Giulia Paroni

Circulating high molecular weight adiponectin isoform is heritable and shares a common genetic background with insulin resistance in nondiabetic White Caucasians from Italy: evidence from a family-based study.

Abstract.  Menzaghi C, Salvemini L, Paroni G, De Bonis C, Mangiacotti D, Fini G, Doria A, Di Paola R, Trischitta V (IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy, Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA, “Sapienza” University; IRCCS Casa Sollievo della Sofferenza‐Mendel Institute, Rome, Italy). Circulating HMW adiponectin isoform is heritable and shares a common genetic background with insulin resistance in nondiabetic White Caucasians from Italy: evidence from a family‐based study. J Intern Med 2010; 267: 287–294.

Development and Validation of a Multidimensional Prognostic Index for Mortality Based on a Standardized Multidimensional Assessment Schedule (MPI-SVaMA) in Community-Dwelling Older Subjects

OBJECTIVES To develop and validate a Multidimensional Prognostic Index (MPI) for mortality based on information collected by the Multidimensional Assessment Schedule (SVaMA), the recommended standard tool for multidimensional assessment of community-dwelling older subjects in seven Italian regions. DESIGN Prospective cohort study. PARTICIPANTS Community-dwelling subjects older than 65 years who underwent an SVaMA evaluation from 2004 to 2010 in Padova Health District, Veneto, Italy. MEASUREMENTS The MPI-SVaMA was calculated as a weighted (weights were derived from multivariate Cox regressions) linear combination of the following nine domains: age, sex, main diagnosis, and six scores, ie, the Short Portable Mental Status Questionnaire, the Barthel index (contains two domains: activities of daily living and mobility), the Exton-Smith scale, the Nursing Care Needs, and the Social Network Support by a structured interview. Subjects were followed for a median of 2 years; those who had not died were followed for at least 1 year. The MPI-SVaMA score ranged from 0 to 1 and 3 grades of severity of the MPI-SVaMA were calculated on the basis of estimated cutoffs. Discriminatory power and calibration were further assessed. RESULTS A total of 12,020 subjects (mean age 81.84 ± 7.97 years) were included. Two random cohorts were selected: (1) a development cohort, ie, 7876 subjects (mean age 81.79 ± 8.05, %females: 63.1) and (2) a validation cohort, ie, 4144 subjects (mean age: 81.95 ± 7.83, %females: 63.7). The discriminatory power for mortality of MPI-SVaMA was 0.828 (95% CI 0.817-0.838) and 0.832 (95% CI 0.818-0.845) at 1 month and 0.791 (95% CI 0.784-0.798) and 0.792 (95% CI 0.783-0.802) at 1 year in development and validation cohorts, respectively. MPI-SVaMA results were well calibrated showing lower than 10% differences between predicted and observed mortality, both in development and validation cohorts. CONCLUSIONS The MPI-SVaMA is an accurate and well-calibrated prognostic tool for mortality in community-dwelling older subjects, and can be used in clinical decision making.

Identification of a metabolic signature for multidimensional impairment and mortality risk in hospitalized older patients

A combination of several metabolic and hormonal adaptations has been proposed to control aging. Little is known regarding the effects of multiple deregulations of these metabolic and hormonal systems in modulating frailty and mortality in hospitalized elderly patients. We measured 17 biological serum parameters from different metabolic/hormonal pathways in 594 hospitalized elderly patients followed up to 1 year who were stratified into three groups according to their multidimensional impairment, evaluated by a Comprehensive Geriatric Assessment (CGA)‐based Multidimensional Prognostic Index (MPI). The mortality incidence rates were 7% at 1 month and 21% at 1 year. Our data show that frailty and mortality rate were positively associated with chronic inflammation and with a down‐regulation of multiple endocrine factors. Of the 17 biomarkers examined, blood levels of IGF‐1, triiodothyronine, C‐reactive protein, erythrocyte sedimentation rate, white blood cell and lymphocyte counts, iron, albumin, total cholesterol, and LDL‐c were significantly associated with both MPI severity grade and mortality. In multivariate Cox proportional hazard model, the following biomarkers most strongly predicted the risk of mortality (adjusted hazard ratio (HR) per 1 quintile increment in predictor distribution): IGF‐1 HR = 0.71 (95% CI: 0.63–0.80), CRP HR = 1.48 (95% CI: 1.32–1.65), hemoglobin HR = 0.82 (95% CI: 0.73–0.92), and glucose HR = 1.17 (95% CI: 1.04–1.30). Multidimensional impairment assessed by MPI is associated with a distinctive metabolic ‘signature’. The concomitant elevation of markers of inflammation, associated with a simultaneous reduction in multiple metabolic and hormonal factors, predicts mortality in hospitalized elderly patients.

Measuring pharmacogenetics in special groups: geriatrics

Introduction: The cytochrome P450 (CYP) enzymes oxidize about 80% of the most commonly used drugs. Older patients form a very interesting clinical group in which an increased prevalence of adverse drug reactions (ADRs) and therapeutic failures (TFs) is observed. Might CYP drug metabolism change with age, and justify the differences in drug response observed in a geriatric setting? Areas covered: A complete overview of the CYP pharmacogenetics with a focus on the epigenetic CYP gene regulation by DNA methylation in the context of advancing age, in which DNA methylation might change. Expert opinion: Responder phenotypes consist of a continuum spanning from ADRs to TFs, with the best responders at the midpoint. CYP genetics is the basis of this continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice. Physiological age-related changes in DNA methylation, the main epigenetic mechanisms regulating gene expression in humans, results in a physiological decrease in CYP gene expression with advancing age. This may be one of the physiological changes that, together with increased drug use, contributed to the higher prevalence of ADRs and TFs observed in the geriatric setting, thus, making geriatrics a special group for pharmacogenetics.

Frailty, disability and physical exercise in the aging process and in chronic kidney disease

Frailty in the elderly is a state of vulnerability to poor resolution of homoeostasis after a stressor event and is a consequence of cumulative decline in many physiological systems during a lifetime. This cumulative decline depletes homoeostatic reserves until minor stressor events trigger disproportionate changes in health status. It is usually associated to adverse health outcomes and to one-year mortality risk. Physical exercise has found to be effective in preventing frailty and disability in this population. Chronic kidney disease (CKD) is also a clinical condition where protein energy-wasting, sarcopenia and dynapenia ,very common symptoms in the frail elderly, may occur. Moreover elderly and CKD patients are both affected by an impaired physical performance that may be reversed by physical exercise with an improvement of the survival rate. These similarities suggest that frailty may be a common pathway of aging and CKD that may induce disability and that can be prevented by a multidimensional approach in which physical exercise plays an important role.

Delusions in Patients with Alzheimer’s Disease: A Multidimensional Approach

In Alzheimers disease (AD) patients with delusions, clinical outcomes and mortality result from a combination of psychological, biological, functional, and environmental factors. We determined the effect of delusions on mortality risk, clinical outcomes linked to comprehensive geriatric assessment (CGA), cognitive, depressive, and neuropsychiatric symptoms (NPS) in 380 consecutive AD patients with Mini-Mental State Examination, Clinical Dementia Rating scale, 15-item Geriatric Depression Scale, and Neuropsychiatric Inventory (NPI), assessing one-year mortality risk using the Multidimensional Prognostic Index (MPI). We included 121 AD patients with delusions (AD-D) and 259 AD patients without delusions (AD-noD). AD-D patients were significantly older, with higher age at onset and cognitive impairment, a more severe stage of dementia, and more depressive symptoms than AD-noD patients. Disease duration was slightly higher in AD-D patients than in those without delusions, although this difference was not statistically significant. At CGA, AD-D patients showed a higher grade of disability in basic and instrumental activities of daily living, and an increased risk of malnutrition and bedsores. The two groups of patients significantly differed in MPI score (AD-D: 0.65 versus AD-noD: 0.51, p <  0.0001) and MPI grade. AD-D patients showed also a significant higher score in NPI of the following NPS than AD-noD patients: hallucinations, agitation/aggression, depression mood, apathy, irritability/lability, aberrant motor activity, sleep disturbances, and eating disorders. Therefore, AD-D patients showed higher dementia severity, and higher impairment in cognitive and depressive symptoms, and several neuropsychiatric domains than AD-noD patients, and this appeared to be associated with higher multidimensional impairment and increased risk of mortality.

Pharmacogenetics in older people: what we know and what we need to know

The prevalence of therapeutic failures (TFs) and adverse drug reactions (ADRs) markedly increased in older subjects. However, both TFs and ADRs did not always appear related to the presence of multiple pharmacologic treatments, a common status in subjects aged 65 and over. Instead, they seem more related to variations in the genes encoding protein metabolizing and transporting drugs. Thus, variations in these proteins may account for the inter-individual differences observed in drug efficacy, including the most severe clinical consequences TFs and ADRs. The genetics of drug metabolizing enzymes (DMEs) and drug transporters (DTs) is a very active area of multidisciplinary research, overlapping the fields of medicine, biology, pharmacology, and genetics. These proteins are virtually responsible for metabolism and disposition, and thus the efficacy, of a number of drugs currently used in clinical practice. This article explored some basic concepts of the pharmacogenetics of DMEs and DTs. We also focused current knowledge of the genetic basis of TFs and ADRs of the most common drugs currently used in geriatric clinics. The knowledge of what we know and what we need to know is needed to advance the application of pharmacogenetics in clinical practice, in order to introduce personalized treatments for elderly people.

Usefulness of the multidimensional prognostic index (MPI) in the management of older patients with chronic kidney disease

In older patients, given the central role of prognosis in clinical decision-making, there is an urgent need to develop accurate, validated, and rigorously tested prognostic indices. Current data suggest that in older patients not only physical but also psychological, cognitive, functional, nutritional, biological, and social factors may contribute to the increased risk of negative outcomes including institutionalization, hospitalization, and mortality. Recently, a Multidimensional Prognostic Index (MPI), derived from a standardized comprehensive geriatric assessment that included information from eight domains, i.e. basal and instrumental activities of daily living, cognitive and nutritional status, the risk for pressure sores, comorbidities, drug use, and co-habitation status was effective in predicting short- and long-term all-cause mortality risk in hospitalized patients with various acute and chronic conditions, including chronic kidney disease (CKD). In a consecutive cohort of patients with CKD the MPI accuracy in predicting mortality was significantly higher than the accuracy of the estimated glomerular filtration rate (eGFR). More recently, findings from hospital-based cohorts suggest that adding MPI information to the eGFR markedly improved the prediction of two-year all-cause mortality in older patients with CKD. While further studies are needed to assess the potential usefulness of this prognostic tool in clinical practice, a multidimensional assessment for all-cause mortality risk prediction should be considered in older patients with CKD. These findings support the concept that considering multidimensional aggregate information is very important for predicting short- and long-term all-cause mortality in older subjects with CKD, and that it may be important for the identification of more suitable management of these patients.

Role of the serotonin transporter gene locus in the response to SSRI treatment of major depressive disorder in late life

It has been suggested that the serotonin or 5-hydroxytriptamine (5-HT) transporter (5-HTT) and its gene-linked polymorphic region (5-HTTLPR) are selective serotonin reuptake inhibitor (SSRI) response modulators in late-life depression (LLD), and particularly in late-life major depressive disorder (MDD). Previous studies differed in design and results. Our study aimed to investigate the solute carrier family 6 (neurotransmitter transporter and serotonin) member 4 (SLC6A4) gene locus, encoding 5-HTT and SSRI treatment response in late-life MDD. For a prospective cohort study, we enrolled 234 patients with late-life MDD to be treated with escitalopram, sertraline, paroxetine or citalopram for 6 months. The SLC6A4 polymorphisms rs4795541 (5-HTTLPR), rs140701 and rs3813034 genotypes spanning the SLC6A4 locus were investigated in blinded fashion. No placebo group was included. We assessed responder or non-responder phenotypes according to a reduction in the 21-item version of the Hamilton Depression Rating Scale (HDRS-21) score of ⩾ 50%. At follow-up, 30% of the late-life MDD patients were non-responders to SSRI treatment. No time-course of symptoms and responses was made. A poor response was associated with a higher baseline HDRS-21 score. We observed a significant over-representation of the rs4795541-S allele in the responder patients (0.436 versus 0.321; p = 0.023). The single S-allele dose-additive effect had OR = 1.74 (95% CI 1.12–2.69) in the additive regression model. Our findings suggested a possible influence of 5-HTTLPR on the SSRI response in patients with late-life MDD, which is potentially useful in identifying the subgroups of LLD patients whom need a different pharmacological approach.

Effect of Obesity, Serum Lipoproteins, and Apolipoprotein E Genotypes on Mortality in Hospitalized Elderly Patients

BACKGROUND The aim of this study was to investigate the relationship among apolipoprotein E (APOE) polymorphism, body mass index (BMI), and dyslipidemia and how these factors modify overall mortality in a cohort of hospitalized elderly patients. METHODS Plasma concentrations of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), BMI, and APOE genotype were evaluated in 1,012 hospitalized elderly patients, who were stratified into three groups according to their baseline BMI and APOE allele status. Multivariate logistic regression analysis was used to assess whether APOE genotype, BMI, and dyslipidemia are associated with mortality, adjusting for potential confounders. Interaction analysis was also performed. RESULTS Obese patients have significantly higher levels of TC and LDL-C compared to normal-weight and overweight subjects, for both sexes. APOE ε4 carriers have significantly higher levels of TC and LDL-C compared with ε2 and ε3 carrier both in males and females. Interaction analysis showed that women with TC < 180  mg/dL, LDL-C < 100  mg/dL, normal weight, and ε3 carrier (odds ratio [OR] = 3.42, 95% confidence interval [CI] 1.36-8.60) and men with LDL-C < 100  mg/dL, HDL-C < 40  mg/dL, and ε3 carrier (OR = 1.97, 95% CI 1.04-3.74) were at highest risk of mortality. CONCLUSIONS In elderly hospitalized patients, obesity and APOE genotype influence the lipid profile and mortality risk. A significant interaction among BMI, dyslipidemia, and APOE genotype was observed that could identify elderly patients with different risks of mortality.