Paola Forti

Homocysteine and folate as risk factors for dementia and Alzheimer disease

BACKGROUNDnIn cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitive impairment and dementia. Incidence studies of this issue are few and have produced conflicting results.nnnOBJECTIVEnWe investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population.nnnDESIGNnA dementia-free cohort of 816 subjects (434 women and 382 men; mean age: 74 y) from an Italian population-based study constituted our study sample. The relation of baseline plasma tHcy to the risk of newly diagnosed dementia and AD on follow-up was examined. A proportional hazards regression model was used to adjust for age, sex, education, apolipoprotein E genotype, vascular risk factors, and serum concentrations of folate and vitamin B-12.nnnRESULTSnOver an average follow-up of 4 y, dementia developed in 112 subjects, including 70 who received a diagnosis of AD. In the subjects with hyperhomocysteinemia (plasma tHcy > 15 micromol/L), the hazard ratio for dementia was 2.08 (95% CI: 1.31, 3.30; P = 0.002). The corresponding hazard ratio for AD was 2.11 (95% CI: 1.19, 3.76; P = 0.011). Independently of hyperhomocysteinemia and other confounders, low folate concentrations (< or = 11.8 nmol/L) were also associated with an increased risk of both dementia (1.87; 95% CI: 1.21, 2.89; P = 0.005) and AD (1.98; 95% CI: 1.15, 3.40; P = 0.014), whereas the association was not significant for vitamin B-12.nnnCONCLUSIONSnElevated plasma tHcy concentrations and low serum folate concentrations are independent predictors of the development of dementia and AD.

Blood inflammatory markers and risk of dementia: The Conselice Study of Brain Aging.

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 Alzheimers 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.

Development of an easy prognostic score for frailty outcomes in the aged

BACKGROUNDnidentification of frailty is recommended in geriatric practice. However, there is a lack of frailty scores combining easy-to-collect predictors from multiple domains.nnnOBJECTIVEnto develop a frailty score including only self-reported information and easy-to-perform standardised measurements recommended in routine geriatric practice.nnnDESIGNnprospective population-based study.nnnSETTING/PARTICIPANTSnincluded 1,007 Italian subjects aged 65 and over.nnnMEASUREMENTSnseventeen 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].nnnMETHODSna 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.nnnRESULTSnnine 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.nnnCONCLUSIONSnnine easy-to-collect predictors may identify aged people at increased risk of adverse health outcomes associated with frailty.

Incidence and etiology of dementia in a large elderly Italian population

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.

Mild Cognitive Impairment: Epidemiology and Dementia Risk in an Elderly Italian Population

OBJECTIVES: To investigate prevalence and incidence of mild cognitive impairment (MCI) and its risk of progression to dementia in an elderly Italian population.

Metabolic Syndrome Prevalence and prediction of mortality in elderly individuals

OBJECTIVE—Little is known about the prevalence of the metabolic syndrome among elderly people in Italy, its association with all-cause mortality, and whether measurement of serum C-reactive protein (CRP) and interleukin (IL)-6 affects this association. RESEARCH DESIGN AND METHODS—The baseline prevalence of metabolic syndrome, diagnosed according to the National Cholesterol Education Program (NCEP) criteria, and all-cause mortality at 4 years were recorded in an Italian population-based cohort (981 subjects, 55% women, aged 65–97 years). A Cox model adjusted for sociodemographic, lifestyle, and medical variables was used to investigate 1) whether metabolic syndrome was a predictor of mortality and 2) how the association was affected by baseline high CRP (>3 mg/l) and IL-6 (>1.33 pg/ml). RESULTS—Overall, metabolic syndrome prevalence was 27.2% [95% CI 24.0–30.5] and higher in women (33.3% [28.7–38.0]) than in men (19.6% [15.5–24.2]). During follow-up, 137 deaths occurred. Using the no metabolic syndrome/no high IL-6 group as the reference, mortality was not associated with the metabolic syndrome alone (multivariable-adjusted hazard ratio 1.24 [0.60–2.59]), only weakly associated with high IL-6 alone (1.66 [1.04–2.63]), but strongly associated with the concurrent presence of metabolic syndrome and high IL-6 (3.26 [2.00–5.33]). High CRP was not a mortality predictor (0.83 [0.58–1.20]) nor did it affect the association of the other variables with mortality. CONCLUSIONS—Metabolic syndrome by NCEP criteria is highly prevalent in the Italian elderly population. It is not itself associated with mortality but may improve the usefulness of IL-6 as a mortality predictor in older age.

Prevalent Depressive Symptoms as a Risk Factor for Conversion to Mild Cognitive Impairment in an Elderly Italian Cohort

OBJECTIVEnTo 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.nnnDESIGNnProspective, population-based, longitudinal cohort study.nnnSETTINGnAdults >or=65 years resident in an Italian municipality.nnnPARTICIPANTSnBaseline 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.nnnMEASUREMENTSnMCI 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.nnnRESULTSnBaseline depressive symptoms (GDS >or=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%).nnnCONCLUSIONSnDepressive 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.

Screening for mild cognitive impairment in elderly ambulatory patients with cognitive complaints

Background and aims: Identification of patients with Mild Cognitive Impairment (MCI) is strongly recommended because of their increased risk of dementia. Two brief global cognitive instruments, the Mini Mental State Examination (MMSE) and the Clock Drawing Test (CDT), were examined as useful screening methods for MCI. Methods: The sensitivity and specificity of MMSE and CDT, scored using the Sunderland and Wolf-Klein methods, were evaluated in 113 elderly individuals with three different MCI subtypes: amnestic, multiple domain impairments, and single non-memory domain. Diagnoses were made on the basis of extensive clinical and neuropsychometric assessment. Results: Used alone, MMSE and CDT at standard cut-offs were highly specific (about 0.80) but rather insensitive (less than 0.50) to all MCI subtypes. By contrast, when used in combination, an abnormal result on either MMSE or CDT scored by the Sunderland method had a specificity of 0.69 [0.57–0.81] and a sensitivity of 0.75 [0.64–0.87] for multiple domain impairments MCI. Results were similar for MMSE in combination with CDT scored by the Wolf-Klein method (specificity 0.71 [0.59–0.83]; sensitivity 0.68 [0.56–0.80]). Conclusions: MMSE and CDT alone are not valid screening methods for MCI detection. In combination, they reach fair sensitivity and specificity for the multiple domain impairment MCI subtype. However, some theoretical concerns relating to this subtype, together with the uncertainty that still lingers about its prognostic value, caution against routine use of MMSE and CDT as MCI screening instruments.

The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study.

The only established genetic determinant of non-Mendelian forms of Alzheimers 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.

Multivariable network associated with cognitive decline and dementia

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.