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.
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.
Pro-inflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their production have been ...shown to be associated with AD. Tumor necrosis factor (TNF)-α is an inflammatory cytokine involved in the local immune response occurring in the central nervous system of AD patients. Genetic variation could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 222 patients (152 women, 70 men; age range 60–87) and 240 non-demented age-matched healthy controls for TNF-α −308 G/A single nucleotide polymorphism (SNP). No significant differences were observed in genotyped frequencies between patients and controls, whereas carriers of −308A showed a significantly lower mean age at onset than non-carriers of this allele. This difference was more evident taking into account ApolipoproteinE (ApoE) status since the lowest age at onset was observed in patients carrying the −308ATNF+/APOE4+ genotypes. In conclusion, our data support previous suggestions that, at least in Caucasians, the TNF gene is a disease modifier gene in patients in which AD is rising, bringing to light the importance of genetic variation at the pro-inflammatory components in the progression of AD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by cognitive deficit with progressive worsening of memory. Recent data indicate that neurons, as well as other brain ...cells, can express enzymes such as cyclooxygenases (COXs) and 5-lipoxygenase (5-LO) which are considered important in inflammatory cells. Moreover, it has been demonstrated that COX-2 and 5-LO enzymes play a considerable role in the pathophysiology of AD. In order to assess the possible role of COX-2 and 5-LO single nucleotide polymorphisms (SNPs) in AD, we examined their distribution in 341 AD patients and 190 controls from Northern Italy. A significant difference was observed in the distribution of the -765G COX-2 and -1708A 5-LO alleles between AD cases and controls (p=0.03 for -765G/C COX-2 SNP; and p=0.007 for -1708G/A 5-LO SNP). Hence, COX-2 -765G and 5-LO -1708A alleles were overrepresented in AD patients and underrepresented in controls. Our data suggest that these alleles of COX-2 and 5-LO could be risk factors for AD. These results seem of some importance for a pharmacogenomic approach.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract It has been hypothesized that polymorphisms of Tumor Necrosis Factor (TNF)-α gene affect the risk of developing Alzheimer's disease (AD). However, results of different studies are often ...inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the TNF-α gene with AD risk. Hence, the results being stated are of a meta-analysis across studies, and that this meta-analysis does not invalidate the results of the individual studies previously performed. Seventeen studies that investigated the association between 5 TNF-α polymorphisms (− 850, − 308, − 863, − 238, and − 1031) and AD were retrieved and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested a significant association between − 850 polymorphism and AD risk (TT vs. TC + CC: pooled odds ratio OR, 1.61; 95% confidence interval CI, 1.08–2.29; p = 0.02) with no evidence of between-study heterogeneity ( χ2 , p > 0.1). Subgroup analysis suggested that the possession of T allele significantly increased the risk of AD associated with carriage of the apolipoprotein E ɛ4 allele in Caucasian Australians and Northern Europeans (TT + TC vs. CC: OR, 1.95; 95% CI, 1.45–2.62; p = 0.00001; p > 0.1; χ2 for heterogeneity, p > 0.1). No significant difference in genotype distribution of − 308 polymorphism in AD was found, with a high degree of between-study heterogeneity. For the − 863 and − 1031 polymorphisms we did not find an association with AD, but significant between-study heterogeneity discouraged genotype data pooling. Only four studies investigated the − 238 variant and the results were not significant. Current findings support an association between − 850 C > T polymorphism and the risk of developing AD; hence, they strengthen the suggestion of a potential role for anti-TNF therapy to maintain physiologic levels of TNF-α.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Inhibitors of tumor necrosis factor-alpha (TNF-α) have deeply changed the therapy of several inflammatory human diseases. For instance, clinical management of rheumatoid arthritis, psoriatic ...arthritis and ankylosing spondylitis have profoundly benefited after the introduction of new therapeutic tools, such as antagonist of TNF-α molecule. These drugs include etanercept, a soluble TNF-α receptor antagonist, three anti-TNF-α antibodies, adalimumab, infliximab, golimumab and certolizumab a humanized Fab fragment combined with polyethylene glycol. These compounds efficiently inhibit several TNF-α biological- mediated effects, however, they have also shown differential clinical efficacy in several trials from different autoimmune diseases. It is of clinical relevance that non-responders to one of these drugs often positively responded to another. Different mechanisms of action and diversity in pharmacokinetics of these three compounds may partially explain different clinical effects. However, partially diverse pathogentic mechanisms in different diseases also contribute to differential therapeutic responses. Therefore, these apparently homogeneous agents can not be considered equivalent in their clinically efficacy. Differential therapeutic actions of these drugs may be advantageously used in clinical practice and further improve the great potential of individual TNF-α inhibitors.
Neurodegenerative processes associated with Alzheimer’s disease (AD) are accompanied by reactive astrogliosis and microglia activation and a role for chronic inflammation in the brain degeneration of ...these patients has been suggested. Moreover impaired immune functions in AD brains might also influence the disease’s progression. Therefore, it is of interest to further characterized inflammatory molecules in the peripheral blood of patients with AD and its relationship with cognitive decline. A complex picture emerged in this pilot study and IL-8, IFN-gamma, MCP-1 and VEGF levels were increased in AD. Levels of P-selectin and L-selectin were decreased in AD and lowest in AD patients with highest cognitive decline. Our findings suggest that these molecules may induce alterations of endothelial regulation and influence neurodegenerative processes of AD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Inflammation plays an important role in progressive degenerative diseases of the CNS, such as Alzheimer's disease, which represents the major cause of cognitive impairment in old age. Alzheimer's ...disease is a complex disease with multifactorial etiology and may represent a good model to investigate the multifaceted functions of immune responses in relation to cognitive decline. This review will discuss the following topics: relationships between inflammation and brain degenerative processes in Alzheimer's disease, the influence of genetic variations in cytokine genes upon the risk of developing Alzheimer's disease and/or the age at onset of the disease, the effects of gene allele polymorphism of immune molecules upon the turnover of these factors in the blood and brain of Alzheimer's disease patients and the association of genetic variations in some of this molecules with cognitive decline.
Gene variants that promote inflammation and cholesterol metabolism have been associated with acute myocardial infarction (AMI) and Alzheimer's disease (AD). We investigated a panel of relevant ...polymorphisms to distinguish genetic backgrounds for AMI and AD: IL10 -1082G/A, IL6 -174G/C, TNF -308G/A, IFNG +874T/A, SERPINA3 -51G/T, HMGCR -911C/A, APOE ε2/3/4 (280 AMI cases, 257 AD cases, and 1307 population controls, all Italian (presumed risk alleles are shown in bold). Six genetic risk sets I to VI were identified by fuzzy latent classification: I had low risk; II and III had low risk before age 65 (II, III); low risk sets lacked pro-inflammatory alleles for HMGCR-TNF-APOE. Pro-inflammatory alleles for SERPINA3-IL10-IFNG were found for high risk sets IV to VI. Set IV 'AMI < age 40, AD < age 65' included risk alleles for HMGCR. Set V 'AMI over a broad range of age' included risk alleles for TNF+IL6. Set VI 'AMI at ages 40 to 55, AD ages 65+' included APOE ε4. Close resemblance to the high risk sets, as indicated by membership scores close to one, defined high relative risks. We conclude that AMI and AD share genetic backgrounds involving cholesterol metabolism and the upregulation of inflammation and that gene-gene interactions in relevant sets of genes may be useful in defining inherited risk for common disorders.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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