Alterazioni topologiche cerebrali in relazione a cambiamenti cognitivi nel Mild Cognitive Impairment e nella malattia di Alzheimer

openLa malattia di Alzheimer (AD) rappresenta una delle malattie neurodegenerative più comuni. Il primo sintomo clinico che generalmente porta un soggetto sotto osservazione è l'emergere di errori di memoria episodica, che però accadono quando la patologia ha già raggiunto certo grado di diffusione. In anni recenti, è stato osservato che queste alterazioni neuronali presentano una certa sovrapposizione con networks cerebrali come il Default Mode Network (DMN) e il Network Frontoparietale (FPN). Tuttavia, non è chiaro se le alterazioni funzionali possano essere rilevate anni prima dell'emergere dei sintomi clinici, nella fase prodromica della malattia, il Mild Cognitive Impairment (MCI), e il loro potere predittivo di progressione da MCI ad AD. In questo studio, abbiamo tentato di risolvere questa lacuna investigando la relazione tra le alterazioni topologiche dei due network sopracitati e l'emergere di difficoltà di memoria episodica dopo 2 anni di follow-up. Pe fare ciò, abbiamo utilizzando uno strumento analitico di recente sviluppo, la graph theory, e una batteria di test specifica che valuta tutti le fasi della memoria (codifica, recupero e ricordo) in un campione di soggetti sani e pazienti MCI. I nostri risultati suggeriscono che un aumento nella segregazione del DMN potrebbe rappresentare un biomarker precoce di peggioramento cognitivo nella codifica di informazioni. In particolare, questo studio enfatizza anche il meccanismo compensatorio funzionale nei nodi prefrontal dello stesso network, i quali potrebbero rappresentare una caratteristica importante della patologia nella sua fase prodromica. Questi risultati potrebbero essere utili nel rilevamento precoce di pazienti ad alto rischio di progressione clinica e per i quali potrebbero ancora attuati interventi di recupero.Alzheimer’s disease (AD) represents the most common neurodegenerative disease. The first clinical symptom that usually brings an individual under clinical attention is the emergence of episodic memory pitfalls, which however occur when the underlying pathology has already reached a certain degree of spreading. In recent years, these neural alterations have been observed to largely overlap with known functional networks, especially the Default Mode (DMN) and the Frontoparietal (FPN) networks. However, much debate exists regarding whether functional alterations can be detected years before symptoms offset, i.e. that is in the prodromal disease stage of Mild Cognitive Impairment (MCI), and their predictive power of MCI-to-AD progression. In this study, we tried to fill this gap by investigating the relationship between topological networks’ alteration and the emergence of episodic memory difficulties at 2 years’ follow-up. We did so using a recently developed neuroimaging analytic tool, namely graph theory, and a specific battery of tests, assessing all stages of memory encoding, retrieval and recall in a sample of MCI patients and healthy controls. Our results suggest that increased DMN segregation might represent an early biomarker of cognitive worsening in episodic memory encoding. In particular, the study emphasizes that functional compensatory mechanisms in prefrontal nodes of the DMN might be a more prominent feature of the pathology at its prodromal stages, representing an early stressor. These findings might be potentially useful in the early detection of patients at higher risk of clinical progression and for whom resilience boosting interventions might still be put in place

Nebivolol: haemodynamic effects and clinical significance of combined beta-blockade and nitric oxide release.

Nebivolol is a third-generation beta-adrenergic receptor antagonist (beta-blocker) with high selectivity for beta(1)-adrenergic receptors. In addition, it causes vasodilatation via interaction with the endothelial L-arginine/nitric oxide (NO) pathway. This dual mechanism of action underlies many of the haemodynamic properties of nebivolol, which include reductions in heart rate and blood pressure (BP), and improvements in systolic and diastolic function. With respect to BP lowering, the NO-mediated effects cause a reduction in peripheral vascular resistance and an increase in stroke volume with preservation of cardiac output. Flow-mediated dilatation and coronary flow reserve are also increased during nebivolol administration. Other haemodynamic effects include beneficial effects on pulmonary artery pressure, pulmonary wedge pressure, exercise capacity and left ventricular ejection fraction. In addition, nebivolol does not appear to have adverse effects on lipid metabolism and insulin sensitivity like traditional beta-blockers. The documented beneficial haemodynamic effects of nebivolol are translated into improved clinical outcomes in patients with hypertension or heart failure. In patients with hypertension, the incidence of bradycardia with nebivolol is often lower than that with other currently available beta-blockers. This, along with peripheral vasodilatation and NO-induced benefits such as antioxidant activity and reversal of endothelial dysfunction, should facilitate better protection from cardiovascular events. In addition, nebivolol has shown an improved tolerability profile, particularly with respect to events commonly associated with beta-blockers, such as fatigue and sexual dysfunction. Data from SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure) showed that significantly fewer nebivolol versus placebo recipients experienced the primary endpoint of all-cause mortality or cardiovascular hospitalization. The benefits of nebivolol therapy were shown to be cost effective. Thus, nebivolol is an effective and well tolerated agent with benefits over and above those of traditional beta-blockade because of its effects on NO release, which give it unique haemodynamic effects, cardioprotective activity and a good tolerability profile

Dietary curcumin : correlation between bioavailability and health potential

The yellow pigment curcumin, extracted from turmeric, is a renowned polyphenol with a broad spectrum of health properties such as antioxidant, anti-inflammatory, anti-cancer, antidiabetic, hepatoprotective, anti-allergic, anti-dermatophyte, and neuroprotective. However, these properties are followed by a poor pharmacokinetic profile which compromises its therapeutic potential. The association of low absorption by the small intestine and the extensive reductive and conjugative metabolism in the liver dramatically weakens the oral bioavailability. Several strategies such as inhibition of curcumin metabolism with adjuvants as well as novel solid and liquid oral delivery systems have been tried to counteract curcumin poor absorption and rapid elimination from the body. Some of these drug deliveries can successfully enhance the solubility, extending the residence in plasma, improving the pharmacokinetic profile and the cellular uptake

Possible genetic implications in the response to cardiac resynchronisation therapy in a patient affected by heart failure

This report presents a case of a patient with idiopathic dilated cardiomyopathy and severe left ventricular systolic dysfunction who underwent cardiac resynchronisation therapy (CRT). During the follow-up a progressive increase in left ventricular ejection fraction was observed, as well as clinical improvement. No cardiovascular events occurred during the follow-up, except for appropriate Implantable Cardioverter Defibrillator (ICD) bursts for fast ventricular tachycardia. Genotyping for adrenoceptor gene polymorphisms detected that the patient was Glu27Glu homozygous carrier. There’s a large interindividual variability in response to CRT. Despite attempts to identify factors having an impact on this therapy, only QRS duration is accepted according to guidelines. Beta-adrenoceptors polymorphisms, modulating sympathetic drive in heart failure and left ventricular remodelling, may have a role in identifying patients with a better response to CRT, in order to target and individualise the patients’ treatment

Sudden death prevention in heart failure: The case of CIBIS III

CIBIS III completes a fundamental scientific phase of a sequence of large clinical trials (1-7) which has established the current therapeutic principles for the management of chronic heart failure (CHF) patients (8). These comprise the use of ACE inhibitors and beta- blockers. However, while ACE inhibitors, by antagonizing the synthesis of angiotensin II, found their natural pathway from hypertension into CHF, betablockers followed a controversial trail. They appeared effective in the BEHAT (9) trial after myocardial infarction (MI) even in patients with depressed left ventricular (LV) function. Nonetheless, the general view of CHF as an almost exclusively cardio-circulatory mechanical disease/remodelling led to the use of inotropic interventions, with non-infrequent negative consequences on mortality (10). Furthermore, this view prevented the conception of using antiadrenergic interventions in CHF which consequently remained a strong contraindication to the use of beta- blockers for many years. Beginning with CIBIS II, a number of trials have proven that beta-blocker therapy improves survival in CHF, with a specific action on arrhythmic sudden cardiac death (SCD) in patients with optimum background therapy, including the use of ACE inhibitors. This did not happen by chance, as a strong experimental ground had already existed.....