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The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the epsilon 4 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 epsilon 4 allele of the APOE gene.

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.

Uncertainty about the definition of frailty is reflected by the development of many ways to identify frail people. We aimed to compare the validity of two frailty measures in participants of the Conselice Study of Brain Aging.Prospective population-based study with 4 year follow up.1,016 subjects aged 65 and over in a rural Italian population.For each participant, a Frailty Index (FI) and a Conselice Study of Brain Aging Score (CSBAS) were determined. The FI was created from 43 deficits according to a standardized methodology; 7 variables derived from a previously validated Easy Prognostic Score comprised the CSBAS.The FI had characteristic properties described in other population samples, with a gamma distribution, a 99% limit of about 0.64 and higher values in women than men. CSBAS and FI were strongly correlated with each other (r = 0.72) and both correlated with age (r = 0.32, r = 0.27, respectively). Each was independently predictive of death in a multivariate model, with greater specificity and sensitivity than age alone.Frailty can be measured by different tools and facilitates a more direct quantification of individual vulnerability than chronological age alone. Though the Frailty Index and the Conselice Study of Brain Aging Score are underpinned by different rationales, clinical utility will continue to motivate their development.

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, α1-antichymotrypsin (ACT), intercellular adhesion molecule 1, and tumor necrosis factor α 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 ≧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.

Background. The associations of endogenous sex hormones with risk of dementia in the elderly population are not well known. Methods. The relationship of baseline serum total estradiol (E2) and free testosterone (FT) to 4-year risk of all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) was examined in a dementia-free, population-based cohort of 433 women (mean age 74 years) and 376 men (mean age 73 years). Multivariable proportional hazards regression was used to adjust for sociodemographic and lifestyle variables, body mass index, apolipoprotein E genotype, cardiovascular conditions, and homocysteinemia. Results. Dementia developed in 71 women (46 AD, 21 VaD) and 39 men (23 AD, 12 VaD). In women with high E2 (serum E2 � 10 pg/mL), the multivariable-adjusted hazard ratio (HR) for dementia was 1.75 (95% confidence interval [CI], 1.06-2.89). The corresponding multivariable-adjusted HR for AD was 1.94 (95% CI, 1.04-3.61), whereas no association was found for VaD. No association with dementia was found for serum FT in women and for either serum E2 or FT in men. Conclusion. High serum E2 is an independent predictor for dementia and AD in elderly women.

Serum interleukin-6 (sIL6) is an acknowledged predictor of all-cause mortality in older age. A common G/C polymorphism has been identified at position −174 of the IL6 gene promoter (IL6−174G>C), but its associations with sIL6 and mortality are still unclear. Data from a population-based elderly cohort (n = 824) were used to study the associations of baseline sIL6 with the IL6−174 C-allele (C+) carrier status and all-cause mortality at 4 years, in the presence and absence of preexisting major diseases (PMD). Analyses were adjusted for socio-demographic factors and body-mass-index. Three-hundred-eighty-eight participants (47.1%) had PMD. Compared to the bottom sIL6 quartile, mortality increased both in presence [Hazard Ratio (HR) = 3.04; 95% confidence interval (CI): 1.48–6.25] and absence of PMD [HR = 3.91; 95%CI: 1.42–10.72] for the third higher sIL6 quartile, but only in presence of PMD for the top sIL6 quartile [HR = 2.30; 95%CI: 1.09–4.83]. In absence of PMD, C+ carrier status did not affect both sIL6 and mortality. In presence of PMD, C+ carrier status was associated with increased baseline sIL6 [odds ratio 2.01; 95%CI: 1.25–3.22, for all sIL6 quartiles above the bottom] but not with increased mortality risk. A survival advantage was even found for C+ carriers with PMD and sIL6 in the top quartile [HR = 0.31, 95%CI: 0.13–0.76]. In conclusion, although associated with increased sIL6 levels in presence of major diseases, the IL6−174 C-allele does not seem to have direct detrimental effects on survival in older age.

The cross-sectional association of functional impairment with several peripheral blood inflammatory markers (increased C-reactive protein (CRP), fibrinogen and leucocyte count, decreased cholesterol and albumin) was studied in 739 elderly community-dwellers. Functional measures included Tinetti test for gait and balance, and basic and Instrumental Activities of Daily Living. When considering each marker individually, only increased CRP was inversely associated with all functional measures independently of demographics, lifestyle, and comorbidity (P0.05). When considering the sum of positive markers, having more than one marker was also inversely associated with all functional measures (P0.05), but no clear gradient of impairment was found across increasing numbers of markers. When considering specific combinations of markers, having both increased CRP and at least another positive marker had a stronger association with functional impairment (P0.01 for all measures) than increased CRP alone (P0.05), or other positive markers alone or in combination (P0.05). In conclusion, in elderly individuals, peripheral blood markers of inflammation are associated with functional impairment independently of potential confounders. A specific combination of CRP with other markers provides a better correlate of functional impairment than both individual markers or a simple count of positive markers.

Literature data consistently show different prevalence estimates of dementia when different classification systems are used in the same population. Very few data are available for the oldest old of the elderly. We investigated the occurrence of dementia among 34 nonagenarians and centenarians according to four classification systems: the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, third edition revised (DSM-III-R) and fourth edition (DSM-IV), the World Health Organization’s International Classification of Diseases, 10th revision (ICD-10), and the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX). Cognitive functioning, work, social function and independence in activities of daily living were evaluated by using an extensive neuropsychological examination. The prevalence (95% CI) of dementia was the following: 47.1% (95% CI 30.3–63.8) with the DSM-III-R criteria, 41.2% (95% CI 24.6–57.7) with the DSM-IV criteria, 29.4% (95% CI 14.1–44.7) with the ICD-10 criteria and 38.2% (95% CI 21.9–54.6) with the CAMDEX. The factors that best predicted disagreement between DSM-III-R and DSM-IV were calculation impairment and the presence or absence of personality changes. DSM-III-R and ICD-10 were differentiated by the weight given to executive functions that all have to be impaired according to ICD-10, whereas progressive deterioration differentiated CAMDEX from DSM-III-R. It should be noted that although the DSM-III-R diagnoses differ by a factor of 1.6 times from the ICD-10 and 1.2 times from the CAMDEX diagnoses, we are speaking about dementia, which is very frequent in nonagenarians and centenarians. Moreover, with regard to public health, an estimation of the number of subjects who will lose their autonomy is rather more useful and informative than simple prevalence figures of dementia by itself. In this light, classification systems, such as the ICD-10, that do not include impairment of social function as a criterion for assessing dementia become less adequate.

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.

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.Prospective population-based cohort.An Italian municipality.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.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.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).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.

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 ≧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.

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.

Objective To examine the association between depressive symptoms and prevalent and incident mild cognitive impairment (MCI) in elderly individuals; to verify whether it is affected by MCI subtype. Design Prospective, population-based, longitudinal cohort study. Setting Adults ≥65 years resident in an Italian municipality. Participants Baseline data are for 595 subjects with no cognitive impairment (NCI) and 72 subjects with prevalent MCI. NCI subjects underwent a 4-year follow-up for incident MCI. Measurements MCI was diagnosed according to international criteria and classified as with (m + MCI) or without memory impairment (m − MCI). Baseline depressive symptoms were measured using the 30-item Geriatric Depression Scale (GDS). Baseline use of antidepressants was also recorded. Results Baseline depressive symptoms (GDS ≥10) were more frequent in prevalent MCI cases (44.4%) than in NCI participants (18.3%). The association was independent of MCI subtype, antidepressant use, and sociodemographic and vascular risk factors. In NCI subjects, baseline depressive symptoms were also associated with increased risk of MCI at follow-up, but only for subjects on antidepressant drugs at baseline (incident cases=72.7%) compared with those without depressive symptoms and not on antidepressant therapy (incident cases=24.0%). The association was independent of other confounders and stronger for m − MCI (incident cases=45.4%) with respect to m + MCI (incident cases=27.3%). Conclusions Depressive symptoms are highly prevalent among elderly MCI subjects and, in cognitively normal elderly individuals, are associated with an increased risk of developing MCI. The association is stronger for the MCI subtype without memory impairment.

Objective: To examine the effect of physical activity on risk of developing Alzheimer disease (AD) and vascular dementia (VaD) in the elderly. Methods: Data are from a prospective population-based cohort of 749 Italian subjects aged 65 and older who, in 1999/2000, were cognitively normal at an extensive assessment for clinically overt and preclinical dementia and, in 2003/2004, underwent follow-up for incident dementia. Baseline physical activity was measured as energy expenditure on activities of different intensity (walking, stair climbing, moderate activities, vigorous activities, and total physical activity). Results: Over 3.9 ± 0.7 years of follow-up there were 86 incident dementia cases (54 AD, 27 VaD). After adjustment for sociodemographic and genetic confounders, VaD risk was significantly lower for the upper tertiles of walking (hazard ratio [HR] 0.27, 95% CI 0.12 to 0.63), moderate (HR 0.29, 95% CI 0.12 to 0.66), and total physical activity (HR 0.24, 95% 0.11 to 0.56) compared to the corresponding lowest tertile. The association persisted after accounting for vascular risk factors and overall health status. After adjustment for sociodemographic and genetic confounders, AD risk was not associated with measures of physical activity and results did not change after further adjustment for vascular risk factors and overall health and functional status. Conclusions: In this cohort, physical activity is associated with a lower risk of vascular dementia but not of Alzheimer disease. Further research is needed about the biologic mechanisms operating between physical activity and cognition.

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.

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 aging brain. In particular, only scarce data are available about the relationship between aging, cognitive status and nutritional factors. In order to address these issues, we planned the Conselice Study, a longitudinal study of physiological and pathological brain aging. The center involved in the study was the municipality of Conselice, (Province of Ravenna), in the Northern-Italian Region Emilia-Romagna. A total of 1,016 subjects aged 65 years and over was enrolled at baseline. Information about cognitive status at 4-years of follow-up was collected from 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 homocysteine as a predictor of dementia.

Mild cognitive impairment (MCI) is regarded as a precursor to dementia, but not all patients with MCI actually develop dementia. As Alzheimer and vascular dementia are thought to share many common etiopathogenetic mechanisms, we investigated whether the vascular risk factor atrial fibrillation affects the risk of conversion to dementia for different MCI subtypes diagnosed according to international criteria.One hundred and eighty elderly outpatients with MCI and 431 elderly outpatients with a normal cognition were followed up for a mean of 3 and 4 years, respectively. The risk of conversion to dementia associated with atrial fibrillation was studied in both samples using a Cox proportional hazards model adjusted for socio-demographic and medical variables.Overall conversion rate to dementia was 10.5 (8.0-13.8 per 100 person-years) in the MCI group and 2.2 (1.5-3.1 per 100 person-years) in the normal cognition group. Atrial fibrillation was significantly associated with conversion to dementia [hazard ratio (HR): 4.63; 95% confidence interval: 1.72-12.46] in the MCI group but not in the cognitively normal group (HR: 1.10; 95% confidence interval: 0.40-3.03).Current diagnostic criteria for MCI subtypes define heterogeneous populations, but atrial fibrillation can be useful in identifying people with increased risk of conversion 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.

Cellular components of both adaptive and innate immune systems produce different chemokines and cytokines, involved in different signalling pathways among cells, and modulate effector function during immune response, playing a key role in the regulation of the type and extent of the immune response in the elderly. We evaluated the circulating concentration of selected chemokines: MCP-1, MIP-1alpha, IL-8, RANTES together with IL-6 and TNF-alpha in plasma obtained from a group of healthy old subjects, in order to highlight possible differences in the synthesis of these factors, assuming that both the cytokine and the chemokine networks are remodelled with ageing. The simultaneous evaluation was performed by a multiplex analysis system. In addition, since micronutrient deficiency may underlie an inflammatory response, the association between chemokine levels and a nutritional element such as zinc was also evaluated, since the immune system is the first system to be affected by changing zinc levels, due to its high cell turnover. A progressive age-related increase of plasma concentrations of all soluble factors was observed. The increment was particularly evident for IL-6, IL-8, MCP-1 and TNF-alpha in the over 85-year-old group in concomitance with increasing percentages of subjects with low circulating levels of zinc. In conclusion, the remodelling of chemokine profiles, skewed to Th2 response by both advanced ages and circulating levels of zinc, might reflect different states of activation and/or responsiveness of the human immune cell/mediator network, thus influencing the ability to develop rapid innate and long-lasting adaptive immune responses with advancing age.

Risk of incident dementia from any cause and Alzheimer's disease (AD) in relation to the IL-1beta-511 (C--T) and IL-6-174 (G--C) polymorphisms was investigated in an Italian elderly cohort (n=791) with 4 years of follow-up. Analyses were adjusted for socio-demographic confounders (age, gender, education), presence of the Apolipoprotein E-epsilon4 allele, and plasma total homocysteine (tHcy), a newly proposed AD risk factor. No significant association was found for the IL-1beta-511 and IL-6-174 polymorphisms with either dementia or AD. However, in the baseline dementia-free cohort considered as a whole, independently of other confounders, IL-1beta-511 T/T homozygotes had lower plasma tHcy than both heterozygotes (P=0.036) and wild-types (P=0.004). These data do not support the hypothesis that the IL-1-beta-511 and IL-6-174 polymorphisms affect dementia or AD risk. The relationship between the AD risk factor plasma tHcy and the IL-1beta-511 polymorphism was never reported before and might explain previous cross-sectional reports of an association between this polymorphism and AD.

Objective: To estimate age- and sex-specific incidence of dementia, Alzheimer disease (AD), and vascular dementia (VaD) in the Conselice Study of Brain Aging, an Italian prospective population-based study, and to assess whether poor education is a risk factor for dementia. Methods: In 1999 to 2000, the baseline study identified a dementia-free cohort of 937 subjects aged 65 years and older who were reexamined in 2003 to 2004 using a two-phase procedure. Results: Information was obtained for 91% of the subjects at risk; 115 incident cases of dementia were identified. Incidence rates per 1,000 person-years were 37.8 (95% CI = 30.0 to 47.7) for dementia, 23.8 (95% CI = 17.3 to 31.7) for AD, and 11.0 (95% CI = 7.2 to 16.9) for VaD. This translates into more than 400,000 new cases of dementia expected per year in Italy. Increasing age was an independent risk factor for both AD and VaD. Poor education was an independent risk factor for AD but not VaD. Sex did not affect dementia risk. Conclusions: In this Italian population-based cohort, incidence of dementia increased with age, and Alzheimer disease (AD) was the most frequent type of dementia. Poor education was associated with a higher risk of AD. Our incidence rates are higher than previously reported in Italy, and provide new estimates for projection of future burden of disease in Italy.

Hyperhomocysteinemia may be a risk factor for cognitive impairment. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in homocysteine (Hcy) metabolism. Both the MTHFR 677C--T and the 1298A--C polymorphisms are associated with mild hyperhomocysteinemia, particularly in conditions of low folate status. The prevalence of these MTHFR polymorphisms and their relationships with plasma total Hcy (tHcy), serum folate and cognitive function was evaluated in 194 elderly Italian individuals: 122 healthy controls (73.8 +/- 7.1 years of age), 24 cognitively- impaired- not-demented individuals (78.6 +/- 9.3 years), and 48 subjects with Alzheimer dementia (AD = 26), vascular dementia (VD =22; 85.5 +/- 7.0 years). Twenty-one percent of all subjects were homozygous for 677C--T and 7 % for 1298A--C polymorphism. No significant relationship was found betweenMTHFR polymorphisms and age, cognitive status and type of dementia. Plasma tHcy did not differ significantly by MTHFR genotypes, but, subjects of all genotypes with low serum folate (12 nmole/l) had higher plasma tHcy (p0.001), than subjects with high serum folate (= 12 nmole/l). The study suggests that 677C--T and 1298A--C polymorphisms are common in the Northern Italian population, but do not significantly affect plasma tHcy levels of elderly individuals, even under conditions of low folate status. The lack of association of age and cognitive function with MTHFR genotypes argues against a negative selection for these polymorphisms.

Recently, novel members of the TNF/TNF receptor superfamily, receptor activator of nuclear factor- kappa B ligand (RANKL), its receptor RANK, and the decoy receptor osteoprotegerin (OPG), have been identified as paracrine mediators of both the immune system and bone functions. The balance of RANK/RANK-L and OPG is critical for osteoclastogenesis modulation and physiological bone remodeling. In order to evaluate whether RANKL/OPG balance is modified by ageing, we analyzed, by imunoassay, systemic levels of OPG and sRANKL in healthy elderly subjects (age range from 70 to over 90 years) and in patients affected by two age-related diseases, osteoarthritis (OA) and polymyalgia rheumatica (PMR), characterized by bone metabolism alteration and involvement of the immune system. We demonstrated that (a) plasma concentrations of OPG increased significantly with age; (b) conversely, sRANKL significantly declined in the group of subjects aged between 81 and 90 years, being similar to the young controls in the other age groups; (c) in OA and PMR, circulating OPG did not differ from plasma levels found in age-matched control groups, while sRANKL concentration was significantly increased compared to controls. Hence, in ageing, the sRANKL/OPG system appears to be modified, with prominent changes in circulating OPG levels; in OA and PMR, the sRANKL/OPG balance alteration was shown to be mainly due to the increase of plasma sRANKL concentration.

Increased levels of plasma total homocysteine (tHcy) may play a role in both cardiovascular diseases (CVD) and old-age dementias via enhancement of vascular inflammation. However, the association between plasma tHcy and serum C-reactive protein (sCRP), taken as a marker of low-grade inflammation, is still uncertain. We investigated this association in normal aging, CVD, and dementia, and examined whether it was modified by the presence of two major comorbid diseases of older age: chronic obstructive pulmonary disease (CPOD) and peptic ulcer (PU). Six hundred-twenty-seven individuals agedor = 65 yr (74+/-7 yr) were selected for this study: 373 healthy controls; 160 patients with CVD but no evidence of comorbid diseases (CVD+/comorbidity-); 46 patients with CVD and concurrent CPOD and/or PU (CVD+/comorbidity+); and 48 patients with dementia. A positive association between plasma tHcy and serum CRP, independent of several confounders (socio-demographic status, known tHcy and sCRP determinants, inflammation markers, traditional vascular risk factors), was found for CVD+/comorbidity+ (p=0.001; not affected by dementia type) and dementia (p=0.001; not affected by dementia type), but not for CVD+/comorbidity- and controls. The results suggest that the association between plasma tHcy and sCRP is more an aspecific reflection of poor health than a specific correlate of vascular inflammation.

Background and Aims: The close association between coeliac disease and autoimmunity prompted us to perform an antibody screening for gluten-sensitive enteropathy in patients with autoimmune thyroid dysfunction. Methods: Sera from 220 patients with autoimmune thyroiditis, 50 euthyroid subjects with thyroid nodules and 250 blood donors were tested for IgA anti-tissue transglutaminase (anti-tTG) and antiendomysial antibodies (EmA). Results: IgA anti-tTG was positive in 7 patients with autoimmune thyroiditis, whereas IgA EmA was found only in 6 of them. Duodenal biopsy confirmed coeliac disease diagnosis disclosing marked and mild villous atrophy in 6 and 1 of them, respectively. All but 2 of the 7 coeliacs did not show any sign of malabsorption. All euthyroid controls were negative for IgA antibodies, whereas 1 blood donor, positive for both IgA anti-tTG and EmA, was found to be coeliac. The prevalence of coeliac disease in patients with autoimmune thyroiditis (3.2%) was significantly higher than that found in blood donors (0.4%) (p = 0.022, Fisher’s exact test). Conclusions: Antibody screening for coeliac disease should be included in the work-up of patients with autoimmune thyroiditis. Either IgA anti-tTG or EmA may be used, even though the former seems to be slightly more sensitive than the latter.

Age-related alterations of DNA repair could be involved in the accumulation of genetic damage with age. Few data suggest a possible alteration with age of the mismatch repair system, evidenced by the acquisition of microsatellite instability. We aimed to point out a possible implication of this repair system in the accumulation of genetic damage with age. Peripheral blood cell DNA from 226 participants, 110 young (25-35 years), 58 old (85-97 years), and 58 centenarian was analyzed at five polymorphic microsatellite loci (CD4, p53, VWA31, TPOX, and FES/FPS) to point out age-related instabilities or modifications in allele frequencies. FES/ FPS microsatellite was the most instable, showing both the appearance of trizygosis in DNA from old participants and differences in allele patterns among age groups, thus indicating an association between increased microsatellite instability and aging, one of the possible causes of which being an impairment of mismatch repair system capacity with age.