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Changes in thickness of granular layer of the cerebellum. (A) Micrograph showed the morphologic changes of granular layer of the cerebellum by HE staining (A1 to A5). Quantitative analysis showed that there was no difference in the thickness of granular layer in the cerebellum at different points after bilateral common carotid artery occlusion (BCCAO) (P>0.05, B), Scale bar, 20 μm.
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Chronic cerebral hypoperfusion (CCH) induces cognitive impairment, but the compensative mechanism of cerebral blood flow (CBF) is not fully understood. The present study mainly investigated dynamic changes in CBF, angiogenesis, and cellular pathology in the cortex, the striatum, and the cerebellum, and also studied cognitive impairment of rats indu...
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Citations
... 58 Vascular alterations can lead to chronic cerebral hypoperfusion, which has been identified as a major driver of the vascular pathology and clinical manifestations of VCID. [79][80][81] One key cerebrovascular alteration in aging brains is microvascular rarefaction. This phenomenon, marked by a decline in vascular density, significantly impacts CBF and brain perfusion. ...
Intra-vital visualization of deep cerebrovascular structures and blood flow in the aging brain has been a difficult challenge in the field of neurovascular research, especially when considering the key role played by the cerebrovasculature in the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD). Traditional imaging methods face difficulties with the thicker skull of older brains, making high-resolution imaging and cerebral blood flow (CBF) assessment challenging. However, functional ultrasound (fUS) imaging, an emerging non-invasive technique, provides real-time CBF insights with notable spatial-temporal resolution. This study introduces an enhanced longitudinal fUS method for aging brains. Using elderly (24-month C57BL/6) mice, we detail replacing the skull with a polymethylpentene window for consistent fUS imaging over extended periods. Ultrasound localization mapping (ULM), involving the injection of a microbubble (<<10 μm) suspension allows for recording of high-resolution microvascular vessels and flows. ULM relies on the localization and tracking of single circulating microbubbles in the blood flow. A FIJI-based analysis interprets these high-quality ULM visuals. Testing on older mouse brains, our method successfully unveils intricate vascular specifics even in-depth, showcasing its utility for longitudinal studies that require ongoing evaluations of CBF and vascular aspects in aging-focused research.
... Frontiers in Neurology 07 frontiersin.org arteries, as demonstrated in an animal model of bilateral carotid artery occlusion (27). Furthermore, the establishment of intracranial collateral circulation is related to the severity and velocity of cerebral vascular stenosis (28). ...
Purpose
Identifying the etiology of acute ischemic stroke (AIS) before endovascular treatment (EVT) is important but challenging. In CT perfusion imaging processed by perfusion software, we observed a phenomenon called patchy profile sign (PPS), that is, the hypoperfusion morphology in RAPID software is a discontinuous sheet pattern. This phenomenon is predominantly observed in patients diagnosed with intracranial atherosclerotic stenosis (ICAS). The study intends to assess whether the PPS can be used to differentiate ICAS from intracranial embolism.
Method
Patients with AIS due to M1 segment occlusion of the MCA who underwent mechanical thrombectomy were retrospectively enrolled. The receiver operating characteristic (ROC) curve analysis was performed to assess the value of PPS in predicting ICAS. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the PPS for prediction of ICAS were calculated.
Results
A total of 51 patients were included in the study. The PPS was observed in 10 of 19 (52.6%) patients with ICAS, and in 2 of 32 (6.3%) patients with intracranial embolism (p < 0.001). Interobserver agreement for identifying PPS was excellent (κ = 0.944). The sensitivity, specificity, PPV, NPV, and accuracy of the PPS for predicting ICAS were 52.6, 93.8, 83.3, 76.9, and 78.4%, respectively.
Conclusion
The PPS on RAPID software is an imaging marker with high specificity for ICAS. Larger sample sizes are imperative to validate the findings.
... Most of the 16-week-old MRL/lpr mice displayed characteristic cognitive dysfunctions (Lu et al. 2021). To assess the reliability of the MRL/lpr model, we employed the MWM test to evaluate learning and spatial memory deficits in each group, as previously described (Jing et al. 2015). Mice were recorded for 5 days at the age of 16 weeks on their times to reach the platform and their routes in the pool. ...
Although vascular dementia (VD) and systemic lupus erythematosus (SLE) may share immune-mediated pathophysiologic processes, the underlying mechanisms are unclear. This study investigated shared gene signatures in SLE versus VD, as well as their potential molecular mechanisms. Bulk RNA sequencing (RNAseq) and single-cell or single-nucleus RNAseq (sc/snRNAseq) datasets from SLE blood samples and VD brain samples were obtained from Gene Expression Omnibus. The identification of genes associated with both SLE and VD was performed using the weighted gene co-expression network analysis (WGCNA) and machine learning algorithms. For the sc/snRNAseq data, an unbiased clustering pipeline based on Seurat and CellChat was used to determine the cellular landscape profile and examine intracellular communication, respectively. The results were subsequently validated using a mice model of SLE with cognitive dysfunction (female MRL/lpr mice). WGCNA and machine learning identified C1QA, LY96, CD163, and MS4A4A as key genes for SLE and VD. sc/snRNAseq analyses revealed that CD163 and MS4A4A were upregulated in mononuclear phagocytes (MPs) from SLE and VD samples and were associated with monocyte-macrophage differentiation. Intriguingly, LGALS9-associated molecular pathway, as the only signaling pathway common between SLE and VD via CellChat analysis, exhibited significant upregulation in cortical microglia of MRL/lpr mice. Our analyses identified C1QA, LY96, CD163, and MS4A4A as potential biomarkers for SLE and VD. Moreover, the upregulation of CD163/MS4A4A and activation of LGALS9 signaling in MPs may contribute to the pathogenesis of VD with SLE. These findings offer novel insight into the mechanisms underlying VD in SLE patients.
... VD is characterized by an increase in ROS production, neuronal damage, activation of microglia and astrogliosis, memory deficits, and behavioral and mood changes [45][46][47]. Hippocampal LTP has been used as an electrophysiologic indicator of the formation and maintenance of memory at the synaptic level [48]. LTP was decreased to 40-77% of the baseline level in the CA1 area of the hippocampus of BCCAO rats compared with shamoperated rats four weeks after surgery [49,50]. ...
... Intracellular ATP concentration is closely related to neuron death and rapidly decreases from the first three days and up to eight weeks after BCCAO [18,46,47]. Thus, damage to neurons begins in the early stages of BCCAO due to a decrease in blood flow and ATP concentration. ...
Vascular dementia (VD), caused by impaired cerebral blood flow, is the most common form of dementia after Alzheimer’s disease (AD) in the elderly and is characterized by severe neuronal damage and cognitive decline. Nitric oxide (NO) is an important determinant of vascular homeostasis, and its deficiency is associated with the progression of VD. In this study, we investigated the role of nitrite ion, a NO metabolite in a botanical mixture (BM) of fermented garlic, fermented Scutellaria baicalensis, and Rhodiola rosea on neuron loss and cognitive impairment using a VD rat model. The BM containing the NO metabolite alleviated cognitive deficits and enhanced neural plasticity, as reflected by an increase in long-term potentiation. The BM also alleviated neuron apoptosis, decreased GFAP expression, and oxidative stress, and increased parvalbumin and brain-derived neurotrophic factor (BDNF) levels. These results indicate that BM exerts neuroprotective effects and alleviates cognitive dysfunction while enhancing neuroplasticity, and thus has therapeutic potential against VD.
... In addition, CCH resulting from the permanent BCCAL is linked with the development of neurodegenerative changes, including impaired BBB permeability, synaptic dysfunction, altered brain-carbohydrate metabolism, neuronal loss, and oxidative stress [25][26][27]. Meanwhile, some studies reported the limitation of utilising BCCAL to model for CCH, including the variability of the outcome associated with the duration of cerebral hypoperfusion and the compensatory vascular mechanism that could not prevent neuronal death [28,29]. In support of vascular contributions to delirium, Int. ...
... Meanwhile, Honda and colleagues (2016) identified a 33% incidence rate of delirium in low-output heart failure and suggested the link possibly associated with cerebral hypoperfusion [53]. CCH during ageing induces brain capillary degeneration and impaired delivery of energy substrates to neuronal tissue, compromising neuronal stability [28,55]. To relate with our delirium model, superimposed LPS administration in CCH rats could further exacerbate cerebral hypoperfusion via nitrous oxide (NO)-induced cerebral vasodilation and impaired cerebral autoregulation, leading to delirium [56,57]. ...
Indoleamine 2,3-dioxygenase (IDO) and the tryptophan–kynurenine pathway (TRP-KP) are upregulated in ageing and could be implicated in the pathogenesis of delirium. This study evaluated the role of IDO/KP in lipopolysaccharide (LPS)-induced delirium in an animal model of chronic cerebral hypoperfusion (CCH), a proposed model for delirium. CCH was induced by a permanent bilateral common carotid artery ligation (BCCAL) in Sprague Dawley rats to trigger chronic neuroinflammation-induced neurodegeneration. Eight weeks after permanent BCCAL, the rats were treated with a single systemic LPS. The rats were divided into three groups: (1) post-BCCAL rats treated with intraperitoneal (i.p.) saline, (2) post-BCCAL rats treated with i.p. LPS 100 μg/kg, and (3) sham-operated rats treated with i.p. LPS 100 μg/kg. Each group consisted of 10 male rats. To elucidate the LPS-induced delirium-like behaviour, natural and learned behaviour changes were assessed by a buried food test (BFT), open field test (OFT), and Y-maze test at 0, 24-, 48-, and 72 h after LPS treatment. Serum was collected after each session of behavioural assessment. The rats were euthanised after the last serum collection, and the hippocampi and cerebral cortex were collected. The TRP-KP neuroactive metabolites were measured in both serum and brain tissues using ELISA. Our data show that LPS treatment in CCH rats was associated with acute, transient, and fluctuated deficits in natural and learned behaviour, consistent with features of delirium. These behaviour deficits were mild compared to the sham-operated rats, which exhibited robust behaviour impairments. Additionally, heightened hippocampal IDO expression in the LPS-treated CCH rats was associated with reduced serum KP activity together with a decrease in the hippocampal quinolinic acid (QA) expression compared to the sham-operated rats, suggested for the presence of endotoxin tolerance through the immunomodulatory activity of IDO in the brain. These data provide new insight into the underlying mechanisms of delirium, and future studies should further explore the role of IDO modulation and its therapeutic potential in delirium.
... Neuronal loss is a typical characteristic feature observed after CCH. Neuronal death was observed in CCH animal models at 1 week and sustained for up to 3 months following CCH, particularly in the striatum, hippocampus, and cortex, showing that neurons in these three areas are more sensitive to CCH (Ni et al., 1995;Cechetti et al., 2012;Jing et al., 2015). Poh et al. (2021a) reported that neuronal death seems to occur at 15 days and 30 days. ...
Chronic cerebral hypoperfusion (CCH) is a major global disease with chronic cerebral blood flow reduction. It is also the main cause of cognitive impairment and neurodegenerative diseases. Pyroptosis, a novel form of cell death, is characterized by the rupture of the cell membrane and the release of pro-inflammatory mediators. In recent years, an increasing number of studies have identified the involvement of pyroptosis and its mediated inflammatory response in the pathological process of CCH. Therefore, preventing the activation of pyroptosis following CCH is beneficial to inhibit the inflammatory cascade and reduce brain injury. In this review, we discuss the research progress on the relationship between pyroptosis and CCH, in order to provide a reference for research in related fields.
... Reduced CBF has been identified as a standard to judge successful establishment of the 2VO model in cognitive impairment and brain injury after CCH 4 . Our data show that compared with CBF measurements before RCCAO, the left and right cerebral CBF decreased to 60%e70% after RCCAO, then the level of CBF remained stable until BCCAO, and further decreased to 40%e50% after BCCAO, confirming that the 2VO model was successfully established 23,24 (Fig. S1AeS1C). Then, the pathological tests, histological tests and behavioral tests were conducted on the 3rd, 7th, 14th, 28th and 42nd day after 2VO. ...
... It is generally believed that cognitive impairment occurs in rats by the 14th or 28th day after 2VO, and the detection of postoperative cognitive impairment is usually conducted at 14, 28, and 42 days after 2VO 24,26,27 . Therefore, we also chose these three time points to investigate postoperative behavioral changes induced by 2VO. ...
... Therefore, we also chose these three time points to investigate postoperative behavioral changes induced by 2VO. In addition, it was reported that both neuronal soma injury and altered autophagy function occurred in gray matter at 14 days after 2VO 24,28 . Importantly, it has been shown that oligodendrocytes are more sensitive to the ischemic environment than neurons 29 . ...
Cognitive impairment caused by chronic cerebral hypoperfusion (CCH) is associated with white matter injury (WMI), possibly through the alteration of autophagy. Here, the autophagy–lysosomal pathway (ALP) dysfunction in white matter (WM) and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion (2VO). The results showed that cognitive impairment occurred by the 28th day after 2VO. Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day. By the 14th day, abnormal accumulation of autophagy substrate, lysosomal dysfunction, and the activation of mechanistic target of rapamycin (MTOR) pathway were observed in WM, paralleled with mature oligodendrocyte death. This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction. To target the ALP dysfunction, enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1 (BECN1) in oligodendrocytes reduced mature oligodendrocyte death, and subsequently alleviated the WMI and cognitive impairment after CCH. These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO, which was associated with the aggravation of WMI and cognitive impairment. This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.
... Emerging evidence has highlighted the role of cerebrovascular dysfunction in the early stage of AD, leading to low blood perfusion, abnormal reduction of Aβ clearance, and neuronal dysfunction. 7,38,44,45 Cerebrovascular protection has attracted increasing attention as the target for AD treatment. 46 Coincidently, we found that EAST36 significantly boosted cerebral perfusion in AD mice, in line with the improvement of neurological performance and cerebrovascular Aβ clearance in AD mice after EAST36. ...
Aims
Cerebrovascular impairment contributes to the pathogenesis of Alzheimer's disease (AD). However, it still lacks effective intervention in clinical practice. Here, we investigated the efficacy of electroacupuncture (EA) in cerebrovascular repair in 3xTg‐AD mice and its mechanism.
Methods
3xTg‐AD mice were employed to evaluate the protective effect of EA at ST36 acupoint (EAST36). Behavioral tests were performed to assess neurological disorders. Laser speckle contrast imaging, immunostaining, and Western blot were applied to determine EAST36‐boosted cerebrovascular repair. The mechanism was explored in 3xTg mice and endothelial cell cultures by melatonin signaling modulation.
Results
EAST36 at 20/100 Hz effectively alleviated the olfactory impairment and anxiety behavior and boosted cerebrovascular repair in AD mice. EAST36 attenuated cerebral microvascular degeneration in AD mice by modulating endothelial cell viability and injury. Consequently, the Aβ deposits and neural damage in AD mice were reversed after EAST36. Mechanistically, we revealed that EAST36 restored melatonin levels in AD mice. Melatonin supplement mimicked the EAST36 effect on cerebrovascular protection in AD mice and endothelial cell cultures. Importantly, blockage of melatonin signaling by antagonist blunted EAST36‐induced cerebrovascular recovery and subsequent neurological improvement.
Conclusions
These findings provided strong evidence to support EAST36 as a potential nonpharmacological therapy against cerebrovascular impairment in AD. Further study is necessary to better understand how EAST36 treatment drives melatonin signaling.
... Ischemic damage of the brain neurons entails severe neurological consequences. Therefore, special attention has been focused on the studies of cerebrovascular diseases, which are the main cause of mortality worldwide [10][11][12]. Comprehensive morphological and morphometric studies of neurons, glial cells and inter-neuronal communication structures are required for a more detailed insight into the neural tissue response to ischemia and defense mechanisms ensuring neuronal survival in ischemia. Therefore, the aim of our study was to compare the histological and immunohistochemical data characteristic of structural and functional changes in neurons, glial cells and synaptic terminals in layers I, III and V of rat brain SMCs after bilateral LCCA. ...
Aim of the study . To explore the structural and functional changes of neurons, glial cells, and synaptic terminals in layers I, III, and V of the sensorimotor cortex (SMC) of the rat brain after bilateral common carotid artery ligation (CCAL).
Material and methods . Incomplete cerebral ischemia was simulated by irreversible bilateral CCAL (2-vessel model of global ischemia without hypotension) on white rats (n=36). Comparative evaluation of the studied SMC structures was performed in the control group (intact rats, n=6) on days 1, 3, 7, 14, and 30 (n=30) after CCAL. Nissl, hematoxylin-eosin staining, and immunohistochemical reactions for NSE, MAP-2, p38, GFAP, and IBA1 were used. Numerical density of pyramidal neurons, astrocytes, oligodendrocytes, microglial cells, and relative area of p38-positive material (synaptic terminals) were determined. Statistical hypotheses were tested using nonparametric methods with Statistica 8.0 software.
Results. After CCAL, the number of degenerative neurons in rat brain SMCs increased. The peak of numerical density of unshrunken neurons was detected after day 1. Later, the numerical density of hyperchromic unshrunken neurons decreased, while that of shrunken neurons increased. These parameters did not reach the control values. The changes in SMC neurons were accompanied by an increase in the numerical density of microglial cells after day 1 and its subsequent decrease. Immunohistochemistry for IBA1 revealed signs of microglial cell activation such as change in shape and loss of processes. Maximum increase in the SMC density of oligodendrocytes was observed on day 7, and that of astrocytes on day 14 after CCAL. The maximum number of NSE-positive neurons occurred on day 1 after CCAL. There was a significant decrease in the number of NSEpositive neurons in SMC layer III on days 3, 7, and 14, and an increase in the number of NSE-positive neurons on day 30. The number of NSE-positive neurons in layer V of the SMC progressively decreased throughout the whole study period. The evolution of changes in the proportion of p38-positive material (synaptic terminal area) differed significantly between the layers of SMC. In the layers I and III, this parameter first decreased (days 1 and 3) and then increased (days 7, 14, and 30). In layer V of SMC, the activation of the protein expression was observed in the acute phase (days 1 and 3), then it decreased on days 7 and 14, and increased again on day 30. The changes found in the numerical density of neurons, glial cells and synaptic terminals were associated with dehydration and overhydration of SMC. We found strong to medium significant associations between the relative area of terminals and neuropil swelling and edema zones.
Conclusion . After CCAL, layers I, III, and V of the SMC of white rats revealed destructive and compensatory changes in neurons, glial cells, and inter-neuronal communication structures. Taken together, all these changes indicate a significant layer-by-layer variability of the neural tissue response to CCAL. Layer III (secondary projection complex) of the SMC was affected to a greater extent. Reorganization of neuronal-glial and interneuronal interrelations occurred along with a prominent neuropil overhydration.
... Полученные в работе данные послужат для уточнения особенностей структурнофункциональной реорганизации аксональных терминалей разных слоев СМК после ПОСА. Выявленные различия могут быть связаны с особенностями нейро-глиальных отношений изученных слоев СМК -атрофией и гипертрофией астроцитов по типу обратимого реактивного глиоза [3,14,18,20]. ...
