Piracetam reduces oxidative stress and mitochondrial function impairment in an in vitro model of vascular dementia.

Vascular dementia (VaD) is the most common cause of dementia in older adults. Due to the lack of effective treatment options, there is an urgent need to find an effective pharmaceutical compound to combat VaD. Piracetam has been reported to improve impaired cognitive function in a variety of conditions in both human and animal models. However, the role and mechanism of Piracetam in VaD remain unclear. Therefore this study aimed to elucidate the effect of Piracetam on a cellular model of VaD in vitro. We found that Piracetam enhanced the growth of OGD-stimulated SH-SY5Y cells. In addition, Piracetam inhibited the oxidative stress of OGD-stimulated SH-SY5Y cells. Further, Piracetam improved mitochondrial function of OGD-stimulated SH-SY5Y cells. Mechanistically, Piracetam inhibited the PI3K/Akt/mTOR pathway in OGD-stimulated SH-SY5Y cells. Collectively, Piracetam improved oxidative stress and mitochondrial dysfunction of OGD-stimulated SH-SY5Y cells through PI3K/Akt/mTOR axis. Hence, Piracetam has the potential to serve as a promising drug of VaD.

Exploratory Transcriptomic Profiling Reveals the Role of Gut Microbiota in Vascular Dementia.

Stroke is the second most common cause of cognitive impairment and dementia. Vascular dementia (VaD), a cognitive impairment following a stroke, is common and significantly impacts the quality of life. We recently demonstrated via gut microbe transplant studies that the gut microbe-dependent trimethylamine-N-oxide (TMAO) pathway impacts stroke severity, both infarct size and long-term cognitive outcomes. However, the molecular mechanisms that underly the role of the microbiome in VaD have not been explored in depth. To address this issue, we performed a comprehensive RNA-sequencing analysis to identify differentially expressed (DE) genes in the ischemic cerebral cortex of mouse brains at pre-stroke and post-stroke day 1 and day 3. A total of 4016, 3752 and 7861 DE genes were identified at pre-stroke and post-stroke day 1 and day 3, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated pathways of neurodegeneration in multiple diseases, chemokine signaling, calcium signaling, and IL-17 signaling as the key enriched pathways. Inflammatory response genes interleukin-1 beta (Il-1ß), chemokines (C-X-C motif chemokine ligand 10 (Cxcl10), chemokine ligand 2 (Ccl2)), and immune system genes (S100 calcium binding protein 8 (S100a8), lipocalin-2 (Lcn2)) were among the most significantly upregulated genes. Hypocretin neuropeptide precursor (Hcrt), a neuropeptide, and transcription factors such as neuronal PAS domain protein 4 (Npas4), GATA binding protein 3 (Gata3), and paired box 7 (Pax7) were among the most significantly downregulated genes. In conclusion, our results indicate that higher plasma TMAO levels induce differential mRNA expression profiles in the ischemic brain tissue in our pre-clinical stroke model, and the predicted pathways provide the molecular basis for regulating the TMAO-enhanced neuroinflammatory response in the brain.

Endothelial Dysfunction in Neurodegenerative Diseases.

The cerebral vascular system stringently regulates cerebral blood flow (CBF). The components of the blood-brain barrier (BBB) protect the brain from pathogenic infections and harmful substances, efflux waste, and exchange substances; however, diseases develop in cases of blood vessel injuries and BBB dysregulation. Vascular pathology is concurrent with the mechanisms underlying aging, Alzheimer's disease (AD), and vascular dementia (VaD), which suggests its involvement in these mechanisms. Therefore, in the present study, we reviewed the role of vascular dysfunction in aging and neurodegenerative diseases, particularly AD and VaD. During the development of the aforementioned diseases, changes occur in the cerebral blood vessel morphology and local cells, which, in turn, alter CBF, fluid dynamics, and vascular integrity. Chronic vascular inflammation and blood vessel dysregulation further exacerbate vascular dysfunction. Multitudinous pathogenic processes affect the cerebrovascular system, whose dysfunction causes cognitive impairment. Knowledge regarding the pathophysiology of vascular dysfunction in neurodegenerative diseases and the underlying molecular mechanisms may lead to the discovery of clinically relevant vascular biomarkers, which may facilitate vascular imaging for disease prevention and treatment.

Case Report of a pathologically confirmed vascular parkinsonism with early cognitive impairment and Behavioral disturbance.

BACKGROUND: Vascular Parkinsonism(VaP) is defined as parkinsonism resulting from cerebral vascular disease(CVD), with presence of variable motor and non-motor signs that are corroborated by clinical, anatomic or imaging findings of cerebrovascular disease. Overlapping syndromes with mixed pathologies make VaP difficult to distinguish from primary neurodegenerative parkinsonism.To understand the clinical and pathological features of VaP,we report a case of autopsy confirmed vascular Parkinsonism that was clinical misdiagnosed as idiopathic Parkinson's disease.Clinical features include early mixed symptoms of dementia,behavioral disturbance and parkinsonism that were similar to Dementia with lewy Body(DLB) and Parkinson disease Dementia(PDD). CASE PRESENTATION: A 84-year-old man presented progressive parkinsonism with prominent postural instability, gait impairment, pseudobulbar, early cognitive impairment, irritability, hallucination, urinary symptoms and poor responsiveness to dopaminergic drugs. He was clinically diagnosed as Parkinson disease(PD). In the post-mortem study, we examined Aß and phospho-tau as pathological biomarker for Alzheimer's disease(AD), α-synucleing in medulla, pons and midbrain for PD and DLB. Hematoxylin and eosin staining in cerebral cortex, cerebellum and brainstem examines vascular pathological changes and microvascular lesion.Neither Lewy bodies in the substantia nigra ,locus ceruleus and cerebrumnor accumulation of Aß, neurofibrillary tangles were noted. Instead, there were many cerebral infarctions and widespread arteriosclerosis in the brain. The final brain autopsy supported a diagnosis of VaP not PD. CONCLUSIONS: This case of pathologically confirmed VaP misdiagnosed as idiopathic PD suggested that we must be vigilant about the possibility of VaP for patients with parkinsonisms, cognitive impairments, early behavioral and psychological symptoms,imaging performances of cerebral small vessel disease and other vascular damages.

Color perception differentiates Alzheimer's Disease (AD) from Vascular Dementia (VaD) patients.

BACKGROUND: Alzheimer's Disease (AD) and Vascular Dementia (VaD) are the most common causes of dementia in older people. Both diseases appear to have similar clinical symptoms, such as deficits in attention and executive function, but specific cognitive domains are affected. Current cohort studies have shown a close relationship between αß deposits and age-related macular degeneration (Johnson et al., 2002; Ratnayaka et al., 2015). Additionally, a close link between the thinning of the retinal nerve fiber (RNFL) and AD patients has been described, while it has been proposed that AD patients suffer from a non-specific type of color blindness (Pache et al., 2003). METHODS: Our study included 103 individuals divided into three groups: A healthy control group (n = 35), AD (n = 32) according to DSM-IV-TR, NINCDS-ADRDA criteria, and VaD (n = 36) based on ΝΙΝDS-AIREN, as well as Magnetic Resonance Imaging (MRI) results. The severity of patient's cognitive impairment, was measured with the Mini-Mental State Examination (MMSE) and was classified according to the Reisberg global deterioration scale (GDS). Visual perception was examined using the Ishihara plates: "Ishihara Color Vision Test - 38 Plate." RESULTS: The three groups were not statistically different for demographic data (age, gender, and education). The Ishihara color blindness test has a sensitivity of 80.6% and a specificity of 87.5% to discriminate AD and VaD patients when an optimal (32.5) cut-off value of performance is used. CONCLUSIONS: Ishihara Color Vision Test - 38 Plate is a promising potential method as an easy and not time-consuming screening test for the differential diagnosis of dementia between AD and VaD.

A Mini-Review of the NADPH oxidases in Vascular Dementia: Correlation with NOXs and Risk Factors for VaD.

Oxidative stress (OS) is one of the factors that cause dementia conditions such as Alzheimer's disease and vascular dementia (VaD). In the pathogenesis of VaD, OS is associated with risk factors that include increased age, hypertension, and stroke. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are a molecular source of reactive oxygen species (ROS). According to recent studies, inhibition of NOX activity can reduce cognitive impairment in animal models of VaD. In this article, we review the evidence linking cognitive impairment with NOX-dependent OS, including the vascular NOX and non-vascular NOX systems, in VaD.

Non-classical monocytes promote neurovascular repair in cerebral small vessel disease associated with microinfarctions via CX3CR1.

Cerebral small vessel disease (cSVD) constitutes a major risk factor for dementia. Monocytes play important roles in cerebrovascular disorders. Herein, we aimed to investigate the contribution of non-classical C-X3-C motif chemokine receptor (CX3CR)1 monocytes to cSVD pathobiology and therapy. To this end, we generated chimeric mice in which CX3CR1 in non-classical monocytes was either functional (CX3CR1GFP/+) or dysfunctional (CX3CR1GFP/GFP). cSVD was induced in mice via the micro-occlusion of cerebral arterioles, and novel immunomodulatory approaches targeting CX3CR1 monocyte production were used. Our findings demonstrate that CX3CR1GFP/+ monocytes transiently infiltrated the ipsilateral hippocampus and were recruited to the microinfarcts 7 days after cSVD, inversely associated with neuronal degeneration and blood-brain barrier (BBB) disruption. Dysfunctional CX3CR1GFP/GFP monocytes failed to infiltrate the injured hippocampus and were associated with exacerbated microinfarctions and accelerated cognitive decline, accompanied with an impaired microvascular structure. Pharmacological stimulation of CX3CR1GFP/+ monocyte generation attenuated neuronal loss and improved cognitive functions by promoting microvascular function and preserving cerebral blood flow (CBF). These changes were associated with elevated levels of pro-angiogenic factors and matrix stabilizers in the blood circulation. The results indicate that non-classical CX3CR1 monocytes promote neurovascular repair after cSVD and constitute a promising target for the development of new therapies.

Differences in pharmacologic and demographic factors in male and female patients with vascular dementia, Alzheimer's disease, and mixed vascular dementia.

Background: Increasing evidence suggests that demographic and pharmacologic factors may play a significant role in the epidemiology of dementia. Sex differences in prevalence also depend on dementia subtypes, such as Alzheimer's dementia (AD), vascular dementia (VaD), and mixed vascular-Alzheimer's dementia (MVAD). Therefore, studies are needed to investigate sex-specific differences, and identify potential therapeutic targets for both sexes. Methods: Data was collected from the Prisma Health-Upstate Alzheimer's registry from 2016 to 2021 for 6,039 VaD patients, 9,290 AD patients, and 412 MVAD patients. A logistic regression was used to determine demographic and pharmacological factors associated with gender differences in patients with VaD, AD, and MVAD. Results: In patients with VaD, African Americans (OR = 1.454, 95% CI, 1.257-1.682, p < 0.001) with increasing age (OR = 1.023, 95% CI, 1.017-1.029, p < 0.001), treated with aripiprazole (OR = 4.395, 95% CI, 2.880-6.707, p < 0.001), were associated with females, whereas patients treated with galantamine (OR = 0.228, 95% CI, 0.116-0.449, p < 0.001), memantine (OR = 0.662, 95% CI, 0.590-0.744, p < 0.001), with a history of tobacco (OR = 0.312, 95% CI, 0.278-0.349, p < 0.001), and ETOH (OR = 0.520, 95% CI, 0.452-0.598, p < 0.001) were associated with males. Among AD patients, African Americans (OR = 1.747, 95% CI, 1.486-2.053, p < 0.001), and Hispanics (OR = 3.668, 95% CI, 1.198-11.231, P = 0.023) treated with buspirone (OR = 1.541, 95% CI, 1.265-1.878, p < 0.001), and citalopram (OR = 1.790, 95% CI, 1.527-2.099, p < 0.001), were associated with females, whereas patients treated with memantine (OR = 0.882, 95% CI, 0.799-0.974, p = 0.013), and with a history of tobacco (OR = 0.247, 95% CI, 0.224-0.273, p < 0.001), and ETOH (OR = 0.627, 95% CI, 0.547-0.718, p < 0.001) were associated with male AD patients. In patients with MVAD, rivastigmine (OR = 3.293, 95% CI, 1.131-9.585, p = 0.029), memantine (OR = 2.816, 95% CI, 1.534-5.168, p < 0.001), and risperidone (OR = 10.515, 95% CI, 3.409-32.437, p < 0.001), were associated with females while patients with an increased length of stay (OR = 0.910, 95% CI, 0.828-1.000, p = 0.049), with a history of tobacco (OR = 0.148, 95% CI, 0.086-0.254, p < 0.001) and ETOH use (OR = 0.229, 95% CI, 0.110-0.477, p < 0.001) were more likely to be associated with males. Conclusions: Our study revealed gender differences and similarities in the demographic and pharmacological factors of VaD, AD, and MVAD. Prospective studies are needed to determine the role of demographic and pharmacological factors in reducing sex-based disparities among VaD, AD, and MVAD patients.

Early therapeutic effects of an Angiopoietin-1 mimetic peptide in middle-aged rats with vascular dementia.

Background: Vascular Dementia (VaD) refers to dementia caused by cerebrovascular disease and/or reduced blood flow to the brain and is the second most common form of dementia after Alzheimer's disease. We previously found that in middle-aged rats subjected to a multiple microinfarction (MMI) model of VaD, treatment with AV-001, a Tie2 receptor agonist, significantly improves short-term memory, long-term memory, as well as improves preference for social novelty compared to control MMI rats. In this study, we tested the early therapeutic effects of AV-001 on inflammation and glymphatic function in rats subjected to VaD. Methods: Male, middle-aged Wistar rats (10-12 m), subjected to MMI, were randomly assigned to MMI and MMI + AV-001 treatment groups. A sham group was included as reference group. MMI was induced by injecting 800 ± 200, 70-100 µm sized, cholesterol crystals into the internal carotid artery. Animals were treated with AV-001 (1 µg/Kg, i.p.) once daily starting at 24 h after MMI. At 14 days after MMI, inflammatory factor expression was evaluated in cerebrospinal fluid (CSF) and brain. Immunostaining was used to evaluate white matter integrity, perivascular space (PVS) and perivascular Aquaporin-4 (AQP4) expression in the brain. An additional set of rats were prepared to test glymphatic function. At 14 days after MMI, 50 µL of 1% Tetramethylrhodamine (3 kD) and FITC conjugated dextran (500 kD) at 1:1 ratio were injected into the CSF. Rats (4-6/group/time point) were sacrificed at 30 min, 3 h, and 6 h from the start of tracer infusion, and brain coronal sections were imaged using a Laser scanning confocal microscope to evaluate tracer intensities in the brain. Result: Treatment of MMI with AV-001 significantly improves white matter integrity in the corpus callosum at 14 days after MMI. MMI induces significant dilation of the PVS, reduces AQP4 expression and impairs glymphatic function compared to Sham rats. AV-001 treatment significantly reduces PVS, increases perivascular AQP4 expression and improves glymphatic function compared to MMI rats. MMI significantly increases, while AV-001 significantly decreases the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), chemokine ligand 9) and anti-angiogenic factors (endostatin, plasminogen activator inhibitor-1, P-selectin) in CSF. MMI significantly increases, while AV-001 significantly reduces brain tissue expression of endostatin, thrombin, TNF-α, PAI-1, CXCL9, and interleukin-6 (IL-6). Conclusion: AV-001 treatment of MMI significantly reduces PVS dilation and increases perivascular AQP4 expression which may contribute to improved glymphatic function compared to MMI rats. AV-001 treatment significantly reduces inflammatory factor expression in the CSF and brain which may contribute to AV-001 treatment induced improvement in white matter integrity and cognitive function.

Understanding brain function in vascular cognitive impairment and dementia with EEG and MEG: A systematic review.

Vascular Cognitive Impairment (VCI) is the second most prevalent dementia after Alzheimer's Disease (AD), and cerebrovascular disease (CBVD) is a major comorbid contributor to the progression of most neurodegenerative diseases. Early differentiation of cognitive impairment is critical given both the high prevalence of CBVD, and that its risk factors are modifiable. The ability for electroencephalogram (EEG) and magnetoencephalogram (MEG) to detect changes in brain functioning for other dementias suggests that they may also be promising biomarkers for early VCI. The present systematic review aims to summarize the literature regarding electrophysiological patterns of mild and major VCI. Despite considerable heterogeneity in clinical definition and electrophysiological methodology, common patterns exist when comparing patients with VCI to healthy controls (HC) and patients with AD, though there is a low specificity when comparing between VCI subgroups. Similar to other dementias, slowed frequency patterns and disrupted inter- and intra-hemispheric connectivity are repeatedly reported for VCI patients, as well as longer latencies and smaller amplitudes in evoked responses. Further study is needed to fully establish MEG and EEG as clinically useful biomarkers, including a clear definition of VCI and standardized methodology, allowing for comparison across groups and consolidation of multicenter efforts.

Treatment With an Angiopoietin-1 Mimetic Peptide Improves Cognitive Outcome in Rats With Vascular Dementia.

Background and Purpose: Vascular dementia (VaD) is a complex neurodegenerative disease affecting cognition and memory. There is a lack of approved pharmacological treatments specifically for VaD. In this study, we investigate the therapeutic effects of AV-001, a Tie2 receptor agonist, in middle-aged rats subjected to a multiple microinfarct (MMI) model of VaD. Methods: Male, 10-12 month-old, Wistar rats were employed. The following experimental groups were used: Sham, MMI, MMI+1 µg/Kg AV-001, MMI+3 µg/Kg AV-001, MMI+6 µg/Kg AV-001. AV-001 treatment was initiated at 1 day after MMI and administered once daily via intraperitoneal injection. An investigator blinded to the experimental groups conducted a battery of neuro-cognitive tests including modified neurological severity score (mNSS) test, novel object recognition test, novel odor recognition test, three chamber social interaction test, and Morris water maze test. Rats were sacrificed at 6 weeks after MMI. Results: There was no mortality observed after 1, 3, or 6 µg/Kg AV-001 treatment in middle-aged rats subjected to MMI. AV-001 treatment (1, 3, or 6 µg/Kg) does not significantly alter blood pressure or heart rate at 6 weeks after MMI compared to baseline values or the MMI control group. Treatment of MMI with 1 or 3 µg/Kg AV-001 treatment does not significantly alter body weight compared to Sham or MMI control group. While 6 µg/Kg AV-001 treated group exhibit significantly lower body weight compared to Sham and MMI control group, the weight loss is evident starting at 1 day after MMI when treatment was initiated and is not significantly different compared to its baseline values at day 0 or day 1 after MMI. AV-001 treatment significantly decreases serum alanine aminotransferase, serum creatinine, and serum troponin I levels compared to the MMI control group; however, all values are within normal range. MMI induces mild neurological deficits in middle-aged rats indicated by low mNSS scores (<6 on a scale of 0-18). Compared to control MMI group, 1 µg/Kg AV-001 treatment group did not exhibit significantly different mNSS scores, while 3 and 6 µg/Kg AV-001 treatment induced significantly worse mNSS scores on days 21-42 and 14-42 after MMI, respectively. MMI in middle-aged rats induces significant cognitive impairment including short-term memory loss, long-term memory loss, reduced preference for social novelty and impaired spatial learning and memory compared to sham control rats. Rats treated with 1 µg/Kg AV-001 exhibit significantly improved short-term and long-term memory, increased preference for social novelty, and improved spatial learning and memory compared to MMI rats. Treatment with 3 µg/Kg AV-001 improves short-term memory and preference for social novelty but does not improve long-term memory or spatial learning and memory compared to MMI rats. Treatment with 6 µg/Kg AV-001 improves only long-term memory compared to MMI rats. Thus, 1 µg/Kg AV-001 treatment was selected as an optimal dose. Treatment of middle-aged rats subjected to MMI with 1 µg/Kg AV-001 significantly increases axon density, myelin density and myelin thickness in the corpus callosum, as well as increases synaptic protein expression, neuronal branching and dendritic spine density in the cortex, oligodendrocytes and oligodendrocyte progenitor cell number in the cortex and striatum and promotes neurogenesis in the subventricular zone compared to control MMI rats. Conclusions: In this study, we present AV-001 as a novel therapeutic agent to improve cognitive function and reduce white matter injury in middle aged-rats subjected to a MMI model of VaD. Treatment of MMI with 1 µg/Kg AV-001 significantly improves cognitive function, and increases axon density, remyelination and neuroplasticity in the brain of middle-aged rats.

Electroacupuncture of the Baihui and Shenting acupoints for vascular dementia in rats through the miR-81/IL-16/PSD-95 pathway.

Background: There is currently no effective treatment for vascular dementia (VaD). Scalp electroacupuncture (EA) has served clinically as an alternative treatment for VaD, but its mechanism is still unclear. In this study, we investigated the effect of EA at the Baihui (GV 20) and Shenting (GV 24) acupoints on spatial learning and memory ability, and the expression level of microRNA-81 (miR-81), interleukin-16 (IL-16), and postsynaptic density protein-95 (PSD-95) in the frontal cortex of VaD rats. Methods: Male Sprague-Dawley rats were randomly divided into four groups, sham, VaD, non-acupuncture (non-AP) and EA group. The VaD model was established by permanent bilateral occlusion of the common carotid arteries. Morris Water Maze was used to assess the rats' spatial learning and memory. Immunochemistry (IHC), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blot analysis were performed to detect the expression level of miR-81, IL-16, and PSD-95. Finally, luciferase assay was used to determine the effect of miR-81 on IL-16 expression in PC12 cells. Results: The space exploration experiment of MWM showed the time and distance of the rat's activities around the platform were decreased in the EA group. Compared to the VaD and non-AP group, the number of terminal deoxynucleotidyl transferase-mediated dUDP nick-end labeling (TUNEL)-positive frontal cortical neurons was significantly decreased in EA group. The number of the PSD-95-positive cells and the miR-81 expression level in the frontal cortical in the EA group was dramatically increased in comparison with the other groups. In the PC12 cell validation experiment, IL-16 expression level was reduced under the condition of the miR-81 mimic treatment, while increased in the miR-81 inhibitor group. The PSD-95 protein level was up-regulated in the small interfering (si)RNA-IL16 group compared to the NC-IL16 groups with or without oxygen/glucose deprivation/reperfusion (OGD/R) conditions (P<0.05). However, this was abolished by miR-81 mimic. Conclusions: In VaD rats, EA may improve spatial learning and memory through miR-81/IL-16/PSD-95 pathway.

Contribution of blood-brain barrier-related blood-borne factors for Alzheimer's disease vs. vascular dementia diagnosis: A pilot study.

Background: Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common types of neurodegenerative dementia among the elderly with similar symptoms of cognitive decline and overlapping neuropsychological profiles. Biological markers to distinguish patients with VaD from AD would be very useful. We aimed to investigate the expression of blood-brain barrier (BBB)-related blood-borne factors of soluble low-density lipoprotein receptor-related protein 1 (sLRP1), cyclophilin A (CyPA), and matrix metalloproteinase 9 (MMP9) and its correlation with cognitive function between patients with AD and VaD. Materials and methods: Plasma levels of sLRP1, CyPA, and MMP9 were analyzed in 26 patients with AD, 27 patients with VaD, and 27 normal controls (NCs). Spearman's rank correlation analysis was used to explore the relationships among biomarker levels, cognitive function, and imaging references. Receiver operating characteristic (ROC) curve analysis was used to discriminate the diagnosis of AD and VaD. Results: Among these BBB-related factors, plasma CyPA levels in the VaD group were significantly higher than that in the AD group (p < 0.05). Plasma sLRP1 levels presented an increasing trend in VaD while maintaining slightly low levels in patients with AD (p > 0.05). Plasma MMP9 in different diagnostic groups displayed the following trend: VaD group > AD group > NC group, but the difference was not statistically significant (p > 0.05). Furthermore, plasma sLRP1 levels were positively related to MoCA scores, and plasma CyPA levels were significantly correlated with MTA scores (p < 0.05) in the AD group. Plasma MMP9 levels were negatively correlated with MoCA scores (p < 0.05) in the VaD groups. No significant correlation was detected between the other factors and different cognitive scores (p > 0.05). ROC analysis showed a good preference of plasma CyPA [AUC = 0.725, 95% CI (0.586-0.865); p = 0.0064] in diagnosis. Conclusion: The plasma CyPA level is a reference index when distinguishing between an AD and subcortical ischemic vascular dementia (SIVD) diagnosis. Blood-derived factors associated with the BBB may provide new insights into the differential diagnosis of neurodegenerative dementia and warrant further investigation.

Construction of a ceRNA immunoregulatory network related to the development of vascular dementia through a weighted gene coexpression network analysis.

BACKGROUND: To date, vascular dementia (VaD) lacks effective treatment in clinical practice. There is also growing evidence that VaD may be closely related to the immune response. The development of high-throughput technology, and the recently discovered group of new mediators called competitive endogenous RNAs (ceRNA), provides a unique opportunity to study the immunomodulation of VaD. METHODS: In this study, we used gene expression profiles in the Gene Expression Omnibus (GEO) database to obtain immune-related gene coexpression modules through a weighted gene coexpression network analysis (WGCNA) and gene enrichment analysis. We extracted and merged long non-coding RNA (lncRNA) and microRNA (miRNA) expressions from the GEO database and mapped them with related databases. Subsequently, we used Cytoscape to construct a lncRNA-miRNA-mRNA network, and then we performed an enrichment analysis on the mRNAs in the network to determine their regulatory function. Subsequently, we used an ImmuCellAI immune infiltration analysis and constructed a ceRNA sub-network of related immune cells. Finally, we conducted a gene set enrichment analysis (GSEA) to determine the potential regulatory pathways of the key factors. RESULTS: As a result, we identified the blue module as the key module of immunity and constructed the related CeRNA network. Immune infiltration analysis showed that natural killer T (NKT) cells may be the key immune cells of VaD. Using a Pearson correlation analysis, we identified that B4GALT1, PPP1R3B, MICB, HHAT, DSC2, DNA2, SCARA3, and lncRNA NEAT1 may be the key factors of VaD. Our subsequent GSEA analysis showed that lncRNA NEAT1 may be regulated by NK cells and toll-like receptors. CONCLUSIONS: Our research provides new therapeutic targets for vascular dementia from the immunological perspective for the first time, including B4GALT1, PPP1R3B, MICB, HHAT, DSC2, DNA2, SCARA3, and lncRNA NEAT1, and our research hopes to provide new treatment options for VaD.

Vascular Dementia and Crosstalk Between the Complement and Coagulation Systems.

Vascular Dementia (VaD) is a neurocognitive disorder caused by reduced blood flow to the brain tissue, resulting in infarction, and is the second most common type of dementia. The complement and coagulation systems are evolutionary host defence mechanisms activated by acute tissue injury to induce inflammation, clot formation and lysis; recent studies have revealed that these systems are closely interlinked. Overactivation of these systems has been recognised to play a key role in the pathogenesis of neurological disorders such as Alzheimer's disease and multiple sclerosis, however their role in VaD has not yet been extensively reviewed. This review aims to bridge the gap in knowledge by collating current understanding of VaD to enable identification of complement and coagulation components involved in the pathogenesis of this disorder that may have their effects amplified or supressed by crosstalk. Exploration of these mechanisms may unveil novel therapeutic targets or biomarkers that would improve current treatment strategies for VaD.

Estrogen receptor involvement in vascular cognitive impairment and vascular dementia pathogenesis and treatment.

Vascular cognitive impairment (VCI) is a term that encompasses a continuum of cognitive disorders with cerebrovascular pathology contribution, ranging from mild cognitive impairment to vascular dementia (VaD). VCI and VaD, thus, represent an interesting intersection between cardiovascular disease and neurodegenerative disorders such as Alzheimer's disease (AD) and a rising area of research in recent years. Although VCI and VaD research has identified various causes and explanations for disease development, many aspects remain unclear, particularly sex differences in VCI (e.g., epidemiology), unlike those available for cardiovascular disease and AD. Despite limited information in the literature, several studies have observed an association of estrogen receptor (ER) polymorphisms and VaD. If further explored, this association could provide valuable insights for novel therapeutic approaches. This review aims to provide a brief epidemiological overview and subsequent discussion exploring concepts of brain aging and involvement of estrogen receptors in potential mechanisms of VCI/VaD pathogenesis and treatment development.

Exploring the mechanism of Yizhi Tongmai decoction in the treatment of vascular dementia through network pharmacology and molecular docking.

BACKGROUND: Vascular dementia (VaD) is a degenerative cerebrovascular disease that leads to progressive decline of patients' cognitive ability and memory. Yizhi Tongmai (YZTM) decoction is an empirical prescription first formulated by Professor Guomin Si. Our previous experiments proved the effectiveness of this prescription in the treatment of VaD. In this study, we aimed to use network pharmacology and molecular docking technology to systematically explain the potential anti-VaD mechanism of YZTM. METHODS: We identified the core compounds of YZTM and their potential targets through the TCMSP, BATMAN, and SwissTargetPrediction databases. Then, we identified the molecular targets of YZTM in VaD using the Online Mendelian Inheritance in Man and GeneCards databases. The common targets of YZTM and VaD were screened out, and then the pathways of these target genes were analyzed using the Database for Annotation, Visualization and Integrated Discovery v6.8. Molecular docking was used to verify the relationship between the core compounds and proteins. RESULTS: Through network pharmacology analysis, we discovered that the 5 core compounds in YZTM exert an anti-VaD effect. The potential mechanism of YZTM anti-VaD may be through inhibiting the NLRP3 inflammasome, TNF signaling pathway, and toll-like receptor signaling pathways. Subsequently, key compounds were docked with related proteins in the NLRP3 inflammasome (NLRP3, ASC, caspase-1, interleukin-18, and interleukin-1 ß) using molecular docking technology. The compounds were found to spontaneously bind to the proteins. CONCLUSIONS: YZTM may exert an anti-VaD effect through inhibition of the NLRP3 inflammasome. In addition, TNF signaling pathway and toll-like receptor signaling pathway may also be its underlying mechanism. The application of network pharmacology and molecular docking technology may provide a novel method for research of Chinese herbal medicine. YZTM may also provide a complementary treatment option for patients with VaD.

Serum Amyloid Biomarkers, Tau Protein and YKL-40 Utility in Detection, Differential Diagnosing, and Monitoring of Dementia.

Introduction: The diagnosis and treatment of dementia is one of the greatest challenges in contemporary health care. The widespread use of dementia biomarkers would improve the quality of life of patients and reduce the economic costs of the disease. The aim of the study was to evaluate the usefulness of proteins related to the Alzheimer's disease pathogenesis-amyloid beta isoform (Aß) and total tau protein (t-tau), as well as the quite recently discovered marker YKL-40 in the most common types of dementia. Methods: 60 dementia (AD-Alzheimer's disease, VaD-vascular dementia, MxD-mixed dementia) and 20 cognitively normal subjects over 60 years old were examined. Subjects with dementia of etiology different than AD or VaD and with neoplastic or chronic inflammatory diseases were excluded. Concentrations of Aß40, Aß42, t-tau, and YKL-40 were measured in serum using ELISA kits on admission and after 4 weeks of inpatient treatment. ANOVA and Tukey's test or Dunn's test were used to perform comparison tests between groups. Correlations were measured using Pearson's coefficient. Biomarker diagnostic utility was assessed with ROC analysis. Results: YKL-40 differentiates between cognitively normal and mild dementia patients with 85% sensitivity and specificity and t-tau with 72% sensitivity and 70% specificity. YKL-40 and t-tau concentrations correlate with each other and with the severity of clinically observed cognitive decline. Conclusions: YKL-40 is a sensitive and specific biomarker of early dementia and, to a lesser extent, of dementia progression, however, many comorbidities may influence its levels. In such conditions, less specific but still reliable t-tau may serve as an alternative marker. Obtained results did not confirm the diagnostic utility of amyloid biomarkers.

Sex Differences in Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis.

Background: Cerebral small vessel disease (SVD) is a common cause of stroke, mild cognitive impairment, dementia and physical impairments. Differences in SVD incidence or severity between males and females are unknown. We assessed sex differences in SVD by assessing the male-to-female ratio (M:F) of recruited participants and incidence of SVD, risk factor presence, distribution, and severity of SVD features. Methods: We assessed four recent systematic reviews on SVD and performed a supplementary search of MEDLINE to identify studies reporting M:F ratio in covert, stroke, or cognitive SVD presentations (registered protocol: CRD42020193995). We meta-analyzed differences in sex ratios across time, countries, SVD severity and presentations, age and risk factors for SVD. Results: Amongst 123 relevant studies (n = 36,910 participants) including 53 community-based, 67 hospital-based and three mixed studies published between 1989 and 2020, more males were recruited in hospital-based than in community-based studies [M:F = 1.16 (0.70) vs. M:F = 0.79 (0.35), respectively; p < 0.001]. More males had moderate to severe SVD [M:F = 1.08 (0.81) vs. M:F = 0.82 (0.47) in healthy to mild SVD; p < 0.001], and stroke presentations where M:F was 1.67 (0.53). M:F did not differ for recent (2015-2020) vs. pre-2015 publications, by geographical region, or age. There were insufficient sex-stratified data to explore M:F and risk factors for SVD. Conclusions: Our results highlight differences in male-to-female ratios in SVD severity and amongst those presenting with stroke that have important clinical and translational implications. Future SVD research should report participant demographics, risk factors and outcomes separately for males and females. Systematic Review Registration: [PROSPERO], identifier [CRD42020193995].

Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors.

Vascular dementia (VaD) constitutes the second most prevalent cause of dementia in the world after Alzheimer's disease (AD). VaD regroups heterogeneous neurological conditions in which the decline of cognitive functions, including executive functions, is associated with structural and functional alterations in the cerebral vasculature. Among these cerebrovascular disorders, major stroke, and cerebral small vessel disease (cSVD) constitute the major risk factors for VaD. These conditions alter neurovascular functions leading to blood-brain barrier (BBB) deregulation, neurovascular coupling dysfunction, and inflammation. Accumulation of neurovascular impairments over time underlies the cognitive function decline associated with VaD. Furthermore, several vascular risk factors, such as hypertension, obesity, and diabetes have been shown to exacerbate neurovascular impairments and thus increase VaD prevalence. Importantly, air pollution constitutes an underestimated risk factor that triggers vascular dysfunction via inflammation and oxidative stress. The review summarizes the current knowledge related to the pathological mechanisms linking neurovascular impairments associated with stroke, cSVD, and vascular risk factors with a particular emphasis on air pollution, to VaD etiology and progression. Furthermore, the review discusses the major challenges to fully elucidate the pathobiology of VaD, as well as research directions to outline new therapeutic interventions.