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.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Among environmental factors likely associated with Alzheimer'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-α genes were analyzed in hippocampus and temporal cortex brain samples from AD and non-demented controls. All subjects were also genotyped for APOE ε, 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-α. mRNA levels of MED23, IL28B, IFN-α from the hippocampus and those of MED23 from the temporal cortex were further decreased in APOE ε4 allele AD carriers. Moreover, rs6598008 polymorphism of IRF7 was significantly associated with decreased hippocampal expression of IRF7, MED23, IL28B, and IFN-α. These findings suggest that AD brains show impaired innate antimicrobial gene expression profiles, and individual genetic makeup, such as positivity for the APOE ε4 and IRF7 A alleles, might affect brain immune efficiency.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
BACKGROUND: In cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitive impairment and dementia. Incidence studies of this issue are few ...and have produced conflicting results. OBJECTIVE: We investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population. DESIGN: A dementia-free cohort of 816 subjects (434 women and 382 men; mean age: 74 y) from an Italian population-based study constituted our study sample. The relation of baseline plasma tHcy to the risk of newly diagnosed dementia and AD on follow-up was examined. A proportional hazards regression model was used to adjust for age, sex, education, apolipoprotein E genotype, vascular risk factors, and serum concentrations of folate and vitamin B-12. RESULTS: Over an average follow-up of 4 y, dementia developed in 112 subjects, including 70 who received a diagnosis of AD. In the subjects with hyperhomocysteinemia (plasma tHcy > 15 micromol/L), the hazard ratio for dementia was 2.08 (95% CI: 1.31, 3.30; P = 0.002). The corresponding hazard ratio for AD was 2.11 (95% CI: 1.19, 3.76; P = 0.011). Independently of hyperhomocysteinemia and other confounders, low folate concentrations (</=11.8 nmol/L) were also associated with an increased risk of both dementia (1.87; 95% CI: 1.21, 2.89; P = 0.005) and AD (1.98; 95% CI: 1.15, 3.40; P = 0.014), whereas the association was not significant for vitamin B-12. CONCLUSIONS: Elevated plasma tHcy concentrations and low serum folate concentrations are independent predictors of the development of dementia and AD.
Full text
Available for:
CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Incidence studies of blood inflammatory markers as predictors of dementia in older age are few and did not take into account hyperhomocysteinemia, although this condition is associated with ...both inflammation and increased risk of dementia. We investigated the relationships of baseline serum C-reactive protein (CRP), serum interleukin 6 (IL6), plasma alpha-1-antichymotrypsin, and hyperhomocysteinemia (defined as plasma total homocysteine > 15 μmol/L) with risk of incident Alzheimer's disease (AD) and vascular dementia (VaD) in a dementia-free Italian population-based elderly cohort ( n = 804, 53.2% women, mean age 74 years) with 4 years of follow-up. No inflammatory marker, alone or in combination, predicted AD risk whereas the combination of high CRP and high IL6 was associated with risk of VaD (HR, 2.56; 95%CI, 1.21–5.50) independently of socio-demographic confounders, traditional risk factors and hyperhomocysteinemia. By contrast, in the same model, hyperhomocysteinemia was independently associated with AD (HR, 1.91; 95%CI, 1.02–3.56) but not VaD risk. Blood inflammatory markers are associated with increased VaD risk but do not predict AD, which seems selectively associated with hyperhomocysteinemia.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
The process of maintaining life for the individual is a constant struggle to preserve his/her integrity. This can come at a price when immunity is involved, namely systemic inflammation. Inflammation ...is not per se a negative phenomenon: it is the response of the immune system to the invasion of viruses or bacteria and other pathogens. During evolution the human organism was set to live 40 or 50 years; today, however, the immune system must remain active for much a longer time. This very long activity leads to a chronic inflammation that slowly but inexorably damages one or several organs: this is a typical phenomenon linked to ageing and it is considered the major risk factor for age-related chronic diseases. Alzheimer's disease, atherosclerosis, diabetes and even sarcopenia and cancer, just to mention a few - have an important inflammatory component, though disease progression seems also dependent on the genetic background of individuals. Emerging evidence suggests that pro-inflammatory genotypes are related to unsuccessful ageing, and, reciprocally, controlling inflammatory status may allow a better chance of successful ageing. In other words, age-related diseases are "the price we pay" for a life-long active immune system: this system has also the potential to harm us later, as its fine tuning becomes compromised. Our immune system has evolved to control pathogens, so pro-inflammatory responses are likely to be evolutionarily programmed to resist fatal infections with pathogens aggressively. Thus, inflammatory genotypes are an important and necessary part of the normal host responses to pathogens in early life, but the overproduction of inflammatory molecules might also cause immune-related inflammatory diseases and eventually death later. Therefore, low responder genotypes involved in regulation of innate defence mechanisms, might better control inflammatory responses and age-related disease development, resulting in an increased chance of long life survival in a "permissive" environment with reduced pathogen load, medical care and increased quality of life.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Recent findings from a genome wide association investigation in a large cohort of patients with Alzheimer's disease (AD) and non demented controls (CTR) showed that a limited set of genes was in a ...strong association (p > l0-5) with the disease.
In this report we suggest that the polymorphism association in 8 of these genes is consistent with a non conventional interpretation of AD etiology.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) result in a genetic signature that might affect individual brain susceptibility to infection by herpes virus family during aging, leading to neuronal loss, inflammation and amyloid deposition.
We hypothesized that such genetic trait may predispose to AD via complex and diverse mechanisms each contributing to an increase of individual susceptibility to brain viral infections.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The prevalence of coronary artery diseases is low among Down Syndrome (DS) patients and they rarely die of atherosclerotic complications. Histopathological investigations showed no increase in ...atherosclerosis, or even a total lack of atherosclerotic changes, in DS AIM: The aim of our study is to investigate the relationship between age and brain-derived neurotrophic factor (BDNF) levels in Down Syndrome (DS).
Three groups of DS patients were studied: the first consisted of 23 children (age 2-14 years); the second of 14 adults (age 20-50 years), the third group of 13 elderly persons (>60 years) and a controls group of 20 healthy patients (age 15-60 years).The analytes of interest were quantified using a biochip array analyzer (Evidence, Randox Ltd., Crumlin, UK).
Plasma BDNF was higher in DS patients than in controls and there was a significant age-related increase. Serum levels of IL-6 and MCP-1 were also higher in DS children and adults, but not in older patients, than in healthy control. High levels of circulating BDNF may protect DS patients from the clinical complications of atherosclerosis. However, the striking drop in peripheral BDNF levels with age might predispose these patients to clinical manifestations of dementia in later life.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Progressive increase of mean age and life expectancy in both industrialized and emerging societies parallels an increment of chronic degenerative diseases (CDD) such as cancer, cardiovascular, ...autoimmune or neurodegenerative diseases among the elderly. CDD are of complex diagnosis, difficult to treat and absorbing an increasing proportion in the health care budgets worldwide. However, recent development in modern medicine especially in genetics, proteomics, and informatics is leading to the discovery of biomarkers associated with different CDD that can be used as indicator of disease's risk in healthy subjects. Therefore, predictive medicine is merging and medical doctors may for the first time anticipate the deleterious effect of CDD and use markers to identify persons with high risk of developing a given CDD before the clinical manifestation of the diseases. This innovative approach may offer substantial advantages, since the promise of personalized medicine is to preserve individual health in people with high risk by starting early treatment or prevention protocols. The pathway is now open, however the road to an effective personalized medicine is still long, several (diagnostic) predictive instruments for different CDD are under development, some ethical issues have to be solved. Operative proposals for the heath care systems are now needed to verify potential benefits of predictive medicine in the clinical practice. In fact, predictive diagnostics, personalized medicine and personalized therapy have the potential of changing classical approaches of modern medicine to CDD.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Classical hallmarks of AD such as amyloid deposition and neurofibrillary tangles do not ...completely explain AD pathogenesis. Recent investigations proposed Aβ peptide as an anti-microbial factor. Our previous works suggested that the concomitant presence of single nucleotide polymorphisms (SNPs) from AD genetic studies might impair antiviral defenses and increase the individual susceptibility to herpes virus infection. Viruses of herpes family by inducing frequent cycles of reactivation and latency constantly challenge the immune response and drive the accumulation of memory T cells. However, the immune system is not able to completely eradicate these viruses. The continuous antigen stimulation activates chronic inflammatory responses that may progressively induce neurodegenerative mechanisms in genetically susceptible elderly. The aim of this paper is to suggest new perspectives in clinical pathogenesis of AD with potential prevention and new medical treatment of the age associated cognitive decline.
PDF
