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Cerebral small vessel disease (SVD) can disrupt the global brain network and lead to cognitive impairment. Conversely, cognitive reserve (CR) can improve one's cognitive ability to handle damaging effects like SVD, partly by optimizing the brain network's organization. Understanding how SVD and CR collectively influence brain networks could be instrumental in preventing cognitive impairment. Recently, brain redundancy has emerged as a critical network protective metric, providing a nuanced perspective of changes in network organization. However, it remains unclear how SVD and CR affect global redundancy and subsequently cognitive function. Here, we included 121 community-dwelling participants who underwent neuropsychological assessments and a multimodal MRI examination. We visually examined common SVD imaging markers and assessed lifespan CR using the Cognitive Reserve Index Questionnaire. We quantified the global redundancy index (RI) based on the dynamic functional connectome. We then conducted multiple linear regressions to explore the specific cognitive domains related to RI and the associations of RI with SVD and CR. We also conducted mediation analyses to explore whether RI mediated the relationships between SVD, CR, and cognition. We found negative correlations of RI with the presence of microbleeds (MBs) and the SVD total score, and a positive correlation of RI with leisure activity-related CR (CRI-leisure). RI was positively correlated with memory and fully mediated the relationships between the MBs, CRI-leisure, and memory. Our study highlights the potential benefits of promoting leisure activities and keeping brain redundancy for memory preservation in older adults, especially those with SVD.
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Doenças de Pequenos Vasos Cerebrais , Disfunção Cognitiva , Reserva Cognitiva , Humanos , Idoso , Pessoa de Meia-Idade , Cognição , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/psicologia , Imageamento por Ressonância Magnética , Doenças de Pequenos Vasos Cerebrais/complicaçõesRESUMO
BACKGROUND: Glymphatic dysfunction is a crucial pathway for dementia. Alzheimer's disease (AD) pathologies co-existing with cerebral small vessel disease (CSVD) is the most common pathogenesis for dementia. We hypothesize that AD pathologies and CSVD could be associated with glymphatic dysfunction, contributing to cognitive impairment. METHOD: Participants completed with amyloid PET, diffusion tensor imaging (DTI), and T2 fluid-attenuated inversion-recovery (FLAIR) sequences were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI). White matter hyperintensities (WMH), the most common CSVD marker, was evaluated from T2FLAIR images and represented the burden of CSVD. Amyloid PET was used to assess Aß aggregation in the brain. We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, the burden of enlarged perivascular spaces (PVS), and choroid plexus volume to reflect glymphatic function. The relationships between WMH burden/Aß aggregation and these glymphatic markers as well as the correlations between glymphatic markers and cognitive function were investigated. Furthermore, we conducted mediation analyses to explore the potential mediating effects of glymphatic markers in the relationship between WMH burden/Aß aggregation and cognition. RESULTS: One hundred and thirty-three participants along the AD continuum were included, consisting of 40 CN - , 48 CN + , 26 MCI + , and 19 AD + participants. Our findings revealed that there were negative associations between whole-brain Aß aggregation (r = - 0.249, p = 0.022) and WMH burden (r = - 0.458, p < 0.001) with DTI-ALPS. Additionally, Aß aggregation (r = 0.223, p = 0.041) and WMH burden (r = 0.294, p = 0.006) were both positively associated with choroid plexus volume. However, we did not observe significant correlations with PVS enlargement severity. DTI-ALPS was positively associated with memory (r = 0.470, FDR-p < 0.001), executive function (r = 0.358, FDR-p = 0.001), visual-spatial (r = 0.223, FDR-p < 0.040), and language (r = 0.419, FDR-p < 0.001). Conversely, choroid plexus volume showed negative correlations with memory (r = - 0.315, FDR-p = 0.007), executive function (r = - 0.321, FDR-p = 0.007), visual-spatial (r = - 0.233, FDR-p = 0.031), and language (r = - 0.261, FDR-p = 0.021). There were no significant correlations between PVS enlargement severity and cognitive performance. In the mediation analysis, we found that DTI-ALPS acted as a mediator in the relationship between WMH burden/Aß accumulation and memory and language performances. CONCLUSION: Our study provided evidence that both AD pathology (Aß) and CSVD were associated with glymphatic dysfunction, which is further related to cognitive impairment. These results may provide a theoretical basis for new targets for treating AD.
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Doença de Alzheimer , Doenças de Pequenos Vasos Cerebrais , Disfunção Cognitiva , Humanos , Doença de Alzheimer/patologia , Imagem de Tensor de Difusão/métodos , Cognição , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Amiloide/metabolismo , Imageamento por Ressonância Magnética , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Proteínas Amiloidogênicas/metabolismoRESUMO
OBJECTIVE: To investigate the effect of cholinergic pathways damage caused by white matter hyperintensities (WMHs) on cognitive function in moyamoya disease (MMD). METHODS: We included 62 patients with MMD from a prospectively enrolled cohort. We evaluated the burden of cholinergic pathways damage caused by WMHs using the Cholinergic Pathways Hyperintensities Scale (CHIPS). Cognitive function was evaluated with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Cognitive impairment was determined according to the cut-off of MMSE and education. Multivariate linear and logistic regression models were used to analyze whether CHIPS was independently associated with cognition. Receiver operating characteristic curve analysis was performed to identify the ability of CHIPS in discriminating cognitive impairment and normal cognition. RESULTS: CHIPS was associated with both MMSE and MoCA (ß = - 0.601 and ß = - 0.672, both p < 0.001). After correcting age, sex, education, volumes of limbic areas, and other factors, CHIPS remained to be independently associated with both MMSE and MoCA (ß = - 0.388 and ß = - 0.334, both p < 0.001). In the logistic regression, only CHIPS was associated with cognitive impairment (odds ratio = 1.431, 95% confidence interval = 1.103 to 1.856, p = 0.007). The optimal cut-off of CHIPS score was 10, yielding a sensitivity of 87.5% and a specificity of 78.3% in identifying MMD patients with cognitive impairment. CONCLUSIONS: The damage of cholinergic pathways caused by WMHs plays an independent effect on cognition and CHIPS could be a useful method in identifying MMD patients likely to be cognitive impairment. CLINICAL RELEVANCE STATEMENT: This study shows that Cholinergic Pathways Hyperintensities Scale (CHIPS) could be a simple and reliable method in identifying cognitive impairment for patients with moyamoya disease. CHIPS could be helpful in clinical practice, such as guiding treatment decisions and predicting outcome. KEY POINTS: ⢠Cholinergic Pathways Hyperintensities Scale was significantly associated with cognitive screening tests in patients with moyamoya disease. ⢠Cholinergic Pathways Hyperintensities Scale plays an independent effect on cognitive impairment in patients with moyamoya disease. ⢠Cholinergic Pathways Hyperintensities Scale shows higher accuracy than education, volumes of limbic areas, and sex in identifying cognitive impairment in moyamoya disease.
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Senile osteoporosis (SOP) is a prevalent manifestation of age-related bone disorders, resulting from the dysregulation between osteoblast (OB)-mediated bone formation and osteoclast (OC)-mediated bone resorption, coupled with the escalating burden of cellular senescence. Traditional Chinese medicine (TCM) herbs, renowned for their remarkable attributes encompassing excellent tolerability, low toxicity, heightened efficacy, and minimal adverse reactions, have gained considerable traction in OP treatment. Emerging evidence substantiates the therapeutic benefits of various TCM formulations and their active constituents, including Zuogui wan, Fructus Ligustri Lucidi, and Resveratrol, in targeting cellular senescence to address SOP. However, a comprehensive review focusing on the therapeutic efficacy of TCM against SOP, with a particular emphasis on senescence, is currently lacking. In this review, we illuminate the pivotal involvement of cellular senescence in SOP and present a comprehensive exploration of TCM formulations and their active ingredients derived from TCM, delineating their potential in SOP treatment through their anti-senescence properties. Notably, we highlight their profound effects on distinct aging models that simulate SOP and various senescence characteristics. Finally, we provide a forward-looking discussion on utilizing TCM as a strategy for targeting cellular senescence and advancing SOP treatment. Our objective is to contribute to the unveiling of safer and more efficacious therapeutic agents for managing SOP.
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Objective: To develop and validate radiomics models on non-enhanced CT for discrimination of arteriovenous malformation (AVM) related hematomas from hypertensive intracerebral hematomas. Materials and methods: A total of 571 patients with acute intraparenchymal hematomas and baseline non-enhanced CT scans were retrospectively analyzed, including 297 cases of AVM related hematomas and 274 cases of hypertensive intracerebral hematomas. The patients were divided into training and validation cohorts in a 7:3 ratio with a random seed. A total of 1,688 radiomics features of hematomas were extracted from non-enhanced CT. Then, the least absolute shrinkage and selection operator (LASSO) regression was applied to select features and construct the radiomics models. In this study, a radiomics-based model was constructed that based on the radiomics features only. Furthermore, a combined model was constructed using radiomics features, clinical characteristics and radiological signs by radiologists' evaluation. In addition, we compared predictive performance of the two models for discrimination of AVM related hematomas from hypertensive intracerebral hematomas. Results: A total of 67 radiomics features were selected to establish radiomics signature via LASSO regression. The radiomics-based model was constructed with 2 classifiers, support vector machine (SVM) and logistic regression (LR). AUCs of the radiomics-based model in the training set were 0.894 and 0.904, in validation set were 0.774 and 0.782 in SVM classifier and LR classifier, respectively. AUCs of the combined model (combined with radiomics, age and calcification) in the training set were 0.976 and 0.981, in validation set were 0.896 and 0.907 in SVM classifier and LR classifier, respectively. The combined model showed greater AUCs than radiomics-based model in both training set and validation set. Conclusion: The combined model using radiomics, age and calcification showed a satisfactory predictive performance for discrimination of AVM related hematomas from hypertensive intracerebral hematomas and hold great potential for personalized clinical decision.
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The Ronchi test is widely used for wavefront measurements in advanced lithography tools, and a physical optics explanation of the Ronchi test based on scalar diffraction theory can be found in numerous publications. However, for high-numerical aperture (high-NA) lithography projection lenses, the vector nature of light should be considered when performing wavefront measurements, especially the effect of polarization aberrations on the wavefront test results. In this paper, a vector model for describing shearing interferometry for high-NA lithography projection lenses is established. In addition to considering the vector nature of light, the vector model also calculates the Ronchigram on the screen of a detector at any distance from a diffraction grating, as opposed to the distance restriction for the Fraunhofer diffraction approximation used by the existing methods. Using the developed mathematical model of the Ronchi test, the Ronchigrams of high-NA lithography projection lenses under non-polarized illumination are simulated, and the effect of the distance between the diffraction grating and the detection screen on the wavefront measurement accuracy are discussed.
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OBJECTIVES: Venous pathology could contribute to the development of parenchymal lesions in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aim to identify presumed periventricular venous infarction (PPVI) in CADASIL and analyze the associations between PPVI, white matter edema, and microstructural integrity within white matter hyperintensities (WMHs) regions. METHODS: We included forty-nine patients with CADASIL from a prospectively enrolled cohort. PPVI was identified according to previously established MRI criteria. White matter edema was evaluated using the free water (FW) index derived from diffusion tensor imaging (DTI), and microstructural integrity was evaluated using FW-corrected DTI parameters. We compared the mean FW values and regional volumes with different levels of FW (ranging from 0.3 to 0.8) in WMHs regions between the PPVI and non-PPVI groups. We used intracranial volume to normalize each volume. We also analyzed the association between FW and microstructural integrity in fiber tracts connected with PPVI. RESULTS: We found 16 PPVIs in 10 of 49 CADASIL patients (20.4%). The PPVI group had larger WMHs volume (0.068 versus 0.046, p = 0.036) and higher FW in WMHs (0.55 versus 0.52, p = 0.032) than the non-PPVI group. Larger areas with high FW content were also found in the PPVI group (threshold: 0.7, 0.47 versus 0.37, p = 0.015; threshold: 0.8, 0.33 versus 0.25, p = 0.003). Furthermore, higher FW correlated with decreased microstructural integrity (p = 0.009) in fiber tracts connected with PPVI. CONCLUSIONS: PPVI was associated with increased FW content and white matter degeneration in CADASIL patients. CLINICAL RELEVANCE STATEMENT: PPVI is an important factor related with WMHs, and therefore, preventing the occurrence of PPVI would be beneficial for patients with CADASIL. KEY POINTS: â¢Presumed periventricular venous infarction is important and occurs in about 20% of patients with CADASIL. â¢Presumed periventricular venous infarction was associated with increased free water content in the regions of white matter hyperintensities. â¢Free water correlated with microstructural degenerations in white matter tracts connected with the presumed periventricular venous infarction.
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CADASIL , Substância Branca , Humanos , CADASIL/complicações , CADASIL/diagnóstico por imagem , CADASIL/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Imagem de Tensor de Difusão , Imageamento por Ressonância Magnética/métodos , Edema/patologia , Água , Encéfalo/patologiaRESUMO
BACKGROUND: Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood. METHODS: The yki -gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1 , Acly , and Fasn et al . RESULTS: In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila . Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients. CONCLUSION: Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.
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Neoplasias Gastrointestinais , Insulinas , Somatomedinas , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Meios de Cultivo Condicionados/farmacologia , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/patologia , Somatomedinas/metabolismo , Insulinas/metabolismo , LipídeosRESUMO
BACKGROUND: Widespread white matter (WM) injury is a hallmark feature of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, controversies about the mechanism of WM tract injury exist persistently. Excessive iron accumulation, frequently reported in CADASIL patients, might cause WM tract injury. PURPOSE: To test the association between iron accumulation and WM tract injury in CADASIL patients. STUDY TYPE: Retrospective. POPULATION: A total of 35 CADASIL patients (age = 50.4 ± 6.4, 62.9% female) and 48 healthy controls (age = 55.7 ± 8.0, 68.8% female). FIELD STRENGTH/SEQUENCE: Diffusion-weighted spin-echo echo-planar sequence; enhanced susceptibility-weighted angiography (ESWAN) gradient echo sequence on a 3 T scanner. ASSESSMENT: The phase images acquired by ESWAN were used to calculate quantitative susceptibility mapping (QSM). Iron accumulation was evaluated in deep gray matters using QSM. WM tract injury was quantified by diffusion metrics based on WM major tracts skeleton. We compared iron deposition between groups and analyzed the correlation between WM tract injury and iron deposition in regions showing significant differences from healthy controls. Exploratory analysis was carried out to investigate whether WM tract injury mediated the relationship between iron deposition and cognitive impairment evaluated by Mini-Mental State Examination (MMSE). STATISTICAL TESTS: General linear model (GLM), partial correlation, stepwise linear regression and mediation analysis were used. The threshold of statistical significance was set as p < 0.05. RESULTS: Compared with healthy controls, CADASIL patients had significantly increased iron deposition in the caudate and putamen. Aberrant iron deposition in these two regions was significantly associated with decreased WM fractional anisotropy (FA) (caudate, r = -0.373ï¼ putamen, r = - 0.421), and increased radial diffusivity (RD) (caudate, r = 0.372; putamen, r = 0.386). Furthermore, WM tract injury mediated the relationship between iron deposition and cognitive impairment. DATA CONCLUSION: Patients with CADASIL show increased iron deposition in the caudate and putamen that is correlated to WM tract injury, which may in turn mediate the association with cognitive impairment. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.
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CADASIL , Substância Branca , Humanos , Feminino , Masculino , CADASIL/complicações , CADASIL/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Estudos Retrospectivos , Imageamento por Ressonância Magnética , Ferro , Encéfalo/diagnóstico por imagemRESUMO
Thermal aberrations caused by absorption of laser beams degrade the image quality of exposure tools during the working process. Many compensators, such as lens movement or lens deformation, are used to compensate for low-order thermal aberrations of optical systems. In this paper, an apparatus with higher-order aberration correction capability is presented. The main principle of the apparatus is to actively heat and cool the lens near the pupil to generate a desired temperature profile to compensate for thermal aberrations. We first introduce the basic concept of the apparatus. Then we establish an analytical model to describe the lens temperature of the apparatus based on its working principle and demonstrate its compensation capability. Finally, an algorithm for dynamic thermal aberrations compensation is proposed to overcome the time lag effects of a thermally controlled lens.
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BACKGROUND: Small vessel disease (SVD) is highly prevalent in the elderly and associated with an increased risk of dementia and stroke. SVD may have disturbed cerebrospinal fluid (CSF) flow, which can compromise waste clearance and accelerate disease progression. METHODS: We retrospectively included 146 SVD patients from a prospectively collected dataset, with one- or two-year follow-up data in 61 patients. The coupling strength between the global blood-oxygen-level-dependent (gBOLD) signal and CSF inflow was used to reflect CSF dynamics. We performed regression analyses to investigate the association between the gBOLD-CSF coupling index and the severity of SVD and vascular risk factors. Longitudinal analysis was carried out to investigate causal relationships. RESULTS: Patients with severe SVD had significantly decreased gBOLD-CSF coupling (ß = -0.180, p = 0.032). Dilation of perivascular spaces in the basal ganglia area (ß = -0.172, p = 0.033) and diabetes (ß = -0.204, p = 0.014) were associated with reduced gBOLD-CSF coupling. In longitudinal analyses, diabetes was associated with faster decline in gBOLD-CSF coupling (ß = 0.20, p = 0.039), while perivascular space (PVS) dilation in the centrum semiovale showed a opposite relationship (ß = -0.20, p = 0.041). The gBOLD-CSF coupling could not predict SVD progression. CONCLUSION: Altered CSF flow is associated with the severity of SVD.
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Doenças de Pequenos Vasos Cerebrais , Sistema Glinfático , Humanos , Idoso , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/complicações , Estudos Retrospectivos , Imageamento por Ressonância Magnética , OxigênioRESUMO
BACKGROUND: Chemokine CXC motif receptor 7 (CXCR7) is an atypical G protein-coupled receptor (GPCR) that signals in a biased fashion. CXCL12/CXCR7 biased signal has been reported to play crucial roles in multiple stages of colorectal cancer (CRC). However, the mechanism of CXCL12/CXCR7 biased signal in promoting CRC progression and metastasis remains obscure. RESULTS: We demonstrate that CXCR7 activation promotes EMT and upregulates the expression of Vimentin and doublecortin-like kinase 1 (DCLK1) in CRC cells with concurrent repression of miR-124-3p and miR-188-5p through YAP1 nuclear translocation. Cell transfection and luciferase assay prove that these miRNAs regulate EMT by targeting Vimentin and DCLK1. More importantly, CXCL12/CXCR7/ß-arrestin1-mediated biased signal induces YAP1 nuclear translocation, which functions as a transcriptional repressor by interacting with Yin Yang 1 (YY1) and recruiting YY1 to the promoters of miR-124-3p and miR-188-5p. Pharmacological inhibitor of YAP1 suppresses EMT and tumor metastasis upon CXCR7 activation in vivo in tumor xenografts of nude mice and inflammatory colonic adenocarcinoma models. Clinically, the expression of CXCR7 is positively correlated with nuclear YAP1 levels and EMT markers. CONCLUSIONS: Our studies reveal a novel mechanism and clinical significance of CXCL12/CXCR7 biased signal in promoting EMT and invasion in CRC progression. These findings highlight the potential of targeting YAP1 nuclear translocation in hampering CXCL12/CXCR7 biased signal-induced metastasis of colorectal cancer.
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White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD), which contributes to about 50% of dementias worldwide. Microstructural alterations in deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In 141 CSVD patients, processing speed was assessed using Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (volume on T2-FLAIR) and diffusion MRI measures. SWM imaging measures had a large contribution to processing speed, despite a relatively low SWM WMH burden. Across all imaging measures, SWM free water (FW) had the strongest association with processing speed, followed by SWM mean diffusivity (MD). SWM FW was the only marker to significantly increase between two subgroups with the lowest WMH burdens. When comparing two subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Mediation analysis revealed that SWM FW fully mediated the association between WMH volume and processing speed, while no mediation effect of MD or DWM FW was observed. Overall, results suggest that the SWM has an important contribution to processing speed, while SWM FW is a sensitive imaging marker associated with cognition in CSVD. This study extends the current understanding of CSVD-related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes.
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Doenças de Pequenos Vasos Cerebrais , Leucoaraiose , Substância Branca , Humanos , Substância Branca/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Cognição , Imageamento por Ressonância MagnéticaRESUMO
Aim: White matter hyperintensities (WMH) and lacunes were important features of cerebral small vessel disease (CSVD), which contributes to 25% of ischemic strokes and 45% of dementias. Currently, the underlying mechanisms of WMH and lacunes are not clear, and the role of hemodynamic changes is not fully investigated. In this study, we aimed to measure the cerebral blood flow (CBF) and arterial transit in CSVD patients and to investigate their association with WMH and lacunes. Methods: We retrospectively analyzed the prospectively collected database of CSVD patients. Ninety-two CSVD patients with complete imaging data were included. We used arterial spin labeling (ASL) with post-labeling delay time (PLD) of 1,525 ms and 2,025 ms to measure CBF respectively, and the difference between CBFPLD1.5 and CBFPLD2.0 was recorded as δCBF. We performed regression analysis to understand the contribution of CBF, δCBF to CSVD imaging markers. Results: We found that CBF derived from both PLDs was associated with WMH volume and the presence of lacune. CBFPLD1.5 was significantly lower than CBFPLD2.0 in CSVD patients, and δCBF was correlated with WMH volume but not the presence of lacune. Furthermore, CBFPLD2.0 and δCBF were both associated with WMH in multiple regression analyses, suggesting an independent effect of delayed arterial transit. On an exploratory basis, we also investigated the relationship between venous disruption on δCBF, and we found that δCBF correlated with deep medullary veins score. Conclusion: Both CBF and arterial transit were associated with WMH. ASL with multiple PLDs could provide additional hemodynamic information to CSVD-related studies.
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C-X-C motif chemokine receptor 7 (CXCR7) is a newly discovered atypical chemokine receptor that binds to C-X-C motif chemokine ligand 12 (CXCL12) with higher affinity than CXCR4 and is associated with the metastasis of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) have been known to promote tumor progression. However, whether CAFs are involved in CXCR7-mediated metastasis of CRC remains elusive. We found a significant positive correlation between CXCR7 expression and CAF activation markers in colonic tissues from clinical specimens and in villin-CXCR7 transgenic mice. RNA sequencing revealed a coordinated increase in the levels of miR-146a-5p and miR-155-5p in CXCR7-overexpressing CRC cells and their exosomes. Importantly, these CRC cell-derived miR-146a-5p and miR-155-5p could be uptaken by CAFs via exosomes and promote the activation of CAFs through JAK2-STAT3/NF-κB signaling by targeting suppressor of cytokine signaling 1 (SOCS1) and zinc finger and BTB domain containing 2 (ZBTB2). Reciprocally, activated CAFs further potently enhanced the invasive capacity of CRC cells. Mechanistically, CAFs transfected with miR-146a-5p and miR-155-5p exhibited a robust increase in the levels of inflammatory cytokines interleukin-6, tumor necrosis factor-α, transforming growth factor-ß, and CXCL12, which trigger the epithelial-mesenchymal transition and pro-metastatic switch of CRC cells. More importantly, the activation of CAFs by miR-146a-5p and miR-155-5p facilitated tumor formation and lung metastasis of CRC in vivo using tumor xenograft models. Our work provides novel insights into CXCR7-mediated CRC metastasis from tumor-stroma interaction and serum exosomal miR-146a-5p and miR-155-5p could serve as potential biomarkers and therapeutic targets for inhibiting CRC metastasis.
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Fibroblastos Associados a Câncer , Neoplasias Colorretais , Exossomos , MicroRNAs , Animais , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Neoplasias Colorretais/patologia , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Repressoras/metabolismoRESUMO
BACKGROUND: Cerebral microinfarcts (CMIs) might cause measurable disruption to brain connections and are associated with cognitive decline, but the association between CMIs and motor impairment is still unclear. OBJECTIVE: To assess the CMIs effect on motor function in vivo and explore the potential neuropathological mechanism based on graph-based network method. METHODS: We identified 133 non-demented middle-aged and elderly participants who underwent MRI scanning, cognitive, and motor assessment. The short physical performance battery (SPPB) assessed motor function, including balance, walking speed, and chair stand. We grouped participants into 34 incident CMIs carriers and 99 non-CMIs carriers as controls, depending on diffusion-weighted imaging. Then we assessed the independent CMIs effects on motor function and explored neural mechanisms of CMIs on motor impairment via mapping of degree centrality (DC) and eigenvector centrality (EC). RESULTS: CMIs carriers had worse motor function than non-carriers. Linear regression analyses showed that CMIs independently contributed to motor function. CMIs carriers had decreased EC in the precuneus, while increased DC and EC in the middle temporal gyrus and increased DC in the inferior frontal gyrus compared to controls (pâ<â0.05, corrected). Correlation analyses showed that EC of precuneus was related to SPPB (râ=â0.25) and balance (râ=â0.27); however, DC (râ=â-0.25) and EC (râ=â-0.25) of middle temporal gyrus was related with SPPB in all participants (pâ<â0.05, corrected). CONCLUSION: CMIs represent an independent risk factor for motor dysfunction. The relationship between CMIs and motor function may be attributed to suppression of functional hub region and compensatory activation of motor-related regions.
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Infarto Encefálico/patologia , Doenças de Pequenos Vasos Cerebrais/patologia , Imageamento por Ressonância Magnética , Desempenho Psicomotor/fisiologia , Idoso , Encéfalo/patologia , Córtex Cerebral/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricosRESUMO
To investigate the association between white matter free water (FW) and common imaging markers of cerebral small vessel diseases (CSVD) in two groups of subjects with different clinical status. One hundred and forty-four community subjects (mean age 60.5) and 84 CSVD subjects (mean age 61.2) were retrospectively included in the present study. All subjects received multi-modal magnetic resonance imaging and clinical assessments. The association between white matter FW and common CSVD imaging markers, including white matter hyperintensities (WMH), dilated perivascular space (PVS), lacunes, and microbleeds, were assessed using simple and multiple regression analysis. The association between FW and cognitive scores were also investigated. White matter FW was positively associated with WMH volume (ß = 0.270, p = 0.001), PVS volume (ß = 0.290, p < 0.001), number of microbleeds (ß = 0.148, p = 0.043), and age (ß = 0.170, p = 0.036) in the community cohort. In the CSVD cohort, FW was positively associated with WMH volume (ß = 0.648, p < 0.001), PVS score (ß = 0.224, p < 0.001), number of lacunes (ß = 0.140, p = 0.046), and sex (ß = 0.125, p = 0.036). The associations between FW and cognitive scores were stronger than conventional CSVD markers in both datasets. White matter FW is a potential composite marker that can sensitively detect cerebral small vessel degeneration and also reflect cognitive impairments.
Assuntos
Doenças de Pequenos Vasos Cerebrais , Doenças Neurodegenerativas , Substância Branca , Biomarcadores , Hemorragia Cerebral/patologia , Doenças de Pequenos Vasos Cerebrais/complicações , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Estudos Retrospectivos , Água , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
Assessing glymphatic function using in-vivo imaging method is of great value for understanding its contribution to major brain diseases. In the present study, we aim to validate the association between a variety of risk factors and a potential index of glymphatic function-Diffusion Tensor Image Analysis Along the Perivascular Space (ALPS index). We enrolled 142 subjects from communities and performed multi-modality magnetic resonance imaging scans. The ALPS index was calculated from diffusion tensor imaging data, and its associations with demographic factors, vascular factors were investigated using regression analyses. We found that the ALPS index was negatively associated with age (ß = -0.284, p < 0.001). Compared to males, females had significantly higher ALPS index (ß = -0.243, p = 0.001). Hypertensive subjects had significantly lower ALPS index compared to non-hypertensive subjects (ß = -0.189, p = 0.013). Furthermore, venous disruption could decrease ALPS index (ß = -0.215, p = 0.003). In general, our results are in consistent with previous conceptions and results from animal studies about the pathophysiology of glymphatic dysfunction. Future studies utilizing this method should consider introducing the above-mentioned factors as important covariates.
RESUMO
Lenticulostriate arteries (LSAs) supply blood to important subcortical areas and are, therefore, essential for maintaining the optimal functioning of the brain's most metabolically active nuclei. Past studies have demonstrated the potential for quantifying the morphology of LSAs as biomarkers of vascular fragility or underlying arteriopathies. Thus, the current study aims to evaluate the morphological features of LSAs, their potential value in cerebrovascular risk stratification, and their concordance with other vascular risk factors in community-dwelling elderly people. A total of 125 community-dwelling elderly subjects who underwent a brain MRI scan were selected from our prospectively collected imaging database. The morphological measures of LSAs were calculated on the vascular skeletons obtained by manual tracing, and the number of LSAs was counted. Additionally, imaging biomarkers of small vessel disease were evaluated, and the diameters of major cerebral arteries were measured. The effects of vascular risk factors on LSA morphometry, as well as the relationship between LSA measures and other imaging biomarkers, were investigated. We found that smokers had shorter (p = 0.04) and straighter LSAs (p < 0.01) compared to nonsmokers, and the presence of hypertension is associated with less tortuous LSAs (p = 0.03) in community-dwelling elderly. Moreover, the middle cerebral artery diameter was positively correlated with LSA count (r = 0.278, p = 0.025) and vessel tortuosity (r = 0.257, p = 0.04). The posterior cerebral artery diameter was positively correlated with vessel tortuosity and vessel length. Considering the scarcity of noninvasive methods for measuring small artery abnormalities in the brain, the LSA morphological measures may provide valuable information to better understand cerebral small vessel degeneration during aging.