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The identification of diagnostic-prognostic biomarkers of dementia has become a global priority due to the prevalence of neurodegenerative diseases in aging populations. The objective of this study was to assess the diagnostic performance of cerebrospinal fluid (CSF) biomarkers across patients affected by either Alzheimer’s disease (AD), tauopathies other than AD (TP), or vascular dementia (VD), and cognitively normal subjects (CNS). One hundred fifty-three patients were recruited and tested for classical AD CSF biomarkers- Amyloid-ß42 and tau proteins - and novel candidate biomarkers - neurofilament (NF-) light and microRNA (miR) -21, -125b, -146a, and -222. All dementia patients had significantly higher concentrations of NF-light compared to CNS, with the TP group displaying the highest NF-light values. A significant inverse correlation was also observed between NF-light and cognitive impairment. Of the four miRNAs analyzed, miR-222 levels were significantly increased in VD patients compared to both CNS and AD. In addition, while NF-light showed a better diagnostic performance than miR-222 and classical AD biomarkers in differentiating TP and VD from CNS, classical AD biomarkers revealed higher performance in discriminating AD from non-AD disorders. Overall, our results suggest that CSF NF-light and miR-222 are promising biomarkers that may help to diagnose non-AD disorders.

Objectives The purpose of this study was to investigate the prognostic weight of multimorbidity and functional impairment over long-term mortality among older patients discharged from acute care hospitals. Design A prospective multicenter observational study. Setting and Participants Our series consisted of 1967 adults aged ≥65 years consecutively admitted to acute care wards in Italy, in the context of the Report-AGE project. Methods After signing a written informed consent, all patients underwent comprehensive geriatric assessment by Inter-RAI Minimum Data Set acute care. The primary endpoint of the present study was long-term mortality. Patients were grouped into 3 functional clusters and 3 disease clusters using the K-medians cluster analysis. The association of functional clusters, disease clusters, and Charlson score categories with long-term mortality was investigated through Cox regression analysis and the intercluster classification agreement was further estimated. Finally, the additive effect of either disease clusters or Charlson score on predictive ability of functional clusters was assessed by using changes in Harrell’s C-index and categorical Net Reclassification Index (NRI). Results Functional clusters, disease clusters, and Charlson score were significant predictors of long-term mortality, but the interclassification agreement was poor. Functional clusters predicted mortality with greater accuracy [C-index 0.66, 95% confidence interval (CI) 0.65–0.68] compared with disease clusters (C-index 0.54, 95% CI 0.53–0.56), and Charlson score (C-index 0.58, 95% CI 0.56–0.59). Adding multimorbidity (NRI 0.23, 95% CI 0.14–0.31) or Charlson score (NRI 0.13, 95% CI 0.03–0.20) to functional cluster model slightly improved the accuracy of prediction. Conclusions and Implications Functional impairment may better predict prognosis compared with multimorbidity, which may be relevant to optimally address individuals’ needs and to design tailored preventive interventions.

Mitochondrial DNA (mtDNA) mutations are considered as a possible primary cause of age-associated neurodegenerative disorders like Parkinson’s disease (PD). To analyze, along the whole mtDNA sequence of PD patients, the presence of non-reference alleles compared to reference alleles, as defined in the revised Cambridge Reference Sequence (rCRS). mtDNA was extracted from whole blood of PD and control groups, and was sequenced using a chip-based resequencing system. 58 nucleotide positions (np) exhibited a different allelic distribution in the two groups; in 81% of them the non-reference alleles were over-represented in PD patients, similar to findings reported in patients with Alzheimer’s disease, albeit in reduced proportion. Closer analysis of the 58 np in PD group showed that they were characterized by low-level heteroplasmy, and that the nucleotide substitutions determined an amino acid change in 84% of cases. These results suggest that mtDNA allelic changes are increased in PD and that age-related neurodegenerative diseases could share a common mechanism involving mtDNA.

Italy is expected to experience the largest growth in persons ≥65 years (20% by 2020). This demographic shift allows for geriatric research on predictive clinical and biological markers of outcomes related to frailty, re-hospitalization and mortality.To describe rationale and methods of the Report-AGE study project of acute care patients in Italian National Research Center on Aging (INRCA) research hospitals.Report-AGE study is a large observational study on health conditions and outcomes of hospitalized elderly patients (≥65 years). The primary objective of the study is to create a high-level data resource of demographics, comprehensive geriatric assessments, clinical and diagnostic information, as well as biological and molecular markers in all older patients admitted to INRCA Hospitals. Assessments in physical and nutritional parameters, co-morbid health conditions, and associations with frailty parameters are ongoing in older hospitalized adults following an acute event. Study collection began in September 2011.Up to date, there are 3479 patients ≥65 years (mean age: 85 ± 7years) with 1543 men and 1936 women enrolled. Data have been recorded regarding functional and clinical parameters before, during hospital admission and at discharge. Data collection for primary outcome analyses related to re-hospitalization and mortality is estimated for September 2016.This study aims at collecting precise clinical data, comprehensive geriatric assessment, risk factors, and biological data from acute care patients. Data will also be used to identify mechanisms underlying frailty in this specific population.This study provides a descriptive epidemiological collection of the health conditions of older in-patients.

The (A/G)-308 polymorphism of the tumor necrosis factor alpha gene (TNF) is associated with age-related diseases, but its influence on longevity is controversial. We genotyped for this polymorphism 747 Italian volunteers (401 women and 346 men, age 19-110 years). By applying a genetic-demographic (GD) approach we found that, in men, the survival function of allele A carriers is lower than that of noncarriers at all the ages (p =.044). After defining (by exploiting again demographic information) three age classes, we found that the frequency of men carrying the A allele decreases with age (p =.019), thus confirming the GD analysis results. The same analyses gave negative results in women. Therefore, allele A has a detrimental effect on life expectancy, and this effect is specific to men. A haplotype analysis carried out in men by screening the TNFa, TNFc, and TNFe microsatellite polymorphisms (spanning about 20 kb) confirmed the association of the TNF region with life expectancy.

IL-6 in vitro production, as well as the serum/plasma concentration of the cytokine, increase with age. In the present investigation, a total of 62 individuals (31 males and 31 females), aged from 29 to 93 years of age (mean age of males: 60.4 years; mean age of females: 59.4 years) were assessed for IL-6 plasma concentration, and for IL-6 in vitro production, using supernatants of 4 h cultured adherent peripheral blood mononuclear cells (aPBMC). The subjects were examined for a C to G transition at nucleotide −174 of the IL-6 gene promoter (−174 C/G locus), and were classified as C allele carriers (C+) or non-carriers (C−). We found that: (i) aPBMC from C+ individuals produced smaller amounts of IL-6 in vitro than C− individuals; (ii) IL-6 production by aPBMC increased with age in C+ but not in C− subjects; (iii) there was no correlation between IL-6 plasma levels and in vitro IL-6 production by aPBMC; (iv) IL-6 C+ individuals had lower plasma levels than C− individuals, and this phenomenon was significant only in men. On the whole our data indicate that the production of IL-6 is genetically controlled and age- and gender-dependent.

Factor structure analyses have revealed the presence of specific biological system markers in healthy humans and diseases. However, this type of approach in very old persons and in type 2 diabetes (T2DM) is lacking. A total sample of 2,137 Italians consisted of two groups: 1,604 healthy and 533 with T2DM. Age (years) was categorized as adults (≤65), old (66-85), oldest old (>85-98) and centenarians (≥99). Specific biomarkers of routine haematological and biochemical testing were tested across each age group. Exploratory factorial analysis (EFA) by principal component method with Varimax rotation was used to identify factors including related variables. Structural equation modelling (SEM) was applied to confirm factor solutions for each age group. EFA and SEM identified specific factor structures according to age in both groups. An age-associated reduction of factor structure was observed from adults to oldest old in the healthy group (explained variance 60.4% vs 50.3%) and from adults to old in the T2DM group (explained variance 57.4% vs 44.2%). Centenarians showed three-factor structure similar to those of adults (explained variance 58.4%). The inflammatory component became the major factor in old group and was the first one in T2DM. SEM analysis in healthy subjects suggested that the glucose levels had an important role in the oldest old. Factorial structure change during healthy ageing was associated with a decrease in complexity but showed an increase in variability and inflammation. Structural relationship changes observed in healthy subjects appeared earlier in diabetic patients and later in centenarians.

Background Geriatric patients with acute non-ST elevation myocardial infarction (NSTEMI) can frequently present atypical symptoms and non-diagnostic electrocardiogram. The detection of modest cardiac troponin T (cTnT) elevation is challenging for physicians needing to routinely triage these patients. Unfortunately, non-coronary diseases, such as acute heart failure (CHF), may cause cTnT elevation. Circulating microRNAs (miRs) have emerged as biomarkers of MI. However, their diagnostic potential needs to be determined in elderly NSTEMI patients. Methods 92 NSTEMI patients (82.6±6.9years old; complicated by CHF in 74% of cases) and 81 patients with acute CHF without AMI (81.3±6.8years old) were enrolled at presentation. A third group comprised 99 age-matched healthy control subjects (CTR). Plasma levels of miR-1, -21, -133a, -208a, -423-5p and -499-5p were analyzed. Results MiR-1, -21 -133a and -423-5p showed a 3- to 10-fold increase and miR-499-5p exhibited >80-fold increase in acute NSTEMI patient vs. CTR. MiR-499-5p and -21 showed a significantly increased expression in NSTEMI vs. CHF. Interestingly, mir-499-5p was comparable to cTnT in discriminating NSTEMI vs. CTR and CHF patients. Its diagnostic accuracy was higher than conventional and hs-cTnT in differentiating NSTEMI (n=31) vs. acute CHF (n=32) patients with modest cTnT elevation at presentation (miR-499-5p AUC=0.86 vs. cTnT AUC=0.68 and vs. hs-cTnT AUC=0.70). Conclusions Circulating miR-499-5p is a sensitive biomarker of acute NSTEMI in the elderly, exhibiting a diagnostic accuracy superior to that of cTnT in patients with modest elevation at presentation.

The functional characteristics of circulating angiogenic cells (CACs) are impaired in congestive heart failure (CHF) patients, suggesting that CAC dysfunction could contribute to CHF pathogenesis. However, the underlying mechanisms are only partly unraveled. No data are currently available regarding telomere/telomerase system in CACs of CHF patients.CACs were obtained from 80 subjects: 40 healthy control subjects (CTR) [median age (IQR), 80 (76-85 yrs)] and 40 patients affected by post-ischemic cardiomyopathy CHF [median age (IQR), 82 (77-89)]. CAC and leukocyte telomere length, assessed as T/S ratio, and telomerase (TERT) activity were determined in all the enrolled subjects. Specificity and sensitivity of CAC and leukocyte T/S in discriminating between CHF and CTR were evaluated using Receiver Operator Characteristic (ROC) curve analysis and reported as AUC values. CD34+/VEGFR2+ number and pro-inflammatory cytokines plasma levels, such as IL-6 and TNF-α, were also measured.CAC T/S and TERT activity were significantly reduced in CHF patients compared to CTR subjects. In leukocytes, only a significant T/S reduction was observed. AUC values were higher for CAC T/S with respect to leukocyte T/S (AUC=0.89, and AUC=0.73, P0.01, respectively). In multivariate analysis, leukocyte T/S, CAC T/S, CAC TERT activity and NT-proBNP levels were confirmed as parameters significantly associated with CHF. CD34+/VEGFR2+ number, IL-6 and TNF-α plasma levels were significantly increased in CHF patients.CACs from CHF patients are characterized by telomere/telomerase system impairment, providing new insight into the clinical relevance of CACs in CHF pathogenesis.

In the present investigation we analysed Interleukin 6 (IL-6) in vitro production by Epstein–Barr virus (EBV)-immortalized B lymphocytes established from 43 subjects, 15 young people and 28 elderly people, including 18 centenarians, after 3, 6, 9, 24, 48 and 72 h of culture. The subjects were genotypized for the C to G transition at nucleotide −174 of IL-6 gene promoter (−174 C/G) and were classified as C allele carriers (C+) and non-carriers (C−). We found that: (i) the interindividual difference in in vitro IL-6 production was wider in elderly individuals in respect to young individuals, leading to different coefficient of variation in the two groups; (ii) the −174 C/G polymorphism had an age-related effect on IL-6 in vitro production. Only among C− people, cells from elderly subjects produced significant higher level of IL-6 than cells from young subjects. These data are consistent with our previous results regarding the IL-6 serum levels in a large group of people of different age, including centenarians. Thus, the EBV-immortalized B lymphocytes can be considered a useful in vitro model for studying the genetic control of IL-6 production and its changes with age.