|Year : 2020 | Volume
| Issue : 3 | Page : 914-919
Total antioxidant capacity as an aging marker in Egyptian patients with Alzheimer disease
Rawhia H El-Edel1, Dalia H Abou-Elela1, Ahmed A Sonbol1, Amr S Shalaby2, Mariam A Fouaad3
1 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Psychiatry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Clinical Pathology, Shebein El Kom, Teaching Hospital, Menoufia, Egypt
|Date of Submission||26-Dec-2018|
|Date of Decision||23-Jan-2019|
|Date of Acceptance||02-Feb-2019|
|Date of Web Publication||30-Sep-2020|
Mariam A Fouaad
Shebin El-Kom, Menoufia
Source of Support: None, Conflict of Interest: None
This study aimed to evaluate the total antioxidant capacity (TAC) as an aging marker in patients with Alzheimer disease (AD).
AD is a neurodegenerative disorder that affects elderly and is the most common type of dementia. Reactive oxygen species is a major risk factor of Alzheimer. Oxidative stress, the most important factor in the pathogenesis of Alzheimer, occurs when reactive oxygen species and reactive nitrogen species increase and/or antioxidant defense system decreases. TAC is a marker of DNA oxidation. These data will explain pathogenesis and prevention and help in the treatment of AD.
Patients and methods
This study was carried on 90 individuals categorized into three groups: group 1 (patients group) included 30 patients with AD, group II (control matched group) included 30 age-matched and sex-matched apparently healthy participants, and group III (pregeriatric group) included 30 apparently healthy participants. Their age was between 30 and 60 years old. The determination of the TAC is performed calorimetrically by the reaction of antioxidants in the sample with a defined amount of exogenously provide hydrogen peroxide.
There was a highly significant decrease in TAC in all studied group. Receiver operating characteristic curve for antioxidant to predict Alzheimer's cases versus control matched group showed that at a cutoff point of less than or equal to 1.16, it had a sensitivity of 73.33%, specificity of 83.33%, positive predictive value of 81.5% and negative predictive value of 75.8%.
Our results indicate a relation between oxidative stress and AD, indicating a possible role of these markers in diagnosis of AD.
Keywords: Alzheimer's disease, antioxidants, dementia, oxidative stress, reactive oxygen species
|How to cite this article:|
El-Edel RH, Abou-Elela DH, Sonbol AA, Shalaby AS, Fouaad MA. Total antioxidant capacity as an aging marker in Egyptian patients with Alzheimer disease. Menoufia Med J 2020;33:914-9
|How to cite this URL:|
El-Edel RH, Abou-Elela DH, Sonbol AA, Shalaby AS, Fouaad MA. Total antioxidant capacity as an aging marker in Egyptian patients with Alzheimer disease. Menoufia Med J [serial online] 2020 [cited 2020 Oct 22];33:914-9. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/914/296690
| Introduction|| |
Alzheimer's disease (AD) is the most common cause of dementia and a great socioeconomic burden in the aging society . In AD, the damage and destruction of neurons eventually affects other parts of the brain, including those that enable a person to carry out basic body functions such as walking and swallowing. AD is ultimately fatal . Considerable research efforts have pointed to the role of innate immunity as the main culprit in the pathogenesis of AD. Glial activation triggered by 'damage signals' activates a pathological molecular cascade that finally leads to hyperphosphorylation and oligomerization of the τ protein. These modifications correlate with the gradual cognitive impairment of patients with the AD. In AD, a continuous activation state of microglia appears to generate neuronal injury and neurodegeneration, producing the outflow of pathological τ from the inner of neurons to the extraneuronal space. Released τ, together with the contribution of ApoE4 protein, would then produce reactivation of microglia, thus inducing a positive feedback that stimulates the vicious cycle in neurodegeneration . Stress oxidative occurs when the production of reactive oxygen species (ROS) and reactive nitrogen species increase and/or antioxidant defense system decreases . ROS are such highly reactive molecules that when present in excess, they overwhelm the protective systems, resulting in cell damage and lipid peroxidation. ROS are constituted in oxidative processes that normally occur at relatively low levels in all cells and tissues . In normal situations, a number of antioxidant mechanisms serve to control ROS production. The imbalance between ROS production and antioxidant power is defined as oxidative stress. The measurements of total antioxidant status (TAS) and total oxidant status are used to predict oxidative status. Especially the measurement of TAS reflects the overall antioxidant state in an organism . Total antioxidant capacity (TAC) is a marker of DNA oxidation produced by oxidation of DNA bases. Considering the importance of oxidative stress in AD, we aimed to determine the plasma levels of TAC in patients with AD and healthy controls. These data may provide additional data in the elucidation of pathogenesis as well as prevention of AD. In addition, reduction of oxidative stress may be helpful in the treatments for AD .
This study aimed to evaluate the TAC as an aging marker in patients with AD.
| Patients and Methods|| |
This study was carried out at Clinical Pathology Department, Menoufia University, and Shebin El-Kom teaching hospital on 90 individuals from October 2017 to July 2018. Informed consent was obtained from both patients and controls. They were categorized into the following groups.
Group 1 (patients group) included 30 patients, and their ages were between 60 and 80 years old. They were selected from geriatric clinic, Ain Shams University Hospital. Group II (control matched group) included 30 age-matched and sex-matched apparently healthy participants. Group III (pregeriatric group) included 30 apparently healthy participants, and their ages were between 30 and 60 years old. Diagnosis was based on standard clinical criteria . Exclusion criteria were (a) brain stroke and brain ischemia, (b) previous severe head trauma, and (c) severe hyperlipidemia. The study was approved by ethical committee of Faculty of Medicine, Menoufia University. All patients are subjected to the following: full medical and family histories; detailed history on lifestyle; and physical examination, including age, sex, smoking status, and presence of macroangiopathic/microangiopathic complications and arterial hypertension (HTN). Diagnosis of AD was based on national institute of neurological and communicative disorders and stroke and the AD and related disorders association (NINCDS/ADRDA) criteria . Moreover, for the patients, mini-mental state examination  as well as computed tomography scans and brain MRI was done. From all of the study groups, 5 ml of venous blood was collected while they were fasting and under complete aseptic condition in plain tube and left to clot for 10–15 min. Serum was separated by centrifugation at 2000 rpm for 10 min. The separated serum was used for clinical chemistry tests. The following laboratory investigations were done: fasting blood sugar and lipid profile, which were measured with a Modular AU680 Automatic Biochemistry Analyzer (Beckman Coulter, Brea, California, USA); thyroid stimulating hormone (TSH), which was assessed by the electrochemiluminescence immunoassay using Cobas E 411 analyzers, Hoffmann–La Roche, Basel & Switzerland); and finally, detection of TAC, which was done by Biodiagnostic and Research Reagent, catalog no. TA 25 13. Trolox equivalent antioxidant capacity assay is generally based on the ability of the antioxidants present in a sample to reduce or inhibit oxidized products generated in the assay. It is based on the principle that when 2,2'-azino-bis(3-ethylbenz-thiazoline-6-sulfonic acid (ABTS) is incubated with a proper chemical, an ABTS radical (ABTS•+) is formed. The ABTS•+ has a blue-green color, with maximum absorption at 505 nm. Antioxidants in the sample reduce ABTS•+, suppressing this color production to a degree that is proportional to their concentrations . Total antioxidant concentration (mmol/l)=(absorbance of blank-absorbance of sample)×3.33.
The data collected were tabulated and analyzed by SPSS (statistical package for the social sciences) version 22.0 on IBM compatible computer, Armonk, New York, USA). Owing to the small sample size, nonparametric statistical analysis was used. Values were presented as mean, with ranges in parenthesis. Kruskal–Wallis test was used for comparison among three or more groups having not normally distributed quantitative variables, whereas one-way analysis of variance test was used for more than two groups. Percentages of categorical variables were compared using the χ2-test. The Spearman correlation coefficient (r) was used to measure the association between two quantitative variables. Receiver operating characteristic (ROC) curve was constructed to calculate the optimized cut-off points for the prediction of AD.
| Results|| |
The demographic and clinical data for each group showed that there were no statistically significant differences among all the studied groups regarding smoking, sex, and family history. However, there were highly statistically significant increases between group I and group III, as well as between group II and group III (P < 0.001) regarding age. Regarding HTN, there were highly statistical significant differences between group I and group III and between group II and group III (P < 0.001). Meanwhile, there was a highly statistically significant increase between group I and group III (P < 0.001) and a statistically significant increase between group II and group III (P < 0.005), but no statistically significant increase between group I and group II regarding diabetes mellitus (DM) (P = 0.598) [Table 1].
Biochemical data showed that there was a statistically significant increase between group I and groups III and between group II and group III regarding fasting blood sugar (P < 0.001). There were no statistically significant increases among all the studied groups (P > 0.05) regarding TSH. Kruskal–Wallis test shows there was a significant decrease among the studied group regarding triglycerides (P < 0.05). Analysis of variance test was done using post-hoc test, which showed there was a significant increase among the studied groups regarding total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) (P < 0.05) [Table 2].
|Table 2: Comparison between the different studied groups according to laboratory tests.|
Click here to view
There was a highly statistical significant decrease among all the studied group regarding total antioxidant [Table 3].
|Table 3: Comparison between the different studied groups according to total antioxidant|
Click here to view
ROC curve for antioxidant to predict Alzheimer's cases versus control matched group showed that at a cutoff point less than or equal to 1.16, it had a sensitivity of 73.33% specificity of 83.33%, positive predictive value of 81.5%, and negative predictive value of 75.8% [Figure 1].
|Figure 1: Receiver operating characteristic curve for total antioxidant capacity to predict Alzheimer's cases versus control matched group.|
Click here to view
| Discussion|| |
AD is a crushing, progressive neurodegenerative disorder presenting with cognitive decline and memory impairments. It can be best termed as a biological and clinical range, covering preclinical (presymptomatic) and clinical (symptomatic) phases, with the latter traditionally subcategorized into mild cognitive impairment owing to AD (prodromal AD) and AD dementia, with mild, moderate, and finally severe late stages .
In the present study, the mean age of the cases was 64.27 ± 6.54 years, with no statistically significant difference between control matched group and patient group, but there were highly statistically significant differences between group I and group III as well as between group II and group III regarding age.
In a study by Montufar et al. , the mean age was 78.04 ± 6.32 years. There was no statistical significant increase in age between control matched group and patient group, which agrees with our results.
A study by Schmidt et al.  stated that there was a statistically significant increase between control matched and patient group regarding age, which disagrees with our obtained results. Moreover, the study by Lopez-Riquelme et al.  agreed with our results, as it showed that patients with AD were older than the control group.
A recent study made by O'Donoghue et al.  reported that there was a statistically significant increase between the two groups according to age, independent on inheritance of Apo E4. It considered old age alone as a risk factor for AD.
In the current study, there were no statistical significant differences among all the studied groups regarding sex and this result is in contrary to a study by Schmidt et al.  which stated that there was a statistically significant difference between control and patient group regarding sex.
The study by Lopez-Riquelme et al.  showed that the frequencies for men and women did not increase significantly in either patients or controls.
In this study, we found no significant statistical decrease among all the studied groups regarding history of smoking. The results were consistent with the results found in a study done by Montufar et al.  which showed no statistically significant differences in smoking among the three groups.
On the contrary, Kimm et al.  found a significant risk of AD in smoking men aged 65 years, which was against our obtained data.
In this study, we found no significant statistical decrease among all the studied groups regarding family history. Loy et al.  found that a family history of Alzheimer's is not necessary for an individual to develop the disease. However, individuals who have a parent, brother, or sister with Alzheimer's are more likely to develop the disease than those who do not have a first-degree relative with Alzheimer's, which agrees with the obtained results.
In our study, ~43.3% of the patients had a history of DM, with a statistically significant decrease between the between group I and group III, as well as between group II and group III, but no statistical differences between group I and group II regarding DM.
In agreement with our study, Raina et al.  stated that there was a statistically significant decrease in between the studied groups regarding DM.
In this study, we found history of HTN in 36.7% of the cases, which showed no statistical significant increase between group I and group II. In a study by Montufar et al. , there was no statistically significant increase in HTN between the two groups, which agrees with our findings.
Kimm et al.  considered HTN a strong risk factor of AD either in the age less than or more than 65 years.
In the present study, there was a statistically significant increase among the studied groups regarding the level of total cholesterol, LDL, triglycerides, and HDL.
Our results were supported Lepara et al. , who observed a statistically significant increase in lipid profile between patients with AD and control subjects regarding serum triglycerides, TC, HDL-C level, LDL-C, and VLDL-C.
In the present study, there was no statistically significant decrease among the studied groups regarding the level of TSH. A study by Chang et al.  suggested that there was no association between thyrotropin and a risk of AD, which supported our results.
However, patients with AD in the study by van Osch et al.  had lower levels of TSH than controls. Lowered TSH was associated with a more than twofold increased risk of AD.
The mechanisms by which thyroid hormones contribute to AD include the following: T3 has been shown to negatively regulate the expression of the amyloid precursor protein gene, T4 has been shown to modulate choline acetyltransferase activity, and transthyretin has been shown to create soluble β-amyloid complexes which lead to formation of senile plaque .
In the present study, there was a significant increase among the studied groups regarding the level of glucose.
A recent study by Zhao et al.  found that there was a statistically significant increase between case and control groups regarding glucose, which agrees with our results.
In the current study, there was a statistically significant decrease between the studied groups regarding TAC (P = 0.001).
Zafrilla et al.  observed low levels of plasma TAC in light-moderate and severe AD groups when compared with healthy control.
Sekler et al.  assessed the plasma level of TAC in patients with AD (mild, intermediate, and advanced disease) versus control groups and found significantly lower TAC in patients with AD (all stages) as compared with control group.
Moreover, Aldred et al.  showed a significant changes in TAC (decrease) in severe AD with respect to controls.
Moslemnezhad et al.  found that TAC levels significantly decreased in patients with AD in comparison with matched control group, which supported our results.
In contrast to the reported studies, some studies, as done by Pulido et al.  and Sinclair et al. , had not found a significant difference in plasma TAC between the AD and control groups.
According to the results obtained from this study, it seems the AD in advanced stages has lower levels of antioxidants. We demonstrated weak antioxidant defense system in patients with severe AD. Moreover, the level of DNA oxidative damage marker was higher. It could be owing to old age, malnutrition, lifestyle, and irregularities in the antioxidant defense system.
Moslemnezhad et al.  supposed the participants of the control group were of similar age, thus the confounding effect of age on the results of this study should be ignored. However, although the patients with coexistent apparent clinical diseases were excluded, the influences of other factors particularly asymptomatic coexistent common chronic medical conditions such as diabetes, cardiovascular, and chronic musculoskeletal disorders cannot be ignored.
| Conclusion|| |
Our results indicate a link between oxidative stress and AD, indicating a possible contributive role of these markers in the development of AD and as an indicator in the discrimination of AD from healthy controls.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Dimitriadis SI, Liparas D. I. Alzheimer's Disease Neuroimaging. How random is the random forest? Random forest algorithm on the service of structural imaging biomarkers for Alzheimer's disease: from Alzheimer's disease neuroimaging initiative (ADNI) database. Neural Regen Res 2018; 13
Gaugler J, James B, Johnson T, Scholz K, Weuve J, Sc D. 2016 Alzheimer's disease facts and figures. Alzheimers Dement 2016; 12
Haines JL. Alzheimer disease: perspectives from epidemiology and genetics. J Law Med Ethics 2018; 46
Dabidi RV, Hosseinzadeh S, Mahjoub S, Hosseinzadeh M, Myers J. Endurance exercise training and diferuloyl methane supplement: changes in neurotrophic factor and oxidative stress induced by lead in rat brain. Biol Sport 2013; 30
Baser H, Can U, Baser S, Hidayetoglu BT, Aslan U, Buyuktorun I, et al
. Serum total oxidant/anti-oxidant status, ischemia-modified albumin and oxidized-low density lipoprotein levels in patients with vitamin D deficiency. Arch Endocrinol Metab 2015; 59
Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004; 37
Mahjoub S, Masrour-Roudsari J. Role of oxidative stress in pathogenesis of metabolic syndrome. Caspian J Intern Med 2012; 3
Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 2012; 71
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34
Folstein MF, Folstein SE, McHugh PR. 'Mini-mental state'. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12
Rubio CP, Hernandez-Ruiz J, Martinez-Subiela S, Tvarijonaviciute A, Ceron JJ. Spectrophotometric assays for total antioxidant capacity (TAC) in dog serum: an update. BMC Vet Res 2016; 12
Aisen PS, Cummings J, Jack Jr CR, Morris JC, Sperling R, Frolich L, et al
. On the path to 2025: understanding the Alzheimer's disease continuum. Alzheimers Res Ther 2017; 9
Montufar S, Calero C, Vinueza R, Correa P, Carrera-Gonzalez A, Villegas F, et al
. Association between the APOE epsilon4 allele and late-onset Alzheimer's disease in an Ecuadorian Mestizo Population. Int J Alzheimers Dis 2017; 2017
Schmidt S, Klaver C, Saunders A, Postel E, de La Paz M, Agarwal A, et al.
Apooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy. Ophthalmic Genet 2002; 23
Lopez-Riquelme N, Alom-Poveda J, Viciano-Morote N, Llinares-Ibor I, Tormo-Diaz C. Apolipoprotein E epsilon4 allele and malondialdehyde level are independent risk factors for Alzheimer's disease. SAGE Open Med 2016; 4
O'Donoghue MC, Murphy SE, Zamboni G, Nobre AC, Mackay CE. APOE genotype and cognition in healthy individuals at risk of Alzheimer's disease: a review. Corte×2018; 104
Kimm H, Lee PH, Shin YJ, Park KS, Jo J, Lee Y, et al
. Mid-life and late-life vascular risk factors and dementia in Korean men and women. Arch Gerontol Geriatr 2011; 52
Loy CT, Schofield PR, Turner AM, Kwok JB. Genetics of dementia. Lancet 2014; 383
Raina SK, Chander V, Raina S, Kumar D, Grover A, Bhardwaj A. Hypertension and diabetes as risk factors for dementia: a secondary post-hoc
analysis from North-West India. Ann Indian Acad Neurol 2015; 18
Lepara O, Valjevac A, Alajbegovic A, Zaciragic A, Nakas-Icindic E. Decreased serum lipids in patients with probable Alzheimer's disease. Bosn J Basic Med Sci 2009; 9
Chang YS, Wu YH, Wang CJ, Tang SH, Chen HL. Higher levels of thyroxine may predict a favorable response to donepezil treatment in patients with Alzheimer disease: a prospective, case-control study. BMC Neurosci 2018; 19
Van Osch LA, Hogervorst E, Combrinck M, Smith AD. Low thyroid-stimulating hormone as an independent risk factor for Alzheimer disease. Neurology 2004; 62
Zhao X, Han Q, Lv Y, Sun L, Gang X, Wang G. Biomarkers for cognitive decline in patients with diabetes mellitus: evidence from clinical studies. Oncotarget 2018; 9
Zafrilla P, Mulero J, Xandri JM, Santo E, Caravaca G, Morillas JM. Oxidative stress in Alzheimer patients in different stages of the disease. Curr Med Chem 2006; 13
Sekler A, Jimenez JM, Rojo L, Pastene E, Fuentes P, Slachevsky A, et al
. Cognitive impairment and Alzheimer's disease: links with oxidative stress and cholesterol metabolism. Neuropsychiatr Dis Treat 2008; 4
Aldred S, Bennett S, Mecocci P. Increased low-density lipoprotein oxidation, but not total plasma protein oxidation, in Alzheimer's disease. Clin Biochem 2010; 43
Moslemnezhad A, Mahjoub S, Moghadasi M. Altered plasma marker of oxidative DNA damage and total antioxidant capacity in patients with Alzheimer's disease. Caspian J Intern Med 2016; 7
Pulido R, Jimenez-Escrig A, Orensanz L, Saura-Calixto F, Jimenez-Escrig A. Study of plasma antioxidant status in Alzheimer's disease. Eur J Neurol 2005; 12
Sinclair AJ, Bayer AJ, Johnston J, Warner C, Maxwell SR. Altered plasma antioxidant status in subjects with Alzheimer's disease and vascular dementia. Int J Geriatr Psychiatry 1998; 13
[Table 1], [Table 2], [Table 3]