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Background In clinical practice, the use of plasma β-Amyloid1–42 (Aβ1–42) as biomarker for Alzheimer's disease is largely limited by the absence of reference values. The aim of this study was to evaluate Aβ1–42 plasma concentrations in cognitively normal subjects and to propose reference values. Methods Plasma samples were obtained from 245 subjects, with a wide age-range (19–89 years), enrolled at the Unit of Laboratory Medicine of the “Azienda Ospedaliera Cardinale G. Panico” (younger subjects) and from a population-based study on aging (GreatAGE study) (older subjects). Three different age-groups were established: young (≤ 34), adult (35 ≤ age ≤ 64) and old (>64). The Innogenetics Elisa kit for plasma Aβ1–42 was used for the analysis. Results The mean (SD) concentration of plasma Aβ1–42 was 17.65 (5.71) pg/mL. A positive trend was found in Aβ1–42 levels across the three age groups (p Conclusion The present study proposes reference values for plasma Aβ1–42. Nevertheless, further studies are needed to confirm these results and corroborate the use of these reference values in clinical practice.

The genetics of tailored medicine (TM), a medicine in which drug types and dosages are tailored to the clinical needs of each patient, greatly overlap cytochrome P450 (CYP) genetics, probably the most active area of multidisciplinary research interrelating the interest of medicine, biology, biochemistry, and pharmacology, and potentially crossing all medical disciplines. The great genetics variability showed by the CYP gene superfamily permitted on one side to encode a series of enzyme capable to metabolize almost all drugs, and on the other side to have specific genetic profiles for each individual, resulting in inter-individual difference in drug efficacy also responsible of severe clinical consequences such as therapeutic failures (TFs) and adverse drug reactions (ADRs), worldwide primary causes of morbidity and mortality in Western countries. Among medical disciplines, neurology, psychiatry and geriatrics resulted the most interesting for TM since the administration of concomitant treatment is a common practice, raising the prevalence of TFs and ADRs in the treatment of neurological and psychiatric diseases. i.e. in older patients with in treatment with acetylcholinesterase inhibitors, antidepressants, and antipsychotics, all substrate of CYPs. Thus, in these clinical settings the genetic analysis of CYPs may be pivotal for the identification of patients to be addressed toward alternative treatments, and tailor drug types and dosages to the individual patient's clinical needs.

Current guidelines suggested a dosage up to 600units (U) of botulinum toxin type A (BoNT-A) (onabotulinumtoxinA or incobotulinumtoxinA) in reducing spastic hypertonia with low prevalence of complications, although a growing body of evidence showed efficacy with the use of high doses (>800U). The available evidence mainly referred to a single set of injections evaluating the efficacy and safety of the neurotoxin 30days after the treatment. In a prospective, non-randomized, open-label study, we studied the safety of repeated higher doses of incobotulinumtoxinA in post-stroke upper and lower limb spasticity. Two years after the first set of injections, we evaluated in 20 stroke survivors with upper and lower limb spasticity the long-term safety of repeated high doses of incobotulinumtoxinA (up to 840U) for a total of eight sets of injections. Patients reported an improvement of their clinical picture concerning a reduction of spasticity measured with the Asworth Scale (AS) for elbow, wrist, fingers and ankle flexor muscles and disability measured with the Disability Assessment Scale (DAS) 30days after the last set of injections (eighth set) compared to the baseline (p

Background: Frailty is a critical intermediate status of the aging process, characterized by an increased risk of negative health-related events, including physical, cognitive, and psychosocial domains/phenotypes. In particular, the psychosocial domain is heterogeneously defined and little explored. We operationalized a new biopsychosocial frailty (BF) construct, easy to implement in clinical and epidemiological settings. Furthermore, we estimated the impact of this new BF construct on the risk of incident dementia and its subtypes. Methods: Out of 5632 older individuals from the Italian Longitudinal Study on Aging, we identified on 1271 subjects specific characteristics mainly based on a Comprehensive Geriatric Assessment for identifying a construct for a BF by a latent class analysis. We obtained a 11-item instrument derived from three items of the Instrumental Activities of Daily Living, six items of the 30-item Geriatric Depression Scale (GDS-30), the cohabitation status of the individuals, and the physical frailty condition. Reliability and scalability of the items involved were estimated. Criterion-related validity of the new BF construct was calculated assessing the independent contribution of baseline BF to incidence of dementia and its subtypes over 3.5 and 7 years. Findings: Three latent classes were identified, one of them highly aggregating (>40%) physical frailty and the items 3 or 10 of the GDS-30. Over a 3.5-year median follow-up, participants with BF showed an increased risk of overall dementia [hazard ratio (HR) 2.16, 95% confidence interval (CI) 1.07-4.37], particularly vascular dementia (VaD) (HR 3.21, 95% CI 1.05-9.75). Similarly, over 7-year of median follow-up, an increased risk of overall dementia (HR 1.84, 95% CI 1.06-3.20), particularly VaD (HR 2.53, 95% CI 1.08-5.91), was also observed. Interpretation: In a large cohort of Italian older individuals without cognitive impairment at baseline, a BF model was a short- and long-term predictor of overall dementia, particularly VaD. Funding Statement: "none declared." Declaration of Interests: "None" Ethics Approval Statement: The study project was approved by the Institutional Review Board of the 8 municipalities of the ILSA.

Resumen Introduccion Las mutaciones del gen forkhead-box-O1 (FoxO1) en el locus 13q14.1 provocan alteraciones en los parametros bioquimicos conduciendo al envejecimiento prematuro. La proteina FoxO1 participa en la regulacion de procesos bioquimicos, que influyen en la regulacion del perfil lipidico y glucemico. Estos parametros son un factor de riesgo de mortalidad en la poblacion anciana. El objeto del estudio fue investigar la relacion entre el locus FoxO1 y los marcadores metabolico-nutricionales. Material y metodos Se investigaron los polimorfismos de nucleotido unico (SNP, del ingles single-nucleotide polymorphisms) rs2721069, rs4943794 y rs7981045 en 594 ancianos hospitalizados (65-99 anos) en una seccion geriatrica, probando la asociacion con los marcadores biologicos mediante el analisis de covarianza (ANCOVA) y del modelo estadistico Genotype Score. Resultados El analisis de ANCOVA bajo distintos modelos geneticos revelo una asociacion significativa. Asumiendo un modelo genetico dominante se observo una asociacion significativa con los niveles de la glucosa para rs2721069 (p = 0,034) y rs4943794 (p = 0,012). Para rs4943794 se observo tambien una asociacion significativa si considerado libre de modelos geneticos (p = 0,039) confirmada en el modelo aditivo (p = 0,012). El modelo estadistico Genotype Score confirmo una asociacion significativa entre FoxO1 SNP y la glucosa, teniendo en cuenta los SNP rs2721069 y rs4943794 en conjunto (p = 0,048; β = 3,198). Conclusiones El envejecimiento es un proceso complejo, resultante de la interaccion entre varios factores, como los ambientales y los geneticos. Nuestros hallazgos sugieren que el locus FoxO1 puede influir en los niveles sericos de glucemia en pacientes hospitalizados mayores, siendo entonces uno de los factores geneticos que contribuyen a un envejecimiento saludable.

Neuropsychiatric symptoms (NPS) in dementia, previously denominated as behavioural and psychological symptoms of dementia, are often more distressing, impairing, and costly than cognitive symptoms, representing a major health burden for older adults. These symptoms are common features of Alzheimer's disease (AD), and are one of the major risk factors for institutionalization. There is a high prevalence of neuropsychiatric disturbances in patients with AD, including depression, anxiety, apathy, psychosis, aggression, and agitation. At present, the role of the apolipoprotein E (APOE) genotypes in the development of NPS or neuropsychiatric syndromes/endophenotypes in AD patients is unclear. In this article, we summarized the findings of the studies of NPS and neuropsychiatric syndromes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between the APOE polymorphism and NPS in late-onset AD, other studies reported a significant association between the APOE ɛ4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. However, current cumulative evidence coming from the few existing longitudinal studies shows no association of APOE genotypes with NPS as a whole in AD. Some negative studies that focused on the distribution of APOE genotypes between AD patients with or without NPS further emphasized the importance of sub-grouping NPS in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, possible lack of statistical power to detect associations in the negative studies, and small sample sizes generating false positives that cannot be consistently replicated. Finally, many reviewed studies were cross-sectional, whereas it would be of paramount importance to evaluate the risk for incident NPS in relation to the APOE genotype in prospectively followed cohorts of AD patients. In fact, identifying predisposing genetic risk factors may allow us to understand the pathophysiological features of neuropsychiatric syndromes or symptoms in AD, so optimizing possible therapeutic options.

The genetics of cytochrome P450 (CYP) is a very active area of multidisciplinary research, overlapping the interest of medicine, biology and pharmacology, being the CYP enzyme system responsible for the metabolism of more than 80% of the commercially available drugs. Variations in CYP encoding genes are responsible for inter-individual differences in CYP production or function, with severe clinical consequences as therapeutic failures (TFs) and adverse drug reactions (ADRs), being ADRs worldwide primary causes of morbidity and mortality in elderly people. In fact, the prevalence of both TFs and ADRs strongly increased in the presence of multiple pharmacological treatments, a common status in subjects aging 65 years and over. The present article explored some basic concepts of human genetics that have important implications in the genetics of CYP. An attempted to transfer these basic concepts to the genetic data reported by the Home Page of The Human Cytochrome P450 (CYP) Allele Nomenclature Committee was also made, focusing on the current knowledge of CYP genetics. The status of what we know and what we need to know is the base for the clinical applications of pharmacogenetics, in which personalized drug treatments constituted the main aim, in particular in patients attending a geriatric ward.

Previous studies examining the association between the interleukin 6 (IL-6)-174 C/G polymorphism and Alzheimer's disease (AD) have yielded conflicting results. Furthermore, the C allele of the IL-6 variable number of tandem repeats (VNTR) polymorphism was associated with a delayed onset and a decreased risk of AD.A total sample of 149 AD patients, and 298 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotyped for the apolipoprotein E (APOE) polymorphism, the VNTR polymorphism in the 3' flanking region, and the -174G/C single-nucleotide polymorphism (SNP) in the promoter region of IL-6 gene on chromosome 7. Furthermore, we performed a haplotype analysis on these two polymorphisms on IL-6 locus.IL-6 VNTR and -174G/C allele and genotype frequencies were similar between AD patients and controls, also after stratification for late-onset (or =65 years) and early-onset (65 years) or APOE epsilon4 status. Furthermore, there was no evidence of linkage disequilibrium between the VNTR and -174G/C polymorphisms, not supporting a previous reported additive effect of both IL-6 polymorphisms on AD risk.Our findings did not support a role of IL-6-174 G/C and IL-6 VNTR polymorphisms in the risk of sporadic AD in southern Italy, suggesting that these polymorphisms of IL-6 gene were at most weak genetic determinants of AD.

Clinical and epidemiologic research has focused on the identification of risk factors that may be modified in predementia syndromes, at a preclinical and early clinical stage of dementing disorders, with specific attention to the role of depression. Our goal was to provide an overview of these studies and more specifically to describe the prevalence and incidence of depression in individuals with mild cognitive impairment (MCI), the possible impact of depressive symptoms on incident MCI, or its progression to dementia and the possible mechanisms behind the observed associations. Prevalence and incidence of depressive symptoms or syndromes in MCI vary as a result of different diagnostic criteria and different sampling and assessment procedures. The prevalence of depression in individuals with MCI was higher in hospital-based studies (median: 44.3%, range: 9%-83%) than in population-based studies (median: 15.7%, range: 3%-63%), reflecting different referral patterns and selection criteria. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. For depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia were conflicting. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, and methodological differences may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and Alzheimer disease, arguing that the underlying neuropathological condition that causes MCI or dementia also causes depressive symptoms. In this scenario, at least in certain subsets of elderly patients, late-life depression, MCI, and dementia could represent a possible clinical continuum.

The genetic epidemiology of sporadic Alzheimer's disease (SAD) remains a very active area of research,making it one of the most prolifically published areas in medicine and biology. Numerous putative candidate genes have been proposed. However, with the exception of apolipoprotein E (APOE), the only confirmed genetic risk factor for SAD, all the other data appear to be not consistent. Nevertheless, the genetic risk for SAD attributable to the APOE gene in the general population is 20-0%, providing a strong evidence for the existence of additional genetic risk factors. The first part of the present article was dedicated to non-APOE genetics of SAD, reviewing chromosomes-by-chromosomes the available data concerning the major candidate genes. The second part of this article focused on some recently discovered aspects of the APOE polymorphism and their implications for SAD. An attempt to identify the future directions for non-APOE genetic research in SAD was also discussed.

The promoter region of the serotonin transporter gene (SLC6A4) shows a 22-bp tandem repeat polymorphism, indicated as polymorphism C, that has been associated to depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding its association with Alzheimer's disease (AD). No data were reported regarding its association with questionable dementia (QD). In this study we investigate for polymorphism C in the SLC6A4 gene 302 elderly subjects with a clinical diagnosis of AD (n=105), QD (n=88) and no cognitive impairment (n=114) attending a geriatric ward. A community-dwelling sample of 390 healthy subjects was also included in the analysis. A significant higher prevalence of the C16/C16 genotype in AD than in QD was observed (37.14% vs. 3%; p=0.041, OR 2.001, 95%CI 1.018-4.024), while no differences in the C16/C14 and C14/C14 genotypes as well as in the estimated allele frequencies were found. No further differences among the three groups of subjects were found, also when they were compared with the community-dwelling sample. These findings suggest that SLC6A4 gene variation may have only a minor role, if any, in AD or QD.

Catalase (CAT) −262 C/T promoter (rs1001179), cathepsin D (CTSD) exon 2 (rs17571), and apolipoprotein E (APOE) gene polymorphisms were studied in 242 patients with sporadic Alzheimer's disease (AD) and 421 unrelated age-, sex-, and ethnically matched control subjects from Apulia (Southern Italy). No statistically significant differences in CAT rs1001179 and CTSD rs17571 genotype and allele distribution between AD cases and healthy controls were observed for the whole AD sample, and when AD group was categorized by age at onset in early- and late-onset AD subsets. Furthermore, we did not find any statistically significant differences in rates between CAT rs1001179 and CTSD rs17571 genotypes and AD controlling for APOE e4 allele status. Our data, at present, do not support a role of two gene polymorphisms of the short arm of the chromosome 11, the CAT rs1001179 and CTSD rs17571, as a possible susceptibility factors for sporadic AD.

Several nonsteroidal anti-inflammatory drugs (NSAIDs) are metabolized by the cytochrome P450 2C9 (CYP2C9). Two common variants of the CYP2C9 gene (CYP2C9*2 and *3) were reported to significantly affect the activity of the CYP2C9 enzyme. The aim of this study was to evaluate the impact of CYP2C9 polymorphisms on the risk of gastroduodenal bleeding in acute NSAID users.This case-control study included 26 patients with endoscopically documented NSAID-related gastroduodenal bleeding lesions and 52 age-, sex- and NSAID use-matched controls with no lesions at endoscopy. Both cases and controls were Helicobacter pylori negative and acute users of an NSAID or cycloxygenase-2 inhibitor that undergoes CYP2C9 metabolism (ie, celecoxib, diclofenac, ibuprofen, naproxen, or piroxicam). Two marker single nucleotide polymorphisms in the CYP2C9 gene, identifying the CYP2C9 *2 and *3 allele, were evaluated in all subjects.Setting the CYP2C9*1/*1 wild type as reference, significantly higher frequencies of CYP2C9*1/*3 (34.6% vs 5.8%; P.001; odds ratio [OR], 12.9; 95% confidence interval [CI], 2.917-57.922) and CYP2C9*1/*2 (26.9% vs 15.4%; P = .036; OR, 3.8; 95% CI, 1.090-13.190) were identified in bleeding versus control patients, whereas no differences between bleeding and controls were observed in the distribution of CYP2C9*2/*3 heterozygotes. Considering allele carriers, the presence of CYP2C9*3 allele was associated with a significant high risk of bleeding (adjusted OR, 7.3; 95% CI, 2.058-26.004).CYP2C9 genotyping may identify subgroups of persons who potentially are at increased risk of gastroduodenal bleeding when treated with NSAIDs metabolized by CYP2C9. Further studies that evaluate the effectiveness of a strategy using CYP2C9 genotyping in NSAID users are needed before genotyping is introduced into clinical practice.

Ku70/80 nonhomologous end-joining activity is essential for resolving random DNA double-strand breaks, and the Ku70/80 protein complex has been proposed as “caretaker” of genomic stability. We studied the Ku70/80 heterodimer activity in a patient affected by multiple basal cell carcinomas with a personal history of moderate exposure to ionizing radiation. The Ku70/80 DNA-binding activity was analyzed, by electrophoretic mobility shift assay, in five tumor biopsies from different sites and at distinct clinical stages, and in three matched normal skin samples from the same patient. As control normal tissues from healthy individuals were also tested. The five basal cell carcinomas were classified as “non aggressive” and “aggressive” on the basis of morphologic parameters and expression of the molecular markers bcl-2, Ki67/MIB1, and p53. A 62% increase in the Ku70/80 DNA-binding activity was found in normal skin from the patient, compared to unexposed individuals (p

A mononucleotide repeat (D310) in mitochondrial DNA has been recently identified as a mutational hot spot in primary tumors. We analyzed 56 tumors for insertion/deletion mutations in the D310 repeat. A total of 13 mutations were detected. The highest frequency of mutations was found for cervical cancer, followed by bladder tumors, breast cancer and endometrial neoplasia. No alterations were observed in four patients suspected of malignancy but without evidence of malignant tumor. We detected identical changes in four of four urine sediments from patients with bladder cancer and in three of three fine needle aspirates of patients with breast cancer. Our results indicate that D310 abnormalities are detectable in cytology specimens from patients with cancer and support the notion that D310 analysis may represent a new molecular tool for cancer detection.

The role of the Apolipoprotein E (APOE) alleles in syndromes associated with focal cerebral atrophy (fronto-temporal dementia, primary progressive aphasia, corticobasal degeneration) is still controversial. We studied the APOE allele distribution in 39 patients with clinically diagnosed syndromes associated with focal cerebral atrophy (FCA), in 50 patients with early-onset probable Alzheimer's disease (EOAD), and in 60 patients with late-onset probable AD (LOAD). The APOE genotype was determined from a blood sample, using polymerase chain reaction and restriction enzyme digestion. The APOE epsilon4 allele frequency was significantly higher in the EOAD (21.0%) and LOAD (33.3%) groups, but not in the FCA group (5.1%), as compared with controls. In our population, the epsilon2 allele frequency was significantly higher in patients with FCA (12.8%) than in controls (4.8%). These results show that the APOE epsilon4 allele is not a risk factor for syndromes associated with FCA. The potential role of the epsilon2 allele in these syndromes needs further investigation.

A total sample of 169 AD patients, and 264 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotypized for alpha-2-macroglobulin (A2M) Val1000/Ile single-nucleotide polymorphism (SNP) (rs669), apolipoprotein E (APOE), and SNPs (+1073 and +1071) in the oxidized low-density lipoprotein receptor-1 (OLR1) gene on chromosome 12. A2M allele and genotype frequencies were similar between AD patients and controls, also after stratification for late onset (/=70 years) and early onset (70 years) or APOE varepsilon4 status. However, there was evidence in support of LD between the OLR1+1071, the OLR1+1073, and the rs669 SNPs, with T-C-A haplotype being associated with significant increased risk of AD in both the whole sample and when we stratified according to early and late onset AD subjects, with the allelic association with AD predominantly from the OLR1+1073 SNP, further supporting the role of OLR1 as a candidate risk gene for sporadic AD.

Higher total cholesterol, cognitive decline, and dementia Francesco Panza a,∗, Vincenzo Solfrizzi a, Alessia D’Introno a, Anna M. Colacicco a, Andrea Santamato b, Davide Seripa c, Alberto Pilotto c,d, Antonio Capurso a, Cristiano Capurso e a Department of Geriatrics, Center for Lipoprotein Metabolism, University of Bari, Policlinico, Piazza Giulio Cesare, 11, 70124 Bari, Italy b Department of Physical Medicine and Rehabilitation, University of Foggia, Foggia, Italy c Laboratory of Geriatrics and Gerontology, Department of Research, “Casa Sollievo dalla Sofferenza”, San Giovanni Rotondo, Foggia, Italy d Geriatric Unit, Department of Medical Sciences, IRCSS, “Casa Sollievo dalla Sofferenza”, San Giovanni Rotondo, Foggia, Italy e Department of Geriatrics, University of Foggia, Foggia, Italy

o relation with Val279Phe polymorphism and Lp-PLA2 enzyme evels. onclusion.– In terms of TT, GT and GG distribution of AD patients nd control groups, TT genotype might be said to be protective or AD. Large-scale studies are needed to identify a haplotype that ight predispose AD, so that people under risk can be screened. S: Reported at Academic Geriatrics Congress 2012, Turkey. isclosure.– No significant relationships.