Explore the vast range of titles available.

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response—particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial-cell activation, white-matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioral and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

The prevalence of cerebrovascular disease increases with age, placing the elderly at a greater lifetime risk for dementia. Vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits from mild cognitive impairment to dementia. VCI and its most severe form, vascular dementia (VaD), is becoming a major public health concern worldwide. As growing efforts are being taken to understand VCI and VaD in animal models and humans, the pathogenesis of the disease is being actively explored. It is postulated that chronic cerebral hypoperfusion (CCH) is a major cause of VCI. CCH activates a molecular and cellular injury cascade that leads to breakdown of the blood brain barrier (BBB) and neurodegeneration. The BBB tightly regulates the movement of substances between the blood and the brain, thereby regulating the microenvironment within the brain parenchyma. Here we illustrate how BBB damage is causal in the pathogenesis of VCI through the increased activation of pathways related to excitotoxicity, oxidative stress, inflammation and matrix metalloproteinases that lead to downstream perivascular damage, leukocyte infiltration and white matter changes in the brain. Thus, CCH-induced BBB damage may initiate and contribute to a vicious cycle, resulting in progressive neuropathological changes of VCI in the brain. This review outlines the molecular and cellular mechanisms that govern BBB breakdown during CCH and highlights the clinical evidence in identifying at-risk VCI patients.

BackgroundCerebral small vessel disease (SVD) has been suggested to be more common in Asians compared with Caucasians. However, data from population-based studies in Asia are lacking. We report on the prevalence, risk factors and consequences of SVD from contemporary studies in three Asian countries using 3-Tesla MRI for the evaluation of SVD.MethodsClinical, cognitive and 3-Tesla brain MRI assessments were performed among participants of three studies from Singapore, Hong Kong and Korea. SVD markers include white matter hyperintensities (WMHs) using the modified Fazekas scale, lacunes and microbleeds. Cognition was assessed using the Mini Mental Status Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Adjustments were made for age, sex and cardiovascular risk factors.ResultsA total of 1797 subjects were available for analysis (mean age: 70.1±6.3 years and 57% women). The prevalence of confluent WMH was 36.6%, lacunes, 24.6% and microbleeds, 26.9%. Presence of all three SVD markers showed a steeper increase with increasing age rising from 1.9% in the lowest to 46.2% in the highest 5-year age strata. The major risk factors for the increased severity of SVD markers were advancing age and hypertension. Moreover, increasing severity of SVD markers was independently associated with worse performance on MMSE and MoCA.ConclusionElderly Asians have a high burden of SVD which was associated with cognitive dysfunction. This suggests that SVD markers should be a potential target for treatment in clinical trials so as to delay progression of cerebrovascular disease and potentially cognitive decline.

There is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1β production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.

Multi-protein complexes, termed “inflammasomes,” are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1β and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-κB and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively. Moreover, these findings provided supporting evidence that treatment with intravenous immunoglobulin (IVIg) preparation can reduce activation of the NF-κB and MAPK signaling pathways resulting in decreased expression and activation of NLRP1 and NLRP3 inflammasomes, as well as increasing expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, in primary cortical neurons and/or cerebral tissue under in vitro and in vivo ischemic conditions. In summary, these results provide compelling evidence that both the NF-κB and MAPK signaling pathways play a pivotal role in regulating the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons and brain tissue under ischemic conditions. In addition, treatment with IVIg preparation decreased the activation of the NF-κB and MAPK signaling pathways, and thus attenuated the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons under ischemic conditions. Hence, these findings suggest that therapeutic interventions that target inflammasome activation in neurons may provide new opportunities in the future treatment of ischemic stroke.

Precise synthesis of polymer brushes to modify the surface of nanoparticles and nanodevices for targeted applications has been one of the major focuses in the community for decades. Here we report a self-assembly-assisted-grafting-to approach to synthesize polymer brushes on flat substrates. In this method, polymers are pre-assembled into two-dimensional polymer single crystals (PSCs) with functional groups on the surface. Chemically coupling the PSCs onto solid substrates leads to the formation of polymer brushes. Exquisite control of the chain folding in PSCs allows us to obtain polymer brushes with well-defined grafting density, tethering points and brush conformation. Extremely high grafting density (2.12 chains per nm 2 ) has been achieved in the synthesized single-tethered polymer brushes. Moreover, polymer loop brushes have been successfully obtained using oddly folded PSCs from telechelic chains. Our approach combines some of the important advantages of conventional ‘grafting-to’ and ‘grafting-from’ methods, and is promising for tailored synthesis of polymer brushes. Polymer brushes, whereby single layers of polymers are tethered to surfaces, can be made by various methods but greater control over their fabrication is desirable. Here, by pre-assembling polymer chains into 2D crystalline sheets, the authors achieve high precision and unprecedented grafting densities.

White matter hyperintensities (WMH) are neuroimaging markers linked to an elevated risk of cognitive decline. WMH severity is typically assessed via visual rating scales and through volumetric segmentation. While visual rating scales are commonly used in clinical practice, they offer limited descriptive power. In contrast, supervised volumetric segmentation requires manually annotated masks, which are labor‐intensive and challenging to scale for large studies. Therefore, our goal was to develop an automated deep‐learning model that can provide accurate and holistic quantification of WMH severity with minimal supervision. We developed WMH‐DualTasker, a deep learning model that simultaneously performs voxel‐wise segmentation and visual rating score prediction. The model employs self‐supervised learning with transformation‐invariant consistency constraints, using WMH visual ratings (ARWMC scale, range 0–30) from clinical settings as the sole supervisory signal. Additionally, we assessed its clinical utility by applying it to identify individuals with mild cognitive impairment (MCI) and to predict dementia conversion. The volumetric quantification performance of WMH‐DualTasker was either superior to or on par with existing supervised methods, as demonstrated on the MICCAI‐WMH dataset (N = 60, Dice = 0.602) and the SINGER dataset (N = 64, Dice = 0.608). Furthermore, the model exhibited strong agreement with clinical visual rating scales on an external dataset (SINGER, MAE = 1.880, K = 0.77). Importantly, WMH severity metrics derived from WMH‐DualTasker improved predictive performance beyond conventional clinical features for MCI classification (AUC = 0.718, p < 0.001) and MCI conversion prediction (AUC = 0.652, p < 0.001) using the ADNI dataset. WMH‐DualTasker substantially reduces the reliance on labor‐intensive manual annotations, facilitating more efficient and scalable quantification of WMH severity in large‐scale population studies. This innovative approach has the potential to advance preventive and precision medicine by enhancing the assessment and management of vascular cognitive impairment associated with WMH. WMH‐DualTasker performs automated segmentation and visual rating prediction of white matter hyperintensities. The model combines self‐supervised consistency with hyperintense mapping to reduce dependency on manual annotations. It demonstrates high accuracy across diverse datasets, supporting efficient, and scalable WMH assessment for large‐scale studies and cognitive impairment.

Disparities in breast cancer stage and mortality by race/ethnicity in the United States are persistent and well known. However, few studies have assessed differences across racial/ethnic subgroups of women broadly defined as Hispanic, Asian, or Pacific Islander, particularly using more recent data. Using data from 17 population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) program, we evaluated the relationships between race/ethnicity and breast cancer stage, hormone receptor status, treatment, and mortality. The cohort consisted of 229,594 women 40–79 years of age diagnosed with invasive breast carcinoma between January 2000 and December 2006, including 176,094 non-Hispanic whites, 20,486 Blacks, 15,835 Hispanic whites, 14,951 Asians, 1,224 Pacific Islanders, and 1,004 American Indians/Alaska Natives. With respect to statistically significant findings, American Indian/Alaska Native, Asian Indian/Pakistani, Black, Filipino, Hawaiian, Mexican, Puerto Rican, and Samoan women had 1.3–7.1-fold higher odds of presenting with stage IV breast cancer compared to non-Hispanic white women. Almost all groups were more likely to be diagnosed with estrogen receptor-negative/progesterone receptor-negative (ER−/PR−) disease with Black and Puerto Rican women having the highest odds ratios (2.4 and 1.9-fold increases, respectively) compared to non-Hispanic whites. Lastly, Black, Hawaiian, Puerto Rican, and Samoan patients had 1.5–1.8-fold elevated risks of breast cancer-specific mortality. Breast cancer disparities persist by race/ethnicity, though there is substantial variation within subgroups of women broadly defined as Hispanic or Asian. Targeted, multi-pronged interventions that are culturally appropriate may be important means of reducing the magnitudes of these disparities.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK , ROS1 , NTRK and MET . These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies. Infant gliomas behave differently to their childhood or adult counterparts. Here, the authors perform a large-scale genetic analysis of these tumours, revealing genetic alterations which may offer therapeutic opportunities.