peritumoral edema (PTE) of gliomas in the high Ki-67 LI group was higher than that in the low Ki-67 LI group (P < 0.05). The AUROC of Ki-67 LI level assessed by the multivariate logistic regression model was 0.800 (95%CI 0.721-0.879). CONCLUSIONS: There was a negative correlation between ADC parameters and Ki-67 LI, and the multivariate logistic regression model combined with peritumoral edema and ADC parameters could improve the prediction ability of Ki-67 LI.

One-year outcome of a lumboperitoneal shunt in older adults with idiopathic normal pressure hydrocephalus.

Background: Lumboperitoneal shunt (LPS) is now an effective surgical modality for idiopathic normal pressure hydrocephalus (iNPH), but there is still a lack of clinical data on LPS in older adult iNPH patients in China. We aim to report the shunt effect and the complications of older adult iNPH patients treated with LPS at a single center in Shanghai, China. Methods: We conducted a retrospective study among adults over 60 years old who were diagnosed as iNPH and treated with LPS from September 2016 to December 2020. The shunt effect was evaluated from two dimensions of functional and symptomatic improvement 3 months and 1 year after surgery, respectively. The potential factors related to the shunt effect one year after surgery were explored by comparing the effect between different subgroups and conducting multivariate logistic regression analysis. Result: A total of 85 patients were included in this study, ranging from 60 to 93 years old, with an average age of 74.7. The function and symptoms were better both 3 months and 1 year after surgery than before (P < 0.001). At the 1-year postoperation follow-up, the functional and symptomatic improvement rates were 72.9% and 90.6%, respectively. The symptomatic improvement rates of gait, urination, and cognition were 74.1%, 72.9%, and 60.0%, respectively. Multivariate logistic regression analysis showed that improvement in function was much more possible in patients with less than 24 months from symptom onset to surgery (OR = 24.57, P < 0.001) and those with disproportionately enlarged subarachnoid-space hydrocephalus (OR = 5.88, P = 0.048); improvement in gait was also more possible in patients with less than 24 months from symptom onset to surgery (OR = 5.29, P = 0.017); improvement in urination was more possible in patients with diabetes (OR = 4.76, P = 0.019), and improvement in cognition was more possible in patients with preoperative modified Rankin scale level lower than 4 (OR = 3.51, P = 0.040). Minor operation-related complications were seen in 27 patients (31.8%) and severe complications in 6 patients (7.1%). Conclusion: LPS could improve the function and symptoms of older adult iNPH patients. Early detection, diagnosis, and treatment of the disease could improve the shunt effect of the patients. Older adult iNPH patients with higher age ranges could achieve comparable shunt results compared with younger adults.

Microglia-induced autophagic death of neurons via IL-6/STAT3/miR-30d signaling following hypoxia/ischemia.

BACKGROUND: There is a relationship between autophagy and the occurrence, maintenance, and progression of several neurodegenerative diseases. The activation of microglia after ischemia contributes to neuronal injury via proinflammatory cytokines and neurotoxic elements. The purpose of this study was to evaluate the function of autophagy in the microglia-mediated death of neuronal cells. METHODS AND RESULTS: Microglial activation by oxygen/glucose deprivation induced both apoptosis and autophagy in neuron-like PC12 cells. Microglia-derived interleukin (IL)-6 induced PC12 cell apoptosis in vitro; however, this effect was inhibited by the autophagy inhibitor chloroquine. Further analysis demonstrated that miR-30d in PC12 cells suppressed microglia-induced PC12 apoptosis and autophagy by directly targeting autophagy protein 5. Moreover, microglia-derived IL-6 activated signal transducer and activator of transcription 3 (STAT3), which can then directly repress miR-30d genes via a conserved STAT3-binding site in its promoter, thereby promoting PC12 cell autophagy and apoptosis. CONCLUSIONS: Our study identified IL-6-dependent autophagy-related signaling between microglia and neurons, which contributed to neuronal apoptosis. Importantly, we also provided potential therapeutic targets for ischemic treatment via the interruption of proinflammatory signaling.

Preoperative and Noninvasive Prediction of Gliomas Histopathological Grades and IDH Molecular Types Using Multiple MRI Characteristics.

Background and Purpose: Gliomas are one of the most common tumors in the central nervous system. This study aimed to explore the correlation between MRI morphological characteristics, apparent diffusion coefficient (ADC) parameters and pathological grades, as well as IDH gene phenotypes of gliomas. Methods: Preoperative MRI data from 166 glioma patients with pathological confirmation were retrospectively analyzed to compare the differences of MRI characteristics and ADC parameters between the low-grade and high-grade gliomas (LGGs vs. HGGs), IDH mutant and wild-type gliomas (IDHmut vs. IDHwt). Multivariate models were constructed to predict the pathological grades and IDH gene phenotypes of gliomas and the performance was assessed by the receiver operating characteristic (ROC) analysis. Results: Two multivariable logistic regression models were developed by incorporating age, ADC parameters, and MRI morphological characteristics to predict pathological grades, and IDH gene phenotypes of gliomas, respectively. The Noninvasive Grading Model classified tumor grades with areas under the ROC curve (AUROC) of 0.934 (95% CI=0.895-0.973), sensitivity of 91.2%, and specificity of 78.6%. The Noninvasive IDH Genotyping Model differentiated IDH types with an AUROC of 0.857 (95% CI=0.787-0.926), sensitivity of 88.2%, and specificity of 63.8%. Conclusion: MRI features were correlated with glioma grades and IDH mutation status. Multivariable logistic regression models combined with MRI morphological characteristics and ADC parameters may provide a noninvasive and preoperative approach to predict glioma grades and IDH mutation status.

Shunt Surgery Efficacy Is Correlated With Baseline Cerebrum Perfusion in Idiopathic Normal Pressure Hydrocephalus: A 3D Pulsed Arterial-Spin Labeling Study.

This study investigated the relationship between preoperative cerebral blood flow (CBF) in patients with idiopathic normal pressure hydrocephalus (INPH) and preoperative clinical symptoms and changes of clinical symptoms after shunt surgery. A total of 32 patients with diagnosed INPH and 18 age-matched healthy controls (HCs) were involved in this study. All subjects underwent magnetic resonance imaging (MRI), including 3D pulsed arterial-spin labeling (PASL) for non-invasive perfusion imaging, and clinical symptom evaluation at baseline, and all patients with INPH were reexamined with clinical tests 1 month postoperatively. Patients with INPH had significantly lower whole-brain CBF than HCs, with the most significant differences in the high convexity, temporal lobe, precuneus, and thalamus. At baseline, there was a significant correlation between the CBF in the middle frontal gyrus, calcarine, inferior and middle temporal gyrus, thalamus, and posterior cingulate gyrus and poor gait manifestation. After shunting, improvements were negatively correlated with preoperative perfusion in the inferior parietal gyrus, inferior occipital gyrus, and middle temporal gyrus. Preoperative CBF in the middle frontal gyrus was positively correlated with the severity of preoperative cognitive impairment and negatively correlated with the change of postoperative MMSE score. There was a moderate positive correlation between anterior cingulate hypoperfusion and improved postoperative urination. Our study revealed that widely distributed and intercorrelated cortical and subcortical pathways are involved in the development of INPH symptoms, and preoperative CBF may be correlative to short-term shunt outcomes.

Preliminary Exploration of the Sequence of Nerve Fiber Bundles Involvement for Idiopathic Normal Pressure Hydrocephalus: A Correlation Analysis Using Diffusion Tensor Imaging.

The study preliminarily explored the sequence and difference of involvement in different neuroanatomical structures in idiopathic normal pressure hydrocephalus (INPH). We retrospectively analyzed the differences in diffusion tensor imaging (DTI) parameters in 15 ROIs [including the bilateral centrum semiovale (CS), corpus callosum (CC) (body, genu, and splenium), head of the caudate nucleus (CN), internal capsule (IC) (anterior and posterior limb), thalamus (TH), and the bilateral frontal horn white matter hyperintensity (FHWMH)] between 27 INPH patients and 11 healthy controls and the correlation between DTI indices and clinical symptoms, as evaluated by the INPH grading scale (INPHGS), the Mini-Mental State Examination (MMSE), and the timed up and go test (TUG-t), before and 1 month after shunt surgery. Significant differences were observed in DTI parameters from the CS (p FA1 = 0.004, p ADC1 = 0.005) and the genu (p FA2 = 0.022; p ADC2 = 0.001) and body (p FA3 = 0.003; p ADC3 = 0.002) of the CC between the groups. The DTI parameters from the CS were strongly correlated with the MMSE score both pre-operatively and post-operatively. There was association between apparent diffusion coefficient (ADC) values of anterior and posterior limbs of the IC and MMSE. The DTI parameters of the head of the CN were correlated with motion, and the ADC value was significantly associated with the MMSE score. The FA value from TH correlated with an improvement in urination after shunt surgery. We considered that different neuroanatomical structures are affected differently by disease due to their positions in neural pathways and characteristics, which is further reflected in clinical symptoms and the prognosis of shunt surgery.

A new index for assessing cerebral ventricular volume in idiopathic normal-pressure hydrocephalus: a comparison with Evans' index.

PURPOSE: To recommend a new simple and explicit index termed the anteroposterior diameter of the lateral ventricle index (ALVI) for assessing brain ventricular size in neuroimaging and to compare Evans index (EI) between idiopathic normal pressure hydrocephalus (iNPH) patients and age-matched healthy elderly subjects. METHODS: Retrospective measurements of ventricular volume (VV), relative VV (RVV), the EI, and the ALVI were taken from thin-section CT scans for 23 pre-shunt-insertion iNPH patients and 62 age-matched healthy elderly volunteers. The area under the receiver operating characteristic (ROC) curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to assess the effectiveness of ALVI scores for predicting VV. RESULTS: The correlations between VV or RVV and ALVI scores (VV, r = 0.957; RVV, r = 0.983) were significantly stronger than the corresponding correlations with EI scores (VV, r = 0.843; RVV, r = 0.840). The AUC for ALVI scores was significantly greater than the AUC for EI scores. Furthermore, with the inclusion of the ALVI, the NRI value was 0.14 and the IDI value was 0.14; these improvements were also statistically significant. CONCLUSION: The ALVI is a more accurate and more explicitly defined marker of VV than the EI and assesses ventricular enlargement effectively. We suggest that ventricular enlargement of the healthy elderly be defined by ALVI > 0.50.

Retraction notice to: Myosin VI contributes to malignant proliferation of human glioma cells.

[This retracts the article on p. 139 in vol. 20, PMID: 26937209.].

Myosin VI contributes to malignant proliferation of human glioma cells.

Previously characterized as a backward motor, myosin VI (MYO6), which belongs to myosin family, moves toward the minus end of the actin track, a direction opposite to all other known myosin members. Recent researches have illuminated the role of MYO6 in human cancers, particularly in prostate cancer. However, the role of MYO6 in glioma has not yet been determined. In this study, to explore the role of MYO6 in human glioma, lentivirus-delivered short hairpin RNA (shRNA) targeting MYO6 was designed to stably down-regulate its endogenous expression in glioblastoma cells U251. Knockdown of MYO6 signifi cantly inhibited viability and proliferation of U251 cells in vitro. Moreover, the cell cycle of U251 cells was arrested at G0/G1 phase with the absence of MYO6, which could contribute to the suppression of cell proliferation. In conclusion, we firstly identified the crucial involvement of MYO6 in human glioma. The inhibition of MYO6 by shRNA might be a potential therapeutic method in human glioma.