Trace Element Selenium Research Articles

Selenium and copper status - potential signposts for neurological remission after traumatic spinal cord injury

IntroductionTraumatic Spinal Cord Injury (TSCI) is a severe incident resulting in loss of motor and sensory function caused by complex pathological mechanisms including massive oxidative stress and extensive inflammatory processes. The essential trace elements selenium (Se) and copper (Cu) play crucial roles as part of the antioxidant defense. HypothesisRemission after TSCI is associated with characteristic dynamics of early changes in serum Cu and Se status. Study designSingle-center prospective observational study. Patients and methodsSerum samples from TSCI patients were analyzed (n = 52); 21 recovered and showed a positive abbreviated injury score (AIS) conversion within 3 months (G1), whereas 21 had no remission (G0). Ten subjects with vertebral fractures without neurological impairment served as control (C). Different time points (at admission, and after 4, 9, 12, and 24 h) were analyzed for total serum Se and Cu concentrations by total reflection X-ray fluorescence, and for Selenoprotein P (SELENOP) and Ceruloplasmin (CP) by sandwich ELISA. ResultsAt admission, CP and SELENOP concentrations were higher in the remission group (G1) than in the non-remission group (G0). Within 24 h, there were marginal changes in Se, SELENOP, Cu and CP concentrations in the groups of controls (C) and G0. In contrast, these parameters decreased significantly in G1. Binary logistic regression analysis including Cu and Se levels at admission in combination with Se and CP levels after 24 h allowed a prediction for potential remission, with an area under the curve (AUC) of 87.7% (CI: 75.1%–100.0%). ConclusionThese data indicate a strong association between temporal changes of the Se and Cu status and the clinical outcome after TSCI. The dynamics observed may reflect an ongoing redistribution of the trace elements in favor of a better anti-inflammatory response and a more successful neurological regeneration.

Nrf2-modulation by seleno-hormetic agents and its potential for radiation protection.

The trace element selenium (Se) is an essential component of selenoproteins and plays a critical role in redox signaling via regulating the activity of selenoenzymes such as thioredoxin reductase-1 and glutathione peroxidases. Se compounds and its metabolites possess a wide range of biological functions including anticancer and cytoprotection effects, modulation of hormetic genes and antioxidant enzyme activities. Radiation-induced injury of normal tissues is a significant side effect for cancer patients who receive radiotherapy in the clinic and the development of new and effective radioprotectors is an important goal of research. Others and we have shown that seleno-compounds have the potential to protect ionizing radiation-induced toxicities in various tissues and cells both in in vitro and in vivo studies. In this review, we discuss the potential utilization of Se compounds with redox-dependent hormetic activity as novel radio-protective agents to alleviate radiation toxicity. The cellular and molecular mechanisms underlying the radioprotection effects of these seleno-hormetic agents are also discussed. These include Nrf2 transcription factor modulation and the consequent upregulation of the adaptive stress response to IR in bone marrow stem cells and hematopoietic precursors.

Amyotrophic lateral sclerosis incidence following exposure to inorganic selenium in drinking water

PDS 63: Chemicals and metals: health effects, Exhibition Hall (PDS), Ground floor, August 27, 2019, 10:30 AM - 12:00 PM Background and aim. Some laboratory and epidemiologic studies have documented an association between high intake of the trace element selenium and risk of amyotrophic lateral sclerosis (ALS), a degenerative disease of the motor neurons. We aimed to further investigate this possible association. Methods. From 1986 through 2015, we followed a community cohort in northern Italy that had been inadvertently exposed in the 1974-86 period to drinking water with unusually high levels of selenium, around 8 µg/l, in its inorganic hexavalent form (selenate). In this cohort, we previously identified a high incidence of ALS during 1986-94. Here we report extended follow-up of this exposed cohort, as well as of an unexposed cohort including over 95,000 municipal residents, for an additional 21 years. We identified incident cases through administrative sources and a specialized registry. Results. During follow-up, 7 and 112 ALS cases were newly diagnosed in the exposed and unexposed cohorts, respectively, yielding incidence rates of 14 and 5 per 100,000 person-years. A Poisson regression analysis adjusting for age, sex, and calendar year produced an overall rate ratio for ALS of 2.8 (95% confidence interval 1.3 - 6) in the entire period of follow-up. The association was stronger earlier than later in follow-up (1986-1994 vs. 1994-2015), and among women than men. All exposed cases were of the sporadic, non-familial form for the disease. Conclusions. Overall, results from this ‘natural experiment’ indicate a positive association between chronic exposure to inorganic hexavalent selenium and ALS incidence, with rates in the exposed cohort declining over time after cessation of exposure. Also taking into account the recognized neurotoxicity of this metalloid, particularly its selective toxicity on motor neurons observed in animal studies, the present study provides additional support for the hypothesis that selenium exposure increases ALS risk.

Role of Selenoproteins in Bacterial Pathogenesis.

The trace element selenium is an essential micronutrient that plays an important role in maintaining homeostasis of several tissues including the immune system of mammals. The vast majority of the biological functions of selenium are mediated via selenoproteins, proteins which incorporate the selenium-containing amino acid selenocysteine. Several bacterial infections of humans and animals are associated with decreased levels of selenium in the blood and an adjunct therapy with selenium often leads to favorable outcomes. Many pathogenic bacteria are also capable of synthesizing selenocysteine suggesting that selenoproteins may have a role in bacterial physiology. Interestingly, the composition of host microbiota is also regulated by dietary selenium levels. Therefore, bacterial pathogens, microbiome, and host immune cells may be competing for a limited supply of selenium. Elucidating how selenium, in particular selenoproteins, may regulate pathogen virulence, microbiome diversity, and host immune response during a bacterial infection is critical for clinical management of infectious diseases.

Crosstalk of Nrf2 with the Trace Elements Selenium, Iron, Zinc, and Copper.

Trace elements, like Cu, Zn, Fe, or Se, are important for the proper functioning of antioxidant enzymes. However, in excessive amounts, they can also act as pro-oxidants. Accordingly, trace elements influence redox-modulated signaling pathways, such as the Nrf2 pathway. Vice versa, Nrf2 target genes belong to the group of transport and metal binding proteins. In order to investigate whether Nrf2 directly regulates the systemic trace element status, we used mice to study the effect of a constitutive, whole-body Nrf2 knockout on the systemic status of Cu, Zn, Fe, and Se. As the loss of selenoproteins under Se-deprived conditions has been described to further enhance Nrf2 activity, we additionally analyzed the combination of Nrf2 knockout with feeding diets that provide either suboptimal, adequate, or supplemented amounts of Se. Experiments revealed that the Nrf2 knockout partially affected the trace element concentrations of Cu, Zn, Fe, or Se in the intestine, liver, and/or plasma. However, aside from Fe, the other three trace elements were only marginally modulated in an Nrf2-dependent manner. Selenium deficiency mainly resulted in increased plasma Zn levels. One putative mediator could be the metal regulatory transcription factor 1, which was up-regulated with an increasing Se supply and downregulated in Se-supplemented Nrf2 knockout mice.

Status of trace elements zinc, copper, and selenium in transfusion dependent beta thalassemic Indian children: a cross sectional study

Background: Maintenance of normal levels of copper, selenium, and zinc play an important part in lessening the morbidities associated with thalassemia major. Levels of these elements have been found to be altered in this chronic transfusion dependent disease from all over the world, but with widely variable results. Besides repeated blood transfusions and use of chelating agents, their levels in thalassemics are affected by genetic and dietary factors also, compelling us to undertake this study in our population. The Objectives of this study was to assessment of serum levels of zinc, copper and selenium in transfusion dependent beta thalassemics. Methods: Cross sectional descriptive study conducted at Thalassemia Day-care Centre of a teaching hospital. Total 64 transfusion dependent thalassemics in the age group 3-18 years were subjected to serum levels of zinc, copper and selenium by inductively coupled plasma mass spectrometry technique. Results: Four (6.25%) had hypozincemia, 15 (23.43%) hypocupremia and one (1.565%) had hypercupremia. Two (3.12%) had higher selenium levels (>190 µgm/l).Conclusions: In contrast to previous studies, hypocupremia has been found to be more prevalent than hypozincemia and hyposelenemia in our population.

Phytochemical Screening and in vitro Antioxidant Activity of Hydro-Ethanolic Extract of Blighia sapida Stem Bark

Blighia sapida is a plant belonging to the family of Sapindaceae. In this study we aimed to carry out the phytochemical screening of hydro-ethanolic (15%) extract of Blighia sapida stem bark and evaluate its in vitro antioxidant activity. It was found that the hydro-ethanolic extract of Blighia sapida stem bark showed the presence of saponin, flavonoid, alkaloid, phenols and ascorbic acid. It also contains trace elements zinc and selenium. Furthermore it showed some scavenging activity but not as such could be compared with the various standards used except for nitric oxide scavenging activity. Keywords : Blighia sapida, phytochemicals, antioxidant, trace elements DOI : 10.7176/JBAH/9-16-04 Publication date : August 31 st 2019

Micronutrient Selenium: Uniqueness and Vital Functions

Abstract—The trace element selenium, which was discovered by Berzelius in 1817, remains poorly investigated and exhibits diverse and surprising functions. We consider it unique for several reasons. First, it is present not only in organic or inorganic compounds but also in the amino acids selenocysteine and selenomethionine, as a key component, and in selenoproteins, which are found in all Domains of life. Second, selenocysteine is the 21st proteinogenic amino acid. Its uniqueness lies not only in the fact that it is encoded by one of the three stop codons of translation but in that its biosynthesis possesses unique features and that this process involves unique cis- and trans-active factors that are necessary for the recognition of this triplet as selenocysteine-encoding to avoid premature translation termination and synthesize full-sized selenoproteins. The maintenance of these cis- and trans-active factors is energy consuming, which suggests the crucial importance of selenoproteins for an organism. In addition, the pathways of amino-acid and selenoprotein biosynthesis have some distinctive features in different Domains of life. Third, the processes and effects of selenium compounds of different origins, in which this micronutrient plays key roles, are strikingly diverse, especially in the regulation of vital functions in mammals. This review uses the most recent data to present a comprehensive view of the properties and functions of selenium and to provide insight into the uniqueness of this micronutrient.

Selenium nanoparticles as anti-infective implant coatings for trauma orthopedics against methicillin-resistant Staphylococcus aureus and epidermidis: in vitro and in vivo assessment.

Background: Bacterial infection is a common and serious complication in orthopedic implants following traumatic injury, which is often associated with extensive soft tissue damage and contaminated wounds. Multidrug-resistant bacteria have been found in these infected wounds, especially in patients who have multi trauma and prolonged stay in intensive care units.Purpose: The objective of this study was to develop a coating on orthopedic implants that is effective against drug-resistant bacteria.Methods and results: We applied nanoparticles (30-70nm) of the trace element selenium (Se) as a coating through surface-induced nucleation-deposition on titanium implants and investigated the antimicrobial activity against drug resistant bacteria including Methicillin-resistant Staphylococcus aureus (MRSA) and Methicillin-resistant Staphylococcus epidermidis (MRSE) in vitro and in an infected femur model in rats.The nanoparticles were shown in vitro to have antimicrobial activity at concentrations as low as 0.5ppm. The nanoparticle coatings strongly inhibited biofilm formation on the implants and reduced the number of viable bacteria in the surrounding tissue following inoculation of implants with biofilm forming doses of bacteria.Conclusion: This study shows a proof of concept for a selenium nanoparticle coatings as a potential anti-infective barrier for orthopedic medical devices in the setting of contamination with multi-resistant bacteria. It also represents one of the few (if only) in vivo assessment of selenium nanoparticle coatings on reducing antibiotic-resistant orthopedic implant infections.

Bacteriological and geochemical features of the groundwater resources: Kettara abandoned mine (Morocco)

Waste water of the Kettara village, as well as the abandoned tailings, constitute a potential environmental issue with direct consequences on air, soil, water resources qualities and, on human health. In this paper, experimental investigations examine the environmental impact which is induced by the wastewater, mine tailings and the lithological factors of rocks. This multidisciplinary research allows to i) understand the transfer of the Metallic Trace Elements (selenium, arsenic, nickel and zinc) and sulfate ions in the fractured shales media, ii) to assess the water potability by using the microbiological analysis. The microbiological results reveal the domestic impact by the presence of several kinds of bacteria in the groundwater resources: E. coli, Fecal coliforms, Total coliforms, Enterococci, Mesophilic Aerobic Flora, Sulphite-reducing bacteria and Salmonella.Selenium, arsenic and the bacteriological contamination of the groundwater could be explained by five kinds of factors: i) the geological formations and the nature of the hydrogeological system (unconfined layer), ii) the groundwater flow, the hydraulic relation between the hydrogeological wells and, the fractures network in the shale aquifer. The piezometric map allows to highlight the groundwater flow from the North-East to North-West and to the South-West, the drainage axis towards the P21 well and the presence of the dividing axis in the contaminated zone by the arsenic, iii) the absence of the unhealthy habitats with permeable traditional septic tanks in the village; iv) the transfer of the spreading animal excrements from the soil to groundwater and, v) the migration of the wastewater towards downstream of the groundwater flow. The presence of the reed beds could explain the reduction of bacteria in the hydrogeological wells of the study area.

Selenoprotein P and its potential role in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease associated with cognitive decline, loss of memory, and progressive cerebral atrophy. The trace element selenium (Se) is known to be involved in brain pathology. Selenoprotein P (SELENOP), as the main Se transport protein, is, to a great extent, responsible for maintaining Se homeostasis and the hierarchy of selenoprotein expression in the body. Adequate Se supply through SELENOP is vital for proper brain development and function. Additionally, SELENOP may be implicated in pathological processes in the central nervous system, including those in AD. The current review summarizes recent findings on the possible role of SELENOP in AD, with a focus on probable mechanisms: Se delivery to neurons, antioxidant activity, cytoskeleton assembly, interaction with redox-active metals (e.g., copper and iron), and misfolded proteins (amyloid beta and tau protein). The use of SELENOP as a biomarker of Se status is also briefly discussed. Epidemiological studies on Se supplementation are beyond the scope of the current review.

Homeostatic changes of some trace elements in geriatric rats in the condition of oxidative stress induced by aluminum and the beneficial role of resveratrol

BackgroundElderly individuals are exposed to trace element imbalances due to the reduced capacity of their organism to utilize minerals in a direct relationship with many circumstances. Objectives and methodsThe aim of this study was to assess the protective role of resveratrol upon the homeostatic changes of some trace elements in geriatric rats in the condition of oxidative stress induced by aluminum exposure. Forty Wistar rats, 18–20 months old, were divided randomly into four groups (n = 10): control (C) - receiving 1 ml of physiologically saline (P.S.) via intraperitoneal (i.p) administration, E1 - 1 ml of P.S. and 1000 ppb aluminum sulphate (AS) in drinking water ad libitum, E2 - 20 mg/kg−1 resveratrol, i.p. and 1000 ppb AS in drinking water, E3 - 20 mg/kg−1 resveratrol i.p. The groups C and E3 received distilled water as drinking water ad libitum. The i.p administrations were once a week for four weeks period. The levels of oxidative stress marker's were analyzed (glutathione, glutathione' peroxidase, superoxide dismutase, and catalase) of the proteins' (total protein, albumin, and hemoglobin) in serum and also the levels of the main trace elements (copper, zinc, iron, selenium, manganese and magnesium) in blood, liver, kidney and spleen. ResultsSignificant decrease (p < 0.05) of total protein (TP), albumin (ALB), catalase (CAT), increase significant (p < 0.05) of glutathione reductase (GSH-r), glutathione peroxidase (GPx) and superoxide dismutase (SOD) in E1 groups, compared with control, E2, and E3 groups was ascertained. There were also observed significant (p < 0.05) decreases in Cu, Zn, Fe and Mg, not significant (p > 0.05) increase of Se and Mn in blood, significant (p < 0.01) increase of Cu, Zn, Mg, Se, Mn in kidney and liver and Fe, in spleen of geriatric rats from E1 group compared to the control group. Insignificant differences (p > 0.05) were recorded in groups which received resveratrol (E2 and E3) compared to the control group, but significant differences (p < 0.05), especially in blood and liver samples, compared to E1. ConclusionsThe results suggest that resveratrol can prevent the homeostatic imbalance of trace elements in geriatric rats in the condition of oxidative stress induced by aluminum exposure.

The paradox in accumulation behavior of cadmium and selenium at different planting times in rice.

The synergistic effects of trace elements selenium (Se) and cadmium (Cd) are well known. But the reasons for the trending accumulation behavior in both trace elements are under debate in the scientific community. The present investigation was conducted to evaluate the impact of heat units on the accumulation behavior in two environments. Se and Cd were applied in three groups (T0; 0:0, T1; 0.4:1, T2; 1:2) mg kg-1. As the time of planting and heat units consumed by the crop to attain its physiological maturity appears to be different. The sunlight may contribute as an important manipulating factor for the accumulation of heavy metals in the plant. The results of the present study indicated that the behavior in the accumulation pattern of both elements appears to be distinct in the same material. The increased fertilizer treatment in soil bulk linearly increased the metal contents in rice grain. The studies between different plant parts disclosed panicle as the primary reservoir for Se and Cd accumulation. The plant sown earlier accumulates more Se than Cd while the plants uptake more Cd when sown 1 month later. The plant completes the critical developmental phases (tillering, heading, and flowering) within 20-30 days interval depending on the variety. But the late-sown plants complete these transitional phases within 9-10 days interval ultimately result in less utilization of heat units. These quick transitional changes may lead to the uptake of an ample amount of Cd contents in rice grain even at a low level of Cd stress (1 and 2 mg kg-1), making rice unsafe for edible purposes. The proper time of planting could be effective in timely acclimatization of Se and Cd sequestration and translocation in rice various components. Graphical Abstract.

Physiological Functions and Metabolisms of Essential Trace Element Selenium: Function of Selenoproteins and Selenium Metabolisms

Physiological Functions and Metabolisms of Essential Trace Element Selenium: Function of Selenoproteins and Selenium Metabolisms

ANTIOXIDANT AND IMMUNOMODULATORY EFFECTS OF NANO-SELENIUM ON RESPONSE OF BROILERS TO ND VACCINE

Trace element selenium occupies a privileged position among the natural antioxidant in addition to its ability to enhance the immune response in several species. The current challenges of supplementation of sodium selenite in poultry diets are always linked to low absorption and increased toxicity. Therefore, it is imperative to embrace new technologies like nanotechnology to get as an alternative source of traditional selenium supplementation in form of the nanoparticles with high bioavailability and low toxicity which will be positively reflected on biological activities of selenium. The present study was conducted to investigate the antioxidant and immunomodulatory effects of different concentrations of Nano-selenium on response of broilers to ND vaccination. A total of one hundred and eighty day old Cobb broilers were randomly allocated in 6 groups with each group applied to 3 replicate of 10 chicks, the first two groups were control negative groups without selenium supplementation and the remaining four groups were dietary supplemented with sodium selenite (0.15ppm) and Nano-selenium at concentration of (0.15ppm), (0.075 ppm) and (0.0375 ppm), respectively. The results showed that Nano-selenium had a superior effect compared to that of the sodium selenite either as an antioxidant or as an immunomodulatory and comparing the control negative groups. The most important results can be summarized in the following points; significant improvement in Feed conversion ratio (FCR), significant enhancement in activities of antioxidant enzymes without adverse effects on tested biochemical parameters as well as significant boosting in antibody titers against ND. In conclusion, Nano-selenium supplementation in commercial broilers diets could be an economically a promising multitask option, particularly when it comes to improving antioxidative status and boosting immune response to NDV (LaSota) vaccination in broilers.

Serum Selenium and Lead Levels: a Possible Link with Diabetes and Associated Proteinuria.

The study assessed trace element selenium (Se) and a heavy metal lead (Pb) in patients with type II diabetes mellitus (T2DM) and its associated proteinuria. Total 275 subjects aged between 30 and 90years were studied: 93 T2DM, 98 T2DM with proteinuria, and 84 as controls. Serum Se and Pb were analyzed by inductively coupled plasma optical emission spectrometer (ICP-OES) and other biochemical indices by ROCHE module COBAS 6000 analyzer. Statistical analysis was done by one-way analysis of variance (ANOVA) at P < 0.0001 followed by Tukey's honest test. Pearson's correlation coefficient was applied to observe the effects of Se and Pb on FPG and ACR. Decreased Se levels were observed in T2DM and T2DM with proteinuria with no significant difference and serum Pb was found within reference range in both groups. Se showed no significant association with FBG and ACR while mid-upper tertile of Pb was significantly associated with ACR of T2DM with the proteinuria group (P < 0.01). Se is known to have a U-shaped relationship with T2DM. Low Se levels in both groups may be due to the effect of disease and its related inflammation. Detected levels of Pb suggest that studied population had lower exposure to it. Association of Pb with ACR showed consistency with the classical studies that even low levels of Pb may cause the renal deterioration.

Examining the Effects of Chronic Selenium Exposure on Traditionally Used Stress Parameters in Juvenile American Alligators (Alligator mississippiensis).

Environmental contaminants, such as the trace element selenium (Se), are a continuing concern to species worldwide due to their potential pathophysiological effects, including their influence on the stress response mediated through glucocorticoids (GCs; stress hormones). Environmental concentrations of Se are increasing due to anthropogenic activities, including the incomplete combustion of coal and subsequent disposal of coal combustion wastes. However, most studies examining how Se affects GCs have been focused on lower trophic organisms. The objectives of this study were to investigate the effects of long-term Se exposure on traditionally used stress parameters and to identify which of these parameters best indicate Se accumulation in liver and kidney of the American alligator (Alligator mississippiensis), a top trophic carnivore found in the southeastern United States and known to inhabit Se-containing areas. Alligators were divided into three dietary treatments and fed prey spiked with 1000 or 2000ppm of selenomethionine (SeMet) or deionized water (control treatment) for 7weeks. Following the 7-week treatment protocol, blood and tissue samples were obtained to measure plasma corticosterone (CORT; the main crocodilian GC), tail scute CORT, the ratio of peripheral blood heterophils (H) to lymphocytes (L) as H/L ratio, and body condition. To evaluate which parameter best indicated Se accumulation in the liver and kidney, principal component and discriminant analyses were performed. The only parameter significantly correlated with liver and kidney Se concentrations was scute CORT. Our results suggest that measurement of CORT in tail scutes compared with plasma CORT, H/L ratios, and body condition is the best indicator of Se-exposure and accumulation in crocodilians.

Selenoneine: a Unique Reactive Selenium Species From the Blood of Tuna With Implications for Human Diseases

The trace element selenium is found in many dietary components, from grains to Brazil nuts. In humans, this chalcogen is essential for many physiological processes. A couple of years ago, selenoneine, a rather unusual seleno-histidine derivative, has been isolated from tuna. Whilst there is a limited number of other naturally occurring small selenium compounds, large quantities of selenoneine can be generated in genetically engineered microorganisms and via chemical synthesis. Due to a rare selenol/selenone tautomerism, this compound exhibits unique redox properties and promising biological activities, which range of traditional antioxidant action to the interaction and subsequent protection of metal ions. Selenoneine may indeed provide a promising lead for a new generation of selenium supplements and chemopreventive agents.

Serum selenium and pancreatic cancer: a prospective study in the Prostate, Lung, Colorectaland Ovarian Cancer Trial cohort.

Pancreatic cancer(PCa) is one of the most lethal cancers with few knownconsistent nutrition-related risk factors. Epidemiologic associations between the trace element selenium and PCa are inconsistent. This study examined the association ofpre-diagnostic serum selenium with incident PCa. We conducted a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Study (PLCO) cohort of men and women 55-70years old at baseline (1993-2001). In total, 303 PCa cases developed during the 17-year follow-up period (1993-2009). We selected two controls (n = 606) for each case who were alive at the time the case was diagnosed whowere matched on age, sex, race, and date of blood draw. We usedconditional logistic regression analysisto calculate the odds ratio (OR) and 95% confidence intervals (CI) adjusting for smoking status and diabetesmellitus. Mean serum selenium concentrations were slightly lower in cases (mean, 95% CI:139.0ng/ml, 135.6-138.9) compared to controls (142.5ng/ml, 140.4-142.4, p = 0.08). Overall, serum selenium was not associated with PCa risk (continuous OR: 0.66; 0.32-1.37). There was no significant interaction by sex, smoking, diabetes, or follow-up time (p > 0.05). Our results do not support the hypothesis that serum selenium is associated with PCa risk.

Selenium and selenium species in the etiology of Alzheimer’s dementia: The potential for bias of the case-control study design

Several human studies imply that the trace element selenium and its species may influence the onset of neurological disease, including Alzheimer’s dementia (AD). Nevertheless, the literature is conflicting, with reported associations between exposure and risk in opposite direction, possibly due to biases in exposure assessment.After conducting a cohort study that detected an excess AD risk associated with higher levels of inorganic-hexavalent selenium in subjects with mild cognitive impairment (MCI), we investigated the relation between selenium and AD using a case-control study design. We determined cerebrospinal fluid levels of selenium species in 56 MCI participants already included in the cohort study, considered as referents, and in 33 patients with established AD.AD risk was inversely correlated with inorganic selenium species and with the organic form bound to selenoprotein P. Selenium bound to other organo-selenium species was positively correlated with AD risk, suggesting compensatory selenoprotein upregulation following increased oxidative stress. The finding of an increased AD risk associated with inorganic-hexavalent selenium from the cohort study was not replicated.This case-control study yielded entirely different results than those generated by a cohort study with a partially overlapping participant population, suggesting that case-control design does not allow to reliably assess the role of selenium exposure in AD etiology. This inability appears to be due to exposure misclassification, falsely indicating an etiologic role of selenium deficiency likely due to reverse causation, and involving most selenium species. The case-control design may instead lend insights into the pathologic process underlying disease progression.