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Aging is accompanied by remodeling of the immune system. With time, this leads to a decline in immune efficacy, resulting in increased vulnerability to infectious diseases, diminished responses to vaccination, and a susceptibility to age-related inflammatory diseases. An age-associated immune alteration, extensively reported in previous studies, is the reduction in the number of peripheral blood naïve cells, with a relative increase in the frequency of memory cells. These two alterations, together with inflamm-aging, are considered the hallmarks of immunosenescence. Because aging is a plastic process, it is influenced by both nutritional and pharmacological interventions. Therefore, the role of nutrition and of immunomodulation in immunosenescence is discussed, due to the multifactorial influence on these hallmarks. The close connection between nutrition, intake of bioactive nutrients and supplements, immune function, and inflammation demonstrate the key role of dietary strategies as regulators of immune response and inflammatory status, hence as possible modulators of the rate of immunosenescence. In addition, potential options for therapeutic intervention are clarified. In particular, the use of interleukin-7 as growth factor for naïve T cells, the function of checkpoint inhibitors in improving T cell responses during aging and, the potential of drugs that inhibit mitogen-activated protein kinases and their interaction with nutrient signaling pathways are discussed. Finally, it is suggested that the inclusion of appropriate combinations of toll-like receptor agonists may enhance the efficacy of vaccination in older adults.

Alzheimer’s Disease (AD) is the most common cause of dementia, having a remarkable social and healthcare burden worldwide. Amyloid β (Aβ) and protein Tau aggregates are disease hallmarks and key players in AD pathogenesis. However, it has been hypothesized that microglia can contribute to AD pathophysiology, as well. Microglia are CNS-resident immune cells belonging to the myeloid lineage of the innate arm of immunity. Under physiological conditions, microglia are in constant motion in order to carry on their housekeeping function, and they maintain an anti-inflammatory, quiescent state, with low expression of cytokines and no phagocytic activity. Upon various stimuli (debris, ATP, misfolded proteins, aggregates and pathogens), microglia acquire a phagocytic function and overexpress cytokine gene modules. This process is generally regarded as microglia activation and implies that the production of pro-inflammatory cytokines is counterbalanced by the synthesis and the release of anti-inflammatory molecules. This mechanism avoids excessive inflammatory response and inappropriate microglial activation, which causes tissue damage and brain homeostasis impairment. Once the pathogenic stimulus has been cleared, activated microglia return to the naïve, anti-inflammatory state. Upon repeated stimuli (as in the case of Aβ deposition in the early stage of AD), activated microglia shift toward a less protective, neurotoxic phenotype, known as “primed” microglia. The main characteristic of primed microglia is their lower capability to turn back toward the naïve, anti-inflammatory state, which makes these cells prone to chronic activation and favours chronic inflammation in the brain. Primed microglia have impaired defence capacity against injury and detrimental effects on the brain microenvironment. Additionally, priming has been associated with AD onset and progression and can represent a promising target for AD treatment strategies. Many factors (genetics, environmental factors, baseline inflammatory status of microglia, ageing) generate an aberrantly activated phenotype that undergoes priming easier and earlier than normally activated microglia do. Novel, promising targets for therapeutic strategies for AD have been sought in the field of microglia activation and, importantly, among those factors influencing the baseline status of these cells. The CX3CL1 pathway could be a valuable target treatment approach in AD, although preliminary findings from the studies in this field are controversial. The current review aims to summarize state of the art on the role of microglia dysfunction in AD pathogenesis and proposes biochemical pathways with possible targets for AD treatment.

Sepsis represents an important global health burden due to its high mortality and morbidity. The rapid detection of sepsis is crucial in order to prevent adverse outcomes and reduce mortality. However, the diagnosis of sepsis is still challenging and many efforts have been made to identify reliable biomarkers. Unfortunately, many investigated biomarkers have several limitations that do not support their introduction in clinical practice, such as moderate diagnostic and prognostic accuracy, long turn-around time, and high-costs. Complete blood count represents instead a precious test that provides a wealth of information on individual health status. It can guide clinicians to early-identify patients at high risk of developing sepsis and to predict adverse outcomes. It has several advantages, being cheap, easy-to-perform, and available in all wards, from the emergency department to the intensive care unit. Noteworthy, it represents a first-level test and an alteration of its parameters must always be considered within the clinical context, and the eventual suspect of sepsis must be confirmed by more specific investigations. In this review, we describe the usefulness of basic and new complete blood count parameters as diagnostic and prognostic biomarkers of sepsis.

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.

Cerebrospinal fluid (CSF) core biomarkers of Alzheimer’s disease (AD), including amyloid peptide beta-42 (Aβ42), Aβ42/40 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 Aβ42, Aβ40, 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 Aβ42, Aβ40, and pTau. A positive correlation of pTau, Aβ42/40 ratio, and pTau/Aβ42 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 Aβ42/40 ratio, pTau/Aβ42 ratio, and pTau could serve as surrogates of the corresponding CSF biomarkers.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a neurotropic virus with a high neuroinvasive potential. Indeed, more than one-third of patients develop neurological symptoms, including confusion, headache, and hypogeusia/ageusia. However, long-term neurological consequences have received little interest compared to respiratory, cardiovascular, and renal manifestations. Several mechanisms have been proposed to explain the potential SARS-CoV-2 neurological injury that could lead to the development of neurodegenerative diseases, including Alzheimer’s Disease (AD). A mutualistic relationship between AD and COVID-19 seems to exist. On the one hand, COVID-19 patients seem to be more prone to developing AD. On the other hand, AD patients could be more susceptible to severe COVID-19. In this review, we sought to provide an overview on the relationship between AD and COVID-19, focusing on the potential role of biomarkers, which could represent precious tool for early identification of COVID-19 patients at high risk of developing AD.

(1) Background: The evaluation of anti-spike protein receptor-binding domain (S-RBD) antibodies represents a useful tool to estimate the individual protection against Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection; (2) Methods: We evaluated anti S-RBD IgG levels by indirect chemiluminescence immunoassay on Maglumi 800 (SNIBE, California) in 2248 vaccinated subjects without previous SARS-CoV-2 infection, 91 vaccinated individuals recovered from COVID-19, and 268 individuals recovered from COVID-19 who had not been vaccinated. Among those who were healthy and vaccinated, 352 subjects performed a re-dosing after about 72 days from the first measurement. (3) Results: Anti S-RBD IgG levels were lower in subjects with previous infection than vaccinated subjects, with or without previous infection (p < 0.001). No difference was observed between vaccinated subjects, with and without previous SARS-CoV-2 infection. Overall, anti-RBD IgG levels were higher in females than males (2110 vs. 1341 BAU/mL; p < 0.001) as well as in subjects with symptoms after vaccination than asymptomatic ones (2085 vs. 1332 BAU/mL; p = 0.001) and lower in older than younger subjects. Finally, a significant decrease in anti-RBD IgG levels was observed within a short period from a complete two-dose cycle vaccination. (4) Conclusions: Our results show an efficacy antibody response after vaccination with age-, time- and sex-related differences.

Vitamin D and cognition is a popular association, which led to a remarkable body of literature data in the past 50 years. The brain can synthesize, catabolize, and receive Vitamin D, which has been proved to regulate many cellular processes in neurons and microglia. Vitamin D helps synaptic plasticity and neurotransmission in dopaminergic neural circuits and exerts anti-inflammatory and neuroprotective activities within the brain by reducing the synthesis of pro-inflammatory cytokines and the oxidative stress load. Further, Vitamin D action in the brain has been related to the clearance of amyloid plaques, which represent a feature of Alzheimer Disease (AD), by the immune cell. Based on these considerations, many studies have investigated the role of circulating Vitamin D levels in patients affected by a cognitive decline to assess Vitamin D’s eventual role as a biomarker or a risk factor in AD. An association between low Vitamin D levels and the onset and progression of AD has been reported, and some interventional studies to evaluate the role of Vitamin D in preventing AD onset have been performed. However, many pitfalls affected the studies available, including substantial discrepancies in the methods used and the lack of standardized data. Despite many studies, it remains unclear whether Vitamin D can have a role in cognitive decline and AD. This narrative review aims to answer two key questions: whether Vitamin D can be used as a reliable tool for diagnosing, predicting prognosis and response to treatment in AD patients, and whether it is a modifiable risk factor for preventing AD onset.

Vitamin D is a steroid hormone regulating calcium-phosphorus homeostasis, immune response and brain function. In the past thirty years, an increasing number of cohort studies, meta-analyses and randomized controlled trials (RTCs) evaluated the serum levels of 25-hydroxyvitamin D [25(OH)D], which is considered the Vitamin D status biomarker, in patients affected by neurological, psychiatric and autoimmune diseases. Although an association between low 25(OH)D serum levels and the prevalence of these diseases has been found, it is still unclear whether the serum 25(OH)D measurement can be clinically useful as a biomarker for diagnosis, prognosis and predicting treatment response in neurodegeneration, mental illness and immune-mediated disorders. The lack of standardized data, as well as discrepancies among the studies (in the analytical methods, cut-offs, endpoints and study sets), weakened the findings achieved, hindered pooling data, and, consequently, hampered drawing conclusions. This narrative review summarizes the main findings from the studies performed on serum 25(OH)D in neurological, psychiatric and autoimmune diseases, and clarifies whether or not serum 25(OH)D can be used as a reliable biomarker in these diseases.

Renal Salt Wasting Syndrome (RSW) is a clinical syndrome with laboratory characteristics completely overlapping with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). No studies have yet investigated the potential role of urodilatin as a diagnostic marker or its involvement in the pathogenesis of RSW. We performed a retrospective observational case-control study, the patients were divided into 3 groups: a group of hyponatremic patients with RSW (cases) and two control groups (subjects without hyponatremia and subjects with hyponatremia from other causes). Main outcomes were assessing the differences in urinary urodilatin values in patients with RSW compared to both control groups and to evaluate the diagnostic power of urodilatin with the analysis of ROC curves. Patients with RSW display significantly higher mean urodilatin levels than both patients with (median 5.46 vs. 0.57 ng/mL, p = 0.006) or without hyponatremia (median 5.46 vs. 0.27 ng/mL, p < 0.001). Diagnostics performances of mean urodilatin levels for RSW diagnosis were evaluated by ROC curve, AUC was 0.94 (95%CI 0.86-1.00). This case-control study has shown interesting results regarding the dosage of urinary urodilatin in patients with RSW, with potentially clarifying implications both regarding the pathogenesis of this syndrome and regarding the diagnosis and therefore the clinical management of patients.