APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Cardiac Biomarkers Release in Preadolescent Athletes After an High Intensity Exercise.

INTRODUCTION: An elevation of cardiac troponins has been described in healthy athletes after endurance exercises. The clinical significance of this increase is unclear and the lack of awareness of this phenomenon may lead to inappropriate management of these subjects. AIM: We sought to determine wether an intensive cycling training could determine a biomarkers elevation. METHODS: We evaluated serum high sensitivity cardiac troponin T, NH(2)-terminal pro-brain natriuretic peptide, CK-MB and CK in 21 healthy male preadolescent athletes (age 9.2 ± 1.7 years) after an intensive cycling training prolonged until muscular exhaustion (mean duration 16'41″). During exercise heart rhythm and rate were monitored with Holter. RESULTS: 62% of the group had an elevation of cardiac biomarkers: specifically, 6 children had an increase in troponin levels; 3 of them had an elevation of pro-brain natriuretic peptides as well. Pro-brain natriuretic peptides resulted increased in 9 subjects. There was no relation between troponin elevation and heart rate, age or exercise duration; subjects with increased pro-brain natriuretic peptides had mean and maximal heart rates lower than children with normal natriuretic peptides levels. Other sports were performed in 50% of subjects with normal troponins and only in 17% of those with increased values. CONCLUSIONS: A short, high-intensity exercise caused an elevation of cardiac biomarkers in 62% of our subjects. The grade of training may influence the release of troponin and this increase is probably related to a temporary discrepancy between O2 delivery and consumption. Increases in natriuretic peptides levels are possibly expression of different adaptations to exercise.

Prevalence of major depressive disorder and dementia in psychogeriatric outpatients.

The relationship between depression and dementia in the elderly has been widely investigated, but the real interplay between these variables is still not clear. This observational study highlights the influence of some basic variables, such as sex and age, in the development of dementia and major depression. It shows (i) the importance of sex in the age of onset of depression and dementia, (ii) the presence of two types of depressive syndrome, the first linked to the development of dementia, the second as reactive depression; (iii) the need for more attention to depressive symptoms in young-elderly men.

Affectivity and sexuality in the elderly: often neglected aspects.

Sexuality and affectivity constitute a complex phenomenon involving many spheres: biological, psychological and social. To investigate these aspects, we distributed a dedicated questionnaire, followed by an interview, to 130 elderly residents in Milan and 100 in Monza. The answers indicated that the elderly communicate their emotions regarding the affective and sexual sphere, with different levels of desire for physical contact. The main variables were sex, age, marital status, co-morbidity and poly-pharmacotherapy, the perception of health status and of oneself, past experiences, cultural conditioning and social factors.

The role of comprehensive geriatric assessment and functional status in evaluating the patterns of antithrombotic use among older people with atrial fibrillation.

Aim of the study is to investigate the use of antithrombotic drugs in older patients with atrial fibrillation (AF) at the time of hospital discharge. We enrolled 399 ≥65 years old patients with AF consecutively admitted to our acute geriatric unit from September 2012 to February 2014. Utilization of antithrombotic drugs, comorbidities, functional, mental and nutritional status were evaluated through a comprehensive geriatric assessment (CGA). A Logistic regression model was used to assess variables associated with antithrombotic use. On admission, 198 patients (49.6%) used oral anticoagulants (OAC), 125 (21.3%) antiplatelets, 32 (8%) low weight molecular heparin (LMWH) and 44 (11%) none of them. At discharge the proportion of patients on OAC increased to 55.7%. Age>90years (OR=2.57, CI=1.28-5.16, p-value=0.008), severe functional impairment (OR=3.38, CI=1.63-7.01, p-value=0.001), polypharmacy (OR=2.07, CI=1.1-3.86, p-value=0.023), HAS-BLED score (OR=1.64, CI=1.09-2.47, p-value=0.019) and ≥1 OAC contraindication (OR=5.01, CI=2.68-9.34, p-value<0.001) were all associated with OAC underuse. In conclusion, OAC is underused in geriatric patients with AF, while antiplatelet, LMWH and no antithrombotic therapy are relatively overused. Factors associated with the decision to not prescribe OAC lie on a mix of clinical and geriatric variables, among which functional status is particularly relevant.

Under-detection of delirium and impact of neurocognitive deficits on in-hospital mortality among acute geriatric and medical wards.

BACKGROUND: Delirium is a neuropsychiatric disorder, triggered by medical precipitants causes. Study aims were to describe the prevalence and impact on in-hospital mortality of delirium identified through ICD-9 codes as well as evidence of neurocognitive deficits demonstrated in a population of older patients admitted to acute medical wards. METHODS: This was a prospective cohort multicenter study of 2521 older patients enrolled in the "Registro Politerapie SIMI (REPOSI)" during the years 2010 and 2012. The diagnosis of delirium was obtained by ICD-9 codes. Cognitive function was evaluated with the Short Blessed Test (SBT) and single SBT items were used as measures of deficits in attention, orientation and memory. Combination of deficits in SBT items was used as a proxy for delirium. Logistic regression was used to evaluate the association with in-hospital mortality of delirium and combined deficits in SBT items. RESULTS: Delirium was coded in 2.9%, while deficits in attention, orientation, and memory were found in 35.4%, 29.7% and 77.5% of patients. Inattention and either disorientation or memory deficits were found in 14.1%, while combination of the 3 deficits in 19.8%. Delirium, as per ICD-9 codes, was not a predictor of in-hospital mortality. In contrast, objective deficits of inattention, in combination with orientation and memory disorders, were stronger predictors after adjusting for covariates. CONCLUSIONS: The documentation of delirium is poor in medical wards of Italian acute hospitals. Neurocognitive deficits on objective testing (in a pattern suggestive of undiagnosed delirium) should be used to raise awareness of delirium, given their association with in-hospital mortality.

The hemochromatosis gene affects the age of onset of sporadic Alzheimer's disease.

In the present study we analysed the genotype of HFE, the gene involved in hemochromatosis, in 107 patients with sporadic late-onset AD and in 99 age-matched non-demented controls. We observed that patients carrying the mutant HFE-H63D allele had a mean age at onset of 71.7 +/- 6.0 years versus 76.6 +/- 5.8 years of those who were homozygous for the wild-type allele (p = 0.001). The frequency of the HFE-H63D mutation was highest (0.22) in the patients aged <70 years at the time of disease onset, whereas it was 0.12 in those with disease onset at an age of 70-80 years, and 0.04 in those aged more than 80 years. The APOE genotype did not significantly modify the effect of HFE on age at onset. We conclude that mild disturbances of iron homeostasis associated with a common genetic determinant may interact with other pathogenic mechanisms involved in AD. HFE mutations may anticipate AD clinical presentation in susceptible individuals.

Age-dependent expression of fibrosis-related genes and collagen deposition in the rat myocardium.

OBJECTIVES: We sought to characterize the evolution, during maturational growth and early ageing, of the messenger abundance of four genes involved in cardiac fibrosis regulation (procollagens alpha2(I) and alpha1(III), transforming growth factors beta1, and beta3) and corroborate it with the alterations in collagen deposition in cardiac interstitium and around coronary arteries. METHODS: Messenger RNA was quantified in LV and RV of 2-, 6-, 12- and 19-month-old male Sprague-Dawley rats (n = 5 per group) with Northern blot analysis. Collagen deposition was quantified with a semi-automated image analyser on Sirius red-stained sections of LV tissue. RESULTS: There was an age-related monotonous decrease of procollagen type I (COL-I) transcript abundance in LV (p < 0.001) but not in RV. Procollagen type III (COL-III) expression decreased rapidly during maturational growth, both in LV and RV. On the other hand, collagen deposition in myocardial interstitium and around coronary arteries was slightly augmented during the maturational period of life (2-12 months), but with a higher rate during early ageing (up to 19 months). This was not accompanied by a significant thickening of the wall of coronary arteries. Transforming growth factor beta1, (TGF-beta1) and transforming growth factor beta3 (TGF-beta3) transcript abundance showed no major variations during ageing. CONCLUSIONS: These results reflect a striking ventricular difference regarding the age-dependent expression of COL-I. The expression of TGF-beta(s), pleiotropic factors known to influence collagen pathway at different levels, does not seem to be profoundly altered during ageing. The discrepancy between protein and COL-I and COL-III mRNA levels indicates differences in age-related mRNA stability and/or regulation of collagen translation.

Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain?

Plasma concentrations of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), C reactive protein (CRP) and alpha-1-antichymotrypsin (ACT) in 145 patients with probable Alzheimer's disease (AD) and 51 non-demented controls were measured. To investigate the cellular activation of peripheral immune system, plasma levels of neopterin were also investigated. Plasma levels of IL-1 were detectable in 17 patients with AD (13%) and only in one control (2%) and average levels of IL-1 were higher in AD patients than in controls (p < 0.001). IL-6 plasma levels were detectable in a higher proportion of AD and controls (53% and 27%, respectively), and were increased in patients with AD (p < 0.001). Plasma levels of ACT were increased in patients with AD (p < 0.001) and CRP levels were in the normal range. Plasma levels of neopterin were slightly lower in AD patients than in controls, but differences were not statistically significant. No significant correlation was observed between IL-1 and IL-6 levels or neopterin and cytokine levels in plasma from AD patients. Plasma levels of ACT negatively correlated with cognitive performances, as assessed by the mini mental state examination (MMSE; R = -0.26, p < 0.02) and positively correlated with the global deterioration state (GDS) of AD patients (R = 0.30, p < 0.007). Present findings suggested that detectable levels of circulating cytokines and increased ACT might not be derived by activation of peripheral immune system of AD patients. Detection of these molecules might be used for monitoring the progression of brain inflammation associated with AD.

Age-associated differences in neutrophil oxidative burst (chemiluminescence).

Phagocytic defensive functions consist of a sequence of events, including migration, phagocytosis, secretion, and the release of reactive oxygen species (ROS). The last of these (also called "oxidative burst") has not received due attention in the elderly, even though it can be considered the most important event in the process of killing an invading microorganism. The aim of the present study was to investigate the oxidative burst activity of polymorphonuclear neutrophil leukocytes (PMNs) in relation to age, using a technique that specifically identifies ROS production: luminol-amplified chemiluminescence (LACL). Besides the use of LACL, a particular feature of the study was the use of five rather than just one or two different stimulants: two particulate (Candida albicans and zymosan) and three soluble ones [N-formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol 12 myristate 13 acetate (PMA), and polyanetholesulfonate (liquoid)]. This approach allowed us to observe a dichotomy between the effects of Candida and zymosan (particulates), which were not significantly different in the elderly subjects compared to the young controls, and those of fMLP, PMA, and liquoid (solubles), which showed a significant reduction in LACL in the elderly group. Considering the different results obtained with the various stimulants adopted that are all believed to have NADPH oxidase as a common final target of oxidative burst, it may be postulated that aging can influence the different transductional pathways in different ways.

BsmI polymorphism of the vitamin D receptor gene in hyperparathyroid or hypoparathyroid dialysis patients.

Since bone mineral density may be influenced by the polymorphisms of the vitamin D receptor (VDR) gene, we studied whether VDR genotypes might drive the progression toward hyperparathyroidism or hypoparathyroidism in patients with end-stage renal disease. On the basis of their parathyroid hormone (PTH) levels, we divided 99 patients undergoing dialysis into 2 groups: 56 patients with hypoparathyroidism (PTH < 104 pg/mL [< 11 pmol/L]) and 43 with hyperparathyroidism (PTH > 261 pg/mL [> 27.5 pmol/L]). The BB polymorphism was more frequent in patients with hypoparathyroidism (34%) than in patients with hyperparathyroidism (16%), but the difference did not reach statistical significance. Patients with the B allele and BB genotype had a significantly lower dialytic age and serum PTH and alkaline phosphatase levels than patients with the b allele and bb genotype. These results suggest that in end-stage renal disease, the BB genotype may mark a higher risk of developing hypoparathyroidism and diminished bone turnover.

Serum marker of type III procollagen in patients with idiopathic hemochromatosis and its relationship to hepatic fibrosis.

A radioimmunoassay for serum procollagen III aminopeptide (sPIIIP) was proposed recently for monitoring hepatic fibroplasia in patients with various inflammatory hepatic lesions. To determine whether sPIIIP also can detect fibroplasia in noninflammatory liver disorders, we measured this index in 16 patients with idiopathic hemochromatosis (IHC) at various stages of the disease and iron overload. Interestingly, we found normal levels of sPIIIP in 12 out of 16 patients examined (75%), despite clear histologic features of fibrosis or cirrhosis. The levels of sPIIIP exhibited no relationship to any of the clinical, laboratory, or histologic parameters of the disease. Thus, unlike other types of cirrhosis, in which sPIIIP is increased, the liver disease in IHC may be a fibrotic process unrelated to type III collagen stimulation. Accordingly, the determination of sPIIIP in these patients is of no value for monitoring the fibrosis associated with the liver disease.

Cytokine antagonists in aged subjects and their relation with cellular immunity.

Host responses to infectious and inflammatory stimuli are altered with aging. Because cytokines and their antagonists are significant factors in these host responses, the present research on aged subjects was designed to investigate plasma concentrations of the cytokines interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) and those of their antagonists IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor (sTNFr). For this research, 122 apparently healthy aged subjects (79.6 +/- 5.8 yr), 39 aged individuals with documented urinary tract infections (UTIs) (81.6 +/- 6.3 yr), and 100 young controls (39.32 +/- 11.2 yr) were included. Plasma IL-1 beta, TNF alpha, IL-1ra, sTNFr (55 kDa), and neopterin were measured using enzyme-linked immunosorbent assay techniques. In subsets of normal aged subjects and UTI patients, we investigated relations between plasma concentrations of cytokine antagonists and IL-2 production by phytohemagglutinin-stimulated peripheral blood mononuclear cells. The results show that plasma concentrations of both IL-1ra and sTNFr were greater in healthy aged subjects than in young controls. Plasma neopterin, a product of activated monocytes/macrophages, was likewise elevated in the aged. IL-1 and TNF were not detectable in the majority of plasma samples. There was a positive correlation between neopterin concentration and both IL-1ra and sTNFr. There was a significant negative correlation between plasma IL-1ra and IL-2 production by phytohemagglutinin-stimulated peripheral blood mononuclear cell in healthy aged subjects. IL-1ra and sTNFr concentrations were significantly greater in patients with UTI than in the healthy aged subjects. In UTI patients IL-2 production in vitro was lower than in healthy subjects, but there was no significant correlation with IL-1ra in plasma. Therefore, plasma concentrations of cytokine antagonists are increased in plasma of apparently healthy aged subjects. Elevated concentrations of neopterin suggest that this increase can be traced to monocyte activation. The negative correlation between plasma IL-1ra and IL-2 production in vitro suggests that enhancement of this cytokine antagonist can contribute to immunodepression of aging. We propose that unapparent infections in aged subjects cause monocyte activation and release of cytokine antagonists. These cytokine antagonists reduce IL-2 production and the capability of T cells to proliferate, thereby inhibiting responses in the elderly.

Age-dependent expression of fibrosis-related genes and collagen deposition in rat kidney cortex.

Because progressive fibrosis is a histological hallmark of the aging kidney, we sought to characterize the course of some fibrosis-related genes [pro-alpha2(I)collagen (COL-I), pro-alpha1(III)collagen (COL-III), and transforming growth factors beta1 and beta3 (TGF-beta1 and TGF-beta3)] of interstitial collagen accumulation [COL-I and COL-III proteins, hydroxyproline (PRO-OH), histology] and its degradation (matrix metalloproteinase MMP-1 and -2) during maturation and early aging in rats. During the lifespan considered we observed no changes in the mRNA, except that COL-I mRNA tended to be up-regulated from 2 to 19 months of age. However, progressive fibrosis was histologically detectable, with COL-I accumulation (p < .05 and p < .01 in 12-month- and 19-month-old rats vs the youngest), and confirmed by the PRO-OH tissue levels (p = .0001); COL-III seemed to be less involved. The MMP-1 protein level decreased significantly in the cortex of 12-month- and 19-month-old rats (p < .05), whereas MMP-2 protein level and activity remained essentially unchanged. These results show that, during aging of the kidney, (i) renal cortex fibrosis is explained by COL-I accumulation as a consequence of an altered balance between its synthesis and degradation, and (ii) the expression of the pleiotropic factor TGF-beta in the renal cortex is not modified.

Left ventricular response to beta-adrenergic stimulation in aging rats.

The incidence of heart failure in the population increases steeply among older people. Overactivation of the sympathetic nervous system is associated to and responsible for worsening of heart failure. This study describes the influence of aging on short-term left ventricular (LV) adaptation to b-adrenergic stimulation in Wistar rats. In controls at 18 mo, interstitial fibrosis was increased with respect to 3-mo-old rats, whereas myocytes dimension and the messenger RNA (mRNA) abundance of atrial natriuretic peptide (ANP), a2(I) procollagen, transforming growth factor (TGF-b1, TGF-b3), and secreted protein, acidic and rich in cysteine (SPARC) were not different. To determine how aging affects LV adaptation to adrenergic stimulation, two groups of animals received isoproterenol (ISO, 1 mg/kg/d) for 3 days. There was no significant difference between young and older rats with respect to increase in LV weight, myocytes dimension, and mRNA abundance of all the genes considered, except a1(III) procollagen. These findings indicate that despite limited compensatory hypertrophy and higher fibrosis, LV from aged nonsenescent rats preserves the capacity to adapt to b-adrenergic stimulation through the upregulation of several genes encoding extracellular matrix-related proteins.

Prognostic value of mitochondrial aspartate aminotransferase in acute myocardial infarction.

In 112 prospectively selected patients suffering from acute myocardial infarction (AMI), the serum CK, CK-MB, LD, HBD, AST and m-AST were determined from the time of admission to hospital and every 12 hours for three days in succession. Sixteen of the enrolled patients died due to complications which arose within the first four days of hospitalization while the rest had a favourable outcome. All enzyme activities were determined at 37 degrees C using routine methods; m-AST was measured using an immunochemical method. The statistical analysis of the results demonstrated that 12 hours after admission, serum m-AST and m-AST/AST ratio were significantly higher in the group of non-survivors compared with patients with a favourable prognosis. No significant differences in CK-MB were observed between survivors and non-survivors during the entire period. True and false positive rates were calculated for these and the other enzymes. An optimum decision level of 34 IU/L was chosen for m-AST and 10% for the m-AST/AST ratio. This gave a percentage of correctly classified patients, after 12 and 24 hours, of 74.9% and 91.9%, respectively. In conclusion, the immunochemical determination of m-AST in patients with AMI seems to be an early prognostic index which is able to distinguish patients with unfavourable outcome.

Fibroblasts from Alzheimer's disease donors do not differ from controls in response to heat shock.

We investigated HSPs mRNA expression in cultured fibroblasts from control and AD patients. Northern blot analysis using probes for HSP70 and HSC73 revealed that HS induced a several fold increase in both mRNA. Under these condition the extent of mRNA increase was similar in controls and AD. HS elicited also a modest increase in sAPP release that was similar in control and AD. The results suggest that the ability of AD fibroblasts to produce a defensive response to HS is preserved.

Apolipoprotein E and alpha-1-antichymotrypsin allele polymorphism in sporadic and familial Alzheimer's disease.

Alzheimer disease (AD) patients with both sporadic and familial forms of AD and non-demented controls were genotyped for common polymorphisms in the signal peptide for alpha-1-antichymotrypsin (ACT) gene and in two different regions of apolipoprotein E (APOE) gene. The ACT TT genotype was over-represented (P = 0.025) in patients with early onset of sporadic AD. In this patient's group ACT TT genotype conferred a significant crude odds ratio for the disease (OR = 2.09; 95% CI = 1.09-4.00, P = 0.025). After adjustment for the APOE epsilon4 and APOE -491 genotypes, logistic regression analysis confirmed that the ACT TT genotype resulted independently associated with early onset AD (adjusted OR = 2.56; 85% CI = 1.3-5.2, P = 0.009). The frequency of APOE epsilon4 allele was increased in AD, as expected (OR = 5.92, 95% CI = 3.60-9.70, P = 0.0001). On the contrary, the APOE -491 A/T genotypes were not associated with AD. No preferential association of the APOE epsilon4 allele or APOE -491 A/T genotypes with ACT A/T alleles was observed in AD. Present findings indicated that subjects with ACT TT genotype had an increased risk of developing AD and suggested that this genotype influenced the risk of an early onset of the disease by affecting the production of ACT molecules.

Apolipoprotein E genotype in senile dementia and Down's syndrome.

Apolipoprotein E genotypes were determined in 30 healthy elderly controls, 42 patients with Alzheimer's disease, 13 subjects with vascular dementia and 31 individuals with Down's syndrome. The frequency of epsilon4 allele carriers was significantly increased in the Alzheimer's disease group (chi(2)=4.918, P<0.05) but also in the vascular dementia subjects (P<0.01, Fisher's exact test). The established relationship between genotype and age at onset of Alzheimer's disease was not statistically significant in these data. Frequencies of the genotypes in the Down's syndrome group did not differ from those of controls. The results obtained in this sample of the Italian population suggest that the apolipoprotein E genotype may be of limited use in the differential diagnosis of dementia.

The 'eye test' in recognition of late-onset Alzheimer's disease.

A rapid and specific diagnostic test for Alzheimer's disease (AD), the prevalent cause of dementia in the elderly, is currently unavailable. The aim of this study was to verify the validity of the recently proposed 'Eye Test' in the identification of AD patients, based on their supposed greater mydriatic response to cholinergic antagonists. We tested the pupillary response to the instillation of 0.01% tropicamide in 48 subjects: 15 patients with probable or possible Alzheimer's disease, five patients with vascular dementia (VD), 16 elderly controls (EC) and 12 young controls (YC). Mean pupil dilation in the treated eye at 30 and 40 min after drops instillation was not significantly different among the four groups. The mean change in anisocoria at 30 min was significantly greater in the AD group (0.90 mm, S.D. 0.83) than in the YC group (0.21 mm, S.D. 0.46), but no significant difference was found among the AD group, the EC group and the VD group. Our results, therefore, do not support the potential usefulness of the pupillary response to dilute tropicamide for identifying individuals with AD.