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Cerebrovascular diseases, especially stroke, are critical and heterogenous clinical conditions associated with high mortality and chronic disability. Genome-wide association studies reveal substantial stroke heritability, though specific genetic variants account for a minor fraction of stroke risk, suggesting an essential role for the epigenome. Epigenome-wide association studies and candidate gene approaches show that DNA methylation patterns significantly influence stroke susceptibility. Additionally, chromatin remodelers and non-coding RNA regulate gene expression in response to ischemic conditions. In this updated review, we summarized the progress of knowledge on epigenetics in the field of ischemic stroke underlying opportunities and challenges.
Cerebrovascular diseases include different clinical conditions, with stroke being the most serious. Stroke is the second leading cause of death and the primary cause of long-term disability globally. It is a multifactorial condition resulting from the interaction among environmental, genetic and epigenetic factors. In the last decades, several authors have explored the role of epigenetics in stroke.Epigenetics involves changes in how our genes work without altering the actual DNA. Fundamental epigenetic mechanisms include DNA methylation, histone modifications, chromatin remodeling and RNA-based mechanisms. Among these, DNA methylation, consisting of adding a methyl group to DNA, is the most studied mechanism in stroke. This summary reviews studies on how these epigenetic mechanisms play a role in stroke by examining human research. Understanding these mechanisms helps in finding better ways to treat or prevent stroke.
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Cerebrospinal fluid (CSF) core biomarkers of Alzheimer's disease (AD), including amyloid peptide beta-42 (Aß42), Aß42/40 ratio, and phosphorylated tau (pTau), are precious tools for supporting AD diagnosis. However, their use in clinical practice is limited due to the invasiveness of CSF collection. Thus, there is intensive research to find alternative, noninvasive, and widely accessible biological matrices to measure AD core biomarkers. In this study, we measured AD core biomarkers in saliva and plasma by a fully automated platform. We enrolled all consecutive patients with cognitive decline. For each patient, we measured Aß42, Aß40, and pTau levels in CSF, saliva, and plasma by Lumipulse G1200 (Fujirebio). We included forty-two patients, of whom 27 had AD. Levels of all biomarkers significantly differed in the three biofluids, with saliva having the lowest and CSF the highest levels of Aß42, Aß40, and pTau. A positive correlation of pTau, Aß42/40 ratio, and pTau/Aß42 ratio levels in CSF and plasma was detected, while no correlation between any biomarker in CSF and saliva was found. Our findings suggest that plasma but not saliva could represent a surrogate biofluid for measuring core AD biomarkers. Specifically, plasma Aß42/40 ratio, pTau/Aß42 ratio, and pTau could serve as surrogates of the corresponding CSF biomarkers.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Saliva , Proteínas tau , Humanos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/metabolismo , Saliva/metabolismo , Saliva/química , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Femenino , Masculino , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/análisis , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/sangre , Proteínas tau/análisis , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/análisis , Mediciones Luminiscentes/métodos , Anciano de 80 o más AñosRESUMEN
BACKGROUND AND AIMS: This study aims to assess the association between APOE genotype and biomarkers of neurodegeneration in Alzheimer's disease (AD). METHODS: We performed a retrospective observational study at the University Hospital "P. Giaccone" in Palermo, Italy. We enrolled patients with cognitive decline, including AD. For each patient, we measured amyloid beta (Aß)42, Aß40, tau protein phosphorylated at threonine 181 (pTau), total tau (tTau), neurogranin, alpha-synuclein, and neurofilament light chain (NfL) in cerebrospinal fluid (CSF). RESULTS: The study population consisted of 194 patients (123 AD and 71 non-AD). AD patients have significantly lower Aß42 levels and Aß42/40 ratio and higher pTau, tTau, and NfLs levels than non-AD patients. In AD patients, the APOEε4 allele is associated with a significantly lower Aß42/40 ratio and higher levels of pTau, tTau, neurogranin, and alpha-synuclein. This association is not observed in non-AD patients. CONCLUSIONS: This study provides evidence of the significant impact of the APOE ε4 allele on neurodegenerative biomarkers in AD patients, highlighting its role in exacerbating amyloid and tau pathology as well as synaptic degeneration.
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Enfermedad de Alzheimer , Apolipoproteína E4 , Biomarcadores , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Masculino , Femenino , Anciano , Apolipoproteína E4/genética , Estudios Retrospectivos , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Persona de Mediana Edad , Anciano de 80 o más AñosRESUMEN
Background: In this study, we explored the accuracy of two new sepsis biomarkers, monocyte distribution width (MDW) and presepsin (PSP), compared to traditional ones, C-reactive protein (CRP) and Procalcitonin (PCT), to identify sepsis and predict intra-hospital mortality by analyzing their kinetic at different time points during hospitalization stay. Methods: We enrolled 104 patients admitted to the intensive care unit (ICU) of University Hospital "Paolo Giaccone", Palermo. Among these, 30 (29%) had a clinical diagnosis of sepsis. MDW, PCT, CRP, and PSP were evaluated at admission (T0), after 24 h (T24), 48 h (T48), 72 h (T72), at day 5 (T5), and at discharge (TD). Results: Patients with sepsis displayed higher levels of PCT and PSP than patients without sepsis at each timepoint; differently, CRP displayed statistically significant differences only at T0, while MDW only at T0 and T24. Patients with increasing levels of PSP displayed lower median survival time than patients with decreasing levels; differences reached statistical significance only at 48 h (20 vs. 29 days, log rank test, p = 0.046). Interestingly, PSP was an independent predictor of ICU mortality at 48 and 72 h after hospital admission. Also, the kinetic of PSP had prognostic value, with increased values at 48 h after admission being associated with reduced survival. Conclusion: Our findings support the role of PSP and its kinetic as a predictor of ICU mortality.
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OBJECTIVES: Non-celiac wheat sensitivity (NCWS) is an emerging clinical condition characterized by gastrointestinal and extraintestinal symptoms following the ingestion of gluten-containing foods in patients without celiac disease (CD) or wheat allergy. Despite the great interest for NCWS, the genetic risk factors still need to be fully clarified. In this study, we first assessed the possible contribution of KIR genes and KIR haplotypes on the genetic predisposition to NCWS. METHODS: Fifty patients with NCWS, 50 patients with CD, and 50 healthy controls (HC) were included in this study. KIR genes and KIR genotyping were investigated in all subjects by polymerase chain reaction with the sequence oligonucleotide probe (PCR-SSOP) method using Luminex technology. RESULTS: We found a statistically different distribution of some KIR genes among NCWS, CD, and HC. Specifically, NCWS showed a decreased frequency of KIR2DL1, -2DL3, -2DL5, -2DS2, -2DS3, -2DS4, -2DS5, and -3DS1 genes, and an increased frequency of -3DL1 gene respect to both CD and HC. No difference was detected in the KIR haplotype expression. At the multivariate analysis, KIR2DL5, -2DS4, and -2DS5 were independent predictors of NCWS. CONCLUSIONS: Our findings suggest a role of KIR genes in NCWS susceptibility, with KIR2DL5, -2DS4, and -2DS5 having a protective effect. Further large-scale multicentric studies are required to validate these preliminary findings.
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Predisposición Genética a la Enfermedad , Haplotipos , Receptores KIR , Hipersensibilidad al Trigo , Humanos , Receptores KIR/genética , Femenino , Masculino , Adulto , Hipersensibilidad al Trigo/genética , Persona de Mediana Edad , Enfermedad Celíaca/genética , Estudios de Casos y Controles , Triticum/genética , Genotipo , Adulto JovenRESUMEN
Neurodegenerative disorders (NDs) represent a group of different diseases characterized by the progressive degeneration and death of the nervous system's cells. The diagnosis is challenging, especially in the early stages, due to no specific clinical signs and symptoms. In this context, laboratory medicine could support clinicians in detecting and differentiating NDs. Indeed, biomarkers could indicate the pathological mechanisms underpinning NDs. The ideal biofluid for detecting the biomarkers of NDs is cerebrospinal fluid (CSF), which has limitations, hampering its widespread use in clinical practice. However, intensive efforts are underway to introduce high-sensitivity analytical methods to detect ND biomarkers in alternative nonivasive biofluid, such as blood or saliva. This study presents an overview of the ND molecular biomarkers currently used in clinical practice. For some diseases, such as Alzheimer's disease or multiple sclerosis, biomarkers are well established and recommended by guidelines. However, for most NDs, intensive research is ongoing to identify reliable and specific biomarkers, and no consensus has yet been achieved.
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Biomarcadores , Enfermedades Neurodegenerativas , Humanos , Biomarcadores/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/metabolismo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genéticaRESUMEN
OBJECTIVES: Monocyte distribution width (MDW) is a measure of monocyte anisocytosis. In this study, we assessed the role of MDW, in comparison to C-reactive protein (CRP), procalcitonin (PCT), and lactate, as a screening and prognostic biomarker of sepsis in intensive care unit (ICU) by longitudinally measuring it in the first 5 days of hospital stay. METHODS: We considered all consecutive patients admitted to the ICU. At admission, patients were classified as septic or not according to Sepsis-3 criteria. MDW, CRP, PCT, and lactate were measured daily in the first 5 days of hospitalization. ICU mortality was also recorded. RESULTS: We included 193 patients, 62 with sepsis and 131 without sepsis (controls). 58% and 26â¯% of the patients, with and without sepsis respectively, died during ICU stay. MDW showed the highest accuracy for sepsis detection, superior to CRP, PCT, and lactate (AUC of 0.840, 0.755, 0.708, 0.622, respectively). At admission, no biomarker predicts ICU mortality in patients with sepsis. The kinetic of all biomarkers during the first 5 days of hospitalization was associated with ICU mortality. Noteworthy, above all, the kinetic of MDW showed the best accuracy. Specifically, an increase or decrease in MDW from day 1-4 and 5 was significantly associated with mortality or survival, respectively. CONCLUSIONS: MDW is a reliable diagnostic and prognostic sepsis biomarker, better than traditional biomarkers.
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Aim: The aim of this study was to develop machine learning (ML) models to mitigate the inappropriate request of Procalcitonin (PCT) in clinical wards. Material and methods: We built six different ML models based on both demographical data, i.e., sex and age, and laboratory parameters, i.e., cell blood count (CBC) parameters, inclusive of monocyte distribution width (MDW), and C-reactive protein (CRP). The dataset included 1667 PCT measurements of different patients. Based on a PCT cut-off of 0.50 ng/mL, we found 1090 negative (65.4%) and 577 positive (34.6%) results. We performed a 70:15:15 train:validation:test splitting based on the outcome. Results: Random Forest, Support Vector Machine and eXtreme Gradient Boosting showed optimal performances for predicting PCT positivity, with an area under the curve ranging from 0.88 to 0.89. Conclusions: The ML models developed could represent a useful tool to predict PCT positivity, avoiding unusefulness PCT requests. ML models are based on laboratory tests commonly ordered together with PCT but have the great advantage to be easy to measure and low-cost.
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Exosomes are small lipid bilayer membrane particles released from all living cells into the extracellular environment. They carry several molecules and have a critical role in cell-cell communication under physiological and pathological conditions. In recent decades, exosomes, and especially their cargo, have emerged as a promising tool for several clinical conditions. However, the literature has become increasingly unambiguous in defining the role of exosomes in chronic cerebrovascular diseases. Because they can pass through the blood-brain barrier, they have great potential to reflect intracerebral changes. They can, thus, provide valuable insight into the mechanisms of central nervous system diseases. The purpose of this review is to describe the literature on the role of exosomal miRNA, which represents the most widely investigated exosomal biomarker, in strokes. First, we provide an overview of exosomes, from biology to isolation and characterization. Then, we describe the relationship between exosomes and stroke pathogenesis. Finally, we summarize the human studies evaluating exosomal miRNA biomarkers of stroke. Although the collective literature supports the potential use of exosomal miRNA as biomarkers of ischemic stroke, there are still several limitations hampering their introduction into clinical practice.
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Sepsis is a life-threatening syndrome due to a dysregulated host response to infection, which can be caused by bacterial, viral, or fungal infection. Thus, it is crucial to know how the different microorganisms influence the levels of a biomarker. In the last decade, monocyte distribution width (MDW) has emerged as a promising sepsis biomarker, especially in acute settings, such as the Emergency Department and Intensive Care Unit. In this article, we explore the relationship between MDW and the different pathogens causing infection. Noteworthy, MDW is not a biological molecule, but it is calculated by a mathematical formula based on monocyte characteristics. Monocytes represent the first line defence against microorganisms and undergo activation upon infection, independently from the invading pathogen. According to the knowledge on the biomarker biology and the few literatures evidence, MDW may be considered a biomarker of sepsis, independent of the causative pathogen. However, further investigations are warranted before drawing definite conclusion.
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Monocitos , Sepsis , Humanos , BiomarcadoresRESUMEN
The detection of serum anti-acetylcholine receptor (AChR) antibodies is currently an important tool for diagnosing myasthenia gravis (MG) since they are present in about 85% of MG patients. Many serological tests are now available. Nevertheless, results from these tests can be different in some patients. The aim of this study is to compare the sensitivity of a commercially available fixed cell-based assay (F-CBA) to that of enzyme-linked immunosorbent assay (ELISA) kits for anti-AChR detection in patients with a diagnosis of MG. Overall, 143 patients with a confirmed MG diagnosis were included in the study. The detection and measurement of serum anti-AChR antibodies were performed by three analytical methods, namely, a competitive ELISA (cELISA), an indirect ELISA (iELISA), and an F-CBA, according to the manufacturers' instructions. Anti-AChR antibody titers were positive in 94/143 (66%) using the cELISA, in 75/143 (52%) using the iELISA and in 61/143 (43%) using the F-CBA (adult and/or fetal). Method agreement, evaluated by concordant pairs and Cohen's kappa, was as follows: cELISA-iELISA: 110/143 (77%), k = 0.53 (95%CI 0.40-0.66); cELISA-F-CBA: 108/143 (76%), k = 0.53 (95%CI 0.41-0.66); iELISA-F-CBA: 121/143 (85%), k = 0.70 (95%CI 0.57-0.80). Our findings show that the cELISA has better analytical performance than the iELISA and F-CBA. However, the iELISA and F-CBA show the highest concordance.
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Sepsis , Infecciones Urinarias , Humanos , Monocitos , Sepsis/diagnóstico , Biomarcadores , Infecciones Urinarias/diagnósticoRESUMEN
BACKGROUND: TAR DNA-binding protein 43 (TDP-43) aggregation in neuronal cells is recognized as a hallmark of amyotrophic lateral sclerosis (ALS). Although the literature strongly supports the pathogenetic role of TDP-43 in ALS pathogenesis, the role of TDP-43 as a biomarker of ALS is controversial. We performed a systematic review and meta-analysis to assess the diagnostic performance of TDP-43 for ALS. METHODS: Relevant publications were identified by a systematic literature search on PubMed and Web of Science from their inception to 8 April 2022. RESULTS: Seven studies, including 472 individuals, of whom 254 had ALS according to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, met the inclusion criteria for our meta-analysis. According to the random-effects model, CSF TDP-43 levels are higher in ALS patients compared with control groups. CONCLUSIONS: CSF TDP-43 could represent a biomarker of ALS, but further studies are mandatory before drawing conclusions.
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Monocyte Distribution Width (MDW) is a new generation cell blood count parameter providing a measure of monocyte anisocytosis. In the last decades, it has emerged as a reliable biomarker of sepsis in the acute setting, especially emergency department, and intensive care unit. MDW has several advantages over commonly used sepsis biomarkers, including low-cost, ease and speed of measurement. The clinical usefulness of MDW has been established in several studies and some clinical laboratory medicines have already implemented it in their routine. In this article, we describe the analytical and clinical features of MDW to guide its appropriate use in clinical practice by integrating the research evidence with real-world laboratory experience. The proper use of a biomarker is critical for improving patients' care and outcome as well as ensuring healthcare quality.
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Monocitos , Sepsis , Humanos , Sepsis/diagnóstico , Biomarcadores , Recuento de Células Sanguíneas , LaboratoriosRESUMEN
The serology surveillance of SARS-CoV-2 antibodies represents a useful tool for monitoring protective immunity in the population. We compared the performance of three SARS-CoV-2 antibody serological immunoassays in 600 vaccinated subjects after the BNT162b2 mRNA COVID-19 vaccine. All serum samples were evaluated by three different immunoassays for detecting anti-SARS-COV-2 antibodies. All SARS-CoV-2 antibody serological immunoassays could detect, when present, a post-vaccine humoral immune response. Median (interquartile range, IQR) anti-S-RBD IgG, Access SARS-CoV-2 IgG (1st IS) and Access SARS-CoV-2 IgG II levels of the subjects investigated were, respectively, 687 BAU/mL (131-2325), 419 IU/mL (58-1091) and 104 AU/mL (14-274). By studying a cohort of unvaccinated subjects, without previous COVID-19 infection, we found a high specificity for all methods. A high correlation was found between IgG titres. Considering the kinetics of subjects with multiple doses, we observed that percentage decreasing gradients were comparable across methods. Our results suggest that all the SARS-CoV-2 antibody serological immunoassays evaluated in this study are suitable for monitoring IgG titers over time. This study contributes to a better understanding of antibody response in vaccinated subjects using some currently available assays.
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Vacuna BNT162 , COVID-19 , Humanos , COVID-19/diagnóstico , Vacunas contra la COVID-19 , Luminiscencia , SARS-CoV-2 , Anticuerpos Antivirales , Inmunoglobulina GRESUMEN
Vascular diseases of the elderly are a topic of enormous interest in clinical practice, as they have great epidemiological significance and lead to ever-increasing healthcare expenditures. The mechanisms underlying these pathologies have been increasingly characterized over the years. It has emerged that endothelial dysfunction and chronic inflammation play a diriment role among the most relevant pathophysiological mechanisms. As one can easily imagine, various processes occur during aging, and several pathways undergo irreversible alterations that can promote the decline and aberrations that trigger the diseases above. Endothelial dysfunction and aging of circulating and resident cells are the main characteristics of the aged organism; they represent the framework within which an enormous array of molecular abnormalities occur and contribute to accelerating and perpetuating the decline of organs and tissues. Recognizing and detailing each of these dysfunctional pathways is helpful for therapeutic purposes, as it allows one to hypothesize the possibility of tailoring interventions to the damaged mechanism and hypothetically limiting the cascade of events that drive the onset of these diseases. With this paper, we have reviewed the scientific literature, analysing the pathophysiological basis of the vascular diseases of the elderly and pausing to reflect on attempts to interrupt the vicious cycle that connotes the diseases of aging, laying the groundwork for therapeutic reasoning and expanding the field of scientific research by moving from a solid foundation.
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Enfermedades Vasculares , Humanos , Enfermedades Vasculares/metabolismo , Inflamación/metabolismo , Senescencia CelularRESUMEN
BACKGROUND: Multiple Sclerosis (MS) is a multifactorial disease whose pathogenesis is the result of interaction among genetic, epigenetic, and environmental factors. Among these, a role for vitamin D hypovitaminosis has emerged in recent decades. Vitamin D levels are influenced by both environmental and genetic factors. Single nucleotide polymorphisms (SNPs) in genes codifying for molecules involved in vitamin D metabolism have been associated with an increased risk of developing MS. However, few studies assessed the association of such SNPs with the severity of the disease. The aim of this observational study was to evaluate the potential association among vitamin D status, MS severity, and vitamin D-related SNPs, alone or in combination. METHODS: In a cohort of 100 MS patients, we genotyped 18 SNPs in the following genes: NAD synthetase 1, CYP2R1, vitamin D binding protein, vitamin D receptor, Retinoid X Receptor-α, KLOTHO, CYP24A1, and CYP27A1. Serum 25(OH)D3 levels were measured by high-performance liquid chromatography. Genotyping was performed by real-time polymerase chain reaction or PCR-RFLP. RESULTS: We did not find any association between SNPs, alone or in combination, and MS severity. CONCLUSION: In this study, we make an initial evaluation of the possible influence of several SNPs in vitamin D-related genes on MS severity.
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Esclerosis Múltiple , Vitamina D , Colestanotriol 26-Monooxigenasa/genética , Familia 2 del Citocromo P450/genética , Humanos , Esclerosis Múltiple/genética , Vitamina D/genética , Vitamina D3 24-Hidroxilasa/genética , VitaminasRESUMEN
(1) Background: Alpha-synuclein (α-syn) is a presynaptic neuronal protein that regulates several neuronal functions. In recent decades, the role of α-syn as a biomarker of neurodegenerative diseases has been explored, especially in synucleinopathies. However, only a few studies have assessed its role as biomarker in other neurological disorders. The aim of the study was to evaluate cerebrospinal fluid (CSF) α-syn levels in several neurological disorders; (2) Methods: We measured CSF α-syn levels by a commercial ELISA kit in 158 patients classified in the following group: controls, Alzheimer's Disease (AD), cerebrovascular diseases, inflammatory central nervous system diseases, other neurological diseases, Parkinson's Disease (PD), and peripheral neuropathy; (3) Results: Patients with PD showed the lowest and patients with AD the highest levels of CSF α-syn (1372 vs. 2912 pg/mL, respectively, p < 0.001). In AD patients, α-syn levels were significantly associated with tau proteins; (4) Conclusions: α-syn could represent a biomarker of neurodegenerative diseases.
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Immunosurveillance by evaluating anti-spike protein receptor-binding domain (S-RBD) antibodies represents a useful tool to estimate the long immunity against Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection. The aim of this study was to evaluate the kinetics of antibody response in vaccine recipients. We measured anti-S-RBD IgG levels by indirect chemiluminescence immunoassay on Maglumi 800 (SNIBE, California) in 1013 healthy individuals naïve to SARS-CoV2 infection after two and three COVID-19 vaccine doses. We found that anti-S-RBD IgG levels are higher in females than males. Antibody levels gradually decrease to a steady state after four months since the peak, and the decay is independent of age, sex, vaccine doses, and baseline antibodies titer. The third dose induces a high anti-S-RBD IgG reactivity in individuals with previous high responses and triggers a moderate-high anti-S-RBD IgG reactivity. The assessment of anti-S-RBD IgG levels is essential for monitoring long-term antibody response. A third SARS-CoV-2 vaccine dose is associated with a significant immunological response. Thus, our results support the efficacy of the vaccine programs and the usefulness of the third dose.