Number Of Plaques Research Articles

Composite cardiac computed tomography angiography score for improved risk assessment in chronic coronary syndromes

Agatston score, the degree of lumen narrowing categorized by CAD-RADS, high-risk atherosclerotic plaque features and pericoronary adipose tissue attenuation (PCAT) are parameters, which can be assessed non-invasively by coronary computed tomography angiography (CCTA) and aid risk stratification in patients with chronic coronary syndromes (CCS). However, few studies have so far compared the prognostic value of all those parameters together. To develop and test the prognostic value of a composite CCTA score, derived from Agatston score, CAD-RADS, high-risk plaques and PCAT in patients undergoing CCTA due to CCS. Consecutive patients with clinical indication for CCTA and available clinical follow-up of ≥ 6 months after the CCTA examination were included. (i) Agatston score, (ii) CAD-RADS, (iii) the number of plaques with at least one high-risk feature and (iv) PCAT in the proximal 4 cm of the right coronary artery (RCA) were measured, and a composite CCTA score was generated considering all four parameters. The primary endpoint encompassed all-cause mortality, myocardial infarction, and coronary revascularization (> 60 days after the CCTA scan) during follow-up. In total, 759 patients (median age 68.0 (IQR 59.0–76.0) years, 352 (46.4%) female) were included. During a median follow-up of 591.5 (IQR 505.5-686.8) days, 39 (5.1%) patients reached the primary endpoint. Cox-proportional regression demonstrated that the Agatston score, the number of high-risk plaques and CAD-RADS predicted the primary endpoint, independent of age and conventional cardiovascular risk factors. The number of high-risk plaques per patient provided the most robust prediction of the primary endpoint (HR = 2.74, 95%CI = 1.56–4.80, p < 0.001), whereas the composite CCTA score outperformed all other parameters (HR = 1.54, 95%CI = 1.19–1.98, p < 0.001). The Agatston score, CAD-RADS and high-risk plaque features may provide complementary prognostic information in patients with CCS. A composite CCTA score, derived by these imaging markers may identify high-risk individuals, who may benefit from more intensified treatment and clinical follow-up in future studies.

Correlation of intracranial and extracranial carotid atherosclerotic plaque characteristics with ischemic stroke recurrence: a high-resolution vessel wall imaging study

ObjectivesTo evaluate the ability of the plaque characteristics of extracranial carotid and intracranial arteries to predict large atherosclerotic ischemic stroke recurrence via head and neck combined high-resolution vessel wall imaging (HR-VWI).MethodsThis prospective cohort study included 169 patients with large atherosclerotic ischemic stroke who underwent head and neck combined HR-VWI from April 2022 to May 2023. The baseline clinical data and atherosclerotic plaque characteristics of the intracranial and extracranial carotid arteries were collected, and the patients were followed up for 1 year, with the endpoint event defined as recurrent ischemic stroke. Clinical and imaging data were compared between the recurrent and nonrecurrent groups. Independent risk factors associated with stroke recurrence were assessed via multivariate Cox regression analysis. The receiver operating characteristic (ROC) curves of the relevant variables were also plotted, and the area under the curve (AUC) was calculated to assess their ability to predict stroke recurrence. Kaplan–Meier survival curves were used to compare the probability of stroke recurrence.ResultsDuring the 12-month follow-up, stroke recurrence occurred in 35 of the 169 patients. Multivariate Cox regression analysis revealed that the total number of intracranial and extracranial carotid plaques (p = 0.010) and coexisting extracranial carotid plaques and intracranial significantly enhanced plaques (p = 0.047) were independent risk factors for recurrent ischemic stroke. The AUCs for predicting stroke recurrence were 0.787 and 0.710, respectively. The Kaplan–Meier survival curve revealed that the risk of stroke recurrence was significantly greater in patients whose total number of intracranial and extracranial carotid plaques was &amp;gt;4.5 than in patients whose total number of plaques was &amp;lt;4.5 (p &amp;lt; 0.001) and was significantly greater in patients with coexisting extracranial carotid plaques and intracranial significantly enhanced plaques than in patients without coexisting plaques (p &amp;lt; 0.001).ConclusionA greater total number of intracranial and extracranial carotid plaques and the coexistence of extracranial carotid plaques and intracranially significantly enhanced plaques are independent risk factors associated with recurrent ischemic stroke. Head and neck combined HR-VWI may provide new indicators for the prediction of stroke recurrence, thus helping clinicians identify high-risk patients and target therapy to reduce the recurrence of ischemic events.

Olfactory Evoked Potentials and Brain MRI Outcomes in Multiple Sclerosis Patients: A Cross-Sectional Study.

Background: Olfactory dysfunction (OD) is an underestimated symptom in multiple sclerosis (MS). Multiple factors may play a role in the OD reported by MS patients, such as ongoing inflammation in the central nervous system (CNS), damage to the olfactory bulbs due to demyelination, and the presence of plaques in brain areas associated with the olfactory system. Indeed, neuroimaging studies in MS have shown a clear association of the OD with the number and activity of MS-related plaques in frontal and temporal brain regions. However, these studies have used only psychophysical tests to evaluate the OD in MS patients. Olfactory Event-Related Potentials (OERPs) are a method to assess olfaction with the clear advantage of its objectivity in comparison with psychophysical tests. The aim of this study was to investigate the association between the parameters of OERP components (latency and amplitude) and the lesion load of the brain regions which are involved in olfaction in a cohort of relapsing-remitting (RR) MS patients. Methods: In this cross-sectional study, we enrolled 30 RRMS patients and 30 healthy controls. The parameters of OERP components and magnetic resonance imaging data (lesions in the CNS) were analyzed in RRMS patients. Results: The association found between the RRMS patient groups with and without OERPs and the number of lesions in the frontal area as well as the correlation between the lesion load in the temporal area and OERP parameters suggest how brain alterations may impact on olfactory performance in MS. In addition, the predictive value of the number of lesions in the frontal and parietal areas for P2 amplitude also highlights the potential for OERP measures to serve as markers for disease progression in MS. Conclusions: This approach to assess the olfaction in MS could improve our understanding of the disease's neurological impact and contribute to the development of new targeted interventions to mitigate olfactory sensory deficits.

Enhancement of memory and reduction of amyloid plaques in alzheimer\'s disease mouse model using cyclic glycine-proline

Amyloid plaques and neurofibrillary tangles are two of the most important signs that can be used to diagnose Alzheimer's disease (AD), which is a neurodegenerative condition. Animal models, such as APP/PS1 mice, are extremely important for advancing our understanding of the factors that contribute to Alzheimer's disease and evaluating potential treatments. The purpose of this study is to investigate the effects of cyclic glycine-proline (cGP), a stable cyclic dipeptide that originates from glutamate, on spatial memory and the accumulation of amyloid plaque in mice with Alzheimer's disease and Parkinson's disease type 1.In order to evaluate the spatial memory of APP/PS1 mice, the Morris Water Maze was utilised after the mice had been administered cGP. To determine the amount of amyloid plaque in the brain, first the staining was done using thioflavin-S, then imaging was performed, and last the results were quantified. Treatment with cGP resulted in a considerable reduction in the quantity of amyloid plaque and an improvement in spatial memory in mice with APP/PS1 mutations. There was a decline in escape latency times, amyloid plaque numbers, and plaque covering percentages in the cortex and hippocampus.There is evidence to suggest that cGP may have therapeutic potential; in a rat model of Alzheimer's disease, it was found to improve cognitive performance and reduce amyloid pathology. The therapeutic potential of cGP in reducing AD pathology and cognitive impairment is demonstrated by these results.

Voluntary running exercise promotes maturation differentiation and myelination of oligodendrocytes around Aβ plaques in the medial prefrontal cortex of APP/PS1 mice.

Previous studies have reported that running exercise could improves myelinization in hippocampus. However, the effects of running exercise on the differentiation and maturation of oligodendrocytes, and myelination surrounding Aβ plaques in the medial prefrontal cortex (mPFC) of the Alzheimer's disease (AD) brain have not been reported. Forty 10-month-old male APP/PS1 AD mice were randomly divided into the AD group and the AD running (AD+RUN) group, while 20 age-matched wild-type littermate mice were included in the WT group. The running group received three-month voluntary running exercise in a running cage, while the AD and WT groups were untreated. After the exercise intervention, all mice were given behavioral tests. The total number of mature oligodendrocytes (CC1+) in the mPFC of mice was precisely quantified using unbiased stereology. Myelin basic protein (MBP) and Aβ plaque, as well as the fluorescence area of MBP surrounding Aβ plaques, and the density and morphology of PDGFα+ cells in the mPFC were analyzed using immunofluorescence. The levels of working memory, cognitive memory, spatial learning and memory ability were decreased significantly in the AD group compared to the WT group, while these functions were significantly improved in the AD+RUN group compared to the AD group. The Aβ plaques in the mPFC were significantly reduced in the AD+RUN group compared to the AD group. The total number of CC1+ cells and the percentage of MBP fluorescence area surrounding Aβ plaques in the mPFC were significantly lower in the AD group compared to the WT group, but they were significantly higher in the AD+RUN group compared to the AD group. The density and branching complexity of PDGFα+ cells surrounding Aβ plaques in the mPFC were significantly higher in the AD group than in the WT group, while the AD+RUN group showed significantly lower density and branching complexity than the AD group. Changes in MBP expression around Aβ plaques, cell density and cell branching complexity of PDGFα+ cells around Aβ plaques were closely related to the number of Aβ plaques in mPFC, and they were also closely related to behavioral changes in mice. Voluntary running exercise could reduce Aβ plaque deposition and promote the maturation and myelination capacity of oligodendrocytes surrounding Aβ plaques in the mPFC of AD mice, thereby improving the learning and memory abilities of APP/PS1 transgenic AD mice.

Mediterranean diet, neutrophil count, and carotid intima-media thickness in secondary prevention: the CORDIOPREV study.

Several studies have supported the role of innate immune system as a key factor in the sterile inflammation underlying the pathophysiology of atherosclerosis in mice. However, its involvement in humans remains unclear. This study aimed to explore the association between neutrophil count, and the intima-media thickness of common carotid arteries (IMT-CC), as well as the potential impact of long-term dietary interventions on these associations. A comprehensive analysis was conducted within the framework of the CORDIOPREV study, a long-term secondary prevention study involving dietary interventions with either a Mediterranean or a low-fat diet. The study evaluated the relationship between absolute neutrophil count and neutrophil-related ratios with IMT-CC at baseline and after 5 and 7 years of dietary intervention. At baseline, patients in the highest tertile of neutrophil count had a higher IMT-CC and number of carotid plaques, when compared to lowest tertile (P < .01 and P < .05, respectively). Logistic regression analyses supported this association. Elevated neutrophil count, neutrophil-to-erythrocyte ratio, and neutrophil-to-HDL ratio were associated with an increased likelihood of having an IMT-CC >.9 mm {odds ratio (OR) 1.17 [95% confidence interval (CI) 1.04-1.35], OR 2.21 (95% CI 1.24-4.12), and OR 1.96 (95% CI 1.09-3.55), respectively}, after adjustment for all variables, which was corroborated by linear regression. Furthermore, a linear mixed-effect model analysis from a longitudinal analysis spanning 5 and 7 years revealed an increase in 1 unit of neutrophils/μl at these time points was associated with a mean increase of .004 (.002) mm in the IMT-CC (P = .031) after adjustment for all variables. Interestingly, in patients exhibiting regression in IMT-CC after 7 years of follow-up, those following a Mediterranean diet showed a significant decrease in neutrophil count after 5 and 7 years (both with P < .05), compared to baseline. These findings suggest that neutrophils may represent a promising target for preventing atherosclerosis. A Mediterranean diet could serve as an effective dietary strategy to reduce neutrophil levels and potentially slow the progression of atherosclerosis, offering a new neutrophil-reducing therapy concept. Further research is essential to gain deeper insights into the role of neutrophils in the pathophysiology of atherosclerotic cardiovascular disease in humans.

Blood Lipid Polygenic Risk Score Development and Application for Atherosclerosis Ultrasound Parameters.

Background: The present study investigates the feasibility of using three previously published genome-wide association studies (GWAS) results on blood lipids to develop polygenic risk scores (PRS) for population samples from the European part of the Russian Federation. Methods: Two population samples were used in the study - one from the Ivanovo region (n = 1673) and one from the Vologda region (n = 817). We investigated three distinct approaches to PRS development: using the straightforward PRS approach with original effect sizes and fine-tuning with PRSice-2 and LDpred2. Results: In total, we constructed 56 PRS scales related to four lipid phenotypes: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglyceride levels. Compared with previous results for the Russian population, we achieved an additional R2 increase of 2-4%, depending on the approach and lipid phenotype studied. Overall, the R2 PRS estimates approached those described for other populations. We also evaluated the clinical utility of blood lipid PRS for predicting carotid and femoral artery atherosclerosis. Specifically, we found that PRS for total cholesterol, low-density lipoprotein cholesterol, and triglycerides were positively correlated with ultrasound parameters of carotid and femoral artery atherosclerosis (ρ = 0.09-0.13, p < 0.001), whereas PRS for high-density lipoprotein cholesterol were inversely correlated with the number of plaques in the femoral arteries (ρ = -0.08, p = 8.71 × 10-3). Conclusions: PRS fine-tuning using PRSice-2 add LDpred2 improves the performance of blood lipid PRS. Our study demonstrates the potential for further use of blood lipid PRS for prediction of atherosclerosis risk.

Novel T-cell subsets as non-invasive biomarkers of vascular damage along the predialysis stages of chronic kidney disease

IntroductionCardiovascular disease is the major cause of premature death in chronic kidney disease (CKD) and vascular damage is often detected belatedly, usually evaluated by expensive and invasive techniques. CKD involves specific risk factors that lead to vascular calcification and atherosclerosis, where inflammation plays a critical role. However, there are few inflammation-related markers to predict vascular damage in CKD. This study aimed to investigate immune populations in pre-dialysis patients to (i) identify subset alterations, (ii) assess longitudinal changes, and (iii) evaluate their applicability as biomarkers of subclinical vascular indices.Methods43 pre-dialysis CKD patients in stages CKD-2 to CKD-5 and 38 controls were recruited at baseline and after 18-month follow-up. Aortic stiffness was determined by carotid-femoral pulse wave velocity (PWV) and abdominal aortic calcification was quantified by the Kauppila index on X-rays. Carotid intima-media thickness, the number of carotid plaques and adventitial neovascularization were evaluated by Superb Microvascular Imaging. Peripheral blood mononuclear cells were isolated and immune cell populations were assessed by flow cytometry: senescent T cells (CD4+CD28null), Tang (CD3+CD31+CD184+) and derived subsets, and monocyte subsets (classical, intermediate and non-classical; and ACE expression).ResultsSenescent T cells were increased in CKD. Despite Tang levels were unchanged compared to controls, this subset exhibited enhanced immunosenescence traits (CD28null and inverted CD4+CD8+ ratio) in CKD. Furthermore, Tang were negatively correlated with CKD progression. Slight alterations within monocyte subsets were observed. These findings were validated at the 18-month follow-up. Tang were correlated with several subclinical indices, and further analyses revealed an independent effect on PWV and their potential value as biomarkers. Intermediate monocytes were positively correlated with PWV.ConclusionPre-dialysis CKD stages are hallmarked by alterations in immune cell populations related to vascular homeostasis, including early T-cell immunosenescence traits and a stage-dependent Tang depletion, which was independently related to vascular stiffness. All these features were replicated upon follow-up, thus providing validation toward our results. Our findings pave the ground for future studies addressing the functional contribution of these cellular mediators at the local level, assessing their potential predictive value in the long-term and implementing preventive strategies in the clinical setting.

Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease

The role of microglia in the amyloid cascade of Alzheimer’s disease (AD) is debated due to conflicting findings. Using a genetic and a pharmacological approach we demonstrate that depletion of microglia before amyloid-β (Aβ) plaque deposition, leads to a reduction in plaque numbers and neuritic dystrophy, confirming their role in plaque initiation. Transplanting human microglia restores Aβ plaque formation. While microglia depletion reduces insoluble Aβ levels, soluble Aβ concentrations stay consistent, challenging the view that microglia clear Aβ. In later stages, microglial depletion decreases plaque compaction and increases neuritic dystrophy, suggesting a protective role. Human microglia with the TREM2R47H/R47H mutation exacerbate plaque pathology, emphasizing the importance of non-reactive microglia in the initiation of the amyloid cascade. Adaptive immune depletion (Rag2-/-) does not affect microglia’s impact on plaque formation. These findings clarify conflicting reports, identifying microglia as key drivers of amyloid pathology, and raise questions about optimal therapeutic strategies for AD.

The Associations of Arterial Stiffness and Central Hemodynamics with Carotid Atherosclerosis in Patients at a High Coronary Risk: A Cross-Sectional Study

Introduction: It is not well-known which indicator, central blood pressure (CBP) or arterial stiffness, has a greater impact on carotid atherosclerosis. This study aimed to assess the associations of carotid atherosclerosis with arterial stiffness and CBP in the same individuals. Methods: A total of 142 patients (mean age: 69 years; 43% female) with documented atherosclerotic cardiovascular disease or multiple risk factors were analyzed. Brachial-ankle pulse wave velocity (baPWV) and CBP measurements, along with carotid ultrasound, were performed on the same day. CBP was assessed using radial artery tonometry. Results: In simple linear regression analysis, only baPWV exhibited a significant correlation with carotid intima-media thickness (CIMT) (r = 0.272; p = 0.001), whereas none of the CBP parameters (systolic, diastolic, pulse pressures, and augmentation index) correlated with CIMT (p > 0.05 for each). Multiple linear regression analysis indicated that baPWV had no significant association with CIMT after adjusting for age (p = 0.264). A higher baPWV (≥1,656 cm/s) was significantly associated with carotid plaque presence, even after accounting for potential confounders (odds ratio: 3.66; 95% confidence interval: 1.65–8.12; p = 0.001). Moreover, as the number of carotid plaques increased, there was a linear rise in baPWV (p < 0.001). None of CBP parameters were associated with the presence of carotid plaque (p > 0.05 for each). Conclusions: Among a high-risk Korean population, baPWV demonstrated a stronger association with carotid plaque presence and extent compared to CBP parameters. Thus, baPWV may serve as a valuable marker for identifying carotid plaque.

The effects of a bioavailable curcumin formulation on Alzheimer's disease pathologies: A potential risk for neuroinflammation

AbstractAlzheimer's disease (AD) is a common cause of dementia characterized by the presence of two proteinaceous deposits in the brain. These pathologies may be a consequence of complex interactions between neurons and glia before the onset of cognitive impairments. Curcumin, a bioactive compound found in turmeric, is a promising candidate for AD because it alleviates neuropathologies in mouse models of the disease. Although its clinical efficacy has been hindered by low oral bioavailability, the development of new formulations may overcome this limitation. The purpose of this study was to determine the effects of a bioavailable curcumin formulation in a mouse model of AD. The formulation was administered to mice in drinking water after encapsulation into micelles using a previously validated method. A neuropathological assessment was performed to determine if it slows or alters the course of the disease. Cognitive performance was not included because it had already been assessed by a previous study. The bioavailable curcumin formulation was unable to alter the size or number of amyloid plaques in a transgenic mouse model. In addition, mechanisms that regulate amyloid beta production were unchanged, suggesting that the disease had not been altered. The number of reactive astrocytes in the hippocampus and dentate gyrus was not altered by curcumin. However, protein levels of glial fibrillary acidic protein were increased overall in the brain, suggesting that it may have aggravated neuroinflammation. Therefore, a higher dosage, despite its enhanced oral bioavailability, may have a potential risk for neuroinflammation.

Assessing multi-target antiviral and antioxidant activities of natural compounds against SARS-CoV-2: an integrated in vitro and in silico study

There is an urgent need for preventive and therapeutic drugs to effectively treat and prevent viral diseases from resurfacing as they emerge during the COVID-19 pandemic. This study aims to assess the antiviral effects of four natural compounds commonly used in traditional medicine to treat SARS-CoV-2 infection. A cytotoxicity, dose-dependent, and plaque reduction assay was performed on Vero CCL-81 cells to figure out their effects on the cells. Quantification of cytokines was assessed. In silico analysis for the selected compound was also evaluated. Results revealed that the compounds could disrupt the viral replication cycle through direct inhibition of the virus or immune system stimulation. The cytotoxicity assay results revealed that the compounds were well tolerated by the cells, indicating that the compounds were not toxic to the cells. This study evaluated the antioxidant capacities of propolis, curcumin, quercetin, and ginseng using ABTS, FRAP, and CUPRAC assays, revealing that propolis exhibited the highest antioxidant activity of ABTS with 1250.40 ± 17.10 μmol Trolox eq/g, with FRAP values reaching 1200.55 ± 15.90 μmol Fe2⁺ eq/g and CUPRAC values of 1150.80 ± 14.20 μmol Trolox eq/g at 1000 µg/mL, highlighting its potential as a potent natural antioxidant. The results of the plaque reduction assay revealed that the compounds could reduce the size and number of plaques, indicating that the compounds could inhibit the virus replication cycle. Subsequently, using molecular docking to analyze the effect of propolis, curcumin, quercetin, and ginseng as inhibitors, it was unveiled that the four compounds are likely to have the potential to inhibit the protease activity, spike protein S1, and RNA polymerase of SARS-CoV-2 and the virus titer was reduced by 100% after post-infection using propolis as an inhibitor control.Graphical

Healthy Dietary Patterns and Lower Atherosclerosis in High-Risk Individuals.

This study investigates associations between diet patterns and the risk of intracranial atherosclerosis (ICAD) in individuals with preexisting hypertension (HTN) or myocardial infarction (MI). 676 autopsied participants (mean age at death =91.1±6.1, 71% women) of a longitudinal clinical neuropathological cohort study, with complete dietary and neuropathology data, were included. Diet scores were computed (median interval to death = 5.9 (3.0, 8.7 years). HTN and MI history was self-reported. Large vessel atherosclerosis was evaluated at the circle of Willis, and severity of intracranial atherosclerosis was assessed based on number of atherosclerotic plaques, extent of vessel involvement, and degree of vessel occlusion to create a 4-level grading system (0-3). All regression models were adjusted for age, sex, education, caloric intake, and APOE4. Of the 676 subjects, 361 (53%) had mild, 142 (21%) had moderate, and 29 (5%) had severe atherosclerosis. There was no direct relationship between diet and atherosclerosis. The relationship between ICAD and MI (OR = 1.38, 95% CI = 0.95, 2.00) showed a nonsignificant trend. HTN (OR = 1.598, 95% CI = 1.15, 2.18) was positively associated with intracranial atherosclerosis. The association of diet with intracranial atherosclerosis differed by history of MI (MIND (p=0.007), MedDiet (p=0.006)). The association between ICAD and the MIND diet also differed by whether HTN was reported (β=-0.212, SE= 0.111, p=0.055) as did the relationship between ICAD and the MedDiet (β = -0.077, SE= 0.035, p=0.029). In stratified analysis, among individuals with preexisting MI (N=130), those with a better diet had lower odds of intracranial atherosclerosis (MedDiet: OR = 0.88, 95% CI = 0.81, 0.96; MIND: OR = 0.69, 95% CI = 0.53, 0.90). A healthy dietary pattern is associated with lower odds of severe intracranial large vessel atherosclerosis in high-risk older adults. In-vivo studies of dietary habits and brain health, specifically in those at high vascular risk are needed.

Valproate Administration to Adult 5xFAD Mice Upregulates Expression of Neprilysin and Improves Olfaction and Memory.

It is well known that the development of neurodegeneration, and especially Alzheimer's disease (AD), is often accompanied by impaired olfaction which precedes memory loss. A neuropeptidase neprilysin (NEP)-a principal amyloid-degrading enzyme in the brain-was also shown to be involved in olfactory signalling. Previously we have demonstrated that 5xFAD mice develop olfactory deficit by the age of 6months which correlated with reduced NEP expression in the brain areas involved in olfactory signalling. The aim of this study was to analyse the effect of administration of a histone deacetylase inhibitor, valproic acid (VA), to adult 5xFAD mice on their olfaction and memory as well as on brain morphology and NEP expression in the parietal cortex (PC) and hippocampus (Hip). The data obtained demonstrated that administration of VA to 7-month-old mice (200mg/kg of body weight) for 28days resulted in improvement of their memory in the Morris water maze as well as olfaction in the odor preference and food search tests. This correlated with increased expression of NEP in the PC and Hip as well as a reduced number of amyloid plaques in these brain areas. This strongly suggests that NEP can be considered an important therapeutic target not only in AD but also in olfactory loss.

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer’s disease

BackgroundThe accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer’s disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored.MethodsWe generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL−G−F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background.ResultsBace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL−G−F/wt). Insoluble Aβ1–40 and Aβ1–42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL−G−F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1.ConclusionOur results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.

FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models.

Endocannabinoids have attracted great interest for their ability to counteract the neuroinflammation underlying Alzheimer's disease (AD). Our study aimed at evaluating whether this activity was also due to a rebalance of autophagic mechanisms in cellular and animal models of AD. We supplied URB597, an inhibitor of Fatty-Acid Amide Hydrolase (FAAH), the degradation enzyme of anandamide, to microglial cultures treated with Aβ25-35, and to Tg2576 transgenic mice, thus increasing the endocannabinoid tone. The addition of URB597 did not alter cell viability and induced microglia polarization toward an anti-inflammatory phenotype, as shown by the modulation of pro- and anti-inflammatory cytokines, as well as M1 and M2 markers; moreover microglia, after URB597 treatment released higher levels of Bdnf and Nrf2, confirming the protective role underlying endocannabinoids increase, as shown by RT-PCR and immunofluorescence experiments. We assessed the number and area of amyloid plaques in animals administered with URB597 compared to untreated animals and the expression of autophagy key markers in the hippocampus and prefrontal cortex from both groups of mice, via immunohistochemistry and ELISA. After URB597 supply, we detected a reduction in the number and areas of amyloid plaques, as detected by Congo Red staining and a reshaping of microglia activation as shown by M1 and M2 markers' modulation. URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD.

Treatment for acute alcoholic-alimentary pancreatitis with peritoneal syndrome

A large number of publications on surgical treatment of acute alcohol-induced pancreatitis (AAP) with peritonitis indicates the importance of the problem and the need for a differentiated approach to treatment. The aim of this study is to determine the optimal treatment policy for acute alcohol-associated pancreatitis with peritonitis. The study included 114 male patients diagnosed with acute alcoholic pancreatitis and peritoneal sepsis, with an average age of 48.6 ± 6.4 years. They were admitted to the surgical departments of clinical hospitals between 2013 and 2023. The diagnosis of AAP was confi med based on clinical, laboratory, and instrumental findings. The classification of acute pancreatitis recommended by the National Clinical Guidelines of the Ministry of Health of the Russian Federation (2015 and 2020) has been applied. The Acute Physiology and Chronic Health Evaluation II (APACHE II) scale has been used to assess the severity and prognosis of the disease, while the Sequential Organ Failure Assessment (SOFA) scale has been used to evaluate organ failure. Based on the results, an algorithm for the treatment of acute alcoholic and alimentary pancreatitis with peritoneal syndrome has been proposed, taking into account the type of pancreatic necrosis, the extent of pancreatic damage, and the nature of fl uid accumulation. For patients with edematous pancreatitis, small-focal sterile pancreatic necrosis, and enzymatic peritonitis, percutaneous ultrasound-guided abdominal and omental drainage is recommended. In severe and moderate acute alcoholic-alimentary pancreatitis, with enzymatic peritonitis (more than 8 points on the APACHE II scale), which is manifested during diagnostic and sanitation laparoscopy by the presence of a hemorrhagic effusion and a large number of plaques of steatonecrosis on the parietal peritoneum and the large omentum, we should use an endovisual method of draining the abdominal cavity and the omentum to minimize anesthesiological and surgical aggression and to form and maintain general cavities, as well as to create good access to the pancreatic area. For patients with large-focal, infected subtotal or total pancreatic necrosis and purulent peritonitis, it is advisable to perform laparotomy, abdominalization of the pancreas, necrectomy, omentobursostomy, and drainage of purulent foci in the abdominal cavity and retroperitoneal tissue.

Chronic low-grade inflammation in patients with systemic sclerosis is associated with increased risk for arteriosclerotic cardiovascular disease.

Vasculopathy is a hallmark of systemic sclerosis (SSc) putting patients at an increased risk of cardiovascular disease. Approximately 20-25% of all SSc patients show prolonged elevated C-reactive protein (CRP) levels and thus signs of chronic low-grade inflammation. While CRP-positivity is an independent predictor of cardiovascular disease in non-SSc populations, the relationship between CRP-positivity and cardiovascular health/atherosclerosis in SSc patients is only incompletely understood. Here, we aimed to assess (1) which general, SSc disease-specific and cardiovascular parameters are associated with CRP-positivity in a cohort of SSc patients with prolonged CRP elevations (CRP+ SSc group) relative to SSc patients without CRP elevations (CRP- SSc group). In addition (2), we aimed to investigate whether prolonged CRP-positivity in SSc patients is associated with a higher cardiovascular risk and an increased atherosclerotic burden. We also aimed to (3) identify via random forest classification modeling which combined cardiovascular and/or SSc-specific parameters could differentiate best between SSc patients with elevated CRP levels (the so-called "inflammatory SSc subtype") and SSc patients without increased CRP levels. Sixty-five SSc patients were recruited and assigned to the CRP+ SSc group (n = 20) if their CRP levels were > 5 mg/L in at least three half-yearly visits within 2 years before enrolment or to the CRP- SSc group (n = 45), respectively. All patients underwent an anamnesis, physical examination, blood draw, and bilateral carotid ultrasound in order to assess arteriosclerotic burden including the presence, number and height of plaques, and carotid intima-media thickness (CIMT) as well as lipid profiles. 10-year ASCVD risk was estimated via the ASCVD risk estimator plus. Statistical evaluation included Spearman's correlations, logistic regression and random forest modeling under 5-fold cross-validation, and permutation testing to determine combinations of cardiovascular variables highly discriminatory for CRP-positivity. SSc groups showed comparable mean age, height, and extent of SSc organ involvement. Regarding cardiovascular health, CRP+ SSc patients exhibited a significantly altered HDL-, LDL-, and triglyceride profile (0.001 ≤ p ≤ 0.017) and a significantly higher 10-year ASCVD risk (p = 0.047), relative to CRP- SSc patients. Additionally, within the subgroup of CRP+ SSc patients, positive correlations between CRP levels and CIMT right (ρ = 0.657, p = 0.002) and mean CIMT left and right (ρ = 0.497, p = 0.026) were seen. Combined ROC models identified the four lipid components (HDL, LDL, total cholesterol, and triglycerides) or the SSc duration and ASCVD category to differentiate with high cross-validated ROC-AUCs (AUC: 0.83 ± 0.15, and AUC: 0.86 ± 0.09, p < 0.001) for prolonged CRP-positivity among SSc patients. Our data indicate that persistent CRP-positivity and thus chronic low-grade inflammation in SSc patients enhance the risk for arteriosclerotic-cardiovascular disease significantly beyond the ASCVD risk observed for our SSc patients without CRP elevations. It seems to be along with a disrupted lipid profile the hallmark of a distinct "inflammatory" subgroup of SSc patients. However, large population-based studies and clinical trials in patients with SSc are needed to validate our findings in a prospective or interventional setting.

Carotid Plaque-Burden scale and outcomes: A real-life study

BackgroundThe value of carotid ultrasound in real-world practice remains controversial. We investigated the outcomes of people with vascular risk factors according to an easy carotid-plaque burden scale (CPB-scale). Predictive yield of the addition CPB-scale to ESC-SCORE2 (CPB-SCORE2 table) was assessed. MethodsA cohort of participants without preexisting cardiovascular disease (CVD) was evaluated for clinical outcomes according to the number of plaques by segment. The usefulness of the CPB-SCORE2 table was investigated. ResultsA total of 1004 patients were followed for a mean of 12.5 years for major adverse cardiovascular events (MACEs) and death. The CPB-scale was independently associated with MACEs; compared to those in the low-risk group, the corresponding adjusted hazard ratios (95% confidence intervals) for MACEs among the intermediate and high-risk groups were 13.1 (4.87–35.5) and 19.4 (7.27–51.9), respectively. Similarly, the risk of death was greater for participants stratified as high-risk than for those in the low-risk group (adjusted HR 3.36 [1.58–7.15]). According to our CPB-SCORE2 table, 149 of 178 (84%) CV events were detected in the high-risk group and exhibited greater sensitivity than did the SCORE2 Table, 84%; vs. 62%; but slightly less specificity, 62%; vs. 68%. Our table shows the improved performance of SCORE2; c-statistics: 0.74 vs. 0.68; p<0.001 for net reclassification index and integrated discrimination index. ConclusionsA simple prognostic CPB-scale was strongly associated with the long-term risk of developing a first MACE and all-cause death. Adding the CPB-scale to the SCORE2 may improve risk prediction with easy applicability in clinical practice.

Using deep learning to detect atherosclerotic plaques on carotid ultrasound images in the UK Biobank

Abstract Background Atherosclerosis is the main underlying cause of cardiovascular disease (CVD). Existing CVD risk assessment tools do not consider the burden of subclinical atherosclerosis. The presence of carotid plaques on carotid ultrasound is a well-known marker of subclinical atherosclerosis. The accumulation of population-scale data on the presence of atherosclerotic plaques, along with deep phenotyping, can allow not only to address the effectiveness of carotid ultrasound in routine clinical practice, but to shed light on the biology of atherosclerosis development. Purpose To develop an effective deep learning model for plaque detection in carotid ultrasound images in the UK Biobank. Methods We used 680 carotid ultrasound images with manually annotated plaques to train a deep learning model employing the YOLOv8 architecture. Different augmentation techniques were used to increase the generalizability of the model. The developed model was applied to automatically detect plaques in raw ultrasound images from 19,507 UK Biobank participants. Logistic and Cox regression were used to explore the associations of plaque presence and number as predicted by the model with conventional CVD risk factors and the risk of future CVD events over follow-up. To explore the genetic architecture of subclinical atherosclerosis, we conducted a genome-wide association study (GWAS) on plaque presence, followed by meta-analysis with data from the CHARGE Consortium. Results Our plaque detection model achieved high classification metrics of accuracy, sensitivity, and specificity (89.3%, 89.5%, and 89.2%, respectively) and detected atherosclerotic plaques in 44% of UK Biobank participants. As expected, plaques were more common among men than women and their prevalence increased linearly with age. Both plaque presence and number of plaques were correlated with conventional CVD risk factors including diabetes, hypertension, and hyperlipidemia, and showed strong associations with future risk of incident CVD events (Hazard Ratio for plaque presence: 1.48 [95%CI: 1.21-1.82], for 2 plaques or more: 1.65, [95% CI: 1.28-2.13]). Incorporating plaque-derived phenotypes minimally altered the C-index of the time-to-event model. GWAS meta-analysis of carotid plaque presence revealed 5 previously known loci, as well as a significant locus including the LPA gene that had not previously been associated with carotid plaque. Conclusion We have developed and implemented an efficient plaque detection model to data from the UK Biobank, which holds significant promise for studying atherosclerosis at a population-wide scale through integration with multiomics data and electronic health records.