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Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer’s disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.

Alzheimer’s disease (AD) is a complex chronic disease of the brain characterized by several neurodegenerative mechanisms and is responsible for most dementia cases in the elderly. Declining immunity during ageing is often associated with peripheral chronic inflammation, and chronic neuroinflammation is a constant component of AD brain pathology. In the Special Issue published in 2021 eight papers were collected regarding different aspects of neurodegeneration associated with AD. Five papers presented and discussed infectious agents involved in brain AD pathology and three discussed data regarding receptors regulation and possible treatment of the disease. Below I will discuss and further elaborate on topics related to infections, inflammation, and neurodegenerative pathways in AD and brain senescence. The topic presented here may contribute to early intervention protocols for preventing or slowing the progression of cognitive deterioration in the elderly.

Among environmental factors likely associated with Alzheimer&rsquo, s disease (AD), persistent virus infections, and age-related progressive decline of immune competence might play a pivotal role. However, AD antimicrobial brain immune responses are poorly investigated. The present study focused on genes involved in antimicrobial defenses, especially against virus infections, in the AD brain. In particular, mRNA levels of IRF7, MED23, IL28B, and IFN-&alpha, genes were analyzed in hippocampus and temporal cortex brain samples from AD and non-demented controls. All subjects were also genotyped for APOE &epsilon, IRF7, MED23, and IL28B gene polymorphisms. Most AD patients showed decreased mRNA levels of all investigated genes in the hippocampus and temporal cortex. However, a small group of AD patients showed increased hippocampal mRNA expression of MED23, IL28B, and IFN-&alpha, mRNA levels of MED23, IL28B, IFN-&alpha, from the hippocampus and those of MED23 from the temporal cortex were further decreased in APOE &epsilon, 4 allele AD carriers. Moreover, rs6598008 polymorphism of IRF7 was significantly associated with decreased hippocampal expression of IRF7, MED23, IL28B, and IFN-&alpha, These findings suggest that AD brains show impaired innate antimicrobial gene expression profiles, and individual genetic makeup, such as positivity for the APOE &epsilon, 4 and IRF7 A alleles, might affect brain immune efficiency.

Traumatic brain injury (TBI) is a mechanical insult to the brain caused by external forces and associated with inflammation and oxidative stress. The patients may show different profiles of neurological recovery and a combination of oxidative damage and inflammatory processes can affect their courses. It is known that an overexpression of cytokines can be seen in peripheral blood in the early hours/days after the injury, but little is known about the weeks and months encompassing the post-acute and chronic phases. In addition, no information is available about the antioxidant responses mediated by the major enzymes that regulate reactive oxygen species levels: superoxide dismutase, catalase, peroxidases, and GSH-related enzymes. This study investigates the 6-month trends of inflammatory markers and antioxidant responses in 22 severe TBI patients with prolonged disorders of consciousness, consecutively recruited in a dedicated neurorehabilitation facility. Patients with a high degree of neurological impairment often show an uncertain outcome. In addition, the profiles of plasma activities were related to the neurological recovery after 12 months. Venous peripheral blood samples were taken blindly as soon as clinical signs and laboratory markers confirmed the absence of infections, 3 and 6 months later. The clinical and neuropsychological assessment continued up to 12 months. Nineteen patients completed the follow-up. In the chronic phase, persistent high plasma levels of cytokines can interfere with cognitive functioning and higher post-acute levels of cytokines [interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL1b, IL6] are associated with poorer cognitive recoveries 12 months later. Moreover, higher IFN-γ, higher TNF-α, and lower glutathione peroxidase activity are associated with greater disability. The results add evidence of persistent inflammatory response, provide information about long-term imbalance of antioxidant activity, and suggest that the over-production of cytokines and the alteration of the redox homeostasis in the post-acute phase might adversely affect the neurological and functional recovery. Inflammatory and antioxidant activity markers might offer a feasible way to highlight some of the processes opposing recovery after a severe TBI.

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even thoug ...

BACKGROUND: Prostate cancer (PCa) displays a strong familiarity component and genetic factors; genes regulating inflammation may have a pivotal role in the disease. Epigenetic changes control chromosomal integrity, gene functions and ultimately carcinogenesis. The enzyme glycine-N-methyltransferase (GNMT) contributes to S-adenosylmethionine level regulation and, by affecting DNA methylation, influences gene expression. The genotype and allele distribution of single-nucleotide polymorphisms (SNPs) in the promoter regions of vascular endothelial growth factor (VEGF), interleukin (IL)-10, IL-1β, alpha-1-antichymotrypsin (ACT) and GNMT genes, the level of global DNA methylation and the influence of GNMT SNP upon DNA methylation in a PCa case-control study have been investigated. METHODS: SNPs of VEGF (rs699947), ACT (rs1884082), IL-1β (rs16944), IL-10 (rs1800896) and GNMT (rs9462856) genes were assessed by PCR or by real-time PCR methods. DNA methylation was assessed by an ELISA assay. RESULTS: Frequencies of the VEGF AA genotype, the IL-10 A allele and GNMT T allele were higher in PCa. The concomitant presence of the AA genotype of VEGF, the A allele of IL-10 and T allele of GNMT increased the risk of PCa. Total DNA methylation was decreased in PCa; control GNMT T carriers (T+) showed the highest level of DNA methylation. CONCLUSIONS: SNPs in VEGF, IL-10 and GNMT genes might have a synergistic role in the development of PCa. The GNMT T allele may influence PCa risk by affecting DNA methylation and prostate gene expression. Our observations might help implement the screening of unaffected subjects with an increased susceptibility to develop PCa.

Genome wide association investigations from large cohorts of patients with Alzheimer's disease (AD) and non demented controls (CTR) showed that a limited set of genes were associated (p > 10 -5) with the disease. A very recent study from our group showed that an additional limited group of SNP in selected genes were associated with AD. In this report we argue that the association of these genes with AD is suggestive of a pivotal role of environmental factors in the pathogenesis of the disease and one of these factors is virus infection. In other words, the genetic signature revealed by genome wide association (GWA) studies discloses a network of genes that might influence the ability of the central nervous system to cope with and fight against the invasion by virus of the herpes family. In fact, Nectin-2 (NC-2); apolipoprotein E (APOE); glycoprotein carcinoembryonic antigen related cell adhesion molecule-16 (CEACAM-16); B-cell lymphoma-3 (Bcl-3); translocase of outer mitochondrial membrane 40 homolog (T0MM-40); complement receptor-1 (CR-l); APOJ or clusterin and C-type lectin domain A family-16 member (CLEC-16A); Phosphatidyl inositol- binding clathrin assembly protein gene (PICALM); ATP-bonding cassette, sub family A, member 7 (ABCA7); membrane spanning A4 (MSA4); CD2 associated protein (CD2AP); cluster of differentiation 33 (CD33); and ephrin receptor A1 (EPHA1) result in a genetic signature that might affect individual brain susceptibility to infection by the herpes virus family during aging, leading to neuronal loss, inflammation, and amyloid deposition.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ĝ‰Currency sign 1 × 10 -5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10 -17; including ADGC data, meta P = 5.0 × 10 -21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10 -14; including ADGC data, meta P = 1.2 × 10 -16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10 -4; including ADGC data, meta P = 8.6 × 10 -9), CD33 (GERAD+, P = 2.2 × 10 -4; including ADGC data, meta P = 1.6 × 10 -9) and EPHA1 (GERAD+, P = 3.4 × 10 -4; including ADGC data, meta P = 6.0 × 10 -10). © 2011 Nature America, Inc. All rights reserved.

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.

Down's syndrome (DS) is the most frequent chromosomal aberration in men. Moreover IDS is considered an atheroma-free model. Plasma levels of interleukin-6 (IL-6), tumor necrosis factor-a high sensitivity (hsTNF-alpha), leptin and adiponectin from non-demented DS subjects of three different age cohorts (2-14, 20-50 and above 60 years) and healthy controls were measured. No clinical and sub-clinical inflammation was apparent in DS patients. Plasma levels of hsTNIF-alpha, IL-6 and leptin were higher in children than in adult and old DS subjects. instead, serum levels of adiponectin were increased in older IDS patients than in DS children and adults. High levels of circulating adiponectin might protect DS from clinical complications of atherosclerosis. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

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.

Eighteen non-institutionalized Down's syndrome (DS) children (mean age: 7.0 +/- 10/12 years) with a history of respiratory tract, auditory and skin infections, low plasma levels of a nonapeptide thymic hormone, i.e. Serum Thymic Factor (STF), high plasma levels of inactive zinc-unbound STF molecules, and reduced absolute number of circulating T-lymphocytes, were given an oral non-pharmacological supplementation of zinc sulphate (1 mg Zn++/kg body weight/day for 2 months; two cycles, 10 months apart) and monitored immunologically before and after each cycle. A dramatic increase of plasma STF level and concomitantly an almost complete disappearance of inactive STF molecules was observed after each cycle. The absolute number of circulating T-lymphocytes was significantly increased by zinc treatment. The marginal zinc deficiency was also corrected without any appreciable influence on copper plasma levels. A reduction of recurrent infections and an improvement in school attendance after zinc supplementation were recorded. These beneficial effects of zinc supplementation were also noted in those DS children who did not show an apparent zinc deficiency, as assessed by measuring zinc plasma level. The reduced number of circulating B lymphocytes and the impaired lymphocyte responsiveness to phytohaemagglutinin and concanavalin A were not restored. On the whole, these findings suggest that there exists a defect in the bio-availability and/or in the utilization of zinc in DS. This alteration, of unknown origin, can be underestimated on the simple basis of the zinc plasma level and can be corrected with moderate nutritional zinc supplementation.

We identified four genetic risk sets for acute myocardial infarction (AMI) from information on functional gene variants that favor inflammation or modulate cholesterol metabolism: IL6 -174 G/C, TNF -308 G/A, IL10 -1082 G/A, SERPINA3 -51 G/T, IFNG +874 T/A, HMGCR -911 C/A, and APOE ε2/3/4; 316 patients and 461 healthy subjects, all Italian. Putative risk alleles are shown underlined. The sets were identified using grade-of-membership analysis. Membership scores in the sets are automatically generated for individuals. The ''low intrinsic risk'' set had alleles that downregulate inflammation and cholesterol synthesis (IL6, TNF, ILl0, HMGCR). ''AMI across a broad age range'' carried multiple proinflammatory alleles (IL6, TNF, IL10, SERPINA3): All 72 persons like this set were affected yet had relatively low plasma cholesterol levels. ''A subset of AMI in middle age'' had numerous proinflammatory alleles (IL6, TNF, SERPINA3, IFNG, HMGCR). ''AMI after age 80'' had a reduced risk set (IL6, IL10, IFNG). A total of 95% of cases had ≥50% membership in the high intrinsic risk sets. We conclude that proinflammatory gene variants taken together strongly determine an individual''s risk for myocardial infarction. This information may better define the pathogenesis of myocardial infarction and identify individuals who might benefit from early interventions.

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.

Down syndrome (DS) might be considered a model for unsuccessful and early aging, possibly accelerated for those who carry the APOE4 allele associated with common age-related diseases, e.g., Alzheimer's disease and a poor prognosis after acute myocardial infarction, causing lower ApoE4 frequencies among the very old in general populations. We compared ApoE genotypic frequencies found for healthy adults (n = 211, age < 40; n = 79, ages 70-79; n = 71, ages > 90) to those found for DS patients (n = 106, mean age 9 years), all living in western Sicily. We found that the frequency of the ApoE23 genotype increased with age among the healthy adults (8.5%, 6.4%, 19.7%; p = 0.024) while ApoE34 frequency decreased (16.1%, 12.6%, 4.1%; p = 0.012). DS patients had APOE34 genotypic frequencies very similar to those found in septuagenarians (9%; p = 0.005). Analyzing results according to surviving rate of persons with DS, an age-related reduction of ApoE3/4 genotype frequency was found comparing =5 years old to >5 years old DS subjects. These results highlight DS as a model to understand the role of APOE4 allele in unsuccessful ageing considering that a number of proinflammatory supernumerary genes (Cu/Zn superoxide dismutase, Ets-2 transcription factors, Down syndrome critical region 1, stress-inducible factor, interferon-alpha receptor and the amyloid precursor protein) are located on chromosome 21 and are implied in the pathologic processes of DS.

A link between cholesterol and Alzheimer's disease (AD) had been suggested. Hydroxy-methylglutaryl-coenzyme A reductase (HMGCR) is the rate limiting enzyme in the synthesis of cholesterol. A single nucleotide polymorphism (SNP) in the promoter of this gene, never described in Italian AD population, was investigated in case-control studies. Genotype distribution and allele frequency in two groups of AD patients and non demented controls were investigated. A cohort of AD patients were also followed up for 2 years, cognitive performances recorded and a possible influence of this SNP on the disease progression was tested. The CC genotype of the HMGCR gene was associated with a reduced risk of AD. Conversely the A allele of this polymorphism was over represented in AD patients. The presence of the A allele was also associated with an accelerated cognitive deterioration in AD patients followed up for 2 years. However, transfection experiments showed that this polymorphism did not directly influence functional activity in luciferase reporter gene assays. This polymorphism of the HMGCR gene appears to be linked to both AD risk and disease progression. Present findings reinforce the notion that abnormal regulation of cholesterol metabolism is a key factor in the pathogenesis of the disease.

The aim of this work was to evaluate whether oral supplementation with zinc sulphate (ZnSO4) could restore thymic endocrine function in patients with Crohn's disease who showed decreased plasma concentrations of zinc and active thymulin, a zinc-dependent thymic hormone. Twenty-seven patients in clinical remission were randomly assigned to receive, for 3 months, one of the following treatments: 60 mg/day ZnSO4; 200 mg/day ZnSO4 or placebo. Plasma thymulin activity and zinc concentrations significantly increased only in patients treated with 200 mg/day ZnSO4. Lymphocyte subpopulations, within the range of normality before zinc supplementation, were unaffected by any of the administered treatments. In conclusion, low plasma concentrations of zinc and thymulin in Crohn's disease patients were restored by the administration of high doses of zinc.

Alzheimer's disease (AD) is a polygenic and multifactorial complex disease, whose etiopathology is still unclear, however several genetic factors have shown to increase the risk of developing the disease. Purine nucleotides and nucleosides play an important role in the brain. Besides their role in neurotransmission and neuromodulation, they are involved in trophic factor release, apoptosis, and inflammatory responses. These mediators may also have a pivotal role in the control of neurodegenerative processes associated with AD. In this report the distribution of the exonic G/A single nucleotide polymorphism (SNP) in purine nucleoside phosphorylase (PNP) gene, resulting in the amino acid substitution serine to glycine at position 51 (G51S), was investigated in a large population of AD patients (n = 321) and non-demented control (n = 208). The PNP polymorphism distribution was not different between patients and controls. The polymorphism distribution was also analyzed in AD patients stratified according to differential progressive rate of cognitive decline during a 2-year follow-up. An increased representation of the PNP AA genotype was observed in AD patients with fast cognitive deterioration in comparison with that from patients with slow deterioration rate. Our findings suggest that the G51S PNP polymorphism is associated with a faster rate of cognitive decline in AD patients, highlighting the important role of purine metabolism in the progression of this neurodegenerative disorder. Copyright © 2007 John Wiley & Sons, Ltd.

Background: Neurodegenerative disorders such Alzheimer's disease (AD) are often characterized by senile plaques and neurofibrillary tangle. In addition, reactive astrogliosis, microglia activation and a chronic inflammation are found in AD brain. Activated microglia has been reported to express a large number of beta chemokines including monocyte chemoattractant protein-1 (MCP-1). The potential role of MCP-1 in AD pathogenesis is supported by the over expression of MCP-1 associated with an increase of amyloid deposition in transgenic mice. MCP-1 protein may be regulated by a single nucleotide polymorphism (SNP) occurring at position -2518 of the MCP-1 gene promoter. In this paper we correlated the A-2518G MCP-1 SNP distribution in three different populations: AD, control and MCI (mild cognitive impairment) population to evaluate whether this SNP might be a risk factor for AD or for MCI-AD conversion. MCP-1 plasma levels were also measured and correlated to the cognitive impairment (CIND) and AD risk.Results: No differences in genotype distribution and allele frequencies of A-2518G MCP-1 SNP among AD patients, MCI subjects and controls were observed even after APOEe4 variation adjustment with logistic regression. However in MCI subjects, followed up for two years, this SNP appears to influence the progression of the disease; being the G allele slightly more frequent in MCI patients that developed AD. MCP-1 plasma levels were different among CIND (cognitive impairment but no dementia), AD and controls. The MCP-1 A-2518G promoter polymorphism did not affect MCP-1 plasma levels within the three populations.Conclusions: MCP-1 G allele did not affect the risk of AD, but slightly influenced MCI conversion to AD and MCP-1 plasma levels were increased in subjects with preclinical AD.

The identification of Alzheimer's disease (AD) biomarkers is crucial to support drug discovery. Within putative biomarkers, peripheral Bdnf levels correlate with cognitive decline and AD, although conflicting findings are reported. Sirtuin 1 (Sirt1) serum levels are lower in AD patients and Presenilin 1 (Psen1) is expressed by blood cells. DNA methylation is altered in AD patients, suggesting that epigenetic mechanisms play a role in AD pathophysiology. The objective of this study was to investigate promoter methylation levels of potential biomarkers in AD cases and controls. Peripheral blood DNA methylation levels were analysed by methylation-specific primer real-time PCR. Bdnf promoter methylation levels did not differ between AD patients and controls. Similarly, Sirt1 promoter revealed minimal levels of methylation which did not display significant differences between groups. No significant difference was revealed between AD patients and controls also in Psen1 methylation, showing a large variability of values among subjects. Although peripheral Bdnf expression is associated with differential promoter methylation in psychiatric and neurological disorders, our results suggest that different mechanisms take place in AD. The finding that the control of Sirt1 protein levels in blood is not exerted through the repression of mRNA expression by promoter hypermethylation is in agreement with previous data. In contrast, other studies reported that Psen1 methylation may be increased or decreased in AD patients, suggesting that additional studies are required. In conclusion, this study shows that peripheral levels of the potential AD biomarker proteins Bdnf, Sirt1, and Psen1 are not regulated by different promoter methylation.

The expression of vascular endothelial growth factor (VEGF) represents one potential mechanism whereby vascular and Alzheimer's disease (AD) pathologies are related. The authors investigated whether AD cases, especially those having a rapid cognitive decline, more commonly carried a functional promoter gene variant for VEGF (-2578C/A) and showed elevated plasma levels of Vegf. In addition, the authors investigated whether patterns of association also were found for mild cognitive impairment (MCI) and conversion from MCI to AD.Group 1 included 317 AD cases and 320 unaffected control subjects. Group 2 included 113 MCI patients and 130 control subjects. Plasma levels of Vegf were measured by chemiluminescence for a subset of group 1. Genotype determinations were made for all subjects.The VEGF AA genotype was associated with an increased risk of developing AD (OR = 1.616, p = 0.046). This genotype also was associated with an accelerated cognitive decline in APOE small epsilon4 positive patients with AD (AA vs. CC OR = 6.5, p = 0.04). The VEGF AA genotype was a risk factor for MCI (OR = 2.5, p = 0.037) and MCI conversion to AD in APOE small epsilon4+ (OR = 6.5, CI = 2.014-20.980; p = 0.002). Vegf plasma levels were higher in patients with AD than controls (230 pg/mL vs. 42 pg/mL), and were even higher in those patients with a fast cognitive decline and the APOE epsilon4 allele.Modulation of VEGF expression is a potential mechanism associated with the risk of developing AD and its clinical deterioration.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western societies mainly accounts for clinical dementia. A high proportion of women are affected by this disease, especially at a very advanced age, which might to a large extent be associated with the fact that women live longer. However, some studies suggest that incidence rates may be really increased in women. For this reason the influence of estrogens on the brain and the decrease of it during menopause are of special interest. After menopause, circulating levels of estrogens markedly decline, influencing several brain processes predicted to influence AD risk. The control of estrogens on oxidative stress, inflammation, and the cerebral vasculature might also be expected to increase AD risk. During the Women's Health Initiative Memory Study--a randomized, placebo-controlled trial of women 65-79 years of age--oral estrogen plus progestin was seen to double the rate of developing dementia, with risk appearing soon after the treatment was initiated. On the basis of current evidence, hormone therapy (HT) is thus not indicated for the prevention of AD. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain and the search for genetic factors influencing the pathogenesis of AD has led to the identification of numerous gene polymorphisms that act as susceptibility modifiers. Accordingly, several reports have indicated that the risk of AD is substantially influenced by several genetic polymorphisms in the promoter region, or other untranslated regions, of genes encoding inflammatory mediators. Here we review several data suggesting that inflammatory genetic variation may contribute to higher AD susceptibility in women too. All together this information may represent the basis both for future recognition of individuals at risk as well as for a pharmacogenomic approach in achieving drug responsiveness.

Down syndrome (DS) is generally considered as an “atheroma-free model”. In this preliminary study, we investigated homocysteine, folate and Vitamin B 12 levels in 13 DS patients (male, average age 60 years) and 20 age-matched individuals. We also studied lipid fractions, and polymorphisms for Cystothionine β-synthase (CBS), 5,10-methyl-tetrahydro-folate reductase (MTHFR) and apolipoprotein E (Apo-E) genes. However, DS patients with the MTHFR TT genotype showed an increased of plasma homocysteine (tHcy). Our results indicate that this group of “healthy old” Down syndrome patients, although showing some classical biochemical risk factors for atherosclerosis, did not suffer clinical cardiovascular alterations.

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.

Background: In cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitiveimpairmentanddementia.Incidencestudiesofthisissuearefew 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 mol/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 (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.

Metabolic activation of peripheral blood leukocytes (chemiluminescence) from 27 children with Down syndrome (DS) and 23 age and sex-matched control children after phagocytic stimulation by opsonized zymosan particles was investigated through a chemiluminescence assay. Using autologous plasma or serum as opsonizing media, phagocytic activity of circulating leukocytes was significantly decreased in DS subjects. A further decrease of phagocytic activity was found in neutrophils from DS children, when normal heterologous plasma or sera were used. On the other hand, sera or plasma from DS subjects significantly increased phagocytic activation of leukocytes from normal donors. In DS subjects opsonizing agents such as serum immunoglobulins and complement fractions were in the normal ranges of concentration. Thus, the impaired chemiluminescence of neutrophils was mainly due to a metabolic impairment at the cellular level. A decreased production of radicals derived from the oxygen metabolism in neutrophils may be an important step of immune derangement leading to the increased incidence of infectious diseases frequently associated with DS.

Increased levels of alpha-1-antichymotrypsin (ACT), a protease inhibitor and an acute phase protein, have been found in the brain and peripheral blood of patients with Alzheimer's disease (AD). Patients from northern Italy with a clinical diagnosis of probable AD, and patients with early onset AD (EOAD) from UK with AD neuropathological diagnosis were genotyped for a new polymorphism in the promoter region of the ACT gene which has been shown to affect ACT expression. A subset of patients with clinical AD from northern Italy was also followed up for 2 years and monitored for cognitive decline. The ACT TT promoter genotype was associated with an increased risk of EOAD independently from the presence of the apolipoprotein E (APOE) epsilon 4 allele. After manifestation of the disease the ACT TT genotype was also associated with faster cognitive decline in patients with the APOE allele epsilon 4. The ACT gene appears to influence the early clinical development of the disease, and the interaction of the ACT and APOE genes affects clinical progression of AD.

Patients with AD often show altered levels of some immune molecules in their peripheral blood which correlate with cognitive impairment. Downs' syndrome (DS) subjects are at high risk of developing Alzheimer's disease (AD). Here we studied immune molecules, such as interleukin-6 (IL-6), C reactive protein (CRP) and neopterin, in the blood of non demented children with DS to investigate whether altered peripheral immune phenotype could be present in this subjects without dementia, many years before the presentation of clinical signs of cognitive deterioration. Plasma levels of neopterin and IL-6 were measured by commercially available ELISA kits, whereas plasma CRP concentration was evaluated by nephelometric immunoassay technique. We studied a group of 40 patients with DS, 20 healthy controls and 100 patients w ith AD. Plasma levels of IL-6 and CRP were significantly higher in DS than in control children. The increase of IL-6 and CRP from DS children was similar to that found in elderly patients with clinical AD. In the present research we have also studied blood levels of neopterin which were in the normal range either in DS or control. Increased or normal levels of this metabolite have been found in the blood of AD patients. However, increased blood neopterin was likely to be only elevated in patients with advanced clinical stage of AD. Peripheral altered immune phenotype in healthy young subjects with DS might be an early sign of CNS alterations leading many years later to cognitive deterioration and dementia.

Down's syndrome (DS) subjects are at high risk of developing Alzheimer's disease (AD). Patients with AD often show altered levels of some immune molecules in their peripheral blood which correlate with cognitive impairment. However, whether the altered peripheral immune phenotype is a late and secondary phenomenon associated with dementia or an early impairment linked to mechanisms controlling neurodegeneration of the central nervous system (CNS) is still an unanswered question. Here we studied immune molecules in the blood of non demented children with DS to investigate whether altered peripheral immune phenotype could be present in these subjects without dementia, many years before the presentation of clinical signs of cognitive deterioration. Plasma levels of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) were significantly higher in DS than in control children. Plasma levels of soluble intercellular adhesion molecule-3 (sICAM-3), soluble vascular cell adhesion molecule-1 (sVCAM-1) and C reactive protein (CRP) were also increased in DS. The increase of IL-6 and CRP from DS children was similar to that found in elderly patients with clinical AD. Peripheral altered immune phenotype in healthy young subjects with DS might be an early sign of CNS alterations leading many years later to cognitive deterioration and dementia.

Genetic background of inflammatory or anti-inflammatory molecules may be helpful in identifying subjects with increased or decrease risk of developing cardiovascular disease. Bi-allele polymorphism (C > T) in the promoter region (-511) of the interleukin-1beta (IL-1beta) gene and the bi-allele polymorphism (G > C) in the promoter region (-174) of interleukin-6 (IL-6) gene were determined in elderly men patients with myocardial infarction (MI) and healthy controls. Each subject was also genotyped for the triallelic polymorphism of the apolipoprotein E epsilon gene. The IL-6C and APOE epsilon4 alleles were independently associated with a mild or moderate increased risk of MI, whilst the allele C of the IL-1beta was not independently linked to MI risk. However, the simultaneous presence of the allele C of IL-1beta, the allele C of IL-6 and epsilon4 allele of APOE was strongly associated with the disease. Data from this cross-sectional study suggest that the functional interaction of these three genes affects pathogenetic mechanisms of MI and an impaired regulation of immune responses plays a pivotal role in the disease. Furthermore, genetic background of inflammatory genes may influence longevity of human species by affecting inflammatory responses associated to cardiovascular diseases. The administration of anti-inflammatory compounds to middle age healthy subjects with increased genetic susceptibility of developing MI might decrease the incidence and prevalence of cardiovascular events in aging.

Two different polymorphic regions of the interleukin-6 (IL-6) gene were investigated in patients with Alzheimer's disease (AD) and non-demented controls. The -174 C allele in the promoter region of IL-6 gene was over-represented in AD patients compared to controls and significantly increased the risk of AD. Moreover, the -174 CC genotype was associated with a high risk of the disease in women. The D allele of a variable number of tandem repeat (VNTR) was in strong linkage disequilibrium with the -174 C allele and slightly increased AD risk. On the other hand, the frequency of the VNTR C allele was decreased in patients with AD and was negatively associated with the risk of developing AD. Both the -174 CC and VNTR DD genotypes were also associated with increased IL-6 levels in the blood and brain from AD. These findings suggest that IL-6 may play a multifaceted role in AD by affecting the turnover of the cytokine.

Background and aims: Inflammation seems to play a role in progressive neurological degenerative diseases such as Alzheimer’s disease (AD). Local inflammatory processes can in fact give rise to direct neurotoxicity, interfere with β-amyloid expression and metabolism, and maintain chronic, intracerebral, acute-phase protein secretion, in turn favoring the formation of β-amyloid fibrils. Accordingly, recent studies show an increased risk for AD associated with certain polymorphisms in the genes encoding some proinflammatory cytokines and acute-phase proteins. To our knowledge, no data have yet been presented on the association between AD and polymorphisms of the interferon(IFN)-γ gene, despite the pivotal role that IFN-γ plays in immune-mediated inflammatory responses. Methods: Using the amplification refractory mutation system method, we evaluated the role of IFN-γ in AD by analyzing, in 111 AD patients and 213 healthy controls, the prevalence of +874T→A single nucleotide polymorphism (SNP), associated with different IFN-γ production. Allele ApoE polymorphisms were assessed by the PCR-based method. Results: No statistically significant differences were observed between AD patients and controls in the frequency of +874 T→A SNP, either on analyzing data as a whole or according to gender. As expected, the frequency of the well-known genetic risk factor APOE-e4 allele was significantly increased in AD patients. However, analyzing the results according to the presence or absence of the APOE-e4 allele, no interactions among ApoE, IFN-γ alleles, gender or age at onset were observed. Conclusions: Our study does not support the hypothesis that IFN-γ SNP may be a genetic risk factor for AD. Further analysis of recently described IFN-γ polymorphisms may clarify the role, if any, of IFN-γ alleles in AD.

Mutations in the class I-like Major Histocompatibility Complex gene HFE are associated with hereditary hemochromatosis (HH), a disorder caused by excessive iron uptake. Three common mutations have been found: C282Y, H63D, and S65C. Moreover, several studies have suggested that HFE mutations may be involved in several age-related chronic diseases such as Alzheimer's disease (AD) and coronary heart disease, but apparently paradoxically also with longevity. In particular, in AD, patients carrying the H63D allele have been suggested to have a mean age at onset of 72 vs. 77 years for those who were homozygous for the wild-type allele. Thus, it seems that H63D mutations may anticipate sporadic AD clinical presentation in susceptible individuals. In the present study, we analysed the HFE genotype in 123 patients with sporadic AD and 152 age-matched controls from Northern Italy. Samples were typed for C282Y, H63D and S65C alleles using the polymerase chain reaction and sequence specific primers. No significant differences were observed in frequencies of the different alleles between controls and AD both for the whole group and when the data were analysed according to gender. In addition, we failed to observe any difference in the age at onset between patients carrying the mutant HFE-H63D allele and those homozygous for the wild-type allele, either in men or women. Also taking into account the presence or absence of the APOE-epsilon 4 allele, no significant differences were observed between carriers of the mutant HFE-H63D allele and those homozygous for the wild-type allele. Thus, our study does not support the suggestion that H63D mutations may anticipate sporadic AD clinical presentation in susceptible individuals.

Studies regarding different viruses of the herpes family, such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), or human herpes virus 6 (HHV-6) in Alzheimer's disease (AD) are scarce. DNA from peripheral blood leukocytes (PBL) and brain samples were analyzed for the presence of CMV, EBV, or HHV-6. All samples were negative for CMV. EBV positivity was 6% in AD brains, whereas 45% of PBL samples from AD patients and 31% from controls were positive for EBV (p = 0.05). HHV-6 showed a 23% positivity in PBL samples from AD and 4% from controls (p = 0.002). 17% of AD brains were HHV-6 positive. Within a group of elderly individuals, followed up for 5 years, EBV-positive or HHV-6-positive PBL increased in those who developed clinical AD. Virus serological positivity was also investigated, and IgG levels for CMV and EBV antigens were also increased in those subjects who developed AD during the follow-up. Our findings suggest that EBV and HHV-6 may be environmental risk factors for cognitive deterioration and progression to AD in elderly persons.

Alzheimer’s disease (AD) is a complex disease resulting in neurodegeneration and cognitive impairment. Investigations on environmental factors implicated in AD are scarce and the etiology of the disease remains up to now obscure. The disease’s pathogenesis may be multi-factorial and different etiological factors may converge during aging and induce an activation of brain microglia and macrophages. This microglia priming will result in chronic neuro-inflammation under chronic antigen activation. Infective agents may prime and drive iper-activation of microglia and be partially responsible of the induction of brain inflammation and decline of cognitive performances. Age-associated immune dis-functions induced by chronic sub-clinical infections appear to substantially contribute to the appearance of neuro-inflammation in the elderly. Individual predisposition to less efficient immune responses is another relevant factor contributing to impaired regulation of inflammatory responses and accelerated cognitive decline. Life-long virus infection may play a pivotal role in activating peripheral and central inflammatory responses and in turn contributing to increased cognitive impairment in preclinical and clinical AD.

Immune defects, thyroid abnormalities, plasma zinc levels, and the presence of gastrointestinal disease were investigated in 43 children with Down's syndrome (DS). Peripheral T lymphocytes with the phenotype of helper cells or cluster of differentiation 4 (CD4) were decreased. Circulating activated T cells (CD3/HLA-DR-positive cells) and large granular lymphocytes (CD16/CD56 positive cells) were increased. Plasma levels of interleukin-6 were higher in DS children than in controls. Serum levels of thyroid-stimulating hormone were increased in DS. Coeliac disease was over-represented in the group of DS children and many of these children also showed increased serum levels of immunoglobulin-G (IgG) specific for gliadin antigen. The increment of serum interleukin-6 was age-related and correlated with anti-gliadin IgG levels in DS. Plasma zinc levels were lower in DS children with coeliac disease and in those with anti-gliadin IgG than in DS without detectable anti-gliadin IgG. Dietary antigens may represent a continuous stimulus for the immune system in this syndrome and interfere with normal immune responses. Altered intestinal absorption of nutrients may in turn affect endocrine functions, brain development, and cognitive performances.

To evaluate the stability and reproducibility of selected peripheral oxidative stress markers and their possible relation to cognitive performance, three different blood samples were taken at 7- to 10-day intervals from 11 patients with probable Alzheimer disease (AD) and 11 nondemented controls. Blood samples were also collected once from 6 patients with vascular dementia (VT). alpha -1-Antichymotrypsin (ACT), C-reactive protein (CRP), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), lactoferrin (LTF), and total lipid peroxidation (LPO) were then measured. Blood levels of ACT and GSH-Px were increased in AD patients but not in patients with VD. Levels of LTF, CRP, and LPO were comparable between AD patients and controls. Erythrocyte SOD activity was increased in AD patients. Blood levels of ACT negatively correlated with LPO levels and positively correlated with scores of the Global Deterioration Scale of AD patients. ACT might be implicated in controlling oxidative damage of blood lipids and their turnover during the progression of AD.

Plasma levels of alpha1-antichymotrypsin (ACT) and interleukin-1beta (IL-1beta) were increased in patients with probable Alzheimer's disease (AD). A common polymorphism within ACT and IL-1beta genes affected plasma levels of ACT or IL-1beta, and AD patients with the ACT T,T or IL-1beta T,T genotype showed the highest levels of plasma ACT or IL-1beta, respectively. The concomitant presence of the ACT T,T and IL-1beta T,T genotypes increased the risk of AD (odds ratio: 5.606, confidence interval: 1.654-18.996) and decreased the age at onset of the disease.

Different age-related immune pathogenetic mechanisms in myasthenia gravis (MG) have been suggested because of restoration after thymectomy (Tx) of altered zinc, thymulin (TH) and T-cell subsets exclusively in early-onset patients (younger50 years), not in late-onset patients (older50 years). In this context interleukin-2 (IL-2), interleukin-6 (IL-6) and thymoma are crucial because both involved in MG pathogenesis and correlated with acetylcholine receptors (AchRs) Ab production. Moreover, IL-2 and IL-6 are zinc-dependent, are altered in aging and related with zinc and TH age-dependent declines. Moreover, zinc is relevant for immune efficiency. In order to confirm these different age-related pathogenetic mechanisms further, the role of thymoma, zinc, TH, IL-2 and IL-6 is studied in MG patients with generalized MG with and without thymoma before and 1 month and 1 year after Tx. The high IL-2, IL-6, zinc, and AChR Ab levels observed before Tx are significantly correlated each other in younger MG patients (50 years) independently by thymoma and in older MG patients (50 years) with thymoma. No correlations exist in older MG patients without thymoma. Thymulin is not correlated with other parameters considered to be both in younger and older MG patients independently by the thymoma. Thymectomy restores zinc; immune parameters and AChR Ab are exclusively in the younger group, not in the older one. These findings suggest that IL-2 and IL-6, via zinc, rather than TH, may be involved in different age-related pathogenetic mechanisms mainly in early-onset MG. By contrast, thymoma may be involved in MG etiology in late-onset representing, as such, a useful discriminant tool for MG etiology between early and late-onset MG patients. Because autoimmune phenomena may rise in aging, a parallelism with altered immune functions during aging is discussed.

Alzheimer disease (AD) patients with both sporadic and familial forms of AD and non-demented controls were genotyped for common polymorphisms in the signal peptide for alpha-1-antichymotrypsin (ACT) gene and in two different regions of apolipoprotein E (APOE) gene. The ACT TT genotype was over-represented (P = 0.025) in patients with early onset of sporadic AD. In this patient's group ACT TT genotype conferred a significant crude odds ratio for the disease (OR = 2.09; 95% CI = 1.09-4.00, P = 0.025). After adjustment for the APOE epsilon4 and APOE -491 genotypes, logistic regression analysis confirmed that the ACT TT genotype resulted independently associated with early onset AD (adjusted OR = 2.56; 85% CI = 1.3-5.2, P = 0.009). The frequency of APOE epsilon4 allele was increased in AD, as expected (OR = 5.92, 95% CI = 3.60-9.70, P = 0.0001). On the contrary, the APOE -491 A/T genotypes were not associated with AD. No preferential association of the APOE epsilon4 allele or APOE -491 A/T genotypes with ACT A/T alleles was observed in AD. Present findings indicated that subjects with ACT TT genotype had an increased risk of developing AD and suggested that this genotype influenced the risk of an early onset of the disease by affecting the production of ACT molecules.

A homogeneous group of 53 Caucasian subjects with high-grade osteosarcoma (OS) was typed for HLA-A and B locus antigens. Although no significant differences in the distribution of these antigens were found in comparison with 425 local controls, a trend towards an increase of HLA-B18 and decrease of HLA-B12 was observed. All the patients underwent amputation plus adjuvant chemotherapy and among the 29 patients with a follow-up longer than one year, 9 out of 10 subjects with HLA-A3 antigens developed metastases within a few months. None of the OS patients had the HLA-A3, B7 haplotype which is present in linkage-disequilibrium in the control population.

Levels of α -1-antichymotrypsin (ACT) were higher in brain homogenates of patients with Alzheimer's disease (AD) than controls. Brain tissues from the same patients and controls were immunostained with antibodies specific for microglia or astrocytes, the leukocyte common antigen (CD45) and glial fibrillary acidic protein (GFAP), respectively. Both activated CD45 and GFAP cells were increased in AD. Astroglia were divided into scattered (CD45sc) and clustered microglia (CD45cl) or scattered (GFAPsc) and clustered astrocytes (GFAPcl). Clustered cells were defined according their tendency to form focal aggregates. CD45cl and GFAPcl cells were present only in AD brain, while CD45sc and GFAPsc positive cells were present either in AD or control brains, with AD brains showing increased numbers of both cell types. A positive correlation between brain ACT levels and the number of GFAPsc positive cells was present in AD. AD patients with APOE 4 allele showed increased levels of ACT and increased CD45sc positive cells. Elevated ACT levels in the brain of AD patients could be interpreted as a metabolic response of astrocytes which might modulate the potentially deleterious activation of microglia cells.

Different molecular forms of alpha-1-antichymotrypsin (ACT) in sera and cerebrospinal fluids from patients with Alzheimer's disease (AD) were detected. Monomeric and polymeric ACT were observed by polyacrylamide gel electrophoresis of both sera and cerebrospinal fluids. ACT polymers were increased in AD patients with the apolipoprotein E (APOE) 4 allele. Increased levels of inactive ACT molecules were also detected in brain homogenates of patients with the APOE 4 allele. Experimental conditions promoting in vitro polymerization of ACT and the effect of polymerization on the biological activity of this serpin were also explored. Incubation of this serpin with prostaglandins of E series (PGE 2) induced ACT polymerization and decreased its activity. Amyloid beta-peptide1-42 did not significantly affected the biological activity of ACT. Inactivation of protease inhibitors by inflammatory molecules such as PGE 2 released from activated microglia in AD brains may promote amyloid deposition and neurodegeneration.

In the elderly, the most common cause of dementia is Alzheimer disease (AD), which is responsible for the age-related progressive neurodegenerative inflammatory condition mediated by the disease. It has been seen that several genetic and environmental factors are involved in AD onset. Epidemiologic data suggest that some genetic determinants of AD might reside in those polymorphisms that regulate immune inflammatory responses, such as the major histocompatibility complex (MHC). Therefore, several MHC polymorphisms have been in the spotlight of a large number of AD association studies. A possible association of HLA-A2 allele with increased susceptibility to AD has been the subject of debate for more than 20 years, even if the results of these studies, in the various populations, are discordant. Thus, to gain insight in this matter, the authors have studied the HLA-A2 allele for a possible association with sporadic AD in a homogeneous population of Italian patients. For this reason, the distribution of HLA-A2 allele in patients with sporadic AD and controls was analyzed by PCR-SSP assay. The results demonstrated a significant difference in the frequency of HLA-A2 allele between patients with sporadic AD and controls (46% versus 38%). Thus, these data confirm a positive role of HLA-A2 allele in the risk of developing AD. However, some of the observed discrepancies may result from clinical or genetic heterogeneity of the populations under study or methodologic biases. Besides, whenever external agents such as viruses play a role, these might different in the various populations leading to various associations. However, it has to be taken into account that there are many molecular HLA-A2 subtypes with different frequencies in various populations. Therefore, further studies should include molecular typing of HLA-A2 subtypes.

Thymic endocrine activity was assessed by a bioassay to determine the basal activity of thymulin (TH), a zinc dependent hormone, and its in vitro reactivation in two different age groups of patients with myasthenia gravis (MG). Before thymectomy, basal TH plasma levels were increased in patients over the age of 50 years. Plasma zinc levels were increased in all patients, this increment being very high in old patients. One year after thymectomy both TH and zinc plasma levels decreased. While zinc plasma levels were within the normal ranges for their respective ages, TH levels were lower in young and higher in old patients than in age comparable controls. Young patients with MG showed increased CD3,DR positive peripheral T-cells as well as lymphocytes with the CD16,CD56 phenotype. An increment of CD3 positive cells along with CD4 and CD16,CD56 positive cells were found in older patients. Thymectomy partially affected blood lymphocyte representation only in young patients, since CD3,DR T-cells decreased one year after surgery. No significant variations in T-cell representation were found in old patients after thymectomy. Immunosuppression in thymectomized patients did not significantly affected TH and zinc plasma levels. Very high levels of TH and the presence of additional alterations in T-lymphocyte subsets in old patients suggested that differential age related pathogenetic immunological mechanisms might be associated with the disease.