Cognitive Impairment In Vascular Dementia Research Articles

Baicalein ameliorates cognitive impairment of vascular dementia rats via suppressing neuroinflammation and regulating intestinal microbiota

Neuroinflammation induced by chronic cerebral hypoperfusion (CCH) plays a crucial role in the pathophysiologic mechanisms of vascular dementia (VD). A growing body of research has found that intestinal microbiota is associated with a variety of central nervous system disorders and that there is a relationship between intestinal microbiota dysbiosis and cognitive dysfunction and inflammatory responses. Baicalein belongs to the class of flavonoids and has a variety of biological functions, including anti-inflammatory, antioxidant and anti-apoptotic. Baicalein has a significant improvement in memory and learning, and can be used as a potential drug for the protection and treatment of central nervous system disorders. Whether baicalein has an ameliorative effect on cognitive impairment in VD, and whether its mechanism is related to the inhibition of inflammatory response and regulation of intestinal microbiota has not been reported. We used bilateral common carotid artery occlusion (BCCAO) to establish a VD rat model. Morris water maze (MWM) test showed that baicalein improved cognitive dysfunction in VD rats. We applied HE staining, immunofluorescence and ELISA to observe that baicalein treatment significantly improved CCH-induced neuronal damage in the CA1 region of the hippocampus, and reduced glial cell activation and release of pro-inflammatory factors. Western blot showed that baicalein inhibited the activation of the TLR4/MyD88/NF-κB signaling pathway in VD rats. We applied 16 S rDNA sequencing to analyze the composition of the intestinal microbiota. The results showed that baicalein modulated the diversity and composition of the intestinal microbiota, and suppressed the relative abundance of inflammation-associated microbiota in VD rats. In conclusion, this study found that baicalein ameliorated cognitive impairment, attenuated hippocampal inflammatory responses, inhibited the TLR4/MyD88/NF-κB signaling pathway, and modulated intestinal microbiota in VD rats.

Chlorogenic Acid Mitigates Ferroptosis by Activating the Nrf2/GPX4 Pathway through Keap1 Blockade in Vascular Dementia Rats

Chlorogenic acid (CGA) is a dietary phenolic acid widely distributed in daily food and plants, but its role in vascular dementia (VaD) is still unclear. Hence, this study aimed to investigate whether CGA could rescue cognitive impairment in VaD, providing a new option for drug discovery. Novel object recognition and Morris water maze experiments revealed that CGA enhanced the learning and memory abilities in VaD rats. Nissl staining, Western blot, and transmission electron microscopy results demonstrated that CGA inhibited neuronal loss in the hippocampal CA1 region of VaD rats, increased the expression of synaptic‐related markers SYP and PSD95, thickened the postsynaptic density, and suppressed mitochondrial ridge rupture in neurons. GSH detection, MDA detection, and Western blot experiments indicated that CGA alleviated hippocampal GSH reduction and MDA elevation and increased the protein levels of GPX4 and SLC7A11. Cell activity, ROS detection, lipid peroxidation detection, intracellular Fe2+ level detection, GSH detection, and Western blot revealed that CGA inhibited the increase of intracellular Fe2+, ROS, and lipid peroxidation induced by OGD in PC12 cells, mitigated GSH reduction, and increased the protein levels of GPX4, SLC7A11, SYP, and PSD95. Western blot and immunofluorescence staining showed that CGA increased the expression of pSer40‐Nrf2 in the hippocampal tissue of VaD rats and PC12 cells, promoting Nrf2 nuclear translocation. Knockdown of Nrf2 prevented CGA from rescuing ferroptosis and synaptic damage induced by OGD in PC12 cells, as well as Nrf2 pathway activation. Molecular docking analysis suggested that CGA competitively bound to the Kelch domain of Keap1 with Nrf2 and then promoted Nrf2 release and activated downstream signaling pathways. In conclusion, our study suggests that CGA may activate the Nrf2 signaling pathway by disrupting the interaction between Nrf2 and Keap1 proteins, thereby inhibiting hippocampal neuronal ferroptosis and synaptic damage and ameliorating cognitive impairment in VaD. Practical Applications. Vascular dementia (VaD) stands as the second most prevalent type of dementia following Alzheimer’s disease. However, there is no effective clinical treatment drug available, and its pathogenic mechanisms remain elusive. This study proposed that CGA might activate the Nrf2‐GPX4 signaling pathway by competitively binding to Keap1, thereby attenuating hippocampal neuronal ferroptosis and synaptic damage and consequently ameliorating cognitive impairment in VaD. Our study may provide a novel option for drug research and development for VaD.

Electroacupuncture inhibits hippocampal neuronal apoptosis and improves cognitive dysfunction in mice with vascular dementia via the JNK signaling pathway.

Electroacupuncture (EA) has been shown to reduce cognitive impairment in vascular dementia (VaD) patients. However, the mechanism of action remains unknown. The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in apoptosis. Herein, we focused on whether EA can inhibit apoptosis and alleviate cognitive impairment by regulating the JNK signaling pathway using a mouse model of VaD induced by modified bilateral common carotid artery occlusion (BCCAo). In experiment I, 60 mice were randomly divided into a Sham group, BCCAo group, BCCAo + EA group, BCCAo + Sham-EA group, BCCAo + SP group (receiving the selective JNK inhibitor SP600125) and BCCAo + SP + EA group. Morris water maze tests, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining and flow cytometry were used to evaluate the effect of the EA intervention on VaD. In experiment II, 30 mice were randomly divided into a Sham group, BCCAo group, BCCAo + EA group, BCCAo + SP group and BCCAo + SP + EA group. Western blotting and real-time reverse transcription polymerase chain reaction were used to detect protein and mRNA expression of key factors in the JNK signaling pathway in the hippocampus. EA, SP600125 and EA + SP600125 significantly inhibited hippocampal apoptosis and improved cognitive impairment in VaD model mice. There were no significant differences between the BCCAo group and the BCCAo + Sham-EA group. EA, EA + SP600125 and SP600125 inhibited the phosphorylation of JNK and caspase-3. EA and EA + SP600125 promoted protein and mRNA expression of B-cell lymphoma 2 (Bcl-2) in the hippocampus of VaD mice and inhibited protein and mRNA expression of activator protein (AP)-1, p53 and Bax. EA can reverse cognitive deficits and inhibit hippocampal neuronal apoptosis in VaD model mice, at least partially through inhibition of the JNK signaling pathway and regulation of apoptosis signals.

Upregulation of PGC-1α Attenuates Oxygen-Glucose Deprivation-Induced Hippocampal Neuronal Injury.

Hippocampal neuronal damage likely underlies cognitive impairment in vascular dementia (VaD). PPARγ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. However, the role and the precise mechanism of how PGC-1α alleviates hippocampal neuronal injury remain unknown. To address this question, HT-22 cells, an immortalized hippocampal neuron cell line, with or without PGC-1α overexpression were subjected to oxygen-glucose deprivation (OGD), which mimics the circumstance of chronic cerebral hypoperfusion in VaD. After OGD, cell viability was assessed using the MTS assay. The mitochondrial function and reactive oxygen species (ROS) were both detected. ChIP-Seq analysis was employed to discover the underlying molecular mechanism of PGC-1α-mediated neuroprotective effects. Our results showed that mitochondrial membrane potentials were increased and ROS production was decreased in PGC-1α overexpressing cells, which increased cell viability. The further bioinformatics analysis from ChIP-Seq data indicated that PGC-1α may participate in the regulation of apoptosis, autophagy, and mitophagy pathways in HT-22 cells. We found that PGC-1α promoted the LC3-II formation and reduced the neuronal apoptosis determined by TUNEL staining. In addition, PGC-1α upregulated the expressions of mitochondrial antioxidants, including SOD2, Trx2, and Prx3. In summary, our findings indicate that PGC-1α may attenuate OGD-induced hippocampal neuronal damage by regulating multiple mechanisms, like autophagy and mitochondrial function. Thus, PGC-1α may be a potential therapeutic target for hippocampal damage associated with cognitive impairment.

Evaluating the Protective Effect of Ginsenoside Re on Hippocampal Mitochondria in a Rat Model of Vascular Dementia

Vascular dementia (VD) is a common disease among elderly individuals that results in cognitive dysfunction. Although pharmaceutical treatments are used to temporarily improve the symptoms, these have side effects, including mental disorders and epilepsy. Therefore, identifying therapeutic strategies for VD which limit side effects would be advantageous. Previous studies have demonstrated the involvement of oxidative stress in the pathogenesis of VD. As the major saponin type of Panax ginseng, Ginsenoside Re, exerts anti-oxidation and anti-inflammation effects, Re may have a therapeutic role in the management of VD. Our aim was to evaluate this potential therapeutic role of Re in a rat model of VD. We compared mitochondrial function in hippocampal neurons in groups with or without Re administration. Our findings show that Re administration can reverse the effects of VD on mitochondrial structure and function in hippocampal neurons, including protecting against a reduction in the number of mitochondria and preventing mitochondrial vacuolization. The relative expression levels of COX IV and PDH-A1 also increased after Re treatment, with a reduction in mitochondrial H2O2 production, in a time-and dose-dependent manner. These improvements in mitochondrial function protected against VD-associated cognitive dysfunction, measured by performance in a Morris water maze. Based on these findings, we concluded that Ginsenoside Re may ameliorate cognitive impairment in VD by inhibiting mitochondrial oxidative stress in the brain. Collectively, we provide valuable experimental data which could inform the development of safe and effective drugs for the management of VD from ischemia.

AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia

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. Inflammasome is an intracellular multi-protein complex that initiates an innate immune response, and is involved in multiple acute and chronic neurological diseases such as ischemic stroke, Alzheimer's disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). While evidence for direct involvement of the inflammasome complex in VaD is lacking, a cytokine profile of plasma from VaD patients found IL-1β to be the most abundant.Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate the effect of chronic cerebral hypoperfusion on the inflammasome signaling pathway. To further examine the functional role of AIM2 inflammasome activation on injury following chronic cerebral hypoperfusion, mice with AIM2 deficiency (AIM2 KO) were studied.Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 KO 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 behavioural 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.

Decreased Serum NCAM Levels Associated with Cognitive Impairment in Vascular Dementia.

Objective Neural cell adhesion molecule (NCAM), a glycoprotein widely distributed in the brain, has recently been shown to regulate neuroplasticity. However, the role of NCAM in vascular dementia (VaD) is still unclear. The purpose of this study is to determine whether NCAM is involved in the course of VaD. Methods Continuous recruitment of VaD patients and control population to join this study. Doctors or nurses are responsible for collecting their clinical characteristics including age, gender, formal education, heart rate, supine systolic blood pressure, supine diastolic blood pressure, fasting glucose, high-density lipoprotein, and low-density lipoprotein. Each participant received the Montreal Cognitive Assessment (MoCA) scale after being enrolled in the group. At the same time, their peripheral blood was collected, and their serum NCAM levels were measured by enzyme-linked immunosorbent assay (ELISA). Results 98 VaD patients and 83 age- and sex-matched controls were enrolled. There was no significant statistical difference between the VaD group and the control group in terms of the comparison of clinical characteristics (p > 0.05). The MoCA score of VaD patients was significantly lower than that of the controls (27.9 ± 1.4 vs. 23.0 ± 2.1 points, p < 0.001). In addition, the circulating NCAM level of VaD patients was also significantly lower than that of controls (21.7 ± 3.8 vs. 17.6 ± 4.2 ng/mL, p < 0.001). The circulating NCAM level of VaD patients was significantly positively correlated with MoCA score (r = 0.285, p = 0.026). After adjusting for clinical characteristics, circulating NCAM levels are still an independent pathogenic factor of VaD (regression coefficient = 0.223, p = 0.034). Conclusions VaD patients have low circulating NCAM levels, which can be used as a potential predictor of VaD.

Acupuncture Can Regulate the Peripheral Immune Cell Spectrum and Inflammatory Environment of the Vascular Dementia Rat, and Improve the Cognitive Dysfunction of the Rats.

ObjectiveThe aim of this study is to analyze the effects of acupuncture on peripheral immune function, inflammation, and cognitive impairment in vascular dementia (VD) rats.MethodsIn this study, 2-month-old healthy male Wistar rats (260–280 g) were assigned to the groups as follows: normal group (Gn, n = 10), sham-operated group (Gs, n = 10), and operated group (Go, n = 45). The Go group was established by permanent, bilateral common carotid artery occlusion (BCCAO). Two months after operation, the operated rats were screened by hidden platform trial and the rats with cognitive dysfunction were further randomly divided into impaired group (Gi), acupoint group (Ga), and non-acupoint group (Gna) with 10 rats in each group. The Ga group was given acupuncture treatment for 14 days with a rest for every 7 days. After treatment, the Morris water maze (MWM) test was performed to evaluate the spatial learning and memory abilities of rats. The lymphocyte subsets in peripheral blood and spleen of rats were measured by flow cytometry. The levels of cytokines [i.e., interleukin (IL)-1β, IL-2, IL-4, IL-10, tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ)], chemokines (i.e., macrophage inflammatory protein-2 (MIP-2)), and other inflammatory mediators (i.e., cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS)) in peripheral blood and hippocampus were measured by enzyme linked immunosorbent assay (ELISA).ResultsCompared with the Gn group, the Gi rats presented long escape latencies to find the platform. After acupuncture treatment, the escape latencies of the Ga group were rescued markedly when compared with the Gi group (P < 0.05). The proportion of CD4 + T lymphocytes in both spleen and peripheral blood in the Ga group increased (P < 0.05) in comparison with the Gi group. There is an obvious reduction in IL-1β (P < 0.05), IL-2 (P < 0.05), TNF-α (P < 0.01), INF-γ (P < 0.01), MIP-2 (P < 0.05), and iNOS (P < 0.01), coming along with the increased levels of IL-4 and IL-10 (P < 0.01) in the Ga group when compared with the Gi group. In addition, the hippocampus proinflammatory factors IL-1β (P < 0.01), IL-2 (P < 0.01), TNF-α (P < 0.05), INF-γ (P < 0.05), MIP-2 (P < 0.05), iNOS (P < 0.01), and COX-2 decreased in the Ga group, whereas the anti-inflammatory factors IL-4 and IL-10 (P < 0.01) increased.ConclusionThere are abnormal immune function and peripheral inflammation in VD rats. Acupuncture can regulate the peripheral immune function and inflammation of the VD rats and can improve the cognitive dysfunction of the rats.

Decreased Levels of Serum IL-34 Associated with Cognitive Impairment in Vascular Dementia.

Objective Interleukin- (IL-) 34 is a new type of cytokine with neuroprotective effects discovered in recent years. However, the relationship between IL-34 and vascular dementia (VaD) has not yet been elucidated. The purpose of this study is to determine whether IL-34 is involved in cognitive impairment of VaD. Methods From January 2017 to December 2020, 84 VaD patients and 60 healthy controls who attended Qingpu Branch of Zhongshan Hospital were prospectively included in the study. Once included in the study, demographic features of all research subjects are collected. They include age, gender, education, white blood cells (WBC), neutrophil, lymphocyte, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), triglycerides (TG), and total cholesterol (TC). Meanwhile, the Montreal Cognitive Assessment (MoCA) scale was used to assess the cognitive function of participants. The serum IL-34 level was determined by enzyme-linked immunosorbent assay (ELISA). Results There was no significant difference between the demographic features of VaD patients and healthy controls (p > 0.05). However, the serum IL-34 levels of VaD patients and healthy controls are 27.6 ± 3.9 pg/ml and 41.8 ± 6.0 pg/ml, respectively, and there is a significant statistical difference between them (p < 0.001). The results of bivariate correlation analysis showed that serum IL-34 levels were significantly positively correlated with MoCA scores (r = 0.371, p = 0.023). Further regression analysis showed that IL-34 was still correlated with MoCA after adjusting for demographic features (β = 0.276, p = 0038). Conclusions Serum IL-34 levels in VaD patients were significantly reduced, which may be an independent predictor of cognitive impairment in VaD patients.

Gastrodin ameliorates learning and memory impairment in rats with vascular dementia by promoting autophagy flux via inhibition of the Ca2+/CaMKII signal pathway.

Vascular dementia (VD) is a common disease that occurs during human aging. Gastrodin (GAS) has potential benefits for the prevention and treatment of VD. In the present study, we investigated the effects of GAS on cognitive dysfunction in rats with VD induced by permanent middle cerebral artery occlusion (pMCAO) and explored the underlying mechanism. Immunohistochemical and western blot analyses revealed that GAS attenuated hippocampal levels of LC3 (microtubule-associated protein 1 light chain 3), p62, and phosphorylated CaMKII (Ca2+-calmodulin stimulated protein kinase II) in VD rats. Additionally, our results revealed that cobalt chloride blocked autophagic flux in HT22 cells, which was confirmed by increased levels of LC3 and p62 when combined with chloroquine. Notably, GAS ameliorated the impaired autophagic flux. Furthermore, we confirmed that GAS combined with KN93 (a CaMKII inhibitor) or CaMKII knockdown did not impact the reduced p62 levels when compared with GAS treatment alone. Furthermore, a co-immunoprecipitation assay demonstrated that endogenous p62 bound to CaMKII, as confirmed by mass spectrometric analysis after the immunoprecipitation of p62 from HT22 cells. These findings revealed that GAS attenuated autophagic flux dysfunction by inhibiting the Ca2+/CaMKII signaling pathway to ameliorate cognitive impairment in VD.

AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia.

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.

Acupuncture Improves White Matter Perfusion and Integrity in Rat Model of Vascular Dementia: An MRI-Based Imaging Study.

White matter lesions induced by chronic cerebral hypoperfusion are associated with cognitive impairment in vascular dementia (VaD). Previous studies have shown that acupuncture can ameliorate the cognitive deficits of individuals with VaD. However, the neuroimaging mechanisms of acupuncture on white matter perfusion and integrity remain elusive. In this study, the VaD model was induced by bilateral common carotid arteries occlusion (BCCAO) in rats. Novel object recognition task and Morris water maze were performed to evaluate short-term memory and spatial learning and memory. Arterial spin labeling and diffusion tensor imaging (DTI) were used to measure the cerebral blood flow (CBF) and the white matter integrity. Pathological examinations detected the myelin loss and concomitant neuroinflammation. The results demonstrate that BCCAO rats with reduced CBF exhibited worse performance and altered DTI parameters, including decreased fractional anisotropy, increased radial diffusivity, and axial diffusivity in white matter regions. Acupuncture ameliorated cognitive impairment, increased CBF, and protected the myelin sheath integrity but not the axons of BCCAO rats. These protective effects of acupuncture on white matter were significantly correlated with improved CBF. Pathological examination confirmed that the loss of myelin basic protein and microglial accumulation associated IL-1β and IL-6 production were attenuated by acupuncture treatment. Our findings suggest that acupuncture protects cognitive function of BCCAO rats by improving white matter perfusion and integrity.

Increased Levels of Serum Neuregulin 1 Associated with Cognitive Impairment in Vascular Dementia.

Objective Neuregulin 1 (NRG 1) is a member of the epidermal growth factor (EGF) family and is believed to play an important role in neuroplasticity. However, the relationship between NRG 1 and vascular dementia (VaD) is poorly understood. The purpose of this study is to explore the correlation between neuregulin 1 and VaD. Patients and Methods. From October 2018 to September 2020, 93 VaD patients and 79 control populations who attended Liaocheng People's Hospital were included in the study. Baseline characteristics including age, gender, years of education, HDL, LDL, FBG, SBP, and DBP are collected. At the same time, peripheral blood was collected, and the concentration of serum NRG 1 was detected by enzyme-linked immunosorbent assay (ELISA). All research subjects received professional cognitive function assessment. Results A total of 93 VaD patients and 79 controls were enrolled. There was no significant difference in age, gender, years of education, HDL, LDL, FBG, SBP, and DBP between the two groups (p > 0.05). However, compared with the control group, VaD patients have lower MoCA and higher serum NRG 1 levels, and the difference is statistically significant (p < 0.001). The correlation analysis of MoCA and baseline characteristics showed that the MoCA score in VaD was significantly negatively correlated with serum NRG 1 (r = −0.374, p = 0.036). The results of multivariate regression showed that the MoCA score of VaD patients was only associated with NRG 1 (β = 0.258, p = 0.012). Conclusions The concentration of serum NRG 1 in VaD patients is significantly increased, which may be an independent risk factor for cognitive impairment in VaD patients.

Elevated Levels of Serum Neurofilament Light Chain Associated with Cognitive Impairment in Vascular Dementia.

Objective Vascular dementia (VaD) is a progressive neurodegenerative disease with cognitive decline caused by cerebrovascular factors. Despite the great progress made in the past decade, VaD still lacks effective treatments and peripheral blood biomarkers. In this study, we tested the level of peripheral blood neurofilament light chain (NfL) in VaD patients and explored its relationship with cognitive impairment. Method A total of 176 study subjects including 80 normal controls (NC) and 96 VaD patients were included in our study. Upon admission, we collected clinical and biochemical characteristics of all research subjects. We also evaluate the Montreal cognitive assessment scale (MoCA) scores of all subjects. The serum NfL level was measured by the single-molecule array (Simoa) method. Results The years of education in the NC group and VaD group were (11.65 ± 3.04) years and (10.53 ± 3.87) years, respectively. Compared with VaD patients, the NC group has a higher level of education (p = 0.037). Furthermore, the results of Simoa indicated that VaD subjects had higher serum NfL levels compared with the NC group [(8.49 ± 2.37) pg/ml vs. (19.26 ± 4.71) pg/ml, p < 0.001]. In terms of other clinical and biochemical characteristics, there was no significant difference between VaD and NC. The Spearman correlation analysis indicated that educational years have a significant positive correlation with MoCA scores (r = 0.238, p = 0.041), while age and serum NfL levels have a significantly negative correlation with MoCA scores (age: r = −0.213, p = 0.040; NfL: r = −0.395, p = 0.027). However, further multiple regression analysis showed that only serum NfL level might serve as an independent risk factor for cognitive decline in VaD (β = 0.317, p = 0.021). Conclusion The serum NfL levels in VaD subjects are significantly elevated, which may be used as a potential peripheral blood marker for predicting cognitive impairment in patients with VaD.

Effect of Obesity on Cognitive Impairment in Vascular Dementia Rat Model via BDNF-ERK-CREB Pathway.

The prevalence of vascular dementia continues to increase with no cure. Thus, it is important identify the aggravating factors of vascular dementia to delay disease progression in patients. Obesity is a well-known risk factor for vascular dementia and causes mild cognitive impairment. In the present study, we evaluated whether obesity exacerbates cognitive impairment in vascular dementia rats and how it affects synaptic plasticity through the BDNF pathway. We randomly assigned 30 Wistar male rats to three groups: sham surgery (Sham), vascular dementia (VaD), and vascular dementia with obesity (OB + VaD). We fed rats a 60% high-fat diet to establish obesity; we then induced vascular dementia using bilateral common carotid artery occlusion. After 6 weeks, we evaluated cognitive function using the Morris water maze and radial arm maze tests. We analyzed post-synaptic density-95 (PSD95) and growth-associated protein-43 (GAP43) to confirm synaptic plasticity. We also evaluated brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase (pERK), and phosphorylated cyclic adenosine monophosphate response element-binding protein (pCREB) in the hippocampus. The OB + VaD group showed the most impaired cognitive function on behavioral tests, with decreases in PSD95. The VaD group showed increased levels of BDNF, pERK, and pCREB, while the OB + VaD group displayed decreased levels. We suggest that obesity exacerbates cognitive impairment in vascular dementia by inhibiting the compensatory increases of BDNF-ERK-CREB pathway.

Association of Serum FAM19A5 with Cognitive Impairment in Vascular Dementia.

Objective Family with sequence similarity 19 member A5 (FAM19A5), a novel chemokine-like peptide, is a secreted protein mainly expressed in the brain. FAM19A5 was recently found to be involved in a variety of neurological diseases; however, its correlation with vascular dementia (VaD) remains unclear. The aim of the study is to explore the association between serum FAM19A5 and cognitive impairment in subjects with VaD. Method 136 VaD subjects and 81 normal controls were recruited in the study. Their demographic and clinical baseline data were collected on admission. All subjects received Mini-Mental State Examination (MMSE) evaluation, which was used to test their cognitive functions. A sandwich enzyme-linked immunosorbent assay (ELISA) was applied to detect the serum levels of FAM19A5. Results No significant differences were found between the two groups regarding the demographic and clinical baseline data (p > 0.05). The serum FAM19A5 levels were significantly higher compared to normal controls (p < 0.001). The Spearman correlation analysis indicated that serum FAM19A5 levels and MMSE scores have a significant negative correlation in VaD patients (r = −0.414, <0.001). Further multiple regression analysis indicated that serum FAM19A5 levels were independent risk predictors for cognitive functions in VaD (β = 0.419, p = 0.031). Conclusion The serum FAM19A5 level of VaD patients is significantly increased, which may serve as a biomarker to predict cognitive function of VaD.

ESC-sEVs Rejuvenate Senescent Hippocampal NSCs by Activating Lysosomes to Improve Cognitive Dysfunction in Vascular Dementia.

Vascular dementia (VD) is one of the most common types of dementia, however, the intrinsic mechanism is unclear and there is still lack of effective medications. In this study, the VD rats exhibit a progressive cognitive impairment, as well as a time‐related increasing in hippocampal neural stem cells (H‐NSCs) senescence, lost and neurogenesis decline. Then, embryonic stem cell‐derived small extracellular vesicles (ESC‐sEVs) are intravenously injected into VD rats. ESC‐sEVs treatment significantly alleviates H‐NSCs senescence, recovers compromised proliferation and neuron differentiation capacity, and reverses cognitive impairment. By microarray analysis and RT‐qPCR it is identified that several miRNAs including miR‐17‐5p, miR‐18a‐5p, miR‐21‐5p, miR‐29a‐3p, and let‐7a‐5p, that can inhibit mTORC1 activation, exist in ESC‐sEVs. ESC‐sEVs rejuvenate H‐NSCs senescence partly by transferring these miRNAs to inhibit mTORC1 activation, promote transcription factor EB (TFEB) nuclear translocation and lysosome resumption. Taken together, these data indicate that H‐NSCs senescence cause cell depletion, neurogenesis reduction, and cognitive impairment in VD. ESC‐sEVs treatment ameliorates H‐NSCs senescence by inhibiting mTORC1 activation, and promoting TFEB nuclear translocation and lysosome resumption, thereby reversing senescence‐related neurogenesis dysfunction and cognitive impairment in VD. The application of ESC‐sEVs may be a novel cell‐free therapeutic tool for patients with VD, as well as other aging‐related diseases.

Acupuncture for cognitive impairment in vascular dementia, Alzheimer’s disease and mild cognitive impairment: A systematic review and meta-analysis

IntroductionCognitive impairment is a worldwide health problem. Numerous studies have been conducted to evaluate the effect of acupuncture on cognitive impairment. However, it is still unclear that if acupuncture shows the same efficacy on cognitive impairment caused by different diseases. Therefore, we conducted a systematic review and meta-analysis based on the current evidence to evaluate the efficacy and safety of acupuncture for cognitive impairment in vascular dementia (VD), Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients. MethodsFive databases were searched from their inception to December 2019. Randomized controlled trials (RCTs) involving VD, AD or MCI treated by acupuncture alone or as part of combination therapy were included. The primary outcomes were the Mini-Mental State Examination and the Hierarchic Dementia Scale. ResultsTwenty-one RCTs (N = 2253) were quantitatively analyzed. For VD, compared with Western medicine (WM), acupuncture showed better Hierarchic Dementia Scale scores (P < 0.01), and acupuncture plus WM also showed better Hierarchic Dementia Scale scores (P < 0.01). For MCI, acupuncture showed a significant improvement in Mini-Mental State Examination (P < 0.01) and picture recognition test scores compared with WM. For AD, WM resulted in better Hierarchic Dementia Scale scores than acupuncture (P < 0.01). Eight trials reported adverse events, 15 out of 2253 patients had adverse events related to acupuncture treatment, and 25 out of 2253 patients had adverse events related to WM treatment. ConclusionAcupuncture may be efficacious for improving cognitive function in patients with VD and MCI. However, the evidence is limited, and larger sample size and more rigorous RCTs should be conducted to verify the effectiveness and safety of acupuncture.

Transcranial Direct Current Stimulation Ameliorates Cognitive Impairment via Modulating Oxidative Stress, Inflammation, and Autophagy in a Rat Model of Vascular Dementia.

To investigate the potential applications and the molecular mechanisms of transcranial direct current stimulation (tDCS) on cognitive impairment in a vascular dementia (VD) animal model. Sprague-Dawley rats were used in this study. VD rat model was induced by modified permanent bilateral common carotid artery occlusion (2-VO) approach. Anodal tDCS was applied to the animals. Morris water maze was used to analyze spatial memory and navigation ability. The pathological changes in the hippocampal CA1 region and cerebral cortex were examined via Hematoxylin-Eosin staining. The rats were sacrificed for the measurement of the level of superoxide (SOD), glutathione (GSH), reactive oxidative species (ROS), malondialdehyd (MDA), Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α level in the hippocampus. Western blot was carried out to measure the hippocampal expression of microtubule-associated protein 1 light chain 3 (LC-3) and p62. Rats with VD have decreased number of neurons in the hippocampus and cerebral cortex, as well as worse cognitive impairment. The proliferation of activated microglia and astroglia, accompanied with attenuation of myelination were observed in the white matter about 1 month after 2-VO operation. These abnormalities were significantly ameliorated by tDCS treatment. Further study revealed that anodal tDCS could suppress the MDA and ROS level, while enhance the SOD and GSH level to reduce the oxidative stress. Anodal tDCS could inhibit hypoperfusion-induced IL-1β, IL-6, and TNF-α expression to attenuate inflammatory response in hippocampus. Moreover, anodal tDCS treatment could alleviate autophagy level. The study has demonstrated a possible therapeutic role of tDCS in the treatment of cognitive impairment in VD.

Экспериментальные модели когнитивных нарушений при нейродегенеративных и органических расстройствах

Animal models of mental disorders play an important role in the study of pathophysiological mechanisms of behavior and translation of these data for the identification of causes, biomarkers and potential treatments of mental disorders in humans. This article presents a review of literature on animal models of Alzheimer's disease, cognitive impairment in vascular dementia and organic brain disease. Pharmacological, genetic models, their mechanisms and typical manifestations are covered. While pharmacological models have been widely used in studies of pathogenesis and treatment of cognitive impairment for many years, more modern transgenic models with their advantages are becoming increasingly popular in recent years. Currently there is no model that would combine all the cognitive, behavioral, biochemical and histological characteristics of a particular type of dementia, but a variety of animal models gives a lot of opportunities for preclinical research.