Mabel Martelli

Homocysteine and folate as risk factors for dementia and Alzheimer disease

BACKGROUND In 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. OBJECTIVE We investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population. DESIGN A 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. RESULTS Over 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. CONCLUSIONS Elevated plasma tHcy concentrations and low serum folate concentrations are independent predictors of the development of dementia and AD.

Conversion of Mild Cognitive Impairment to Dementia: Predictive Role of Mild Cognitive Impairment Subtypes and Vascular Risk Factors

Mild cognitive impairment (MCI) is regarded as a precursor to dementia, but not all patients with MCI develop dementia. We followed up 165 elderly outpatients with MCI for a mean of 3 years. The aims were (1) to investigate the risk of conversion to dementia for different MCI subtypes diagnosed according to standardized criteria (amnestic; impairment of memory plus other cognitive domains; nonamnestic); (2) to assess whether the risk of conversion was affected by several established and emerging vascular risk factors. Forty-eight subjects (29%) converted to dementia, and the risk of conversion was doubled for amnestic MCI with respect to the other subtypes. Independently of MCI subtype, risk of conversion was associated with atrial fibrillation and low serum folate levels. Our results show that current diagnostic criteria for MCI define heterogeneous populations, but some potentially treatable vascular risk factors may be of help in predicting conversion to dementia.

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.

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.

Interleukin-1β and interleukin-6 gene polymorphisms as risk factors for AD: A prospective study

Risk of incident dementia from any cause and Alzheimers 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.

Plasma homocysteine and inflammation in elderly patients with cardiovascular disease and dementia

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 aged > or = 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.

Peripheral blood markers of inflammation and functional impairment in elderly community-dwellers

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 (P < 0.05). When considering the sum of positive markers, having more than one marker was also inversely associated with all functional measures (P < 0.05), 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 (P < 0.01 for all measures) than increased CRP alone (P > 0.05), or other positive markers alone or in combination (P < 0.05). 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.