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Up to 80% of castration-resistant prostate cancer (CRPC) patients develop bone metastases during the natural history of disease and about 25% harbor mutations in DNA damage repair (DDR) genes. This retrospective observational study evaluated the prevalence of DDR alterations in CRPC patients and their effect on the clinical outcomes associated with bone metastases. The mutational status of CRPC patients was analyzed per FoundationOne ® analysis in tissue biopsy or, when it was not possible, in liquid biopsy performed at the onset of metastatic CRPC (mCRPC). The impact of DDR gene mutations on bone-related efficacy endpoints was evaluated at the time of mCRPC diagnoses. In total, 121 mCRPC patients with bone metastases were included: 38 patients had mutations in at least one DDR gene, the remaining 83 ones had a non-mutated DDR status. DDR mutated status was associated with bone metastases volume ( p = 0.006), but did not affect SRE (skeletal-related events) incidence and time to SRE onset. Liquid and tissue biopsies were both available for 61 patients with no statistically significant difference in terms of incidence and type of molecular DDR alterations. Mutated DDR status was associated with higher bone metastasic volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed.

Abnormalities in the plasma amino acid and/or urinary organic acid profile have been reported in autism spectrum disorder (ASD). An imbalance between excitatory and inhibitory neuronal activity has been proposed as a mechanism to explain dysfunctional brain networks in ASD, as also suggested by the increased risk of epilepsy in this disorder. This study explored the possible association between presence of EEG paroxysmal abnormalities and the metabolic profile of plasma amino acids and urinary organic acids in children with ASD. In a sample of 55 children with ASD (81.8% male, mean age 53.67 months), EEGs were recorded, and 24 plasma amino acids and 56 urinary organic acids analyzed. EEG epileptiform discharges were found in 36 (65%) children. A LASSO regression, adjusted by age and sex, was applied to evaluate the association of plasma amino acids and urinary organic acids profiles with the presence of EEG epileptiform discharges. Plasma levels of threonine (THR) (coefficient = -0.02, p = 0.04) and urinary concentration of 3-Hydroxy-3-Methylglutaric acid (HMGA) (coefficient = 0.04, p = 0.02) were found to be associated with the presence of epileptiform discharges. These results suggest that altered redox mechanisms might be linked to epileptiform brain activity in ASD.

Background: Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor (AR) copy number (CN)., Methods: Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI., Results: Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24-5.12, p=0.011), AKR1C3 (HR=2.01, 1.06-3.81, p=0.031), AR (HR=2.70, 1.46-5.01, p=0.002), EPCAM (HR=3.75, 2.10-6.71, p< 0.0001), PSMA (HR=2.09, 1.19-3.66, p=0.01), MDK (HR=3.35, 1.83-6.13, p< 0.0001), and HPRT1 (HR=2.46, 1.44-4.18, p=0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97-31.22, p=0.05), AR (OR=8.71, 2.32-32.25, p=0.001), EPCAM (OR=7.26, 1.47-35.73, p=0.015), PSMA (OR=3.86, 1.10-13.50, p=0.035), MDK (OR=6.84, 1.87-24.98, p=0.004), and HPRT1 (OR=7.41, 1.82-30.19, p=0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 (p=0.05), EPCAM (p=0.02), and MDK (p=0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47-8.17], p=0.004)., Conclusions: Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis., Trial Registration: Clinicaltrials.gov NCT03381326 . Retrospectively registered on 18 December 2017., (© 2022. The Author(s).)

Gynecological tumors are malignancies with both high morbidity and mortality. To date, only a few chemotherapeutic agents have shown efficacy against these cancer types (only ovarian cancer responds to several agents, especially platinum-based combinations). Within this context, the discovery of immune checkpoint inhibitors has led to numerous clinical studies being carried out that have also demonstrated their activity in these cancer types. More recently, following the development of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, this strategy was also tested in solid tumors, including gynecological cancers. In this article, we focus on the molecular basis of gynecological tumors that makes them potential candidates for immunotherapy. We also provide an overview of the main immunotherapy studies divided by tumor type and report on CAR technology and the studies currently underway in the area of gynecological malignancies.

Introduction: Enzalutamide is the first characterized second-generation nonsteroidal androgen receptor inhibitor (ARi). Its efficacy has been established in several clinical trials evaluating its role in different settings of prostate cancer. Recently, enzalutamide has been approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC)., Areas Covered: In this paper, the authors describe the chemical structure and pharmacologic characteristics of enzalutamide, providing a summary of clinical trials evaluating its efficacy and safety in prostate cancer patients., Expert Opinion: Enzalutamide adds to the growing arsenal of ARi used in nmCRPC. An improvement in metastasis-free survival was observed with the use of these new treatment options; recently released preliminary data report also an OS benefit. These novel agents are generally well tolerated, but their safety profiles differ slightly. Since head-to-head comparisons between ARi in nmCRPC are lacking, the adverse events profile, as well as drug availability, costs, and considerations on treatment-sequencing, would most likely influence the selection of the individual agent in this setting. Further research is needed to improve treatment selection and clarify many unsolved issues. Abbreviations ARi: nonsteroidal androgen receptor inhibitor; nmCRPC: nonmetastatic castration resistant prostate cancer; ADT: androgen deprivation therapy; OS: overall survival; PSA: prostate specific antigen; FDA: Food and Drug Administration; AR: Androgen Receptor; MFS: metastasis free survival; PSA-DT: PSA doubling time; HR: hazard ratio; CI: confidence interval; AEs: adverse events; mCRPC: metastatic castration resistant prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; rPFS: radiographic progression-free survival; OR: odds ratio.

Purpose: Biomarkers for treatment personalization in metastatic castration-resistant prostate cancer (mCRPC) could help improve patient outcomes. Multiple tests on blood have reported associations with poorer outcome, including serum lactate dehydrogenase (LDH), chromogranin A (CGA), neutrophil:lymphocyte ratio (NLR), and, recently, copy number (CN) of androgen receptor (AR) in plasma DNA. Biologic data suggest an association between choline uptake and AR signaling. We aimed to integrate 18 F -fluorocholine (FCH) uptake on positron emission tomography/computed tomography (PET/CT) scanning with plasma AR CN and other routinely obtained circulating biomarkers to evaluate their association with outcome., Materials and Methods: We determined plasma AR CN by digital droplet polymerase chain reaction from 105 mCRPC samples collected before abiraterone (n = 65) or enzalutamide (n = 40) therapy in the before (n = 26) and after (n = 79) chemotherapy settings. Pretreatment serum LDH, CGA, and NLR were also measured. FCH-PET/CT scan was performed at baseline, and maximum standardized uptake value (SUV max ), total lesion activity (TLA), and metabolic tumor volume (MTV) were calculated. Main end points were the correlation of FCH-PET/CT parameters with circulating biomarkers and their impact on outcome., Results: Plasma AR CN gain was observed in 27 patients (25.7%), and it correlated significantly with higher median SUV max , TLA, and MTV values ( P < .001). Kaplan-Meier curves showed significantly worse progression-free survival and overall survival in patients with plasma AR gain and higher SUV max , TLA, and MTV values ( P < .001 in each prognostic group). Conversely, no association was reported for prostate-specific antigen response. On multivariable analysis of overall survival, we showed as independent factors AR gain (hazard ratio [HR], 1.92; 95% CI, 1.07 to 3.47; P = .029), presence of visceral metastasis (HR, 3.04; 95% CI, 1.66 to 5.58; P = < .001), LDH (HR, 2.95; 95% CI, 1.72 to 5.05; P < .001), NLR (HR, 3.51; 95% CI, 2.14 to 5.74; P < .001), serum CGA (HR, 3.36; 95% CI, 1.99 to 5.67; P < .001), and MTV (HR, 2.09; 95% CI, 1.25 to 3.50; P = .005)., Conclusion: Our results indicate the potential usefulness of integrating functional imaging with plasma DNA analysis and other noninvasive biomarkers as a tool to improve treatment selection for CRPC. A larger prospective evaluation is warranted.

The therapeutic landscape of prostate cancer has expanded rapidly over the past 10 years, and there is now an even greater need to understand the biological mechanisms of resistance and to develop noninvasive biomarkers to guide treatment. The androgen receptor (AR) is known to be involved in the pathogenesis and progression of prostate cancer. Recently, highly sensitive next-generation sequencing and PCR-based methods for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma were established in cell-free DNA (cfDNA) of patients with castration-resistant prostate cancer (CRPC) treated with different drugs. The study of cfDNA holds great promise for improving treatment in CRPC, especially in the advanced stage of the disease. Recent findings showed the significant association of plasma AR aberrations with clinical outcome in CRPC patients treated with AR-directed therapies, whereas no association was observed in patients treated with taxanes. This suggests the potential for using plasma AR as a biomarker for selecting treatment, i.e., hormone therapy or chemotherapy, and the possibility of modulating taxane dose. In recent years, plasma AR status has also been investigated in association with novel agents, such as 177 Lu-PSMA radioligand therapy and PARP inhibitors. This review will focus on AR testing in plasma that may have clinical utility for treatment selection in advanced prostate cancer.

Immunotherapy represents the new era of cancer treatment because of its promising results in various cancer types. In urological tumors, the use of the immune-checkpoint inhibitors (ICIs) is increasingly spreading. Although not all patients and not all diseases respond equally well to immunotherapy, there is an increasing need to find predictive markers of response to ICIs. Patient- and tumor-related factors may be involved in primary and secondary resistance to immunotherapy: tumor-derived protein and cytokines, tumor mutational burden, and patient performance status and comorbidities can condition tumor response to ICIs. Recently, some of these factors have been evaluated as potential biomarkers of response, with conflicting results. To date, the expression of programmed death-ligand 1 (PD-L1) and the presence of deficient mismatch repair (dMMR) in tumor tissue are the only biomarkers capable of guiding the clinician's decision in urothelial cancer and prostate cancer, respectively. In this review, we performed a comprehensive search of the main publications on biomarkers that are predictive of response to ICIs in urological cancers. Our aim was to understand whether existing data have the potential to drive clinical decision-making in the near future., Competing Interests: Ugo De Giorgi has received personal fees for advisory board/consultancy from Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Novartis, Pfizer, and Sanofi. Other authors declare no conflicts of interest., (Copyright © 2019 Giuseppe Schepisi et al.)

Purpose: Our study aims to investigate the association between copy number of the androgen receptor (AR) and testosterone levels in metastatic castration-resistant prostate cancer (mCRPC) treated with second-generation antiandrogen therapies., Materials and Methods: We retrospectively collected data from mCRPC treated with abiraterone acetate and enzalutamide. Serum testosterone levels were collected at baseline, at 3 months since the start of therapy and at disease progression. A cohort of cases treated with docetaxel was also used to evaluate the impact of testosterone levels., Results: Patients treated with abiraterone with AR copy number aberrations and basal testosterone levels below 0.09 nmol/L had worse progression-free survival (PFS) compared to patients with no AR copy number abnormalities (8.5 vs 2.9 months, P = 0.005). No relevant differences were observed in the enzalutamide group with a PFS of 3.9 months (no AR gain) vs 2.7 months ( AR gain, P = 0.004) for patients with below 0.09 nmol/L testosterone levels. Similar results are obtained for univariate analysis for overall survival (OS). The negative prognostic role of AR copy number gain in OS for both treatment groups (25.5 vs 10.6 months, P = 0.0002 for abiraterone and 14.1 vs 8.3 months, P = 0.031 for enzalutamide) was confirmed, and it was recognized the negative prognostic impact of testosteronemia below 0.09 only for patients treated with enzalutamide (8.8 vs 42.8 months, P = 0.016). On multivariate analysis for patients treated with abiraterone, low testosterone levels below 0.09 and plasma AR gain were significantly associated with worse PFS and OS. These data are confirmed in the enzalutamide group for PFS., Conclusions: Testosterone levels and the AR copy number alterations were considered as independent prognostic factors. The results of this study show that serum testosteronemia associated with changes in copy number of AR gene could represent a noninvasive biomarker useful to identify a subgroup of patients with worse prognosis that can benefit less from second-generation antiandrogen therapies in the mCRPC setting., (© 2019 Wiley Periodical, Inc.)

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

Testicular cancer is the most frequent tumor in young males aged 15-39 years. As cure rates are currently around 90%, the prevalence of survivors is increasing. However, a disease-free condition does not necessarily correspond to a life free of physical and psychosocial health problems. The aim of this review was to explore psychosocial morbidity among testicular cancer survivors. A literature search was conducted in three electronic databases (PubMed, Medline, and Embase). The results of the search on cancer survivors were then combined with those of the search on psychosocial concerns and work performance. Eighty-four publications met the inclusion criteria. Physical, psychological, work-related problems and changing perspectives about work and life in general influenced life and career decisions among testicular cancer survivors. Individual health, sexual relationships and work problems, affect several important aspects of survival and significantly influence the QoL of long-term survivors.

Background: The management of visceral leishmaniasis (VL) in HIV-infected patients is often complex with patients experiencing higher mortality rates, more toxic side effects and a higher possibility of treatment failure and relapse than HIV-negative individuals with VL., Case Presentation: We report on successful salvage therapy in two HIV-infected patients suffering with disseminated cutaneous and visceral leishmaniasis, recalcitrant to therapy with liposomal amphotericin B. After the employment of combination anti-leishmanial treatment, parasite genomes were not detectable up to the last follow up visit, 57 and 78 weeks after treatment onset, respectively. CD4+ lymphocyte counts fluctuated over time, but were generally higher than counts detected at treatment onset, which likely contributed to protection against VL relapse., Conclusions: Results achieved with the anti-leishmanial combination treatment were promising, but are based on only two patients. Future investigation is necessary to confirm the efficacy of this salvage therapy in sustaining the immunological response and control of VL.

Prostate cancer is one of the most common malignant neoplasms in men worldwide, and is the fifth cause of cancer-related death. In recent years, a new generation of therapies have been approved for the management of metastatic disease. Moreover, the development of new immunotherapeutic drugs has become a novel frontier for the treatment of several tumor types; to date, numerous studies have investigated their potential activity, including in prostate cancer. In this article, we discuss the role of emerging immunotherapeutic drugs in prostate cancer patients., Competing Interests: The authors declare no conflict of interest.

Serotonin syndrome (SS), a potentially life-threatening adverse drug reaction caused by excessive serotonergic agonism in central and peripheral nervous system serotonergic receptors, may be caused by a single drug or a combination of drugs with serotonergic activity. The syndrome results in a variety of mental, autonomic and neuromuscular changes, which can range in severity from mild to life-threatening. To our knowledge, we present the first reported case of SS associated with linezolid and methadone with a brief review of the literature.

Background: Prevalence of metabolic syndrome (MetS) increases with age, but its association with all-cause mortality in older persons remains uncertain. This study investigated the association of all-cause mortality with MetS and its individual components in older men and women., Methods: A total of 917 men and 1043 women aged 65 years and older from two Italian population-based cohorts were included in the study. MetS was defined according to four different definitions: National Cholesterol Education Program (NCEP), NCEP revised according to the American Heart Association and National Heart Lung Blood Institute (NCEP-R), International Diabetes Organization (IDF) and Joint Interim Statement (JIS). All of these definitions include abdominal obesity, hyperglycaemia, hypertriglyceridaemia, low high-density lipoprotein cholesterol and hypertension. Hazard Ratios (HR) and their corresponding 95% confidence interval (95%CI) estimated from multivariable-adjusted Cox regression models were used to investigate the associations of all-cause mortality with baseline MetS status and individual MetS components., Results: After 6·5 ± 1·8 years of follow-up, there were 179 deaths among women and 193 among men. Mortality risk was increased in women with MetS by any definition, regardless of individual components, but limited to age 70-79 years (NCEP, HR = 2·02, 95%CI, 1·16-3·53; NCEP-R, HR = 2·51, 95%CI, 1·45-4·34; IDF, HR = 2·16, 95%CI, 1·26-3·72; JIS, HR = 2·16, 95%CI, 1·26-3·72). Mortality risk of men was associated with hypertriglyceridaemia below age 70 years (HR = 2·50, 95%CI, 1·19-5·25), but unrelated to MetS status., Conclusions: Metabolic Syndrome is associated with all-cause mortality in older women but not in men. The association, however, is limited to a narrow age range., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Low serum dehydroepiandrosterone sulfate (DHEAS) is common in older persons with poor health. The geriatric syndrome of physical frailty is associated with a higher risk of developing fatal and nonfatal health outcomes. However, the association of DHEAS with frailty is uncertain. This study investigated the association of serum DHEAS with frailty and its related adverse outcomes in 416 men and 504 women aged ≥65 years from an Italian prospective population-based cohort study. At baseline, frailty status was defined according to the physical phenotype, and serum DHEAS was measured in a fasting venous blood sample. After 4 years, subjects were reassessed for incident frailty and occurrence of nonfatal frailty-related outcomes (hospital admission, nursing home placement, disability, falls, and fractures). All-cause mortality after 8 years was also recorded. Incident frailty was inversely associated with baseline log-transformed DHEAS in men (odds ratio [OR]=0.35, 95% confidence interval [CI] 0.14-0.88, p=0.026) but not in women. Independent of baseline frailty status, women in the lowest DHEAS quartile compared to the upper three quartiles had a higher risk of hospital admission (OR=0.44, 95% CI 0.21-0.91, p=0.027) and nursing home placement (OR=0.27, 95% CI 0.08-0.95, p=0.041). Baseline log-transformed serum DHEAS was also inversely associated with mortality risk, but limited to women with concurrent frailty (hazard ratio [HR]=0.27, 95% CI 0.11-0.68, p=0.005) or preexisting major diseases (HR=0.57, 95% CI 0.33-0.98, p=0.041). These findings suggest that DHEAS is associated with incident frailty in older men and with fatal and nonfatal frailty-related adverse outcomes in older women.

This study aimed to compare the predictive accuracy for several frailty-related adverse health outcomes of a cumulative index derived from the Italian population-based elderly cohort of the Conselice Study of Brain Aging (CSBA), which takes into account multiple different domains (demographic, clinical, functional, and nutritional parameters), with that of an index derived from the Study of Osteoporotic Fractures (SOF), modified for application to the CSBA database and henceforth called mSOF, which is exclusively focused on muscular fitness. Data are for 1007 CSBA participants aged ≥ 65 years. Investigated adverse outcomes included 4- and 7-year risk of death and 4-year risk of fractures, falls, disability, hospitalization, and nursing home placement. Accuracy for prediction of these outcomes was investigated using area under the curve (AUC) statistics. CSBA index performed better than mSOF index for prediction of mortality (p<0.001), hospitalization (p=0.002), and nursing home placement (p=0.049). For all outcomes excluding falls, frailty defined by CSBA index had a slightly lower specificity but a much higher sensitivity than frailty defined by mSOF Index. In conclusion, in this elderly cohort, the multidimensional CSBA index is a better predictor of frailty-related adverse health outcomes than the unidimensional mSOF index., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: It is unclear whether in late life serum thyroid-stimulating hormone (TSH) predicts risk of developing cognitive impairment., Objective: This study investigated the prospective relationship of serum TSH with the risk of developing mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD) in an elderly cohort with a 4-year follow-up., Methods: Data are for 660 subjects aged 65 years and older from an Italian population-based cohort who were cognitively normal at an extensive assessment in 1999/2000 and underwent follow-up assessment in 2003/2004. Serum TSH was measured at baseline. Multinomial logistic models adjusted for sociodemographic and cardiovascular risk factors were used to investigate the association of serum TSH (both as a tertile and continuous log-transformed variable) with risk of incident MCI, AD and VaD diagnosed according to international criteria., Results: Over 3.8 ± 0.7 years of follow-up, there were 149 incident MCI cases (77 with impairment of memory and 72 with impairment of nonmemory domains) and 86 incident dementia cases (53 with AD, 28 with VaD). No association between baseline TSH and risk of developing any MCI subtype or AD was found. The highest TSH tertile had a threefold higher increased risk of VaD (OR: 3.25, 95% CI: 1.01-10.77, p = 0.048) compared to the lowest tertile. Risk of VaD increased about 60% for each 1 SD increase in log-transformed TSH (OR: 1.61, 95% CI: 1.06-2.44, p = 0.025)., Conclusions: In this elderly cohort, baseline TSH was not related to the risk of developing MCI or AD, but high TSH was associated with an increased risk of VaD. These results suggest further need for research using larger samples to examine the role of TSH as a predictor of VaD and the role of thyroid autoimmunity in vascular cognitive impairment., (Copyright © 2011 S. Karger AG, Basel.)

Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The population longitudinal study named "The Conselice Study" has been the focus of the present investigation. 65 years old or older participants of this population study on brain aging were followed up for 5 years: 937 subjects completed the follow-up. Relationships of 46 genetic, phenotypic, clinical and nutritional factors on incident cognitive decline and incident dementia cases were investigated., Results: A new statistical approach, called the Auto Contractive Map (AutoCM) was applied to find relationship between variables and a possible hierarchy in the relevance of each variable with incident dementia. This method, based on an artificial adaptive system, was able to define the association strength of each variable with all the others. Moreover, few variables resulted to be aggregation points in the variable connectivity map related to cognitive decline and dementia. Gene variants and cognate phenotypic variables showed differential degrees of relevance to brain aging and dementia. A risk map for age associated cognitive decline and dementia has been constructed and will be presented and discussed., Conclusion: This map of variables may be use to identify subjects with increased risk of developing cognitive decline end/or dementia and provide pivotal information for early intervention protocols for prevention of dementia.

Among the age-related diseases, the development of cognitive impairments, in particular dementia, is the most devastating for the individual and has great social and healthcare costs. Accurate information is needed about the prevalence and incidence of cognitive disorders and the physiology of the ageing brain. In particular, only scant data are available about the relationship between ageing, cognitive status and nutritional factors. In order to address these issues we planned the Conselice Study of Brain Ageing, a longitudinal study of physiologic and pathologic brain ageing. The center involved in the study was the municipality of Conselice, Ravenna province, in the Northern Italian region Emilia-Romagna. A total of 1016 subjects aged 65 and over was enrolled at baseline. Information about cognitive status at 4-years of follow-up was collected for 940 of them. These data have been used to estimate prevalence and incidence of dementia in the elderly Italian population and to investigate the possible role of baseline blood homocysteine as risk factors for dementia.

We studied whether increased blood homocysteine is a predictor for incident depression in a population-based cohort aged >or=65. A total of 240 men and 217 women were identified at baseline and were assessed 4 years later for depression (Geriatric Depression Scale, GDS >or=10 or use of antidepressants). Risk of incident depression was estimated for the highest gender-specific tertile of baseline plasma homocysteine compared to the other tertiles combined in a reference group. As deficiencies of B(12) and folate are the main determinant of increased blood homocysteine in old age, serum concentrations of these vitamins were also measured. In women only, the highest homocysteine tertile was associated with incident depression. However, women with combined serum B(12)/folate deficiency had the highest blood homocysteine but also a lower depression risk than vitamin-replete women. In conclusion, the data only moderately support the hypothesis that blood homocysteine is a predictor of depression., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To investigate the association between metabolic syndrome (MetS; a clustering of cardiovascular risk factors including abdominal obesity, hypertension, dyslipidemia, and hyperglycemia, each of which has been individually associated with dementia) and incident dementia, Alzheimer's disease (AD), and vascular dementia (VaD) in older adults before and after the age of 75., Design: Prospective population-based cohort., Setting: An Italian municipality., Participants: A community-based sample of 749 subjects aged 65 and older who, in 1999/2000, were free of cognitive impairment and, in 2003/04, underwent follow-up for incident dementia., Measurements: The relationship between incident overall dementia, AD, and VaD and MetS. Dementia was defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. MetS was defined according to the National Cholesterol Education Program criteria., Results: Risk of overall dementia and its subtypes was not associated with MetS or any MetS component in participants younger than 75. In participants aged 75 and older, MetS was associated with a lower risk of AD (hazard ratio (HR)=0.33, 95% confidence interval (CI)=0.12-0.94) but not of VaD, and abdominal obesity was associated with a lower risk of overall dementia (HR=0.53, 95% CI=0.28-0.98)., Conclusion: MetS measured in late life is not associated with risk of dementia. After age 75, persons with MetS may even be at lower risk for AD.

Data mining of a large data base from the population longitudinal study named "The Conselice Study" has been the focus of the present investigation. Initially, 65 years old or older participants were interviewed, underwent medical and cognitive examination, and were followed up for 5 years: 937 subjects completed the follow-up. Relationships of 35 genetic and/or phenotypic factors with incident cognitive decline and dementia were investigated. The new mathematical approach, called the Auto Contractive Map (AutoCM), was able to show the differential importance of each variables. This new variable processing created a semantic connectivity map that: (a) preserved non-linear associations; (b) showed connection schemes; (c) captured the complex dynamics of adaptive interactions. This method, based on an artificial adaptive system, was able to define the association strength of each variable with all the others. Few variables resulted to be aggregation points and were considered as major biological hubs. Three hubs were identified in the hydroxyl-methyl-gutaryl-CoA reductase (HMGCR) enzyme, plasma cholesterol levels and age. Gene variants and cognate phenotypic variables showed differential degrees of relevance to brain aging and dementia. This data analysis method was compared with another mathematical model called mutual information relevance network and results are presented and discussed.

Background: It is unclear whether high levels of blood inflammatory proteins are associated with the risk of developing depression in late life., Methods: Blood C-reactive protein, interleukin (IL)-6, 1 -antichymotrypsin (ACT), intercellular adhesion molecule 1, and tumor necrosis factor were measured in an elderly cohort (n = 968). Major depression diagnosed according to clinical criteria and relevant depressive symptoms measured by the Geriatric Depression Scale (score 6 10) were assessed at baseline and 4 year later., Results: Baseline IL-6 and ACT were increased in both prevalent major depression and relevant depressive symptoms. Baseline ACT was increased in incident major depression. All associations weakened below significance after adjustment for possible confounders and multiple comparisons., Conclusions: Blood inflammatory proteins do not predict the risk of developing depression in older age., (2010 S. Karger AG, Basel.)

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene.

Background: CLOX, a clock drawing test protocol uniquely sensitive to impairment of executive functions, has been proposed as a screening tool for mild cognitive impairment (MCI), but data about its diagnostic efficiency are lacking., Methods: There are data for 196 subjects, age >or=60 years, referred to a memory clinic for cognitive complaints. After extensive neuropsychological testing, 64 were diagnosed as cognitively normal and 132 with MCI., Results: At standard cutoffs, both CLOX subtests had a fair specificity (CLOX1 72%, CLOX2 92%) but unacceptably low values of sensitivity (CLOX1 54%, CLOX2 28%) and likelihood ratio (CLOX1 1.91, CLOX2 3.59) for MCI. The use of different cutoffs or the combination of CLOX with the Mini-Mental State Examination (MMSE) did not statistically increase diagnostic efficiency., Conclusion: CLOX, either alone or in combination with MMSE, is not a useful screening test for MCI in a clinical setting., (Copyright 2010 S. Karger AG, Basel.)

Background: Evidence that vitamin E may preserve cognitive function in elderly subjects is conflicting. The most abundant and most investigated form of vitamin E in humans is alpha-tocopherol, but other antioxidant tocopherols (beta, gamma, and delta) exist in nature., Objective: We aimed to investigate plasma concentrations of the natural tocopherols and the tocopherol oxidation markers alpha-tocopherylquinone (alphaTQ) and 5-nitro-gamma-tocopherol (5NGT) in relation to cognitive function in the elderly., Design: Baseline plasma tocopherols and their oxidation markers were measured in 761 elderly Italian subjects from a population-based cohort assessed in 1999-2000 for mild cognitive impairment (MCI) and dementia. In 2003-2004, information about cognitive status was collected for 615 of the 666 subjects without baseline cognitive impairment. Tocopherols and oxidation markers were analyzed as plasma absolute values divided by serum total cholesterol because lipids affect their blood availability. Analyses were adjusted for sociodemographic, genetic, lifestyle, and medical confounders., Results: Compared with the corresponding lowest tertile, the risk of prevalent dementia was higher for the highest tertile of delta-tocopherol/cholesterol [odds ratio (OR): 3.87; 95% CI: 1.46, 10.27] and alphaTQ/cholesterol (4.02; 1.45, 11.14), but the risk of incident dementia was not directly associated with plasma vitamin E metabolites. A U-shaped association, with lower risk for intermediate tertiles, was found for prevalent MCI with 5NGT/cholesterol (0.39; 0.17, 0.91) and for incident dementia with gamma-tocopherol/cholesterol (hazard ratio: 0.42; 95% CI: 0.22, 0.84)., Conclusions: Plasma concentrations of some non-alpha-tocopherol forms of vitamin E are associated with cognitive impairment in elderly people. However, the associations depend on concurrent cholesterol concentration and need further investigation.

Background: identification of frailty is recommended in geriatric practice. However, there is a lack of frailty scores combining easy-to-collect predictors from multiple domains., Objective: to develop a frailty score including only self-reported information and easy-to-perform standardised measurements recommended in routine geriatric practice., Design: prospective population-based study., Setting/participants: included 1,007 Italian subjects aged 65 and over., Measurements: seventeen baseline possible mortality predictors from several domains, 4-year risk of mortality and other adverse health outcomes associated with frailty [fractures, hospitalisation, and new and worsening activities of daily living (ADL) disability]., Methods: a multivariate Cox model was used to identify the best sub-group of independent predictors and to develop a mortality prognostic score, defined as the number of adverse predictors present. Logistic regression was used to verify whether the score also predicted risk of other frailty outcomes in the cohort survivors., Results: nine independent mortality predictors were identified. Among subjects with score > or =3, each one point increase in the score was associated with a doubling in mortality risk and, among survivors, with an increased risk of all the other adverse health outcomes., Conclusions: nine easy-to-collect predictors may identify aged people at increased risk of adverse health outcomes associated with frailty.

alpha-1-antichymotrypsin (ACT), is an acute phase protein and a protease inhibitor produced by the liver and brain. ACT is involved in the pathogenesis of Alzheimer's disease (AD), since elevated ACT concentration was found in cerebrospinal fluid (CSF) and brain from AD. ACT has also been shown to influence amyloid deposition in vitro and in animal models of AD. In this investigation 830 healthy controls, 69 subjects with cognitive impairment and not dementia (CIND), 53 patients with severe clinical AD and 142 patients with mild AD were investigated. Plasma levels of ACT were measured with a new competitive immune enzyme linked immune-assay (ELISA). ACT levels were higher in AD patients than in CIND or controls. An age dependent increase of plasma ACT was present in both healthy elderly and CIND. Patients with mild clinical AD were followed up for two years and stratified according to the rate of clinical deterioration. CT plasma levels were elevated in AD patients that showed an accelerated rate of cognitive deterioration during the follow up; this increment being prominent in AD with the Apolipoprotein E (APOE) epsilon 4 allele. Therefore, increased peripheral ACT levels in APOE 4 positive patients appear to predict an accelerated clinical progression. Plasma ACT might be used as a surrogate marker to monitor the conversion of pre-dementia stages to AD and the progression of the disease. The development of compounds able to interfere with the ACT biological activity (protease inhibition and/or promotion of amyloid deposition) might have therapeutic relevance for the disease.

Objectives: To investigate prevalence and incidence of mild cognitive impairment (MCI) and its risk of progression to dementia in an elderly Italian population., Design: Longitudinal., Setting: Population-based cohort aged 65 and older resident in an Italian municipality., Participants: A total of 1,016 subjects underwent baseline evaluation in 1999/2000. In 2003/04, information about cognitive outcome was collected for 745 participants who were free of dementia at baseline., Measurements: MCI (classified as with or without impairment of the memory domain), dementia, Alzheimer's dementia (AD), and vascular dementia (VaD) diagnosed according to current international criteria., Results: Overall prevalence of MCI was 7.7% (95% confidence interval (CI)=6.1-9.7 %) and was greater with older age and poor education. During 4 years of follow-up, 155 incident MCI cases were diagnosed, with an incidence rate of 76.8 (95% CI=66.8-88.4) per 1,000 person-years. Approximately half of prevalent and incident MCI cases had memory impairment. Compared with normal cognition, multivariable-adjusted risk for progression from MCI with memory impairment to dementia was 4.78 (95% CI=2.78-8.07) for any dementia, 5.92 (95% CI=3.20-10.91) for AD, and 1.61 (95% CI=0.37-7.00) for VaD. No association with dementia risk was found for MCI without memory impairment. Approximately one-third of MCI cases with memory impairment did not progress to dementia., Conclusion: MCI occurs often in this elderly Italian cohort and is associated with greater risk of AD, but only when the impairment involves the memory domain. However, a substantial proportion of MCI cases with memory impairment do not progress to dementia.

Incidence studies of blood inflammatory markers as predictors of dementia in older age are few and did not take into account hyperhomocysteinemia, although this condition is associated with both inflammation and increased risk of dementia. We investigated the relationships of baseline serum C-reactive protein (CRP), serum interleukin 6 (IL6), plasma alpha-1-antichymotrypsin, and hyperhomocysteinemia (defined as plasma total homocysteine>15 micromol/L) with risk of incident Alzheimer's disease (AD) and vascular dementia (VaD) in a dementia-free Italian population-based elderly cohort (n=804, 53.2% women, mean age 74 years) with 4 years of follow-up. No inflammatory marker, alone or in combination, predicted AD risk whereas the combination of high CRP and high IL6 was associated with risk of VaD (HR, 2.56; 95%CI, 1.21-5.50) independently of socio-demographic confounders, traditional risk factors and hyperhomocysteinemia. By contrast, in the same model, hyperhomocysteinemia was independently associated with AD (HR, 1.91; 95%CI, 1.02-3.56) but not VaD risk. Blood inflammatory markers are associated with increased VaD risk but do not predict AD, which seems selectively associated with hyperhomocysteinemia.