Plasma Cystatin C Correlates with Plasma NfL Levels and Predicts Disease Progression in Parkinson's Disease.

INTRODUCTION: Previous studies reported increased plasma levels of cystatin C (Cys-C) in Parkinson's disease (PD) and claimed for a possible association with disease severity and progression. The aim of this study was to evaluate plasma Cys-C in PD and healthy controls (HC) and test its association with markers of peripheral inflammation, neurodegeneration, and clinical progression in a longitudinal study. METHODS: Plasma Cys-C, high-sensitive C-reactive protein, interleukin 6, and neurofilament light chain (NfL) were assessed at the baseline in 71 consecutive non-demented PD and 69 HC. PD patients underwent an extensive motor and cognitive assessment at baseline and after 2 years of follow-up. The association of Cys-C with disease severity was evaluated in a multilinear model adjusted for the effect of age, sex, disease duration, and peripheral inflammation. RESULTS: Cys-C levels appeared to be higher in PD compared to controls and correlated with the plasma neuronal marker NfL (r = 0.204, p = 0.046). In longitudinal analyses, PD patients with higher Cys-C levels exhibited faster motor progression at 2 years of follow-up independently from the peripheral inflammatory profile. CONCLUSIONS: Cys-C was associated with higher NfL levels and a remarkably faster motor progression in PD independently from peripheral inflammation. Further studies are needed in order to understand the mechanisms underpinning the association of Cys-C with higher neuronal damage markers in neurodegenerative diseases.

Familial late-onset Alzheimer's disease: description of an Italian family with four affected siblings and one case of early-onset dementia in the preceding generation.

We describe a family composed of six siblings, four of which affected by late-onset Alzheimer's disease (LOAD). We constructed the family pedigree, evaluated mutations usually associated with early-onset Alzheimer's disease (APP, PSEN1, PSEN2), and assessed polymorphisms in the apolipoprotein E (APOE) gene and in cytokine genes that we had previously found to be associated with a higher risk of LOAD (IL-10, IL-6, TNF-α). Results showed that all subjects carried one ε4 allele of the APOE gene and those with the earliest age of onset exhibited the AA (-1082) IL-10 and the CC (-174) IL-6 genotypes. The only male had a genetic profile which also included the A (-308) TNF-α allele. These data confirm the role of the APOE gene as genetic risk factor in LOAD, and suggest that the risk of developing AD may be governed by a "susceptibility profile" involving polymorphisms in inflammatory genes.

Sodium glucose co-transporter 2 inhibitors and quality of life in patients with heart failure: a comprehensive systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2i) are one of the cornerstones of heart failure (HF) therapy. While benefits in terms of HF hospitalizations and death are well established, their impact on quality-of-life (QoL) has not been systematically investigated. OBJECTIVE: This systematic review and meta-analysis aims to evaluate the impact of SGLT2i treatment on QoL in patients with HF, by analysing data from randomized clinical trials (RCTs). METHODS: We identified a total of 23 RCTs that investigated the role of SGLT2i on quality of life in patients with HF, irrespective of their left ventricular ejection fraction (LVEF). RCTs that used Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) to assess QoL and had a minimum follow-up of 3 months were included. The difference in mean change of the KCCQ-OSS between the SGLT2i group and the standard of care (SOC) group at 3 and 6 months from baseline was considered as the outcome measure. FINDINGS: Fourteen RCTs (21 737 patients) were included in the analysis. A significant improvement in KCCQ-OSS over time (p < 0.001) was observed in both patients receiving SOC and those receiving SGLT2i in addition. The pooled estimate showed a significant improvement of 1.94 points [95% confidence interval (CI), 1.41-2.46] in KCCQ-OSS mean change at 3 months and of 2.18 points (95% CI, 1.13-3.24) at 6 months from baseline, with SGLT2i compared to SOC alone, irrespective of LVEF. A greater improvement in KCCQ-OSS was observed among patients with a recent episode of worsening HF compared to those with chronic stable HF. CONCLUSIONS: Among patients with HF, irrespective of their LVEF and clinical status, the addition of SGLT2i to SOC demonstrated a significant improvement in quality of life as early as at 3-month follow-up.

OPTImal PHARMacological therapy for patients with heart failure: Rationale and design of the OPTIPHARM-HF registry.

AIMS: Patients with heart failure (HF) remain often undertreated for multiple reasons, including treatment inertia, contraindications, and intolerance. The OPTIimal PHARMacological therapy for patients with Heart Failure (OPTIPHARM-HF) registry is designed to evaluate the prevalence of evidence-based medical treatment prescription and titration, as well as the causes of its underuse, in a broad real-world population of consecutive patients with HF across the whole ejection fraction spectrum and among different clinical phenotypes. METHODS: The OPTIPHARM-HF registry (NCT06192524) is a prospective, multicenter, observational, national study of adult patients with symptomatic HF, as defined by current international guidelines, regardless of ejection fraction. Both outpatients and inpatients with chronic and acute decompensated HF will be recruited. The study will enroll up to 2500 patients with chronic HF at approximately 35 Italian HF centres. Patients will be followed for a maximum duration of 24 months. The primary objective of the OPTIPHARM-HF registry is to assess prescription and adherence to evidence-based guideline-directed medical therapy (GDMT) in patients with HF. The primary outcome is to describe the prevalence of GDMT use according to target guideline recommendation. Secondary objectives include implementation of comorbidity treatment, evaluation of sequence of treatment introduction and up-titration, description of GDMT implementation in the specific HF population, main causes of GDMT underuse, and assessment of cumulative rate of cardiovascular events. CONCLUSION: The OPTIPHARM-HF registry will provide important implications for improving patient care and adoption of recommended medical therapy into clinical practice among HF patients.

Telemedicine for the treatment of heart failure: new opportunities after COVID-19.

ABSTRACT: During the Coronavirus Disease 2019 (COVID-19) pandemic, the epidemiology of heart failure significantly changed with reduced access to health system resources and a worsening of patients' outcome. Understanding the causes of these phenomena could be important to refine the management of heart failure during and after the pandemic. Telemedicine was associated with an improvement in heart failure outcomes in several studies; therefore, it may help in refining the out-of-hospital care of heart failure. In this review, the authors describe the changes in heart failure epidemiology during the COVID-19 pandemic; analyse available evidence on use and benefit of telemedicine during the pandemic and prepandemic periods; and discuss approaches to optimize the home-based or outpatient heart failure management in the future, beyond the pandemic.

Inflammation in acute heart failure.

Acute heart failure (AHF) represents a common clinical scenario that requires prompt evaluation and therapy and that is characterized by a high risk of mortality or subsequent rehospitalizations. The pathophysiology leading to AHF decompensation is still not fully understood. Significant activation of inflammatory pathways has been identified in patients with AHF, particularly in its most severe forms, and it has been hypothesized that systemic inflammation has a role in AHF pathogenesis. Several inflammatory mediators and cytokines, such as high sensitivity C-reactive protein, tumor necrosis factor-α, interleukin-6, interleukin-1, soluble suppression of tumorigenicity 2 and galectin-3, have been shown to play a role in the pathogenesis, development and worsening of this condition with an independent prediction of adverse outcomes. This manuscript reviews the prevalence and prognostic value of systemic inflammation in AHF, as well as the potential role of anti-inflammatory therapies, focusing on available evidence from clinical trials and ongoing studies.

Age-Dependent Neuropsychiatric Symptoms in the NF-κB/c-Rel Knockout Mouse Model of Parkinson's Disease.

Non-motor symptoms are frequently observed in Parkinson's disease (PD) and precede the onset of motor deficits by years. Among them, neuropsychiatric symptoms, including anxiety, depression, and apathy, are increasingly considered as a major challenge for patients with PD and their caregivers. We recently reported that mice lacking the nuclear factor-κB (NF-κB)/c-Rel protein (c-rel-/- mice) develop an age-dependent PD-like pathology and phenotype characterized by the onset of non-motor symptoms, including constipation and hyposmia, starting at 2 months of age, and motor deficits at 18 months. To assess whether c-rel-/- mice also suffer from neuropsychiatric symptoms, in this study we tested different cohorts of wild-type (wt) and c-rel-/- mice at 3, 6, 12, and 18-20 months with different behavioral tests. Mice lacking c-Rel displayed anxiety and depressive-like behavior starting in the premotor phase at 12 months, as indicated by the analysis with the open field (OF) test and the forced swim test with water wheel (FST), respectively. A deficit in the goal-oriented nesting building test was detected at 18-20 months, suggesting apathetic behavior. Taken together, these results indicate that c-rel-/- mice recapitulate the onset and the progression of PD-related neuropsychiatric symptoms. Therefore, this animal model may represent a valuable tool to study the prodromal stage of PD and for testing new therapeutic strategies to alleviate neuropsychiatric symptoms.

Synergistic association of resveratrol and histone deacetylase inhibitors as treatment in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, progressive paralysis and finally death. Despite the research efforts, currently there is no cure for ALS. In recent years, multiple epigenetic mechanisms have been associated with neurodegenerative diseases. A pathological role for histone hypoacetylation and the abnormal NF-κB/RelA activation involving deacetylation of lysines, with the exclusion of lysine 310, has been established in ALS. Recent findings indicate that the pathological acetylation state of NF-κB/RelA and histone 3 (H3) occurring in the SOD1(G93A) murine model of ALS can be corrected by the synergistic combination of low doses of the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator resveratrol and the histone deacetylase (HDAC) inhibitors MS-275 (entinostat) or valproate. The combination of the epigenetic drugs, by rescuing RelA and the H3 acetylation state, promotes a beneficial and sexually dimorphic effect on disease onset, survival and motor neurons degeneration. In this mini review, we discuss the potential of the epigenetic combination of resveratrol with HDAC inhibitors in the ALS treatment.

From Preclinical Stroke Models to Humans: Polyphenols in the Prevention and Treatment of Stroke.

Polyphenols are an important family of molecules of vegetal origin present in many medicinal and edible plants, which represent important alimentary sources in the human diet. Polyphenols are known for their beneficial health effects and have been investigated for their potential protective role against various pathologies, including cancer, brain dysfunctions, cardiovascular diseases and stroke. The prevention of stroke promoted by polyphenols relies mainly on their effect on cardio- and cerebrovascular systems. However, a growing body of evidence from preclinical models of stroke points out a neuroprotective role of these molecules. Notably, in many preclinical studies, the polyphenolic compounds were effective also when administered after the stroke onset, suggesting their possible use in promoting recovery of patients suffering from stroke. Here, we review the effects of the major polyphenols in cellular and in vivo models of both ischemic and hemorrhagic stroke in immature and adult brains. The results from human studies are also reported.

Corrigendum to "Peripheral Blood Mononuclear Cells as a Laboratory to Study Dementia in the Elderly".

[This corrects the article DOI: 10.1155/2014/169203.].

Protein signature in cerebrospinal fluid and serum of Alzheimer's disease patients: The case of apolipoprotein A-1 proteoforms.

In the diagnosis of Alzheimer's disease (AD) total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and the 42 amino acid isoform of alpha ß-amyloid (Aß) are well established surrogate CSF markers. However, there is a constant need for new diagnostic markers to identify the disease at a very early stage. The identification of new molecules for AD diagnosis and monitoring in CSF is hampered by several "confounding" factors including intra- and inter-individual, pre-analytical and analytical variabilities. In an attempt to partially overcome patient's variability and to determine new molecules significantly dysregulated in CSF, we assessed the proteome profile of low molecular weight protein species in CSF and serum of the same patients. CSFs and sera from 36 ADs, 32 iNPHs (idiopathic normal pressure hydrocephalus) and 12 controls were compared by MALDI profiling (non-parametric statistics, CV<20%, AUC>0.750). After protein identification by mass spectrometry, the proteoform composition was assessed by 2-D DIGE/MS. Results indicated that CSF of iNPH can be used as control. Serum and CSF of AD patients shows a specific protein profile compared to iNPH samples. A variation (p<0.01) of Apo A-1 levels in AD, together with a specific dysregulation of Apo A-1 proteoforms was observed. The profiling of CSF and serum of the same patients, suggests that the decrement of total Apo A-1 occurs specifically in CSF. Serum and CSF of AD shows a characteristic Apo A-1 proteoform pattern suggesting it as potential marker which can support the clinical workflow adopted for AD diagnosis and progression.

Adenosine Type A2A Receptor in Peripheral Cell from Patients with Alzheimer's Disease, Vascular Dementia, and Idiopathic Normal Pressure Hydrocephalus: A New/Old Potential Target.

As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer's disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies.

Down-regulation of adenosine A1 and A2A receptors in peripheral cells from idiopathic normal-pressure hydrocephalus patients.

Idiopathic normal-pressure hydrocephalus (iNPH) is a neurological disease that usually develops in the elderly. Natural history of iNPH is still unknown. It has been hypothesized that cerebrovascular diseases could have a role in etiology of chronic hydrocephalus and studies show an increased prevalence of cardiovascular diseases in iNPH patients. Moreover, evidences show a possible alteration of immune system in iNPH patients. Adenosine (Ado) is a metabolite produced in response to metabolic stress and injury. Adenosine and its receptors play an important role in vascular protection and in the modulation of inflammatory reactions and neuroinflammation. Our aim is to evaluate gene and protein expression of A1R and A2AR in the peripheral blood mononuclear cells (PBMCs) from iNPH patients compared to control subjects. We investigate if Ado system, that plays an important role in central nervous system, in vascular system, and also in inflammation, is involved in pathophysiology of iNPH disease. Our analysis showed that A1R mRNA levels and A1R density in PBMCs from iNPH patients were significantly lower than CT subjects (0.84 ± 0.12 and 2.42 ± 0.42, p<0.001 and 0.31 ± 0.02 and 0.42 ± 0.04, p=0.043; respectively). About A2AR, the gene expression in PBMCs was significantly lower in iNPH than CT (0.65 ± 0.09 and 1.5 ± 0.14, p<0.001) as well as there was a trend in protein expression: iNPH and CT (0.51 ± 0.05 and 0.62 ± 0.03; p=0.172). This preliminary study underlines the involvement of Ado system in iNPH disease whose pathophysiology is still unclear.

Impact of vitamin D receptor polymorphisms in centenarians.

Vitamin D is a seco-sterol produced endogenously in the skin or obtained from certain foods. It exerts its action through binding to intracellular vitamin D receptor (VDR). Lately, the role of vitamin D has been revised regarding its potential advantage on delaying the process of aging. The aim of this study was to assess the contribution of VDR gene polymorphisms in healthy aging and longevity. We evaluated the frequency of four polymorphisms of the VDR gene (FokI, BsmI, ApaI, and TaqI) in centenarians (102 subjects, mean age: 102.3 ± 0.3 years), compared to septuagenarians (163 subjects, mean age: 73.0 ± 0.6 years) and we analyzed a variety of pathophysiologically relevant functions in centenarians. BsmI and ApaI provided a significant association with longevity: there was a highly significant difference in the frequency of BsmI genotypes (p = 0.037), ApaI genotypes (p = 0.022), and ApaI alleles (p = 0.050) in centenarians versus septuagenarians. Furthermore, we found a significant correlation of all the VDR gene polymorphisms in centenarians with some measured variables such as hand grip strength, body mass index, blood pressure, HDL cholesterol, and mini-mental state examination. We also found a correlation with the prevalence of medical history of hypertension, acute myocardial infarction, angina, venous insufficiency, dementia, chronic obstructive pulmonary disease, and arthrosis. In conclusion, this study proposes a new scenario in which the variability of the VDR gene is relevant in the aging process and emphasizes the role of VDR genetic background in determining healthy aging.

Gene promoter methylation and expression of Pin1 differ between patients with frontotemporal dementia and Alzheimer's disease.

Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD) share the accumulation of fibrillar aggregates of misfolded proteins. To better understand these neurodegenerative diseases and identify biomarkers in easily accessible cells, we investigated DNA methylation at Pin1 gene promoter and its expression in peripheral blood mononuclear cells of FTD patients. We found a lower gene expression of Pin1 with a higher DNA methylation in three CpG sites at Pin1 gene promoter analysed in FTD subjects, in contrast to a higher gene expression with a lower methylation in AD subjects and controls. These data suggest an important and distinct involvement of Pin1 in these two types of dementia.

Leukocyte Telomere Length in Alzheimer's Disease Patients with a Different Rate of Progression.

BACKGROUND: Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes. OBJECTIVE: The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-ß (Aß)-stimulated PBMC. METHODS: We enrolled 31 late-onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up ≤3 points) or fast progressing AD (ADF) (MMSE decline ≥5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay. RESULTS: TL (mean±SD) for HE, ADS, and ADF was 2.3±0.1, 2.0±0.1, and 2.5±0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p = 0.034) and to ADF (p = 0.005). MMSE decline correlated with TL in AD (R2 = 0.284; p = 0.008). We found a significant difference in IL-10 production between unstimulated and Aß-stimulated PBMC from ADS (40.7±13.7 versus 59.0±27.0; p = 0.004) but not from ADF (39.7±14.4 versus 42.2±22.4). HE showed a trend toward significance (47.1±25.4 versus 55.3±27.9; p = 0.10). CONCLUSION: PBMC from ADF may be characterized by an impaired response induced by Aß and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression.

Interleukin-10 Production in Response to Amyloid-ß Differs between Slow and Fast Decliners in Patients with Alzheimer's Disease.

We investigated IL-10 and IL-6 production in amyloid-ß (Aß) stimulated peripheral blood mononuclear cells (PBMCs) in twenty Alzheimer's disease (AD) patients with slow progression, eleven with fast progression, and twenty age-matched controls. Promoter polymorphisms in IL-10 (position -592, -819, -1082), IL-6 (-174), transforming growth factor-ß1 (TGF-ß1) (-10, -25), interferon-γ (IFN-γ) (-874), and tumor necrosis factor-α (TNF-α) (-308) genes were analyzed. IL-10 production after Aß stimulation was high in PBMCs from slow decliners and almost completely abrogated in fast decliners. Association between AA IFN-γ low-producing genotype and fast progression was demonstrated. Investigations in a larger sample will clarify these findings.

Different adenosine A2A receptor expression in peripheral cells from elderly patients with vascular dementia and Alzheimer's disease.

The line between vascular dementia (VaD) and Alzheimer's disease (AD) is often blurred. In this study we investigated whether adenosine A2A receptor (A2AR) expression can be used to differentiate between VaD and AD. We evaluated the expression of this receptor in the peripheral blood mononuclear cells of patients with VaD, mild cognitive impairment, AD, and controls. We found statistically significant lower levels of A2AR mRNA in VaD compared to AD subjects. These data suggest that A2AR expression may help in the differential diagnosis between VaD and AD.

Peripheral blood mononuclear cells as a laboratory to study dementia in the elderly.

The steady and dramatic increase in the incidence of Alzheimer's disease (AD) and the lack of effective treatments have stimulated the search for strategies to prevent or delay its onset and/or progression. Since the diagnosis of dementia requires a number of established features that are present when the disease is fully developed, but not always in the early stages, the need for a biological marker has proven to be urgent, in terms of both diagnosis and monitoring of AD. AD has been shown to affect peripheral blood mononuclear cells (PBMCs) that are a critical component of the immune system which provide defence against infection. Although studies are continuously supplying additional data that emphasize the central role of inflammation in AD, PBMCs have not been sufficiently investigated in this context. Delineating biochemical alterations in AD blood constituents may prove valuable in identifying accessible footprints that reflect degenerative processes within the Central Nervous System (CNS). In this review, we address the role of biomarkers in AD with a focus on the notion that PBMCs may serve as a peripheral laboratory to find molecular signatures that could aid in differential diagnosis with other forms of dementia and in monitoring of disease progression.

Leukocyte telomere length and prevalence of age-related diseases in semisupercentenarians, centenarians and centenarians' offspring.

Centenarians and their offspring are increasingly considered a useful model to study and characterize the mechanisms underlying healthy aging and longevity. The aim of this project is to compare the prevalence of age-related diseases and telomere length (TL), a marker of biological age and mortality, across five groups of subjects: semisupercentenarians (SSCENT) (105-109years old), centenarians (CENT) (100-104years old), centenarians' offspring (CO), age- and gender-matched offspring of parents who both died at an age in line with life expectancy (CT) and age- and gender-matched offspring of both non-long-lived parents (NLO). Information was collected on lifestyle, past and current diseases, medical history and medication use. SSCENT displayed a lower prevalence of acute myocardial infarction (p=0.027), angina (p=0.016) and depression (p=0.021) relative to CENT. CO appeared to be healthier compared to CT who, in turn, displayed a lower prevalence of both arrhythmia (p=0.034) and hypertension (p=0.046) than NLO, characterized by the lowest parental longevity. Interestingly, CO and SSCENT exhibited the longest (p<0.001) and the shortest (p<0.001) telomeres respectively while CENT showed no difference in TL compared to the younger CT and NLO. Our results strengthen the hypothesis that the longevity of parents may influence the health status of their offspring. Moreover, our data also suggest that both CENT and their offspring may be characterized by a better TL maintenance which, in turn, may contribute to their longevity and healthy aging. The observation that SSCENT showed considerable shorter telomeres compared to CENT may suggest a progressive impairment of TL maintenance mechanisms over the transition from centenarian to semisupercentenarian age.