Early Preclinical Stages Research Articles

Ligand-based prediction of hERG-mediated cardiotoxicity based on the integration of different machine learning techniques.

Drug-induced cardiotoxicity is a common side effect of drugs in clinical use or under postmarket surveillance and is commonly due to off-target interactions with the cardiac human-ether-a-go-go-related (hERG) potassium channel. Therefore, prioritizing drug candidates based on their hERG blocking potential is a mandatory step in the early preclinical stage of a drug discovery program. Herein, we trained and properly validated 30 ligand-based classifiers of hERG-related cardiotoxicity based on 7,963 curated compounds extracted by the freely accessible repository ChEMBL (version 25). Different machine learning algorithms were tested, namely, random forest, K-nearest neighbors, gradient boosting, extreme gradient boosting, multilayer perceptron, and support vector machine. The application of 1) the best practices for data curation, 2) the feature selection method VSURF, and 3) the synthetic minority oversampling technique (SMOTE) to properly handle the unbalanced data, allowed for the development of highly predictive models (BAMAX = 0.91, AUCMAX = 0.95). Remarkably, the undertaken temporal validation approach not only supported the predictivity of the herein presented classifiers but also suggested their ability to outperform those models commonly used in the literature. From a more methodological point of view, the study put forward a new computational workflow, freely available in the GitHub repository (https://github.com/PDelre93/hERG-QSAR), as valuable for building highly predictive models of hERG-mediated cardiotoxicity.

The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer's disease.

The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc. The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results. The focus of this article is on the innovative design of the study. The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.

Pharmacokinetic and Pharmacodynamic Modeling of siRNA Therapeutics - a Minireview.

The approval of four small interfering RNA (siRNA) products in the past few years has demonstrated unequivocally the therapeutic potential of this novel modality. Three such products (givosiran, lumasiran and inclisiran) are liver-targeted, using tris N-acetylgalactosamine (GalNAc)3 as the targeting ligand. Upon subcutaneous administration, GalNAc-conjugated siRNAs rapidly distribute into the liver via asialoglycoprotein receptor (ASGPR) mediated uptake in the hepatocytes, resulting in fast elimination from the systemic circulation. Patisiran, on the other hand, has been formulated in a lipid nanoparticle for optimal delivery to the liver. While several publications have described preclinical and clinical pharmacokinetic (PK) and pharmacodynamic (PD) results, including absorption, distribution, metabolism, and elimination (ADME) profiles in selected species as well as limited modeling efforts for siRNA therapeutics, there is no systematic review of the PK and PD models developed for these agents or work summarizing the utility and application(s) of such models in drug development and regulatory review. Here, we provide a mini-review of the current state of modeling efforts for siRNA therapeutics within the early preclinical, translational, and clinical stages of siRNA development. Diverse modeling methods including simple compartmental, mechanistic and systems PK/PD, physiologically-based PK (PBPK), population PK/PD, and dose-response-time models are introduced and reviewed. The utility of such models in development and regulatory review for siRNA therapeutics is also discussed with examples. Finally, the current knowledge gaps in mechanism of action of siRNA and resulting challenges in model development are summarized. The goal of this minireview is to trigger cross-functional discussion amongst all key stakeholders to generate key experimental datasets and align on current assumptions, model structures, and approaches to facilitate development and application of robust PK/PD models for siRNA therapeutics.

Development of early diagnosis of Parkinson's disease on animal models based on the intranasal administration of α-methyl-p-tyrosine methyl ester in a gel system.

The fight against neurodegenerative diseases, including Parkinson's disease (PD), is a global challenge of this century. The effectiveness of current PD therapy is limited, since it is diagnosed many years after the onset, following the death of most nigrostriatal dopaminergic neurons regulating motor function. PD treatment could be greatly improved if it was started at an early (preclinical) stage. For this purpose, it is necessary to develop an early diagnosis of PD, which is the goal of our study. We have developed an early diagnosis of PD on animal models using a provocative test by intranasal administration of α-methyl-p-tyrosine methyl ester (αMPTME), a reversible inhibitor of dopamine synthesis. First, we produced the provocative agent, αMPTME in gel, and showed its safety and penetration into the brain bypassing the blood-brain barrier. Then, the optimal dose of αMPTME and time after administration were selected, at which the level of dopamine in the striatum of intact animals decreases, but does not reach the 30% threshold for the appearance of motor disorders in PD patients. Finally, we proved on animal models that intranasal administration of αMPTME can serve as a diagnostic test for preclinical PD. Indeed, intranasal administration of αMPTME to mice in a model of PD at the preclinical stage reversibly reduced the dopamine level in the striatum to the 30% threshold causing short-term motor disorders. Thus, using animal models of PD, we have developed a provocative test for the preclinical diagnosis of PD, a fundamentally new technology in neurology.

Сравнительный анализ электрофизиологических и периметрических показателей у пациентов с подозрением на глаукому

Purpose. To compare electrophysiological and perimetric parameters in patients with suspected glaucoma. Materials and methods. 42 patients (84 eyes) with a diagnosis of suspected glaucoma were examined in the RSNPCMG. Visual acuity of patients with ametropia correction was 0.9–1.0. Refractive errors did not exceed 3.0 diopters, concomitant visual analyzer disorders were not detected. None of the examined patients received local drug hypotensive therapy at the time of diagnosis. The average age of the patients was 50.5 ± 2.5 years. The comparison group consisted of 20 people without changes in visual functions of the corresponding gender and age. Electrophysiological and perimetric methods were used: blue-yellow threshold static perimetry, color-component blue-yellow electroretinography of the study of the visual organ to assess the functional state of the visual system with standard methods of examination of the visual organ. Results. The results of standard and color-component methods of perimetry research, as well as electrophysiological indicators were processed using the applied package of research methods Statistica 6.0. When analyzing the main functional perimetric indices and the nature of the topography and depth of defects of the central field of vision (MD, PSD, CPSD), a significant change in the thresholds of light sensitivity of the blue-yellow perimetry relative to the standard method of investigation was noted. When conducting electrophysiological studies, the criteria that have the greatest similarity in damage to the S-cone system of the retina were selected: PERG, oscillatory potentials, synecolumbular electroretinography (S-CON ERG). Conclusion. 1. The developed complex of functional research methods makes it possible to identify the presence of changes in the visual system at the early preclinical stages of the development of glaucoma optic neuropathy. 2. The proposed method of separation of light and color component channels of the visual analyzer increases the sensitivity and specificity of the lesion of the retina of the optic nerve in the development of glaucoma changes. 3. Indicators of oscillatory potentials of ERG are a predictor of ischemic retinal changes in glaucoma. 4. The results of the studies indicate the presence of specific S-cone channels and the effectiveness of detecting damage to retinal ganglion cells using the coniocellular retinal response system. Key words: oscillator potentials, glaucomatous optic neuropathy, blue cone ERG, retinal ganglion cells.

Deciphering miR-520c-3p as a probable target for immunometabolism in non-small cell lung cancer using systems biology approach

Background: Non-small cell lung cancer (NSCLC) is considered to have more than 80% of all lung cancer cases, making it the leading cause of cancer-related deaths globally. MicroRNA (miRNA) deregulation has been seen often in NSCLC and has been linked to the disease’s genesis, progression, and metastasis via affecting their target genes.Materials and Methods: Our study focused on the functionality of down-regulated miRNAs in NSCLC. For this study, we used 91 miRNAs reported to be down-regulated in NSCLC. The targets of these miRNAs were chosen from miRNA databases with functionality in NSCLC, including miRBase, miRDB, miRTV, and others. Inter-regulatory miRNA-NSCLC networks were generated. Simulated annealing was used to improve the network’s resilience and understandability. GSEA was used to examine 24607 genes reported experimentally in order to gain physiologically relevant information about the target miR-520c-3p.Results: The study revealed functional prominence on miR-520c-3p, down-regulated during NSCLC. The involvement of miR-520c-3p in the PI3K/AKT/mTOR signaling pathway was recognized.Conclusions: The therapeutic usage by designing a synthetic circuit of miR-520c-3p was explored, which may help in suppressing tumors in NSCLC. Our study holds promise for the successful deployment of currently proposed miRNA-based therapies for malignant disorders, which are still in the early pre-clinical stages of development.

Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA)

ABSTRACT Introduction Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disease which is characterised by muscle atrophy and early death in most patients. Risdiplam is the third overall and first oral drug approved for SMA with disease-modifying potential. Risdiplam acts as a survival motor neuron 2 (SMN2) pre-mRNA splicing modifier with satisfactory safety and efficacy profile. This review aims to critically appraise the place of risdiplam in the map of SMA therapeutics. Areas covered This review gives an overview of the current market for SMA and presents the mechanism of action and the pharmacological properties of risdiplam. It also outlines the development of risdiplam from early preclinical stages through to the most recently published results from phase 2/3 clinical trials. Risdiplam has proved its efficacy in pivotal trials for SMA Types 1, 2, and 3 with a satisfactory safety profile. Expert opinion In the absence of comparative data with the other two approved drugs, the role of risdiplam in the treatment algorithm of affected individuals is examined in three different patient populations based on the age and diagnosis method (newborn screening or clinical, symptom-driven diagnosis). Long-term data and real-world data will play a fundamental role in its future.

Early-stage Alzheimer disease: getting trial-ready.

Slowing the progression of Alzheimer disease (AD) might be the greatest unmet medical need of our time. Although one AD therapeutic has received a controversial accelerated approval from the FDA, more effective and accessible therapies are urgently needed. Consensus is growing that for meaningful disease modification in AD, therapeutic intervention must be initiated at very early (preclinical or prodromal) stages of the disease. Although the methods for such early-stage clinical trials have been developed, identification and recruitment of the required asymptomatic or minimally symptomatic study participants takes many years and requires substantial funds. As an example, in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease Trial (the first phase III trial to be performed in preclinical AD), 3.5 years and more than 5,900 screens were required to recruit and randomize 1,169 participants. A new clinical trials infrastructure is required to increase the efficiency of recruitment and accelerate therapeutic progress. Collaborations in North America, Europe and Asia are now addressing this need by establishing trial-ready cohorts of individuals with preclinical and prodromal AD. These collaborations are employing innovative methods to engage the target population, assess risk of brain amyloid accumulation, select participants for biomarker studies and determine eligibility for trials. In the future, these programmes could provide effective tools for pursuing the primary prevention of AD. Here, we review the lessons learned from the AD trial-ready cohorts that have been established to date, with the aim of informing ongoing and future efforts towards efficient, cost-effective trial recruitment.

Ahead of the Curve: The Arc Institute Aims to Reshape the Biomedical Research Landscape

Ahead of the Curve: The Arc Institute Aims to Reshape the Biomedical Research Landscape

Activation of Non-Canonical Autophagic Pathway through Inhibition of Non-Integrin Laminin Receptor in Neuronal Cells.

To fight neurodegenerative diseases, several therapeutic strategies have been proposed that, to date, are either ineffective or at the early preclinical stages. Intracellular protein aggregates represent the cause of about 70% of neurodegenerative disorders, such as Alzheimer’s disease. Thus, autophagy, i.e., lysosomal degradation of macromolecules, could be employed in this context as a therapeutic strategy. Searching for a compound that stimulates this process led us to the identification of a 37/67kDa laminin receptor inhibitor, NSC48478. We have analysed the effects of this small molecule on the autophagic process in mouse neuronal cells and found that NSC48478 induces the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3-I) into the LC3-phosphatidylethanolamine conjugate (LC3-II). Interestingly, upon NSC48478 treatment, the contribution of membranes to the autophagic process derived mainly from the non-canonical m-TOR-independent endocytic pathway, involving the Rab proteins that control endocytosis and vesicle recycling. Finally, qRT-PCR analysis suggests that, while the expression of key genes linked to canonical autophagy was unchanged, the main genes related to the positive regulation of endocytosis (pinocytosis and receptor mediated), along with genes regulating vesicle fusion and autolysosomal maturation, were upregulated under NSC48478 conditions. These results strongly suggest that 37/67 kDa inhibitor could be a useful tool for future studies in pathological conditions.

Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment

The receptor tyrosine kinase, MERTK, plays an essential role in homeostasis of the retina via efferocytosis of shed outer nuclear segments of photoreceptors. The Royal College of Surgeons rat model of retinal degeneration has been linked to loss-of-function of MERTK, and together with the MERTK knock-out mouse, phenocopy retinitis pigmentosa in humans with MERTK mutations. Given recent efforts and interest in MERTK as a potential immuno-oncology target, development of a strategy to assess ocular safety at an early pre-clinical stage is critical. We have applied a state-of-the-art, multi-modal imaging platform to assess the in vivo effects of pharmacological inhibition of MERTK in mice. This involved the application of mass spectrometry imaging (MSI) to characterize the ocular spatial distribution of our highly selective MERTK inhibitor; AZ14145845, together with histopathology and transmission electron microscopy to characterize pathological and ultra-structural change in response to MERTK inhibition. In addition, we assessed the utility of a human retinal in vitro cell model to identify perturbation of phagocytosis post MERTK inhibition. We identified high localized total compound concentrations in the retinal pigment epithelium (RPE) and retinal lesions following 28 days of treatment with AZ14145845. These lesions were present in 4 of 8 treated animals, and were characterized by a thinning of the outer nuclear layer, loss of photoreceptors (PR) and accumulation of photoreceptor outer segments at the interface of the RPE and PRs. Furthermore, the lesions were very similar to that shown in the RCS rat and MERTK knock-out mouse, suggesting a MERTK-induced mechanism of PR cell death. This was further supported by the observation of reduced phagocytosis in the human retinal cell model following treatment with AZ14145845. Our study provides a viable, translational strategy to investigate the pre-clinical toxicity of MERTK inhibitors but is equally transferrable to novel chemotypes.

Toward a Disease-Modifying Therapy of Alpha-Synucleinopathies: New Molecules and New Approaches Came into the Limelight.

The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that the aggregation and spread of alpha-synuclein aggregation pathology activate numerous pathogenic mechanisms that contribute to neurodegeneration and, ultimately, to disease progression. Therefore, the development of a safe and effective disease-modifying therapy that limits or prevents the accumulation of the toxic intermediate products of alpha-synuclein aggregation and the spread of alpha-synuclein aggregation pathology could provide significant positive clinical outcomes in PD/DLB cohorts. It has been suggested that this goal can be achieved by reducing the intracellular and/or extracellular levels of monomeric and already aggregated alpha-synuclein. The principal aim of this review is to critically evaluate the potential of therapeutic strategies that target the post-transcriptional steps of alpha-synuclein production and immunotherapy-based approaches to alpha-synuclein degradation in PD/DLB patients. Strategies aimed at the downregulation of alpha-synuclein production are at an early preclinical stage of drug development and, although they have shown promise in animal models of alpha-synuclein aggregation, many limitations need to be resolved before in-human clinical trials can be seriously considered. In contrast, many strategies aimed at the degradation of alpha-synuclein using immunotherapeutic approaches are at a more advanced stage of development, with some in-human Phase II clinical trials currently in progress. Translational barriers for both strategies include the limitations of alpha-synuclein aggregation models, poor understanding of the therapeutic window for the alpha-synuclein knockdown, and variability in alpha-synuclein pathology across patient cohorts. Overcoming such barriers should be the main focus of further studies. However, it is already clear that these strategies do have the potential to achieve a disease-modifying effect in PD and DLB.

PENSA study for the prevention of cognitive decline in APOE‐ɛ4 carriers with subjective cognitive decline: Baseline preliminary demographic and neuropsychological description of the study population

AbstractBackgroundIn the absence of effective treatments to reverse cognitive deterioration related to Alzheimer's disease (AD), nonpharmacological secondary prevention interventions at early preclinical stages have been found to be a promising strategy to prevent cognitive decline. In this context, the PENSA study, framed within the WW‐FINGERS consortium, is a randomized clinical trial involving cognitively normal elderly individuals with an increased risk of developing AD (meeting subjective cognitive decline, SCD‐plus criteria and being APOE‐ɛ4 carriers). The aim of the study is to evaluate the efficacy of a multimodal personalized lifestyle intervention (dietary and physical activity counseling and cognitive training) combined with a dietary supplement, epigallocatechin gallate (EGCG) in slowing down cognitive decline.MethodIn this work we present the baseline sociodemographic, mood and cognitive characteristics of the already enrolled sample. Cognitive function was measured with the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS‐PACC) and adding to this original version the interference score from the Stroop Color and Word Test and the Five Digit Test (ADCS‐PACC‐Plus‐exe). Additionally, the Digit Span, the Boston Naming Test and the Animal Fluency Test were administered. Psychological distress was measured with the Hospital Anxiety and Depression Scale.ResultOn January 2021 the study had enrolled 68 individuals (62% women) with a mean (SD) age of 67.4 (4.6) years and the following APOE genotype: 83% ɛ3/ɛ4, 13% ɛ4/ɛ4 and 4% ɛ2/ɛ4. Most had higher education (66.2%) and 84% were retired (Table 1). Mild and moderate symptoms of psychological distress were present in 14.7% and 23.5% of participants, respectively. The mean (SD) number of cognitive domains affected (memory, concentration, language, visuospatial skills), measured by an ad‐hoc SCD questionnaire, were 2.54 (±0.9). 77.3% of participants referred memory centered complaints. Considering the different domains, participants reported alterations on memory (97.1%), concentration (73.5%), language (67.6%) and visuospatial skills (11.8%). SCD profiles are shown in Figure 1. Table 2 shows the ADCS‐PACC‐Plus‐exe scores.ConclusionThe PENSA study will provide valuable information on the effect of a lifestyle intervention supplemented with EGCG to prevent cognitive decline and will aid to share light on the benefit of these strategies in people at‐risk of developing AD.

Modeling brain‐predicted age from functional connectivity in early‐stage and preclinical Alzheimer disease

AbstractBackgroundThe “brain‐predicted age” approach summarizes complex age relationships with neuroimaging features by quantifying apparent brain age compared to normative trajectories. Advanced brain‐predicted age has been observed in many studies of symptomatic Alzheimer disease (AD), but the effects of preclinical AD have not been investigated. Prior studies have typically modeled brain aging with structural MRI, but other modalities, including resting‐state functional connectivity (FC), are underexplored. Here we modeled FC‐predicted brain age and tested its relationships with preclinical and symptomatic AD.MethodWe calculated FC correlation matrices between 300 regions of interest in 493 cognitively normal (clinical dementia rating [CDR]=0), amyloid‐negative (CSF pTau/Aβ42 ratio and/or amyloid PET Centiloid) control participants (18‐91 years old). We trained a Gaussian process regression model to predict age from these FC features using 10‐fold cross‐validation. We applied the trained model to a separate set of 153 amyloid‐negative, 143 preclinical AD (CDR=0, amyloid‐positive), and 183 symptomatic AD participants (CDR>0). Finally, we tested group differences in FC‐predicted brain age between the AD samples and continuous relationships with biomarkers of amyloid (CSF Aβ42, amyloid PET Centiloid), tau (CSF pTau‐181, tau PET [AV‐1451]), and neurodegeneration (CSF NfL, hippocampal volume), controlling for true age as a covariate.ResultThe FC‐based model accurately predicted age in the training set (R2 =.72, mean absolute error=8.14, Figure 1). FC‐predicted brain age was 2.43 years older in symptomatic AD compared to cognitively normal controls (p<.001, Cohen’s d=0.38, Figure 2A), but was 1.90 years younger in preclinical AD compared to amyloid‐negative controls (p=.011, Cohen’s d=‐0.29, Figure 2B). Greater FC‐predicted brain age was associated with smaller hippocampal volume (p=.009, Figure 3F), but also with lower CSF pTau‐181 (p=.012, Figure 3C). Relationships between FC‐predicted age and other AD biomarkers were not significant (p’s>.20, Figure 3).ConclusionElevated FC‐predicted brain age may reflect advanced brain aging in FC networks during symptomatic AD. This finding is consistent with previous models based on structural MRI. Reduced FC‐predicted brain age in amyloid‐positive participants may reflect compensation during early preclinical stages, but this interpretation requires further investigation. FC‐predicted brain age may be a sensitive biomarker in future models of healthy aging and symptomatic AD.

Soluble amyloid-beta isoforms predict downstream Alzheimer\u2019s disease pathology

BackgroundChanges in soluble amyloid-beta (Aβ) levels in cerebrospinal fluid (CSF) are detectable at early preclinical stages of Alzheimer’s disease (AD). However, whether Aβ levels can predict downstream AD pathological features in cognitively unimpaired (CU) individuals remains unclear. With this in mind, we aimed at investigating whether a combination of soluble Aβ isoforms can predict tau pathology (T+) and neurodegeneration (N+) positivity.MethodsWe used CSF measurements of three soluble Aβ peptides (Aβ1–38, Aβ1–40 and Aβ1–42) in CU individuals (n = 318) as input features in machine learning (ML) models aiming at predicting T+ and N+. Input data was used for building 2046 tuned predictive ML models with a nested cross-validation technique. Additionally, proteomics data was employed to investigate the functional enrichment of biological processes altered in T+ and N+ individuals.ResultsOur findings indicate that Aβ isoforms can predict T+ and N+ with an area under the curve (AUC) of 0.929 and 0.936, respectively. Additionally, proteomics analysis identified 17 differentially expressed proteins (DEPs) in individuals wrongly classified by our ML model. More specifically, enrichment analysis of gene ontology biological processes revealed an upregulation in myelinization and glucose metabolism-related processes in CU individuals wrongly predicted as T+. A significant enrichment of DEPs in pathways including biosynthesis of amino acids, glycolysis/gluconeogenesis, carbon metabolism, cell adhesion molecules and prion disease was also observed.ConclusionsOur results demonstrate that, by applying a refined ML analysis, a combination of Aβ isoforms can predict T+ and N+ with a high AUC. CSF proteomics analysis highlighted a promising group of proteins that can be further explored for improving T+ and N+ prediction.

Breast cancer screening during the adverse COVID-19 epidemiological situation

Purpose of the study. To evaluate the results of breast cancer screening (BC) in the conditions of an unfavorable epidemiological situation COVID‑19 based on the analysis of the BC screening project in the Kaluga Region.Patients and methods. Screening system: creation and implementation in practice of mobile mammography complexes (MMC); training of medical personnel in the method of conducting a standardized mammographic examination (ME); quality control of ME; "Cloud" storage and software development for archiving patients; an independent review of mammograms by certified specialists; expert review of images in case of discrepancies in diagnoses; referral of patients diagnosed with BI-RADS IV and V to the regional oncological dispensary for further examination and treatment. From 04.2018 to 12.2020 patients were examined on MMC according to the BC screening protocol. We examined 47367 patients over the age of 40 years. SD 57.66 ± 8.17 years (38-93). During the COVID‑19 pandemic, imaging of breast diseases must be carried out in compliance with all safety regulations for both personnel and patients. Balancing the need to avoid delays in diagnosing BC while preventing infection requires careful attention to personal protective equipment, handling of diagnostic equipment, diagnostic facilities, and physical distancing and vigilance to maintain these measures.Results. From 07.2020 to 11.2020: a total of 10736 studies have been carried out. In the context of new coronavirus infection, we noted an increased demand among patients wishing to undergo BC screening. The flow of patients over the same period of previous years was less, which indicates the demand and justification for screening mammography and the use of MMC in an unfavorable epidemiological situation. 174 patients received category BI-RADS IV-V and were referred for a follow-up examination and required treatment at an oncological dispensary. In 39 patients (22.4 %), BC was verified, and appropriate treatment was carried out. In 135 cases, benign processes were verified.Conclusion. BC screening should not be stopped against the backdrop of the COVID‑19 epidemic since a delay in BC diagnosis later threatens to reveal more voluminous processes with a worse prognosis for treatment and rehabilitation than timely detected changes in the mammary glands in the early preclinical stages of the disease.

CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.

Background and ObjectivesTo determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers.MethodsThis cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers.ResultsAll CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions.DiscussionCSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration.Trial Registration InformationClinicalTrials.gov Identifier NCT02485730.

A\u03b2 initiates brain hypometabolism, network dysfunction and behavioral abnormalities via NOX2-induced oxidative stress in mice

A predominant trigger and driver of sporadic Alzheimer’s disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences have remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind Aβ1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aβ1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.

The short physical performance battery and incident heart failure among older women: the OPACH study

ObjectiveReduced functional capacity is a hallmark of early pre-clinical stages of heart failure (HF). The Short Physical Performance Battery (SPPB) is a valid measure of lower extremity physical function, has relatively low implementation burden, and is associated with cardiovascular disease and mortality. However, the SPPB-HF association is understudied in older women among whom HF burden is high. MethodsWomen (n = 5325; mean age 79 ± 7 years; 34% Black, 18% Hispanic, and 49% White) without prior HF completed the SPPB consisting of standing balance, strength, and walking tests that were summarized as a composite score from 0 (lowest) to 12 (highest), categorized as very low (0–3), low (4–6), medium (7–9), or high (10–12). Participants were followed for up to 8 years for incident HF (306 cases identified). Cox proportional hazards regression estimated hazard ratios (HR) adjusting for age, race/ethnicity, education, smoking, alcohol, diabetes, hypertension, COPD, osteoarthritis, depression, BMI, systolic blood pressure, lipids, glucose, and accelerometer-measured moderate-vigorous physical activity (MVPA) and sedentary time. ResultsIncident HF cases (crude rate per 1000 person-years) in the four SPPB categories (very low to high) were 34 (26.0), 79 (14.5), 128 (9.3), and 65 (5.6). Corresponding multivariable-adjusted HRs (95% CIs) were 2.22 (1.34–3.66), 1.63 (1.11–2.38), 1.39 (1.00–1.94), and 1.00 (referent; P-trend<0.001). Higher HF risk was associated with lower SPPB in women with major modifiable HF risk factors including obesity (HR per 3-unit SPPB decrement: present HR = 1.41, absent HR = 1.41), hypertension (present HR = 1.45, absent HR = 1.30), diabetes (present HR = 1.32, absent HR = 1.44), and lower accelerometer-measured MVPA (<45 min/day HR = 1.29, ≥45 min/day HR = 1.60); all P-interaction>0.10. ConclusionLower SPPB scores were associated with greater risk of incident HF in older women even after accounting for differences in HF risk factors and objectively measured PA. Implementing the SPPB in clinical settings could potentially enhance individual-level HF risk assessment, which should be further explored.

Speckle-tracking echocardiography in early diagnosis of lipotoxic myocardial damage in epicardial obesity

Epicardial obesity (EO) can lead to lipotoxic myocardial damage with the development of myocardial fibrosis, which underlie the impairment of left ventricular (LV) diastolic function. The identification of markers of lipotoxic myocardial damage is important at an early preclinical stage for preventive measures. Objective. To study the relationship of plasma levels of markers of insulin resistance and lipotoxic fibrosis with the parameters of LV mechanics in patients with EO. We hypothesized that there are significant differences in plasma levels of markers of insulin resistance and myocardial fibrosis and that they are associated with the parameters of LV mechanics in EO. Design and methods. The study included 143 men. Inclusion criteria: general obesity I–III degree. Exclusion criteria: type 2 diabetes mellitus, hypertension, LV diastolic dysfunction based on echocardiography (Echo). Patients were divided into 2 groups: EO (+) with epicardial fat thickness (tEAT) ≥ 7 mm (n = 70); EO (–) with tEAT &lt; 7 mm (n = 31). All patients were assessed for glucose, blood insulin, profibrotic factors and free fatty acids (FFA) using enzyme-linked immunosorbent assay. HOMA-IR insulin sensitivity index was calculated as (insulin × glucose)/22,5. With the help of speckle-tracking Echo, the mechanics of LV were studied (LV twisting, LV twisting ratio, time to LV twisting peak, LV untwisting ratio, time to LV untwisting peak). Results. The patients with EO (+) showed a statistically significant increase in the level of FFA up to 0,82 (0,39; 1,30) mmol/L (&lt; 0,0001) and HOMA-IR index up to 3,89 (2,02; 5,76) (&lt; 0,0001) in comparison with the group EO (–). There was a statistically significant effect of tEAT on the level of FFA (F = 7,90; p = 0,006) and on the development of insulin resistance (F = 14,85; p &lt; 0,001). The correlation analysis in the EO (+) group showed the relationship between FFA and type III collagen (r = 0,29, p = 0,01) and procollagen type I carboxy-terminal propeptide (PICP) (r = 0,26, p = 0,03), as well as between HOMA-IR and MMP-3 (r = 0,30, p = 0,01). In the EO (–) group, the relationship of profibrotic factors with the level of FFA and HOMA-IR was not found. There was also a significant relationship between LV untwisting ratio and level of FFA (r = 0,24, p = 0,04) in the group EO (+). Conclusions. Thus, an increase in the level of FFA in patients with EO may be accompanied by an increase in the level of some profibrotic factors and a LV untwisting violation determined by speckle-tracking Echo. Our data supports the need for assessing the FFA level and speckle-tracking Echo for the early diagnosis of LV diastolic dysfunction in patients with EO.