Signal enhancement ratio of multi-phase contrast-enhanced MRI: an imaging biomarker for survival in pancreatic adenocarcinoma.

OBJECTIVES: To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. METHODS: This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. RESULTS: The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). CONCLUSION: SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. CLINICAL RELEVANCE STATEMENT: The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. KEY POINTS: Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.

LiverRisk score: An accurate, cost-effective tool to predict fibrosis, liver-related, and diabetes-related mortality in the general population.

BACKGROUND: Noninvasive and early assessment of liver fibrosis is of great significance and is challenging. We aimed to evaluate the predictive performance and cost-effectiveness of the LiverRisk score for liver fibrosis and liver-related and diabetes-related mortality in the general population. METHODS: The general population from the NHANES 2017-March 2020, NHANES 1999-2018, and UK Biobank 2006-2010 were included in the cross-sectional cohort (n = 3,770), along with the NHANES follow-up cohort (n = 25,317) and the UK Biobank follow-up cohort (n = 17,259). The cost-effectiveness analysis was performed using TreeAge Pro software. Liver stiffness measurements ≥10 kPa were defined as compensated advanced chronic liver disease (cACLD). FINDINGS: Compared to conventional scores, the LiverRisk score had significantly better accuracy and calibration in predicting liver fibrosis, with an area under the receiver operating characteristic curve (AUC) of 0.76 (0.72-0.79) for cACLD. According to the updated thresholds of LiverRisk score (6 and 10), we reclassified the population into three groups: low, medium, and high risk. The AUCs of LiverRisk score for predicting liver-related and diabetes-related mortality at 5, 10, and 15 years were all above 0.8, with better performance than the Fibrosis-4 score. Furthermore, compared to the low-risk group, the medium-risk and high-risk groups in the two follow-up cohorts had a significantly higher risk of liver-related and diabetes-related mortality. Finally, the cost-effectiveness analysis showed that the incremental cost-effectiveness ratio for LiverRisk score compared to FIB-4 was USD $18,170 per additional quality-adjusted life-year (QALY) gained, below the willingness-to-pay threshold of $50,000/QALY. CONCLUSIONS: The LiverRisk score is an accurate, cost-effective tool to predict liver fibrosis and liver-related and diabetes-related mortality in the general population. FUNDING: The National Natural Science Foundation of China (nos. 82330060, 92059202, and 92359304); the Key Research and Development Program of Jiangsu Province (BE2023767a); the Fundamental Research Fund of Southeast University (3290002303A2); Changjiang Scholars Talent Cultivation Project of Zhongda Hospital of Southeast University (2023YJXYYRCPY03); and the Research Personnel Cultivation Program of Zhongda Hospital Southeast University (CZXM-GSP-RC125).

The image quality and diagnostic performance of CT perfusion-derived CT angiography versus that of conventional CT angiography.

Background: The combination of computed tomography angiography (CTA) and computed tomography perfusion (CTP) evaluation of cerebral perfusion status and vascular conditions can improve the diagnostic accuracy of infarction, ischemia, and vascular occlusion in stroke patients, as well as a comprehensive assessment of cerebral edema, collateral circulation, and blood perfusion in the lesion area. However, the consequent radiation safety and contrast agent nephropathy have aroused increasing concern. The purpose of this study was to assess the image quality and diagnostic accuracy of CTA images derived from CTP data, and to explore the feasibility of replacing conventional CTA. Methods: A total of 31 consecutive patients with suspected acute ischemic stroke were retrospectively analyzed. All patients underwent head and neck CTA and brain CTP examinations. All the CTP images were transmitted to the ShuKun artificial intelligence system, which reconstructs CTA derived from CTP (CTA-DF-CTP). The images were divided into 2 groups, including CTA-DF-CTP (Group A) and conventional CTA (Group B). The CT attenuation values, subjective image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), image quality, CT volume dose index (CTDIvol), dose length product (DLP), and effective radiation dose (ED) were compared between the 2 groups. Moreover, the consistency of vascular stenosis and stenosis degree between the 2 groups were measured and evaluated. Results: There were no significant differences in image noise, SNR, or CNR between Groups A and B (P>0.05). The CT attenuation values of the arteries were higher in Group A than in B [internal carotid artery (ICA) =548±112 vs. 454±85 Hounsfield units (HU), middle cerebral artery (MCA) =453±118 vs. 388±70 HU, and basilar artery (BA) =431±99 vs. 360±83 HU] (P<0.01). The image quality of the 2 groups met the requirement of clinical diagnosis (4.97±0.18 vs. 4.94±0.25). No significant difference was found in subjective evaluation (P>0.05). In Group A compared with Group B, the following reductions were observed: CTDIvol (10.7%; 100.8 vs. 112.9 mGy), DLP (23.0%; 1,613±0 vs. 2,093±88 mGy·cm), and ED (23.0%; 5.00±0.00 vs. 6.49±0.27 mSv). Conclusions: CTA-DF-CTP data provide diagnostic accuracy and image quality similar to those of conventional CTA of head and neck CTA.

Predicting Microvascular Invasion in Hepatocellular Carcinoma Using CT-based Radiomics Model.

Background Prediction of microvascular invasion (MVI) may help determine treatment strategies for hepatocellular carcinoma (HCC). Purpose To develop a radiomics approach for predicting MVI status based on preoperative multiphase CT images and to identify MVI-associated differentially expressed genes. Materials and Methods Patients with pathologically proven HCC from May 2012 to September 2020 were retrospectively included from four medical centers. Radiomics features were extracted from tumors and peritumor regions on preoperative registration or subtraction CT images. In the training set, these features were used to build five radiomics models via logistic regression after feature reduction. The models were tested using internal and external test sets against a pathologic reference standard to calculate area under the receiver operating characteristic curve (AUC). The optimal AUC radiomics model and clinical-radiologic characteristics were combined to build the hybrid model. The log-rank test was used in the outcome cohort (Kunming center) to analyze early recurrence-free survival and overall survival based on high versus low model-derived score. RNA sequencing data from The Cancer Image Archive were used for gene expression analysis. Results A total of 773 patients (median age, 59 years; IQR, 49-64 years; 633 men) were divided into the training set (n = 334), internal test set (n = 142), external test set (n = 141), outcome cohort (n = 121), and RNA sequencing analysis set (n = 35). The AUCs from the radiomics and hybrid models, respectively, were 0.76 and 0.86 for the internal test set and 0.72 and 0.84 for the external test set. Early recurrence-free survival (P < .01) and overall survival (P < .007) can be categorized using the hybrid model. Differentially expressed genes in patients with findings positive for MVI were involved in glucose metabolism. Conclusion The hybrid model showed the best performance in prediction of MVI. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Summers in this issue.

Beyond collaterals: brain frailty additionally improves prediction of clinical outcome in acute ischemic stroke.

OBJECTIVES: We aimed to investigate the additional significance of cerebral small vessel disease (SVD) beyond collaterals in determining the clinical outcome after acute ischemic stroke (AIS). METHODS: We retrospectively reviewed large vessel-involved stroke patients who had baseline CTA within 24 h after symptom onset and had an MRI scan 5 days after admission from October 1, 2018, to October 31, 2021. Collaterals and SVD markers (including atrophy, leukoaraiosis, lacunes, and perivascular space) were graded on CT angiography and MR images, respectively. Modified Rankin Scale (mRS) score at 90 days was recorded, and mRS ≤ 2 was regarded as a good clinical outcome. The associations between SVD markers, collaterals, and mRS were analyzed using logistic and causal mediation regression. RESULTS: We finally enrolled 119 patients (70 ± 13 years). The multivariable regression showed atrophy (evidence: OR 0.05 [95% CI 0.01-0.31], p = 0.002; severe: OR 0.08 [95% CI 0.01-0.44], p = 0.007) and evidence of lacune (OR 0.30 [95% CI 0.08-0.96], p = 0.049) were associated with poor clinical outcomes after correcting covariables. Collaterals mediated 25.74% of the effect of atrophy on poor clinical outcomes (p < 0.001), while lacune impacted clinical outcomes without collaterals' mediation effect (p = 0.54). The classification model with atrophy and lacune had a significantly higher AUC than without markers to distinguish good and poor outcomes (p = 0.036). CONCLUSIONS: Beyond collaterals, brain frailty, specifically assessed by atrophy and lacune, was essential in evaluating stroke patients and could additionally improve the stroke outcome prediction. KEY POINTS: • Beyond collaterals, brain frailty, specifically assessed by brain atrophy and lacune, was still an independent risk factor of unfavorable clinical outcomes after AIS. • Adding brain atrophy and lacune into the model has an extra benefit in predicting stroke outcomes. • The effect of atrophy on stroke outcomes was proportionally mediated through collaterals, but about three-quarters of the effect of brain atrophy and the total effect of lacune directly impacted stroke outcomes without a mediation effect of collaterals.

Consensus report from the 9th International Forum for Liver Magnetic Resonance Imaging: applications of gadoxetic acid-enhanced imaging.

OBJECTIVES: The 9th International Forum for Liver Magnetic Resonance Imaging (MRI) was held in Singapore in September 2019, bringing together radiologists and allied specialists to discuss the latest developments in and formulate consensus statements for liver MRI, including the applications of gadoxetic acid-enhanced imaging. METHODS: As at previous Liver Forums, the meeting was held over 2 days. Presentations by the faculty on days 1 and 2 and breakout group discussions on day 1 were followed by delegate voting on consensus statements presented on day 2. Presentations and discussions centered on two main meeting themes relating to the use of gadoxetic acid-enhanced MRI in primary liver cancer and metastatic liver disease. RESULTS AND CONCLUSIONS: Gadoxetic acid-enhanced MRI offers the ability to monitor response to systemic therapy and to assist in pre-surgical/pre-interventional planning in liver metastases. In hepatocellular carcinoma, gadoxetic acid-enhanced MRI provides precise staging information for accurate treatment decision-making and follow-up post therapy. Gadoxetic acid-enhanced MRI also has potential, currently investigational, indications for the functional assessment of the liver and the biliary system. Additional voting sessions at the Liver Forum debated the role of multidisciplinary care in the management of patients with liver disease, evidence to support the use of abbreviated imaging protocols, and the importance of standardizing nomenclature in international guidelines in order to increase the sharing of scientific data and improve the communication between centers. KEY POINTS: • Gadoxetic acid-enhanced MRI is the preferred imaging method for pre-surgical or pre-interventional planning for liver metastases after systemic therapy. • Gadoxetic acid-enhanced MRI provides accurate staging of HCC before and after treatment with locoregional/biologic therapies. • Abbreviated protocols for gadoxetic acid-enhanced MRI offer potential time and cost savings, but more evidence is necessary. The use of gadoxetic acid-enhanced MRI for the assessment of liver and biliary function is under active investigation.

Disrupted Amygdala Connectivity Is Associated With Elevated Anxiety in Sensorineural Hearing Loss.

Background and Purpose: Hearing loss is associated with rising risks of emotional impairments, suggesting emotional processing networks might be involved in the neural plasticity after hearing loss. This study was conducted to explore how functional connectivity of the amygdala reconfigures in the auditory deprived brain and better understand the neural mechanisms underlying hearing loss-related emotional disturbances. Methods: In total, 38 chronic sensorineural hearing loss (SNHL) patients and 37 healthy controls were recruited for multimodal magnetic resonance imaging scanning and neuropsychological assessments. Voxel-wise functional connectivity (FC) maps of both the left and right amygdala were conducted and compared between the SNHL patients and healthy controls. The uncinate fasciculus (UF), an association fiber pathway, was reconstructed in both groups. The track number, mean track length, fractional anisotropy (FA) and mean diffusion values of the left and right UF were further quantified, respectively. Besides, Pearson's correlation analyses were conducted to investigate the relationship between the functional/structural abnormalities and the negative emotional states in SNHL patients. Results: The SNHL patients presented higher depressive and anxious levels compared to the healthy controls. Decreased FCs were detected between the amygdala and the auditory cortex, striatum, multimodal processing areas, and frontoparietal control areas in the SNHL patients. The amygdala was found to be structurally connected with several FC decreased regions through the UF. Moreover, the hypo-synchronization and the white matter impairment were both found to be associated with patients' elevated anxious status. Conclusions: These functional and structural findings depicted the reconfiguration of the amygdala in SNHL, which provided a new perspective toward the functional circuit mechanisms targeting the emotional impairments related to hearing loss.

Collateral Status at Single-Phase and Multiphase CT Angiography versus CT Perfusion for Outcome Prediction in Anterior Circulation Acute Ischemic Stroke.

Background Collateral status assessed with single- or multiphase CT angiography can be used to predict outcome in patients with acute ischemic stroke (AIS); however, little is known about whether these measures could be comparable with CT perfusion parameters. Purpose To compare the predictive ability of collateral score systems assessed with single- or multiphase CT angiography and CT perfusion parameters in determining clinical outcomes in patients with AIS. Materials and Methods In this retrospective study, data obtained from October 2017 to August 2018 in consecutive patients with AIS caused by isolated anterior circulation large artery occlusion and that were obtained within 24 hours after onset were reviewed. The collateral score was assessed by using established scoring systems described by Menon et al. The correlations between single- and multiphase collateral scores, hypoperfusion, and ischemic core volume and final infarct volume (FIV) determined by follow-up diffusion-weighted imaging or unenhanced CT were studied. Receiver operating characteristic curves and multivariable logistic regression analysis were performed to assess the predictive ability of scoring systems and CT perfusion parameters for a favorable clinical outcome. Results A total of 119 patients (median age, 75 years; interquartile range, 66-82 years; 74 men) were included. Both single- and multiphase Menon scores had a moderate negative correlation with FIV (r = -0.43, P < .001; r = -0.44, P < .001). Receiver operating characteristic curve analysis revealed the multiphase Menon score performed better than the single-phase Menon score (area under the curve [AUC], 0.72 vs 0.64; P = .045) in the prediction of a favorable 90-day modified Rankin scale score. There was no difference between multiphase Menon score and hypoperfusion volume (AUC, 0.72 vs 0.72; P = .97) or ischemic core volume (AUC, 0.72 vs 0.71; P = .94). Multivariable analysis showed multiphase Menon score was an independent predictor of good clinical outcomes (odds ratio = 3.04, P = .001). Conclusion Multiphase Menon score performed better than single-phase Menon score and was comparable with CT perfusion parameters in determining clinical outcomes in patients with acute ischemic stroke. © RSNA, 2020.

Penumbra-based radiomics signature as prognostic biomarkers for thrombolysis of acute ischemic stroke patients: a multicenter cohort study.

BACKGROUND AND PURPOSE: This study aimed at developing a radiomics signature (R score) as prognostic biomarkers based on penumbra quantification and to validate the radiomics nomogram to predict the clinical outcomes for thrombolysis for acute ischemic stroke (AIS) patients. METHODS: In total, 168 patients collected from seven centers were retrospectively included. A score of mismatch was defined as MIS. Based on a short-term clinical label, 456 radiomics features were evaluated with feature selection methods. R score was constructed with the selected features. To compare the predictive capabilities of the clinical factors, MIS, and R score, three nomograms were developed and evaluated, according to the short-term clinical assessment on day 7. Finally, the radiomics nomogram was validated by predicting the 3-month clinical outcomes of AIS patients, in an external cohort. RESULTS: R scores were found to be significantly higher in patients with favorable clinical outcomes in both training and validation datasets. The predictive value of the radiomics nomogram estimating favorable clinical outcomes was modest, with a concordance index (C-index) of 0.695 [95% confidence interval (CI) 0.667-0.723) in an external validation dataset. In addition, the area under curve (AUC) of the radiomics nomogram predicting favorable clinical outcome reached 0.886 (95% CI 0.809-0.963) on day 7 and 0.777 (95% CI 0.666-0.888) at 3 months. CONCLUSIONS: The radiomics signature is an independent biomarker for estimating the clinical outcomes in AIS patients. By improving the individualized prediction of the clinical outcome for AIS patients 3 months after onset, the radiomics nomogram adds more value to the current clinical decision-making process.

Renal Functional MRI and Its Application.

Renal function varies according to the nature and stage of diseases. Renal functional magnetic resonance imaging (fMRI), a technique considered superior to the most common method used to estimate the glomerular filtration rate, allows for noninvasive, accurate measurements of renal structures and functions in both animals and humans. It has become increasingly prevalent in research and clinical applications. In recent years, renal fMRI has developed rapidly with progress in MRI hardware and emerging postprocessing algorithms. Function-related imaging markers can be acquired via renal fMRI, encompassing water molecular diffusion, perfusion, and oxygenation. This review focuses on the progression and challenges of the main renal fMRI methods, including dynamic contrast-enhanced MRI, blood oxygen level-dependent MRI, diffusion-weighted imaging, diffusion tensor imaging, arterial spin labeling, fat fraction imaging, and their recent clinical applications. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:863-881.

Development and validation of a penumbra-based predictive model for thrombolysis outcome in acute ischemic stroke patients.

The use of thrombolysis in acute ischemic stroke is restricted to a small proportion of patients because of the rigid 4·5-h window. With advanced imaging-based patient selection strategy, rescuing penumbra is critical to improving clinical outcomes. In this study, we included 155 acute ischemic stroke patients (84 patients in training dataset, age from 43 to 80, 59 males; 71 patients in validation dataset, age from 36 to 80, 45 males) who underwent MR scan within the first 9-h after onset, from 7 independent centers. Based on the mismatch concept, penumbra and core area were identified and quantitatively analyzed. Moreover, predictive models were developed and validated to provide an approach for identifying patients who may benefit from thrombolytic therapy. Predictive models were constructed, and corresponding areas under the curve (AUC) were calculated to explore their performances in predicting clinical outcomes. Additionally, the models were validated using an independent dataset both on Day-7 and Day-90. Significant correlations were detected between the mismatch ratio and clinical assessments in both the training and validation datasets. Treatment option, baseline systolic blood pressure, National Institutes of Health Stroke Scale score, mismatch ratio, and three regional radiological parameters were selected as biomarkers in the combined model to predict clinical outcomes of acute ischemic stroke patients. With the external validation, this predictive model reached AUCs of 0·863 as short-term validation and 0·778 as long-term validation. This model has the potential to provide quantitative biomarkers that aid patient selection for thrombolysis either within or beyond the current time window.

Elderly population have a decreased aneurysmal subarachnoid hemorrhage incidence rate than Middle aged population: a descriptive analysis of 8,144 cases in mainland China.

PURPOSE: Rupture of an intracranial aneurysm is a life-threatening acute cerebrovascular event. The purpose of this study was to investigate whether aneurysmal subarachnoid haemorrhage (SAH) incidence rate is higher or lower in elderly population than in middle aged population. MATERIALS AND METHODS: Aneurysmal SAH cases were collected retrospectively from the archives of 21 hospitals in Mainland China. All the cases were collected from September 2016 and backward consecutively for a period of time up to 8 years. SAH was initially diagnosed by brain computed tomography (CT). CT angiography (CTA) or digital subtraction angiography (DSA) was followed and SAH was confirmed to be due to cerebral aneurysm rupture. For cases when multiple bleeding occurred, the age of the first SAH was used in this study. The total incidence from all hospitals at each age group were summed together for females and males respectively; then adjusted by the total population number at each age group for females and males which was from the 2010 population census of the People's Republic of China. RESULTS: In total there were 8,144 cases of intracranial aneurysmal SAH, with 4,861 females and 3,283 males. For females the relative aneurysmal SAH incidence rate started to decrease after around 65 years old, while for males the relative aneurysmal SAH incidence rate started to decrease after around 53 years old. CONCLUSION: Our data tentatively suggest elderly patients may be at a reduced risk of rupture compared with patients who are younger while have similar other risk factors.

Bone Marrow Endothelial Progenitor Cell Transplantation After Ischemic Stroke: An Investigation Into Its Possible Mechanism.

AIMS: We tested the hypothesis that endothelial progenitor cell (EPC)-mediated functional recovery after stroke may be associated with the endothelial nitric oxide synthase (eNOS)/brain-derived neurotrophic factor (BDNF) signaling pathway. METHODS: Mice were infused with either EPCs or saline after being subjected to middle cerebral artery occlusion. The EPC-treated mice also received intravenous injections of either Nω-nitro-l-arginine methyl ester (L-NAME, the NOS inhibitor) or saline. RESULTS: The activation of eNOS and the expression of BDNF were significantly increased in ischemic brain of the EPC-treated mice, along with increased angiogenesis and neurogenesis. On diffusion tensor imaging (DTI), significant increases in fractional anisotropy and fiber count were observed in white matter, indicating axonal growth stimulated by EPCs. However, the EPC-treated mice that were received an L-NAME injection failed to exhibit the observed increases in angiogenesis, neurogenesis, and axonal growth. In addition, the neurons cocultured with EPCs in vitro exhibited the increased expression of BDNF and decreased apoptosis after oxygen-glucose deprivation compared with the control group. This EPC-induced protective effect was virtually absent in the L-NAME treatment group. CONCLUSION: The eNOS/BDNF pathway may be involved in the EPC-mediated functional recovery of stroke mice. DTI is feasible for dynamically tracking the orientation of axonal projections after EPC treatment.

Aberrant functional connectivity of default-mode network in type 2 diabetes patients.

OBJECTIVES: Type 2 diabetes mellitus is associated with increased risk for dementia. Patients with impaired cognition often show default-mode network disruption. We aimed to investigate the integrity of a default-mode network in diabetic patients by using independent component analysis, and to explore the relationship between network abnormalities, neurocognitive performance and diabetic variables. METHODS: Forty-two patients with type 2 diabetes and 42 well-matched healthy controls were included and underwent resting-state functional MRI in a 3 Tesla unit. Independent component analysis was adopted to extract the default-mode network, including its anterior and posterior components. Z-maps of both sub-networks were compared between the two groups and correlated with each clinical variable. RESULTS: Patients showed increased connectivity around the medial prefrontal cortex in the anterior sub-network, but decreased connectivity around the posterior cingulate cortex in the posterior sub-network. The decreased connectivity in the posterior part was significantly correlated with the score on Complex Figure Test-delay recall test (r = 0.359, p = 0.020), the time spent on Trail-Making Test-part B (r = -0.346, p = 0.025) and the insulin resistance level (r = -0.404, p = 0.024). CONCLUSION: Dissociation pattern in the default-mode network was found in diabetic patients, which might provide powerful new insights into the neural mechanisms that underlie the diabetes-related cognitive decline. KEY POINTS: • Type 2 diabetes mellitus is associated with impaired cognition • Default- mode network plays a central role in maintaining normal cognition • Network connectivity within the default mode was disrupted in type 2 diabetes patients • Decreased network connectivity was correlated with cognitive performance and insulin resistance level • Disrupted default-mode network might explain the impaired cognition in diabetic population.

LOX-1-Targeted Iron Oxide Nanoparticles Detect Early Diabetic Nephropathy in db/db Mice.

PURPOSE: Activation of the low-density lipoprotein receptor 1 (LOX-1) contributes to pervasive inflammation in early diabetic nephropathy (DN). This study determined the feasibility of anti-LOX-1-ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) for noninvasive detection of inflammatory renal lesions in early DN. PROCEDURES: Anti-mouse LOX-1 antibody was conjugated to polyethyleneglycol-coated USPIOs. In vitro analysis of USPIOs uptake was performed in RAW264.7 macrophages. DN and control mice were imaged by MRI prior to and 24 h after contrast treatment. RESULTS: Anti-LOX-1 USPIOs were selectively taken up by macrophages, and kidney T2* MRI showed a lower signal intensity in the cortex of DN mice after 24 h administration of anti-LOX-1 USPIOs. Positive Perl's staining in DN lesions, indicating the presence of iron oxide, was consistent with immunohistochemistry indicating the presence of LOX-1 and CD68. CONCLUSIONS: This report shows that anti-LOX-1 USPIOs detect LOX-1-enriched inflammatory renal lesions in early DN mice. Our study provides important information for characterizing and monitoring early DN.

Cystamine improves functional recovery via axon remodeling and neuroprotection after stroke in mice.

AIMS: Stroke is a leading cause of disability. However, there is no pharmacological therapy available for promoting recovery. Although treatment of stroke with cystamine has gained increasing interest, the detailed mechanisms underlying this process remain elusive. Thus, our aim is to examine the effect of cystamine on the function recovery after stroke and investigate further cystamine mechanisms. METHODS: Adult male C57BL/6J mice were subjected to photothrombotic model of focal stroke or sham operation. Cystamine or saline was administered intraperitoneally at 24 h after stroke. Functional recovery was analyzed using behavioral tests; axon remodeling was analyzed using magnetic resonance diffusion tensor imaging (DTI) and histological assessment. ANA-12, an antagonist of tropomyosin-related kinase B (TrkB), was administrated to examine the mechanisms underlying the neuroprotection mediated by cystamine. RESULTS: Treatment with cystamine resulted in amelioration of impaired function with concomitant enhancement of axonal remodeling. Cystamine treatment significantly increased brain-derived neurotrophic factor (BDNF) levels and phosphorylation of TrkB in brain after stroke. Cystamine significantly enhanced neuronal progenitor cell proliferation, neuronal survival, and plasticity through BDNF/TrkB pathway. CONCLUSIONS: These data provide evidence to investigate the promising utility of cystamine for therapy of stroke in a variety of ways, acting principally through BDNF/TrkB pathway.

Aberrant spontaneous brain activity in chronic tinnitus patients revealed by resting-state functional MRI.

OBJECTIVE: The neural mechanisms that give rise to the phantom sound of tinnitus are poorly understood. This study aims to investigate whether aberrant spontaneous brain activity exists in chronic tinnitus patients using resting-state functional magnetic resonance imaging (fMRI) technique. MATERIALS AND METHODS: A total of 31 patients with chronic tinnitus patients and 32 healthy age-, sex-, and education-matched healthy controls were prospectively examined. Both groups had normal hearing thresholds. We calculated the amplitude of low-frequency fluctuations (ALFFs) of fMRI signals to measure spontaneous neuronal activity and detect the relationship between fMRI information and clinical data of tinnitus. RESULTS: Compared with healthy controls, we observed significant increased ALFF within several selected regions including the right middle temporal gyrus (MTG), right superior frontal gyrus (SFG), and right angular gyrus; decreased ALFF was detected in the left cuneus, right middle occipital gyrus and bilateral thalamus. Moreover, tinnitus distress correlated positively with increased ALFF in right MTG and right SFG; tinnitus duration correlated positively with higher ALFF values in right SFG. CONCLUSIONS: The present study confirms that chronic tinnitus patients have aberrant ALFF in many brain regions, which is associated with specific clinical tinnitus characteristics. ALFF disturbance in specific brain regions might be used to identify the neuro-pathophysiological mechanisms in chronic tinnitus patients.

Magnetic resonance imaging of post-ischemic blood-brain barrier damage with PEGylated iron oxide nanoparticles.

Blood-brain barrier (BBB) damage during ischemia may induce devastating consequences like cerebral edema and hemorrhagic transformation. This study presents a novel strategy for dynamically imaging of BBB damage with PEGylated supermagnetic iron oxide nanoparticles (SPIONs) as contrast agents. The employment of SPIONs as contrast agents made it possible to dynamically image the BBB permeability alterations and ischemic lesions simultaneously with T2-weighted MRI, and the monitoring could last up to 24 h with a single administration of PEGylated SPIONs in vivo. The ability of the PEGylated SPIONs to highlight BBB damage by MRI was demonstrated by the colocalization of PEGylated SPIONs with Gd-DTPA after intravenous injection of SPION-PEG/Gd-DTPA into a mouse. The immunohistochemical staining also confirmed the leakage of SPION-PEG from cerebral vessels into parenchyma. This study provides a novel and convenient route for imaging BBB alteration in the experimental ischemic stroke model.

Aberrant brain functional connectivity related to insulin resistance in type 2 diabetes: a resting-state fMRI study.

OBJECTIVE: Type 2 diabetes is characterized by insulin resistance, which is involved in the development of Alzheimer disease. This study aims to investigate the relationship between abnormal resting-state brain functional connectivity and insulin resistance in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 30 patients with type 2 diabetes and 31 healthy well-matched volunteers were prospectively examined. Resting-state brain functional connectivity analysis was used to examine the correlation between the posterior cingulate cortex (PCC) and whole-brain regions. The possible relationships between functional connectivity measures and insulin resistance were evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Compared with healthy controls, we observed significantly decreased functional connectivity of the PCC within some selected regions, including the right middle temporal gyrus (MTG), left lingual gyrus, left middle occipital gyrus, and left precentral gyrus; increased functional connectivity of the PCC was detected in the left cerebellum posterior lobe, right superior frontal gyrus, and right middle frontal gyrus. A significant negative correlation was found between the PCC-right MTG connectivity and HOMA-IR in type 2 diabetic patients (P = 0.014; r = -0.446). CONCLUSIONS: Type 2 diabetic patients develop aberrant functional connectivity of the PCC, which is associated with insulin resistance in selected brain regions. Resting-state connectivity disturbance of PCC-MTG may be a central role for evaluating the cognitive dysfunction in type 2 diabetes.

In vivo MRI detection of carotid atherosclerotic lesions and kidney inflammation in ApoE-deficient mice by using LOX-1 targeted iron nanoparticles.

Lectin-like Oxidized Low-Density Lipoprotein Receptor 1 (LOX-1) plays a key role in atherosclerotic plaque initiation, formation and rupture, as well as in hyperlipidemia-induced glomerular disease. Here we report a sensitive, specific and biocompatible LOX-1-targeted-USPIO for the noninvasive MR imaging of LOX-1 within carotid atherosclerotic lesions and glomerular disease in apoE-deficient mice. In vitro analysis showed the highest uptake of targeted USPIOs in only activated RAW264.7 macrophages, and in vivo MRI studies showed signal loss in carotid atherosclerotic lesions after administration of targeted USPIOs at 8h and 24h. These areas of signal loss were correlated with the presence of nanoparticles in the atherosclerotic lesions, and immunohistochemistry and Perl's staining confirmed the co-localization of the LOX-1/macrophages/MMP-9 and targeted nanoparticles. Finally, additional studies suggest that this targeted probe may have potential to noninvasively image early glomerular disease. This finding may provide important methods for characterizing vulnerable atherosclerotic plaques and hyperlipidemia-induced glomerular diseases. FROM THE CLINICAL EDITOR: A functionalized USPIO-based negative contrast material was used in this study, demonstrating feasibility of sensitive MRI-based detection of atherosclerotic plaque formation in the carotid arteries and in the renal cortex, paving the way to potential future clinical applications.