Antonio Capurso

Vascular risk factors, incidence of MCI, and rates of progression to dementia.

Objective: To estimate prevalence, incidence, and rate of progression of mild cognitive impairment (MCI) to dementia and correlated vascular risk factors with incident MCI and its progression to dementia. Methods: The authors evaluated 2,963 individuals from the population-based sample of 5,632 subjects 65 to 84 years old, at the first (1992 to 1993) and second survey (1995 to 1996) of the Italian Longitudinal Study on Aging (ILSA), with a 3.5-year follow-up. Dementia, Alzheimer disease (AD), vascular dementia (VaD), other types of dementia, and MCI were classified using current clinical criteria. Results: Among the 2,963 participants, 139 MCI patients were diagnosed at the first ILSA survey. During the 3.5-year follow-up, 113 new events of MCI were diagnosed with an estimated incidence rate of 21.5 per 1,000 person-years. We found a progression rate to dementia (all causes) of 3.8/100 person-years. Specific progression rates for AD, VaD, and other types of dementia were 2.3, 1.3, and 0.3/100 person-years. Furthermore, age was a risk factor for incident MCI (RR: 5.93, 95% CI: 3.17 to 11.10), while education was protective (RR: 0.06, 95% CI: 0.03 to 0.10), and serum total cholesterol evidenced a borderline nonsignificant trend for a protective effect. There was a nonsignificant trend for stroke as a risk factor of progression of MCI to dementia. Conclusions: In this population, among those who progressed to dementia, 60% progressed to AD and 33% to VaD. Vascular risk factors influence incident mild cognitive impairment and the rate of progression to dementia.

Late-life depression, mild cognitive impairment, and dementia: possible continuum?

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 role of diet in cognitive decline.

Summary. Recent findings suggest a possible role of diet in age-related cognitive decline, and cognitive impairment of both degenerative (Alzheimers disease, AD) or vascular origin. In particular, in an older population of Southern Italy with a typical Mediterranean diet, high monounsaturated fatty acids energy intake appeared to be associated with a high protection against cognitive decline. In addition, dietary fat and energy in older people seem to be risk factors, while fish consumption and cereals are found to reduce the prevalence of AD in the European and North American countries. Moreover, foods with large amounts of aluminium-containing additives or aluminium from drinking water may affect the risk of developing AD. Vitamin deficiencies, especially vitamin B6, B12 and folates, and antioxidant deficiencies (vitamins E and C) could also influence the memory capabilities and have an effect on cognitive decline. Dietary anti-oxidants and supplements and specific macronutrients of the diet may act synergistically with other protective factors opening new possibilities of intervention for cognitive decline.

Dietary intake of unsaturated fatty acids and age-related cognitive decline: A 8.5-year follow-up of the Italian Longitudinal Study on Aging

There is evidence from a population-based study of an inverse relationship between monounsaturated fatty acids (MUFA) energy intake and age-related cognitive decline (ARCD), while high polyunsaturated fatty acids (PUFA) intake was positively associated with cognitive impairment in elderly subjects. We investigated the possible role of MUFA and PUFA on age-related cognitive changes. A population-based, prospective study was carried out on 278, 186, and 95 nondemented elderly subjects (65-84 years) evaluated for global cognitive functions (Mini-Mental State Examination, MMSE) at the first (1992-1993), second (1995-1996), and third survey (2000-2001), respectively, from the randomized cohort of Casamassima, Bari, Italy (n=704), one of the eight centers of the Italian Longitudinal Study on Aging (ILSA). MUFA and PUFA intakes were assessed at baseline with a semi-quantitative food frequency questionnaire. High MUFA and PUFA energy intakes and total energy intake were significantly associated with a better cognitive performance in a 8.5-year follow-up. In this prospective population-based study on older nondemented subjects with a typical Mediterranean diet, high MUFA and PUFA intakes appeared to be protective against ARCD.

Mediterranean diet and cognitive decline

OBJECTIVE To investigate the possible role of diet in age-related cognitive decline (ARCD) and cognitive impairment of both degenerative (Alzheimers disease, AD) and vascular (vascular dementia, VaD) origin. DESIGN Literature review. RESULTS In an elderly population of southern Italy with a typical Mediterranean diet, high energy intake of monounsaturated fatty acids (MUFA) appeared to be associated with a high level of protection against ARCD. In addition, dietary fat and energy in the elderly seem to be risk factors, while fish consumption and cereals are found to reduce the prevalence of AD in European and North American countries. Finally, the relative risk of dementia (AD and VaD) was lower in the subjects of a French cohort who drank three or four glasses of red wine each day compared with total abstainers. CONCLUSION Essential components of the Mediterranean diet--MUFA, cereals and wine--seem to be protective against cognitive decline. As such, dietary antioxidants and supplements, specific macronutrients of the Mediterranean diet, oestrogens and anti-inflammatory drugs may act synergistically with other protective factors, opening up new therapeutic interventions for cognitive decline.

From excess adiposity to insulin resistance: The role of free fatty acids

With a positive caloric balance, adipocytes undergo excessive hypertrophy, which causes adipocyte dysfunction, as well as adipose tissue endocrine and immune responses. A preferential site of fat accumulation is the abdominal-perivisceral region, due to peculiar factors of the adipose tissue in such sites, namely an excess of glucocorticoid activity, which promotes the accumulation of fat; and the greater metabolic activity and sensitivity to lipolysis, due to increased number and activity of β3-adrenoceptors and, partly, to reduced activity of α2-adrenoceptors. As a consequence, more free fatty acids (FFA) are released into the portal system. Hypertrophic adipocytes begin to secrete low levels of TNF-α, which stimulate preadipocytes and endothelial cells to produce MCP-1, in turn responsible for attracting macrophages to the adipose tissue, thus developing a state of chronic low-grade inflammation which is causally linked to insulin resistance. Excess of circulating FFA, TNF-α and other factors induces insulin resistance. FFA cause insulin resistance by inhibiting insulin signaling through the activation of serin-kinases, i.e. protein kinase C-Θ, and the kinases JNK and IKK, which promote a mechanism of serine phosphorylation of Insulin Receptor Substrates (IRS), leading to interruption of the downstream insulin receptor (IR) signaling. TNF-α, secreted by hypertrophic adipocytes and adipose tissue macrophages, also inhibits IR signaling by a double mechanism of serine-phosphorylation and tyrosine-dephosphorylation of IRS-1, causing inactivation and degradation of IRS-1 and a consequent stop of IR signaling. Such mechanisms explain the transition from excess adiposity to insulin resistance, key to the further development of type 2 diabetes.

High monounsaturated fatty acids intake protects against age-related cognitive decline

Objective: To study the relationships between dietary macronutrient intakes and age-related changes in cognitive functions. Methods: We investigated these associations in the prevalence survey (1992 through 1993) of the Italian Longitudinal Study on Aging (ILSA). The population-based sample of 5,632 subjects of the ILSA, age 65 to 84 years, was identified from the electoral rolls of eight Italian municipalities. In this study, standardized test batteries assessing global cognitive functions (Mini-Mental State Examination [MMSE]), selective attention (Digit Cancellation Test [DCT]), and episodic memory (Babcock Story Recall Test), and a semi-quantitative food frequency questionnaire evaluating macronutrient energy intakes, were performed on 278 nondemented elderly subjects from the randomized cohort of Casamassima, Bari (n = 704). Results: There was an inverse relationship between monounsaturated fatty acids (MUFAs) energy intake and cognitive decline (MMSE < 24). The effect of education on the odds of having a MMSE score <24 decreased exponentially with the increase of MUFA intakes (over 2,400 kJ; odds ratio, 0.69). Moreover, a significant inverse association was observed between MUFA intakes and DCT score (odds ratio, 0.99). No association was found between nutritional variables and episodic memory. Conclusions: In an elderly population of Southern Italy with a typical Mediterranean diet, high MUFA intakes appeared to be protective against age-related cognitive decline. Prospective clinical trials are needed to evaluate the impact of specific dietary macronutrient intakes on the age-related changes of cognitive functions.

Lipid metabolism in cognitive decline and dementia

This review will focus on the current knowledge on circulating serum and plasma risk factors of cognitive decline of degenerative (Alzheimers disease, AD) or vascular origin (vascular dementia, VaD) linked to cholesterol homeostasis and lipoprotein disturbances, i.e. total cholesterol (TC), 24S-hydroxy-cholesterol, lipoprotein(a) (Lp(a)), or apolipoprotein E (APOE). These measures linked to lipoprotein metabolism appear to be altered in AD, VaD, or predementia syndrome relative to controls, but with contrasting results. At present, several studies have demonstrated the dependence of APOE serum levels upon the APOE genotype, nonetheless serum APOE levels seems not to be a credible risk factor or a biochemical marker for AD instead of APOE genotyping. In fact, there was no consistent association of serum or plasma apoE protein levels with the disease when controlled for APOE genotype. In addition, there are some evidence that higher Lp(a) levels could be linked with AD, although there are studies suggesting an increased presence of low molecular weight apo(a) in AD, VaD, and frontotemporal dementia, that are associated with elevated Lp(a) levels. In fact, the apo(a) gene is highly polymorphic in length due to variation in the numbers of a sequence encoding the apo(a) kringle 4 domain, and plasma levels of Lp(a) are inversely correlated with apo(a) size. Furthermore, although serum/plasma levels of TC and 24S-hydroxycholesterol are not credible diagnostic markers for AD and cognitive decline, the current evidence suggests that they may be modifiable risk/protective factors. The prevailing wisdom is that high TC is a risk factor for dementia. However, the relationship between TC and dementia may vary considerably depending on when cholesterol is measured over the life course or, alternatively, in relation to the underlying course of the disease. Several observational studies have suggested that statins, which are effective in lowering cholesterol, may reduce the risk of dementia, but the results of these reports are inconclusive. Thus, more studies with long-term follow-up and serial assessments of TC are needed to further clarify the causal relationship between cholesterol and dementia.

CIND and MCI in the Italian elderly: Frequency, vascular risk factors, progression to dementia

Using data from the Italian Longitudinal Study on Aging (ILSA), Di Carlo et al. reported a higher (16.1%) prevalence of mild cognitive impairment (MCI) than we reported in this same elderly population (3.2%).1 An explanation for this difference may be the more liberal criterion for MCI (subjects not scoring >1 SD below the mean of an age- and education-adjusted mean on the Mini-Mental State Examination [MMSE]) than used by studies using more conventional criteria.2 Using more conventional criteria (subjects not scoring >1.5 SDs below mean age- and education-adjusted on the MMSE and scoring >10th percentile below age- and education-adjusted on Babcock Story Recall Test [assessing episodic memory]) in exactly the same cohort, we found a prevalence rate of 3.2% for MCI.3 This diagnosis did not exclude subjects with mild impairment on activities of daily living and instrumental activities of daily living and individuals affected by numerous comorbidities not influencing global cognitive functions. Therefore, they may be well represented by aMCI.3 Prevalence estimates of amnestic variants of MCI in other worldwide population-based studies are consistent with those reported in our study: 3% in France (Eugeria Longitudinal Study of Cognitive Aging); 3.1% in Germany (Leipzig Longitudinal Study of the Aged); 3.02% in Canada (Canadian Study of Health and Aging); and 3.2% in the United States (MoVIES study).2 Two exceptions were 5% reported in an urban community in northern Manhattan,4 closer to the MCI prevalence rate reported in our study rather than those estimated in the study …

Dietary fatty acids intake: possible role in cognitive decline and dementia

There is a recent increase in the level of interest in the possible role of dietary fatty acids in age-related cognitive decline, and cognitive impairment of both degenerative (Alzheimers disease, AD) or vascular origin. At present, several studies suggested that an increase of saturated fatty acids (SFA) could have negative effects on cognitive functions. Furthermore, a clear reduction of risk of cognitive decline has been found in a population sample with a high intake of polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). These findings were confirmed by studies in which high intakes of n-6 PUFA, n-3 PUFA, MUFA, and weekly fish consumption, providing large amount of n-3 PUFA, appear to be protective against the risk of AD. In our elderly population from Southern Italy, elevated unsaturated fatty acids intake (MUFA and PUFA), high levels of antioxidant compounds, and very low SFA intake could act synergistically in improving cognitive performance. Epidemiological studies on the association between diet and cognitive decline suggested a possible role of fatty acids intake in maintaining adequate cognitive functioning and possibly in preventing or delaying the onset of dementia, both of degenerative or vascular origin. Appropriate dietary measures or supplementation with specific micro- and macronutrients might open new ways for the prevention and management of cognitive decline and dementia.