Exploring cortical morphology biomarkers of amnesic mild cognitive impairment using novel fractal dimension-based structural MRI analysis.

Amnestic mild cognitive impairment (aMCI) is considered as an intermediate stage of Alzheimer's disease, but no MRI biomarkers currently distinguish aMCI from healthy individuals effectively. Fractal dimension, a quantitative parameter, provides superior morphological information compared to conventional cortical thickness methods. Few studies have used cortical fractal dimension values to differentiate aMCI from healthy controls. In this study, we aim to build an automated discriminator for accurately distinguishing aMCI using fractal dimension measures of the cerebral cortex. Thirty aMCI patients and 30 health controls underwent structural MRI of the brain. First, the atrophy of participants' cortical sub-regions of Desikan-Killiany cortical atlas was assessed using fractal dimension and cortical thickness. The fractal dimension is more sensitive than cortical thickness in reducing dimensional effects and may accurately reflect morphological changes of the cortex in aMCI. The aMCI group had significantly lower fractal dimension values in the bilateral temporal lobes, right limbic lobe and right parietal lobe, whereas they showed significantly lower cortical thickness values only in the bilateral temporal lobes. Fractal dimension analysis was able to depict most of the significantly different focal regions detected by cortical thickness, but additionally with more regions. Second, applying the measured fractal dimensions (and cortical thickness) of both cerebral hemispheres, an unsupervised discriminator was built for the aMCI and healthy controls. The proposed fractal dimension-based method achieves 80.54% accuracy in discriminating aMCI from healthy controls. The fractal dimension appears to be a promising biomarker for cortical morphology changes that can discriminate patients with aMCI from healthy controls.

Alteration of the Intra- and Inter-Lobe Connectivity of the Brain Structural Network in Normal Aging.

The morphological changes in cortical parcellated regions during aging and whether these atrophies may cause brain structural network intra- and inter-lobe connectivity alterations are subjects that have been minimally explored. In this study, a novel fractal dimension-based structural network was proposed to measure atrophy of 68 parcellated cortical regions. Alterations of structural network parameters, including intra- and inter-lobe connectivity, were detected in a middle-aged group (30-45 years old) and an elderly group (50-65 years old). The elderly group exhibited significant lateralized atrophy in the left hemisphere, and most of these fractal dimension atrophied regions were included in the regions of the "last-in, first-out" model. Globally, the elderly group had lower modularity values, smaller component size modules, and fewer bilateral association fibers. They had lower intra-lobe connectivity in the frontal and parietal lobes, but higher intra-lobe connectivity in the temporal and occipital lobes. Both groups exhibited similar inter-lobe connecting pattern. The elderly group revealed separations, sparser long association fibers, commissural fibers, and lateral inter-lobe connectivity lost effect, mainly in the right hemisphere. New wiring and reconfiguring modules may have occurred within the brain structural network to compensate for connectivity, decreasing and preventing functional loss in cerebral intra- and inter-lobe connectivity.

10-Point CT-ASPECTS-based reperfusion therapy for unknown onset stroke.

Under the time-based criteria, patients with unknown onset stroke (UOS) are ineligible for reperfusion therapies. However, previous studies suggest that some patients with UOS may benefit from reperfusion. Several imaging modalities have been suggested to select patients for intervention, but the optimal imaging criteria are still controversial. Herein we present a series of four cases using 10-point CT-ASPECTS to support our decision of reperfusion therapy. We decided based on history, symptoms, and the 10-point CT-ASPECTS alone. Each patient's history suggested that the stroke just took place. All four patients had apparent clinical symptoms, with 10-point CT-ASPECTS. All of them had a reduction in their NIHSS after the reperfusion therapy. 10-point CT-ASPECTS could be used to support the presumption that the stroke just happens in patients with UOS. Further study is warranted to elucidate the value of CT-ASPECTS for UOS patients.

Phantom-based standardization of CT angiography images for spot sign detection.

PURPOSE: The CT angiography (CTA) spot sign is a strong predictor of hematoma expansion in intracerebral hemorrhage (ICH). However, CTA parameters vary widely across centers and may negatively impact spot sign accuracy in predicting ICH expansion. We developed a CT iodine calibration phantom that was scanned at different institutions in a large multicenter ICH clinical trial to determine the effect of image standardization on spot sign detection and performance. METHODS: A custom phantom containing known concentrations of iodine was designed and scanned using the stroke CT protocol at each institution. Custom software was developed to read the CT volume datasets and calculate the Hounsfield unit as a function of iodine concentration for each phantom scan. CTA images obtained within 8 h from symptom onset were analyzed by two trained readers comparing the calibrated vs. uncalibrated density cutoffs for spot sign identification. ICH expansion was defined as hematoma volume growth >33%. RESULTS: A total of 90 subjects qualified for the study, of whom 17/83 (20.5%) experienced ICH expansion. The number of spot sign positive scans was higher in the calibrated analysis (67.8 vs 38.9% p < 0.001). All spot signs identified in the non-calibrated analysis remained positive after calibration. Calibrated CTA images had higher sensitivity for ICH expansion (76 vs 52%) but inferior specificity (35 vs 63%) compared with uncalibrated images. CONCLUSION: Normalization of CTA images using phantom data is a feasible strategy to obtain consistent image quantification for spot sign analysis across different sites and may improve sensitivity for identification of ICH expansion.

Associations of diabetes status and glucose measures with outcomes after endovascular therapy in patients with acute ischemic stroke: an analysis of the nationwide TREAT-AIS registry.

Background: Hyperglycemia affects the outcomes of endovascular therapy (EVT) for acute ischemic stroke (AIS). This study compares the predictive ability of diabetes status and glucose measures on EVT outcomes using nationwide registry data. Methods: The study included 1,097 AIS patients who underwent EVT from the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke. The variables analyzed included diabetes status, admission glucose, glycated hemoglobin (HbA1c), admission glucose-to-HbA1c ratio (GAR), and outcomes such as 90-day poor functional outcome (modified Rankin Scale score ≥ 2) and symptomatic intracranial hemorrhage (SICH). Multivariable analyses investigated the independent effects of diabetes status and glucose measures on outcomes. A receiver operating characteristic (ROC) analysis was performed to compare their predictive abilities. Results: The multivariable analysis showed that individuals with known diabetes had a higher likelihood of poor functional outcomes (odds ratios [ORs] 2.10 to 2.58) and SICH (ORs 3.28 to 4.30) compared to those without diabetes. Higher quartiles of admission glucose and GAR were associated with poor functional outcomes and SICH. Higher quartiles of HbA1c were significantly associated with poor functional outcomes. However, patients in the second HbA1c quartile (5.6-5.8%) showed a non-significant tendency toward good functional outcomes compared to those in the lowest quartile (<5.6%). The ROC analysis indicated that diabetes status and admission glucose had higher predictive abilities for poor functional outcomes, while admission glucose and GAR were better predictors for SICH. Conclusion: In AIS patients undergoing EVT, diabetes status, admission glucose, and GAR were associated with 90-day poor functional outcomes and SICH. Admission glucose was likely the most suitable glucose measure for predicting outcomes after EVT.

Decreased Brain Structural Network Connectivity in Patients with Mild Cognitive Impairment: A Novel Fractal Dimension Analysis.

Mild cognitive impairment (MCI) is widely regarded to be the intermediate stage to Alzheimer's disease. Cerebral morphological alteration in cortical subregions can provide an accurate predictor for early recognition of MCI. Thirty patients with MCI and thirty healthy control subjects participated in this study. The Desikan-Killiany cortical atlas was applied to segment participants' cerebral cortex into 68 subregions. A complexity measure termed fractal dimension (FD) was applied to assess morphological changes in cortical subregions of participants. The MCI group revealed significantly decreased FD values in the bilateral temporal lobes, right parietal lobe including the medial temporal, fusiform, para hippocampal, and also the orbitofrontal lobes. We further proposed a novel FD-based brain structural network to compare network parameters, including intra- and inter-lobular connectivity between groups. The control group had five modules, and the MCI group had six modules in their brain networks. The MCI group demonstrated shrinkage of modular sizes with fewer components integrated, and significantly decreased global modularity in the brain network. The MCI group had lower intra- and inter-lobular connectivity in all lobes. Between cerebral lobes, the MCI patients may maintain nodal connections between both hemispheres to reduce connectivity loss in the lateral hemispheres. The method and results presented in this study could be a suitable tool for early detection of MCI.

Using Fractal Dimension Analysis with the Desikan-Killiany Atlas to Assess the Effects of Normal Aging on Subregional Cortex Alterations in Adulthood.

Normal aging is associated with functional and structural alterations in the human brain. The effects of normal aging and gender on morphological changes in specific regions of the brain are unknown. The fractal dimension (FD) can be a quantitative measure of cerebral folding. In this study, we used 3D-FD analysis with the Desikan-Killiany (DK) atlas to assess subregional morphological changes in adulthood. A total of 258 participants (112 women and 146 men) aged 30-85 years participated in this study. Participants in the middle-age group exhibited a decreased FD in the lateral frontal lobes, which then spread to the temporal and parietal lobes. Men exhibited an earlier and more significant decrease in FD values, mainly in the right frontal and left parietal lobes. Men exhibited more of a decrease in FD values in the subregions on the left than those in the right, whereas women exhibited more of a decrease in the lateral subregions. Older men were at a higher risk of developing mild cognitive impairment (MCI) and exhibited age-related memory decline earlier than women. Our FD analysis using the DK atlas-based prediagnosis may provide a suitable tool for assessing normal aging and neurodegeneration between groups or in individual patients.

Caspase­dependent apoptotic death by gadolinium chloride (GdCl3) via reactive oxygen species production and MAPK signaling in rat C6 glioma cells.

Gadolinium (Gd) compounds serve as magnetic resonance imaging contrast agents and exert certain anticancer activities. Yet, the molecular signaling underlying the antitumor effect of Gd chloride (GdCl3) on glioma remains unclear. In the present study, we aimed to ascertain the apoptotic mechanisms of GdCl3 on rat glioma C6 cells. Our results demonstrated that GdCl3 significantly reduced cell viability and shrunk cell morphology of C6 cells in a concentration­dependent manner. GdCl3 led to apoptotic C6 cell death as detected by TUNEL staining. An increase in cleaved caspase­3, cleaved caspase­8 and cleaved caspase­9 occurred in GdCl3­treated C6 cells as detected by immunoblotting analysis. The activities of caspase­3, caspase­8 and caspase­9 were increased, and the specific inhibitors of caspase­3/­8/­9 individually reversed cell viability, which caused apoptotic death in C6 cells prior to GdCl3 exposure. GdCl3 also caused an elevation in the cytoplasmic Ca2+ level and reactive oxygen species (ROS) production, as well as the loss of mitochondrial membrane potential (ΔΨm) as shown by flow cytometric analysis in C6 cells. The results from the immunoblotting analysis demonstrated that there were upregulated protein levels of cytochrome c and Bax but a downregulated protein level of Bcl­2 in C6 cells after GdCl3 treatment. Additionally, GdCl3 decreased the protein levels of phosphorylated­extracellular signal­regulated kinases, phosphorylated­c­Jun N­terminal kinase and phosphorylated­p38 mitogen­activated protein kinases in C6 cells. In conclusion, ROS production and MAPKs signaling pathways contribute to GdCl3­induced caspase cascade­mediated apoptosis in C6 cells. Our findings provide a better understanding of the molecular mechanisms underlying the role of GdCl3 in rat glioma C6 cells.

Gadolinium chloride elicits apoptosis in human osteosarcoma U-2 OS cells through extrinsic signaling, intrinsic pathway and endoplasmic reticulum stress.

Gadolinium (Gd) compounds are important as magnetic resonance imaging (MRI) contrast agents, and are potential anticancer agents. However, no report has shown the effect of gadolinium chloride (GdCl3) on osteosarcoma in vitro. The present study investigated the apoptotic mechanism of GdCl3 on human osteosarcoma U-2 OS cells. Our results indicated that GdCl3 significantly reduced cell viability of U-2 OS cells in a concentration-dependent manner. GdCl3 led to apoptotic cell shrinkage and DNA fragmentation in U-2 OS cells as revealed by morphologic changes and TUNEL staining. Colorimetric assay analyses also showed that activities of caspase-3, caspase-8, caspase-9 and caspase-4 occurred in GdCl3-treated U-2 OS cells. Pretreatment of cells with pan-caspase inhibitor (Z-VAD-FMK) and specific inhibitors of caspase-3/-8/-9 significantly reduced cell death caused by GdCl3. The increase of cytoplasmic Ca2+ level, ROS production and the decrease of mitochondria membrane potential (ΔΨm) were observed by flow cytometric analysis in U-2 OS cells after GdCl3 exposure. Western blot analyses demonstrated that the levels of Fas, FasL, cytochrome c, Apaf-1, GADD153 and GRP78 were upregulated in GdCl3-treated U-2 OS cells. In conclusion, death receptor, mitochondria-dependent and endoplasmic reticulum (ER) stress pathways contribute to GdCl3-induced apoptosis in U-2 OS cells. GdCl3 might have potential to be used in treatment of osteosarcoma patients.

Cell Signaling and Differential Protein Expression in Neuronal Differentiation of Bone Marrow Mesenchymal Stem Cells with Hypermethylated Salvador/Warts/Hippo (SWH) Pathway Genes.

Human mesenchymal stem cells (MSCs) modified by targeting DNA hypermethylation of genes in the Salvador/Warts/Hippo pathway were induced to differentiate into neuronal cells in vitro. The differentiated cells secreted a significant level of brain-derived neurotrophy factor (BDNF) and the expression of BDNF receptor tyrosine receptor kinase B (TrkB) correlated well with the secretion of BDNF. In the differentiating cells, CREB was active after the binding of growth factors to induce phosphorylation of ERK in the MAPK/ERK pathway. Downstream of phosphorylated CREB led to the functional maturation of differentiated cells and secretion of BDNF, which contributed to the sustained expression of pERK and pCREB. In summary, both PI3K/Akt and MAPK/ERK signaling pathways play important roles in the neuronal differentiation of MSCs. The main function of the PI3K/Akt pathway is to maintain cell survival during neural differentiation; whereas the role of the MAPK/ERK pathway is probably to promote the maturation of differentiated MSCs. Further, cellular levels of protein kinase C epsilon type (PKC-ε) and kinesin heavy chain (KIF5B) increased with time of induction, whereas the level of NME/NM23 nucleoside diphosphate kinase 1 (Nm23-H1) decreased during the time course of differentiation. The correlation between PKC-ε and TrkB suggested that there is cross-talk between PKC-ε and the PI3K/Akt signaling pathway.

Different MRI signs in predicting the treatment efficacy of epidural blood patch in spontaneous intracranial hypotension: a case report.

The current mainstay of treatment in spontaneous intracranial hypotension (SIH) is an epidural blood patch (EBP). Although magnetic resonance imaging (MRI) has a well-established role in the diagnosis of SIH, imaging features regarding the treatment efficacy of EBP have rarely been discussed. We therefore sought to investigate and compare the sequential brain MRI studies before and after EBP by evaluating the changes of the following intracranial structures-the contour of the transverse dural sinus (TDS), tension of the pituitary stalk (or the infundibulum), and thickness of the dura mater. We found that the progressive reversals of these structures are predictive of an effective EBP.

Onyx embolization of a lingual arteriovenous malformation.

Head and neck arteriovenous malformations (AVMs), including lingual AVMs, are unusual and rare. There are many treatment options including sclerotherapy, endovascular or percutaneous embolization, and surgical excision. A combination of preoperative embolization and surgical resection is commonly used for head and neck AVMs. However, in most cases, surgical resection causes significant morbidity. Single-modality approaches such as transarterial embolization are sometimes performed. Herein, we used the copolymer Onyx (ethylene-vinyl alcohol copolymer) as an embolizing agent and obtained satisfactory therapeutic outcomes. To our knowledge, this is the first report of lingual AVMs treated using Onyx embolization.

Reversal in the diameter of the superior ophthalmic vein after an epidural blood patch in a case of spontaneous intracranial hypotension.

Spontaneous intracranial hypotension (SIH) is caused by single or multiple cerebrospinal fluid (CSF) leaks in the spine with the prototypical symptom of postural headache. One of the characteristic MRI features in SIH is intracranial venous engorgement. This report presents a case of SIH with engorgement of the bilateral superior ophthalmic veins (SOVs) which resume their normal diameters by the third day of successful epidural blood patches (EBPs). We define this phenomenon as the "reversal of the SOV" sign.