Chronic-Relapsing cutaneous leukocytoclastic vasculitis in a young patient with reduced EBV-specific T cell response using enzyme-linked immunospot (ELISPOT) assay successfully treated with Valaciclovir.

Among different pathogens, opportunistic viral infection caused by EBV is particularly relevant. This gammaherpesvirus, belonging to the Herpesviridae family, may complicate the disease course in different clinical settings by inducing pathological EBV pictures in patients with a defective immunologic response. Our report evaluated EBV-specific T cell responses by IFN- γ ELISPOT assay, which revealed defective EBV specific immunological response.

Leukocytoclastic Vasculitis Associated with HHV6-A/ciHHV6-A and HHV6-B Coinfection in an Immunocompetent Woman.

BACKGROUND AND OBJECTIVE: Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis that can be limited to the skin but may also affect other organs. Often, its cause is unknown. LCV has previously been reported to occur with the reactivation of human herpesvirus 6 (HHV-6). Here, we report a second instance of HHV-6 reactivation in a 43-year-old woman with idiopathic cutaneous LCV. CASE DESCRIPTION: In this case, the patient was immunocompetent, and testing revealed that she had inherited chromosomally integrated human herpesvirus 6 variant A (iciHHV6-A) with a parallel skin infection of HHV-6B. The integrated ciHHV-6A strain was found to be transcriptionally active in the blood, while HHV-6B late antigen was detected in a skin biopsy. The patient's rash was not accompanied by fever nor systemic symptoms and resolved over four weeks without any therapeutic intervention. CONCLUSION: In light of the transcriptional activity documented in our case, further examination of a possible role for HHV-6 in the etiology of LCV is warranted.

Metabolic syndrome, mild cognitive impairment, and progression to dementia. The Italian Longitudinal Study on Aging.

We investigated the relationship of metabolic syndrome (MetS) and its individual components with incidence of mild cognitive impairment (MCI) and its progression to dementia in a large longitudinal Italian population-based sample with a 3.5-year follow-up. A total of 2097 participants from a sample of 5632 65-84-year-old subjects from the Italian Longitudinal Study on Aging were evaluated. MetS was defined according to the Third Adults Treatment Panel of the National Cholesterol Education Program criteria. MCI, dementia, Alzheimer's disease (AD), and vascular dementia (VaD) were classified using current published criteria. Among MCI patients those with MetS (N=49) had a higher risk of progression to dementia (HR, 4.40; 95% CI, 1.30-14.82) compared with those without MetS (N=72). After a multivariate adjustment, the risk in MCI patients with MetS approximately doubled (multivariate adjusted HR, 7.80, 95% CI 1.29-47.20) compared with those MCI without MetS. Finally, among non-cognitively impaired individuals there were no significant differences in risks of developing MCI in those who were affected by MetS (N=608) in comparison with those without MetS (N=837), as well as excluding those individuals with undernutrition or low inflammatory status with or without undernutrition. In our population, among MCI patients the presence of MetS independently predicted an increased risk of progression to dementia over 3.5 years of follow-up.

Metabolic syndrome and the risk of vascular dementia: the Italian Longitudinal Study on Ageing.

OBJECTIVE: The authors investigated the relationship of metabolic syndrome (MetS) and its individual components with incident dementia in a prospective population-based study with a 3.5-year follow-up. METHODS: A total of 2097 participants from a sample of 5632 subjects (65-84 years old) from the Italian Longitudinal Study on Ageing were evaluated. MetS was defined according to the Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Dementia, Alzheimer disease (AD) and vascular dementia (VaD) were classified using current published criteria. RESULTS: MetS subjects (N=918) compared with those without MetS (N=1179) had an increased risk for VaD (1.63% vs 0.85%, adjusted hazard ratio (HR) 3.71, 95% CI 1.40 to 9.83). After excluding 338 subjects with baseline undernutrition, MetS subjects compared with those without MetS had an elevated risk of VaD (adjusted HR, 3.82; 95% CI 1.32 to 11.06). Moreover, those with MetS and high inflammation had a still further higher risk of VaD (multivariate adjusted HR, 9.55; 95% CI 1.17 to 78.17) compared with those without MetS and high inflammation. On the other hand, those with MetS and low inflammation compared with those without MetS and low inflammation did not exhibit a significant increased risk of VaD (adjusted HR, 3.31, 95% CI 0.91 to 12.14). Finally, a synergistic MetS effect versus its individual component effects was verified on the risk of VaD. CONCLUSION: In our population, MetS subjects had an elevated risk of VaD that increased after excluding patients with baseline undernutrition and selecting MetS subjects with high inflammation.

Interleukin 6-174 G/C promoter and variable number of tandem repeats (VNTR) gene polymorphisms in sporadic Alzheimer's disease.

BACKGROUND: Previous studies examining the association between the interleukin 6 (IL-6)-174 C/G polymorphism and Alzheimer's disease (AD) have yielded conflicting results. Furthermore, the C allele of the IL-6 variable number of tandem repeats (VNTR) polymorphism was associated with a delayed onset and a decreased risk of AD. METHODS: A total sample of 149 AD patients, and 298 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotyped for the apolipoprotein E (APOE) polymorphism, the VNTR polymorphism in the 3' flanking region, and the -174G/C single-nucleotide polymorphism (SNP) in the promoter region of IL-6 gene on chromosome 7. Furthermore, we performed a haplotype analysis on these two polymorphisms on IL-6 locus. RESULTS: IL-6 VNTR and -174G/C allele and genotype frequencies were similar between AD patients and controls, also after stratification for late-onset (> or =65 years) and early-onset (<65 years) or APOE epsilon4 status. Furthermore, there was no evidence of linkage disequilibrium between the VNTR and -174G/C polymorphisms, not supporting a previous reported additive effect of both IL-6 polymorphisms on AD risk. CONCLUSIONS: Our findings did not support a role of IL-6-174 G/C and IL-6 VNTR polymorphisms in the risk of sporadic AD in southern Italy, suggesting that these polymorphisms of IL-6 gene were at most weak genetic determinants of AD.

Alpha-2-macroglobulin gene, oxidized low-density lipoprotein receptor-1 locus, and sporadic Alzheimer's disease.

A total sample of 169 AD patients, and 264 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotypized for alpha-2-macroglobulin (A2M) Val1000/Ile single-nucleotide polymorphism (SNP) (rs669), apolipoprotein E (APOE), and SNPs (+1073 and +1071) in the oxidized low-density lipoprotein receptor-1 (OLR1) gene on chromosome 12. A2M allele and genotype frequencies were similar between AD patients and controls, also after stratification for late onset (>/=70 years) and early onset (<70 years) or APOE varepsilon4 status. However, there was evidence in support of LD between the OLR1+1071, the OLR1+1073, and the rs669 SNPs, with T-C-A haplotype being associated with significant increased risk of AD in both the whole sample and when we stratified according to early and late onset AD subjects, with the allelic association with AD predominantly from the OLR1+1073 SNP, further supporting the role of OLR1 as a candidate risk gene for sporadic AD.

Lifestyle-related factors in predementia and dementia syndromes.

Cognitive decline and dementia have a deep impact on the health and quality of life of older subjects and their caregivers. Since the therapeutic options currently available have demonstrated limited efficacy, the search for preventive strategies for cognitive decline and dementia are mandatory. A possible role of lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes and the cognitive decline of degenerative (Alzheimer's disease [AD]) or vascular origin. At present, cumulative evidence suggests that vascular risk factors may be important in the development of mild cognitive impairment (MCI), dementia and AD. Moderate alcohol drinking has been proposed as a protective factor against MCI and dementia in several longitudinal studies, but contrasting findings also exist. The Mediterranean diet could therefore be an interesting model with which to further study the association between dietary patterns and cognitive functioning, given the suggested role of many components of this diet (monounsaturated fatty acids, polyunsaturated fatty acids, cereals and red wine) in contrasting cognitive impairment and dementia. The association between low education and predementia and dementia syndromes is supported by the majority of studies, but very few studies have investigated whether this association may be attributed with lifestyle factors that covary with education. Studies in the literature seem to identify in physical exercise one promising strategy in decreasing cognitive decline, but some of the limitations of these studies do not allow us to draw definite conclusions. At present, in older subjects, healthy diets, antioxidant supplements, the prevention of nutritional deficiencies, and moderate physical activity could be considered the first line of defense against the development and progression of predementia and dementia syndromes. However, in most cases, these were only observational studies, and results are awaited from large multicenter randomized clinical trials in older persons that may clarify the possible synergy, for example, between moderate exercise, physical activity and healthy Mediterranean diet on cognition in the elderly.

Lipoproteins, vascular-related genetic factors, and human longevity.

The relationships among lipoprotein metabolism, genetic vascular factors, vascular disease, and Alzheimer's disease suggest that the examination of centenarian populations in relation to certain genes or lipoprotein metabolism provide insights into human longevity. The findings on the higher frequency of the apolipoprotein E epsilon4 allele in middle-aged subjects than in centenarians were substantially confirmed. On the contrary, recent findings did not confirm previous data on increased prevalence of the high-risk angiotensin I converting enzyme D allele in French centenarians. The variability in the strength of association between angiotensin I converting enzyme polymorphism and longevity could be related to regional differences in angiotensin I converting enzyme D allele frequency in Europe recently showed, as also recently reported for apolipoprotein Eepsilon2 and epsilon4 allele in centenarians. Indeed some studies of lipoprotein profiles in centenarians have also had contradictory outcomes, with evidence of lower serum levels of high-density lipoprotein cholesterol, with higher high-density lipoprotein 2 cholesterol subfraction, larger high-density lipoprotein and low-density lipoprotein particle sizes, and higher lipoprotein(a) concentration in centenarians, which is apparently disadvantageous for human longevity. Elevated lipoprotein(a) serum levels, increasing the risk for cerebrovascular disease, may play a role in determining clinical Alzheimer's disease, but lipoprotein(a) elevation in centenarians, in the absence of other coronary artery disease risk factors, appears as a positive survival factor. In different populations, there are significant trends in the reduction of serum apolipoprotein E levels from apolipoprotein E epsilon2- to epsilon4-carriers and significant differences in serum apolipoprotein E levels with respect to age in epsilon4-carriers but only after adjustment for high-density lipoprotein cholesterol. While further studies are needed to confirm the possible role of apolipoprotein E concentration as putative longevity factor this paper provides an overview of many of the investigated vascular factors with respect to longevity.

[Predementia syndromes and mild cognitive impairment: diagnosis and progression to dementia]. / Sindromi pre-demenziali e deficit cognitivo lieve: diagnosi e progressione verso la demenza.

Different diagnostic criteria and terms have been proposed to describe clinical predementia syndromes in the elderly, although the epidemiology of these syndromes has not been thoroughly investigated. Particular interest in Mild Cognitive Impairment (MCI) arises from the fact that MCI is thought to be a prodromal phase and therefore highly predictive of subsequent Alzheimer's disease (AD). Several studies have suggested that most of the patients who met the MCI criteria will progress to AD, but rates of conversion to AD and dementia vary widely among studies, partly because of the characteristics of the population studied and the length of follow-up. Furthermore, recent findings suggest that in population-based studies the MCI classification is unstable, in contrast with clinic-based studies where progression is more uniform.

[Depression in old age: a diagnostic and therapeutic challenge]. / Depressione dell'anziano: una sfida diagnostica e terapeutica.

In old age, depression mainly affects those with chronic medical illness, severe disability or mental decline. Depression in elderly worsens the outcomes of many medical illness and increases mortality. Age-related processes, including arteriosclerosis, inflammatory and degenerative diseases, may compromise the integrity of prefrontostriatal pathways and amygdala leading to increased vulnerability to depression. Environmental factors, such as impoverishment, isolation, relocation, caregiving and bereavement, contribute to further increase susceptibility to depression or triggering depression in already vulnerable elderly people. Suitable treatment of depression in elderly reduces the symptoms, prevents suicidal ideation, improves cognitive and functional status and helps patients to develop the skills needed to cope with their disability or psychosocial adversity. Prevention of depression in given pathological conditions may greatly improve the outcomes, mostly the recovery of function and quality of life, as well as the mortality risk. Therefore, it should be considered the opportunity of a depression prophylaxis, particularly in those circumstances in which the risk of depression is noteworthy increased, such as stroke, cancer, institutionalization, etc.

Macronutrients, aluminium from drinking water and foods, and other metals in cognitive decline and dementia.

A possible role of the macronutrients and the basic elements of carbohydrates (glucose administration or depletion), proteins (amino acids such as tryptophan and tyrosine), and fat (unsaturated fatty acids) was recently proposed for age-related changes of cognitive function, and the cognitive decline of degenerative (AD) or vascular origin. The availability and utilization of glucose has been implicated in cognitive function not only as a result of nutritional and systemic metabolic conditions, but also, although speculatively, as a crucial phase of the mechanism of action of molecules used as cognitive-enhancers. Furthermore, many lines of evidence have focused on the importance of oxidative stress mechanisms and free radical damage in AD pathogenesis. In addition, epidemiological studies have recently reported an association between alcohol and the incidence of AD and predementia syndromes. Foods with large amounts of aluminium-containing additives or aluminium from drinking water may affect the risk of developing AD, aluminium more likely acting as a cofactor somewhere in the cascade of events leading to the demented brain. A role for other metals in dementia have been speculated, given the encouraging results reported from studies on peripheral zinc concentrations, zinc supplementation, serum copper, either bound with ceruloplasmin or not, and iron metabolism in AD. Nonetheless, more data are needed to support a possible role of these metals in dementing diseases. Healthy diets, antioxidant supplements, and the prevention of nutritional deficiencies or exposure to foods and water with high content of metals could be considered the first line of defence against the development and progression of cognitive decline.

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 (Alzheimer's 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.

Cognitive frailty: Predementia syndrome and vascular risk factors.

With increasing emphasis on early diagnosis of Alzheimer disease (AD), clinical research has focused on the identification of risk factors that may be modified at a preclinical and early clinical stage of dementing disorders. Prevalence and incidence of different predementia syndromes vary as a result of different diagnostic criteria, as well as different sampling and assessment procedures. Particular interest in mild cognitive impairment (MCI) arises from the fact that MCI is thought to be a prodromal phase and therefore highly predictive of subsequent AD. Furthermore, many of the risk factors for cerebrovascular disease (CVD) and vascular dementia (VaD), including serum total cholesterol, hypertension, atherosclerosis, and apolipoprotein E (APOE) genotype have also been shown to increase the risk of AD. Both vascular factors and APOE epsilon4 allele have been associated with higher risk of AD. Some recent studies suggested further that CVD or vascular factors increased the risk of conversion of MCI to dementia. This review will focus on the possible role of vascular risk factors in modulating the risk of age-related cognitive decline, and the progression of predementia syndrome such as MCI to dementia.

Circulating biomarkers of cognitive decline and dementia.

Plasma and serum biochemical markers proposed for cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin and predementia syndromes (mild cognitive impairment and other related entities) are based on pathophysiologic processes such as lipoprotein metabolism (total cholesterol, apolipoprotein E, 24S-hydroxy-cholesterol), and vascular disease (homocysteine, lipoprotein(a)); SP formation (amyloid beta(Abeta)-protein, Abeta autoantibodies, platelet APP isoforms), oxidative stress (isoprostanes, vitamin E), and inflammation (cytokines). This review will focus on the current knowledge on circulating serum and plasma biomarkers of cognitive decline and dementia that are linked to cholesterol homeostasis and lipoprotein abnormalities, senile plaque formation and amyloid precursor protein (APP) metabolism, oxidative stress, and inflammatory reactions. Special emphasis will, however, be placed on biomarkers related to lipoprotein metabolism and vascular disease. Analytically, most plasma and serum proteins or metabolites lack reproducibility, sensitivity, or specificity for the diagnosis, risk and progression assessment, or therapeutic monitoring of AD and other dementing disorders. Measures linked to lipoprotein metabolism and vascular disease, APP metabolism, oxidative stress, or inflammation appear altered in AD relative to controls, but lack sufficient discriminatory power. Measures combining several biomarkers or incorporating a range of proteins in plasma and small molecule metabolites are promising approaches for the development of plasma or serum-based diagnostic tests for AD and other dementing disorders, as well as for predementia syndromes.

Current knowledge of chromosome 12 susceptibility genes for late-onset Alzheimer's disease.

In the last decade, it has become more apparent the important role genes play in the development of late-onset Alzheimer's disease (AD). Great efforts, involving human genome scans and candidate gene studies, have been given towards identifying susceptibility genes for AD. A number of regions on different chromosomes have been reported to demonstrate linkage for AD. Of these, findings on chromosome 12 are some of the most compelling. Worldwide genetic association studies pre-dating and subsequent to recent linkage studies have identified and focused upon a number of genes that map to the areas of reported linkage on chromosome 12, however, analyses of those genes studied to date, on the whole, remain inconclusive and ambiguous. This paper reviews studies that have provided evidence of linkage for AD on chromosome 12 and in turn discusses the work conducted to date on candidate genes that have been identified and map to the chromosome 12 regions of interest.

Candidate genes for late-onset Alzheimer's disease: focus on chromosome 12.

In recent years, there was an increasing interest on candidate genes may play an important role in the development of Alzheimer's disease (AD). Several genome wide screens have undertaken so far or expanded recently, and suggested a number of genomic areas that may contain novel susceptibility genes for AD, in particular most compelling have been the findings on chromosome 12. Polymorphisms in different susceptibility genes on chromosome 12 (A2M, LRP1, CP2 and OLR1) are now being suggested as possible genetic markers for increased risk of developing AD. However, many of these studies are controversial and have shown conflicting results. Thus far, the search for the chromosome 12 Alzheimer's gene must continue and there are several other genes in this region that we are looking at. In this article, we focused on the current knowledge of the genetics of familial late-onset and sporadic AD linked to the chromosome 12, and the future search for other candidate genes.

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.

Current epidemiology of mild cognitive impairment and other predementia syndromes.

A variety of clinically-defined predementia syndromes, with differing diagnostic criteria and nomenclature, have been proposed to describe nondisabling symptomatic cognitive deficits arising in elderly persons. Incidence and prevalence of different predementia syndromes vary as a result of different diagnostic criteria, sampling, and assessment procedures. The incidence rates of all predementia syndromes increase with age and are higher in subjects with less education; but age, educational background, and gender are not consistently related to prevalence rates. There is particular interest in "Mild Cognitive Impairment (MCI)" because this predementia syndrome is thought to be a prodromal phase of Alzheimer disease (AD). Several studies have suggested that most patients who meet MCI criteria will progress to AD, but rates of conversion to AD and dementia vary widely among studies. Furthermore, MCI definition is less consistent in population-based studies than clinical studies, in which progression to AD is also more consistent. To clarify the sources of discrepant findings in the literature, this review summarizes existing epidemiological studies of the defined clinical predementia syndromes and their progression to dementia.