https://orcid.org/0009-0004-2287-577X
Figures
Abstract
Background
Cerebrovascular accidents (CVAs) are among the most common complications of patients today. As the prevalence of ischemic CVAs rises, detecting related risk factors is crucial. Metal concentration has previously been considered a major risk factor in several neural complications, and in this study, we will investigate this.
Methods
In this case-control study, 70 CVA (clinically approved ischemic stroke cases by imaging and NIH Stroke Scale (NIHSS)) and 70 individuals with no history of CVA controls were enrolled as the control group. The serum level of several metals, including Fe (Iron), Co (Cobalt), Ni (Nickel), Cu (copper), Zn (Zinc), Mn (Manganese), Pb (lead), Hg (Mercury), has been assessed using Inductively coupled plasma mass spectrometry (ICP-MS) method. Logistic regression (LR) has also been used to determine the association between metals’ levels and CVA occurrence.
Results
As the mean age of the CVA group was 48.68 ± 15.25 years and for the non-CVA group was 47.89 ± 9.65 years, the result indicated that the serum level of Cu and Pb has been statically higher in the CVA group (respectively; P < 0.001 and P = 0.002) and Ni level was significantly lower (P = 0.003). Other measured metals’ levels (Fe, Co, Ni, Mn, Hg) were not significantly different between CVA and non-CVA groups. In the LR model, all Cu, Pb, and Zn metals had a P value of 0.03 and an odd ratio (OR) and confidence interval (CI) of 1.34 (1.02–1.75), 1.19 (1.01–1.39) and 1.01 (1.001–1.02) respectively.
Citation: Jamebozorgi K, Kooshki A, Saljoughi M, Sanjari M, Ahmadi Z, Mosavi Mirzaei SM (2025) Cerebrovascular accidents association between serum trace elements and toxic metals level, a case-control study. PLoS ONE 20(2): e0317731. https://doi.org/10.1371/journal.pone.0317731
Editor: Amirmohammad Khalaji, Tehran University of Medical Sciences, IRAN, ISLAMIC REPUBLIC OF
Received: June 29, 2024; Accepted: January 5, 2025; Published: February 3, 2025
Copyright: © 2025 Jamebozorgi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting information files.
Funding: Birjand University of Medical Sciences supported this work.
Competing interests: The authors declare that they have no conflict of interest.
1. Introduction
Known as the most common cause of disability worldwide and third in line responsible for deaths globally, cerebrovascular accidents (CVAs) are one of the most common and also fatal diseases that can occur in one person’s lifetime [1–3]. According to the World’s Stroke Organization, there are about 13.7 million new cases of stroke each year, and the prevalence of stroke can vary from 2 to 15% depending on the age [4,5]. Attributed yearly deaths due to CVA were around 5.5 million cases in 2016 and increased to 6.55 million cases by 2019 [6,7]. It is estimated that CVA is the second cause of death and the third cause of death and disability worldwide [8]. In 2019, the prevalence, mortality, and disability-adjusted life-years (DALY) of CVA was estimated to be around 143 million among 12.2 cases of CVA in just one year, which is a significant number [6].
As the estimates for CVAs are expected to go higher, there are well-known risk factors such as dyslipidemia, high blood pressure, smoking, alcohol, lack of stuffiest physical activity, obesity, and unhealthy diet that can majorly alter the chance of a CVA [9]. Some new risk factors, such as environmental and pollutants, affect the prevalence of CVA. For instance, the oxidative stress pathways and production of free radicals are key and most discussed topics, increasing the risk of several diseases, including CVA. Toxic metals such as mercury (Hg) and lead (Pb) are known to alter oxidative stress pathways and increase the level of reactive oxygen species (ROS) [10]. These metals can also alter the risk of CVA indirectly by increasing the risk of diseases related to CVA, such as hypertension, myocardial infarction, cardiac arrhythmia, and thrombosis [11,12].
Regarding the effect of trace elements on the prevalence of CVAs, the data is limited, and their effect and mechanism of probable action still need to be completely understood. A study indicates a higher level of Iron (Fe) and lower levels of serum zinc (Zn), copper [13], and manganese [14] in acute hemorrhagic stroke patients compared to controls [15]. On the other hand, another study reported lower levels of Zn and Mn but lower levels of Cu in stroke patients [16]. Other studies resulted in lower levels of Fe and a higher level of Zn, Pb, and nickel (Ni) serum levels in stroke patients compared to controls [17].
The role of the disbalance of metals in the pathogenesis of stroke is confirmed by the neuroprotective properties of metal-chelation therapy in CVA patients [18].
Therefore, due to the increase in the probability of exposure to toxic and other metals in today’s industrial world and the increase in CVA among all age groups, especially the elderly, in this case-control study, we tend to measure the serum levels of several toxic metals and trace elements in the ischemic CVA patients and compare the results with non-CVA individuals who do not have a history of CVA.
2. Method
2.1. Study population
This study was a single-center, case-control study conducted in Birjand, Iran, From March 2022 to March 2023 in Vali Asr Hospital, Birjand, Iran.
In this study, 35 CVA (clinically approved ischemic stroke cases by imaging and NIH Stroke Scale (NIHSS)) and 35 individuals with no history of CVA controls were enrolled as the control group between March 2022 and March 2023. The subjects of the case group were selected from among the hospitalized patients with CVA in Vali Asr Hospital, Birjand. The subjects of the control group were selected from people who had no history of stroke, heart attack, high blood pressure, and diabetes. The two groups were matched for age, gender, and occupation. Once the study objectives and confidentiality of the obtained data were explained to the participants, they signed written consent forms for participation. Demographic data, including age, gender, education, marital status, occupation, opium use, and history of smoking were collected from the subjects.
All experiments involving human participants in this study followed the relevant guidelines and regulations. Before the commencement of the study, approval for the experimental protocols was obtained from the Birjand University of Medical Sciences (IR.BUMS.REC.1399.072). Informed consent was obtained from all subjects or their legal guardians before they participated in the study.
2.2. Serum collection and analysis
In this study, on May 15th, 2023, patients and controls were referred for blood collection. Case and control individuals consent for participating and donating blood samples for this study. No fasting was required for this test. An individual’s blood was taken by venipuncture of an antecubital vein. Approximetly, 20 milliliters of blood were taken from each patient in a vacuum tube. The individuals were in siting position and according to the protocol. The samples were centrifuged in room temperature within the first 30 minutes, and serum was collected.
Serum samples underwent digestion using a nitric acid and perchloric acid mixture in a 2:1 v/v ratio. Five ccs of each serum sample were transferred into 25-ml glass test tubes for acid digestion. Subsequently, two ccs of 65% pure nitric acid (Merck, Germany) were added to each serum sample, and the mixture was left at room temperature overnight for gradual digestion. Following this, one cc of 72% perchloric acid (Merck, Germany) was introduced to the mixed specimens, and the resulting mixture was subjected to a 4-hour digestion process in a hot water bath (Bain-Marie) at 98 °C until complete digestion was achieved (Dos Santosa et al., 2018). After digestion, the samples were allowed to cool to ambient temperature, and subsequent dilution was carried out using 25 ml of deionized water. Finally, the samples prepared for toxic metal analysis were measured using an Agilent 7900 ICP-MS.
All standard solutions utilized for metal analysis in this study were prepared from Merck standards with a concentration of 1000 ppm. The concentrations of toxic metals (Pb, Cu, Ni, Cr, Co, Fe, Hg, Mn, and Zn) in this investigation were expressed in micrograms per deciliter. The ICP-MS performance parameters were configured as follows: radiofrequency power—1.5 kW; plasma gas flow rate—15 l per minute; carrier gas flow—1.01 l per minute; constituent gas—0.15 l per minute; sample absorption rate—1.7; sample depth—10 mm; detector mode—auto; scan type—peak hopping (three sweeps per reading and three readings per repetition); and scan number—3.
2.3. Statistical analysis
Data analysis was conducted using Stata version 17. characteristics of the study population were depicted using means (standard deviation: SD) and numbers (%) for categorical variables. Medians (interquartile range: IQR) were reported for covariates exhibiting a skewed distribution. A comparison of baseline characteristics between individuals with and without ischemic CVA employed the Student’s t-test for continuous variables, the chi-square test for categorical variables, and the Mann-Whitney test for skewed variables. We used logistic regression models to investigate the association between heavy metal levels and the occurrence of CVA. The significance level was set at 5%. Odds Ratio (OR) and Confidence Interval (CI) were used to report the data. For logistic regression, data analysis was conducted using R4.3.
3. Results
3.1. Characteristics of the study population
The results of the demographic information 70 participants (62/8 Male/Female) with a mean age of 48.25 ± 12.45 years are reported in Table 1, which indicates that the two groups exhibit similarities in age distribution, opium use, and being smokers. No significant difference between the ischemic CVA and non-CVA groups has been observed in any measured demographic data factors.
3.2. Toxic metals levels comparison between CVA and non-CVA group
The comparison data illustrating the levels of toxic metals in two distinct groups is presented in Table 2. Comparing the fundamental characteristics of the two groups (CVA and non-CVA controls), we observed that individuals with CVA exhibited higher levels of Cu) Z = 7.17, p < 0.001 (and Pb) Z = 3.13, P = 0.002 (and lower levels of Ni (Z = 2.95, p = 0.003) compared to those without history of CVA. Other metals were not statistically different between CVA and non-CVA groups (Fe; Z = 0.64, P = 0.52, Co; T = 0.71, P = 0.48, Zn; Z = 1.94, P = 0.05, Mn; Z = 0.06, P = 0.94, Hg; Z = 1.92, P = 0.05).
3.3. The association between metals serum concentration measurements and CVA using logistic regression (LR) model
The findings from the logistic regression model are outlined in Table 3. The Cu, Zn, and pb variables demonstrated a significant relationship with the likelihood of CVA. An increase of one unit in pb level was associated with a 19% increase in chance of CVA (OR:1.19, 95% CI:1.01–1.39). An increase of one unit in Cu levels was associated with a 34% increase in the chance of stroke (OR:1.34, 95% CI: 1.02–1.75), while a similar increase in Zn levels showed a 1% rise (OR:1.01, 95% CI:1.001–1.02)
The logistic regression model results, categorized by quartiles of toxic metals, are presented in Table 4. People with pb level in the highest quartile had a 9.17 times higher chance of CVA than those in the lowest quartile (OR: 9.17,95% CI: 1.87–44.99). The chance of CVA decreased by 97%, 92%, and 98% in the first, second, and third quartiles of Ni levels, respectively, compared to the lowest quartile (OR:1.85, 95% CI:0.48–7.18, OR:1.48, 95% CI:0.37–5.94, OR:2.61, 95% CI:0.65–10.47). In the upper quartiles, Mn and Hg levels demonstrated a 90% and 86% reduction in the chance of stroke, respectively, compared to the lower quartile (OR:0.04, 95% CI:0.004–0.38, OR:0.24, 95% CI:0.06–1.04).
4. Discussion
The levels of toxic metals have been observed in two groups, indicating that Cu, Zn, and Pb are higher in individuals suffering from CVA than in normal controls. Additionally, our findings indicate that the decrease in Ni levels is associated with an increased risk of ischemic stroke. Individuals with higher lead levels are more likely to have a stroke compared to those in the lower quartile. On the other hand, manganese and mercury levels showed a 90% and 86% reduction in stroke probability compared to the lower quartile. These findings are unique and have not been broadly discussed in similar studies.
Trace elements and toxic metals play a vital role in various physiological processes; however, excessive exposure to toxic metals and toxicity can be catastrophic for human health [19–22]. Evidence suggests that exposure to chemicals, especially toxic metals, also plays a significant role in causing strokes [3,23,24]. Some studies have indicated the potential role of vascular inflammation due to toxic metals and explained that excessive ROS production may activate inflammatory pathways and thus accelerate cerebral small vessel disease progression. Toxic metals pose a serious health risk to humans due to their ability to alter and damage DNA and membranes and disrupt the functioning of proteins and enzymes, which can lead to CVA [25,26].
Other results of this study indicated that increased copper levels were associated with the risk of CVA. Copper is a rare and essential element, yet it is toxic. Copper is exposed to humans through air and soil food, but most of its exposure is due to agricultural matters [27] and meat consumption [28]. Several functions for this trace element have been suggested, such as angiogenesis, neurohormone homeostasis, brain development, and even regulation of gene expression [29]. Though, as mentioned, this element is crucial for health, excessive amounts of Cu can be toxic, like we see in Wilson’s disease, which is a genetic mutation in ATP7B leading to excessive amounts of Cu in the body and, therefore, several neurological problems [30]. A cohort study involving 4035 middle-aged French participants showed that serum copper is associated with a 30% increase in cardiovascular disease (CVD) mortality compared to extreme quartiles (mean concentration of 952.5 micrograms per liter) [31].
Furthermore, the results of several other studies also indicated an association between serum copper levels and increased risk of CVA mortality [32,33]. In this regard, Hu and colleagues also reached a similar conclusion in their study. In this study, which involved 1255 participants matched for age, gender, and location, it was found that baseline plasma copper is positively associated with the risk of ischemic stroke [34]. However, this study was conducted based on plasma copper. Overall, several molecular mechanisms that may be involved in toxic metal-induced stroke have been described, such as oxidative stress, apoptosis, inflammation, cerebral microvascular damage, endothelial dysfunction, matrix metalloproteinase expression, and amyloid angiopathy [23]. Patwa and colleagues also demonstrated in their study that copper leads to amyloid deposition in the brain, which is the primary cause of cerebral amyloid angiopathy [35]. As a 2023 review indicates, a higher level of copper ion in aging populations shows a significant relation between copper and vascular aging [36]. Furthermore, copper also increases blood pressure through oxidative stress and inflammation, and serum copper levels above 130 micrograms per deciliter increase blood pressure sensitivity by 1.99 times. Since many factors influence stroke, further research is needed for a better understanding of the relationship between serum copper and stroke risk.
Another study result is the association between serum zinc levels and stroke. It was found in this study that the higher the level of zinc, the higher the risk of stroke. Some studies have shown that the type of stroke is associated with zinc levels [37]. The results of the Huang study are consistent with the present study’s findings [38]. The study by Huang and colleagues, a meta-analysis study, showed that serum zinc levels in patients with ischemic stroke were significantly higher than those in the control group. However, a significant association between zinc levels and the risk of hemorrhagic stroke was not found [38]. It has been identified that elevated Zinc levels inhibit the absorption of Copper and Iron, increase ROS production in mitochondria, disrupt metabolic enzyme activity, and activate apoptotic proteins. Zinc homeostasis disturbance leads to Alzheimer’s disease, brain damage, ischemic stroke, and other conditions [39].
Interestingly, it is worth mentioning that low zinc levels are associated with stroke. Two other cross-sectional studies also showed that serum zinc levels are significantly lower among stroke patients compared to the control group, and low serum zinc levels are associated with increased severity of acute stroke in stroke patients [13,40]. However, these findings suggest the need for further research in this area and investigation into appropriate dosage.
The results of this study indicate that an increase in lead levels is associated with an increased risk of stroke, and there is a direct correlation between them. Additionally, individuals with higher lead levels had a 9.17 times higher probability of ischemic CVA than those in the lower quartile. A meta-analysis conducted by Bao and colleagues on 38 studies involving 642,014 participants showed that lead is significantly associated with the risk of stroke. However, two other metals (Arsenic and Mercury) had less impact on the risk of stroke. This study also suggested that the association is likely dose-dependent [41].
Furthermore, a case-control study examined the association of 45 mineral elements with stroke in 92 patients. Blood lead levels were significantly higher and were associated with stroke [42]. The studies mentioned above confirm these results. However, one study reported an association between serum mercury and Myocardial Infarction. At the same time, non-significant differences were observed in serum and urine levels of lead, arsenic, and cadmium [43].
What is clear is that lead possesses specific toxic properties in fibrinolysis, proliferation, and extracellular matrix formation in smooth muscle cells and endothelial cells, which can lead to vascular disorders, including arterial sclerosis, in laboratory animals. Furthermore, some animal studies indicate that lead may cause significant damage to cerebral vascular endothelium and disrupt cerebral microvessels’ function by altering cerebral blood flow. Therefore, lead may play a role in developing cerebral atherosclerosis and CVA [44].
The results of this study specified that lower levels of nickel are associated with an increased risk of stroke. In this regard, Li and colleagues [45] and Skalny [14] stated in their studies that nickel and some other metals (such as cadmium, arsenic, mercury, and aluminum) are associated with the pathophysiology of stroke.
The analysis of the results of this study showed that both excessive increase and severe decrease in manganese are associated with ischemic stroke. The study’s results by Alikunju and colleagues [46] are consistent with the present study. Alikunju and colleagues [46] stated in their case report study that rarely, manganese neurotoxicity can present as stroke; only one case in a published report has been documented. This study mentioned that higher levels of manganese in red blood cells are associated with greater accumulation in the brain. In addition to the above cases, Wen and colleagues [47] conducted a case-control study on 1277 individuals to investigate the relationship between several plasma metals and the risk of ischemic stroke. The results of this study are consistent with the present study, indicating that the concentration of various metals, including manganese, in patients with ischemic stroke was significantly higher than in control individuals [47]. Mechanisms of manganese-induced issues have been studied, including oxidative stress, mitochondrial dysfunction, glutamate toxicity, protein misfolding, inflammation, autophagy, mitophagy, endoplasmic reticulum stress, and apoptosis [47–49]. Additionally, another study mentioned that manganese induces proteolytic cleavage of protein kinase C-delta (PKC-δ), one of the essential factors in brain damage, and is also a major factor in the neuroprotective activity of the protein alpha-synuclein [39].
As a strength of this study, this is the first study that assesses these metals in the Persian population. Assessing all these metals together with some of the most common confounding factors like smoking and opium use is the other strength of the study. Some limitations in this study should be taken into account. Firstly, as this is one of the few studies assessing these metals’ levels in CVA patients, the number of cases and ethnicity are limited. Future studies can assess these metals in more cases with various ethnicities to better demonstrate this effect. Secondly, as hemorrhagic stroke is less frequent, the cases were not adequate to form a separate group. Lastly, since our study was a case-control study, determining the cause and effect needs to be more studied in this field. It is suggested that future studies use hemorrhagic stroke patients’ groups to evaluate the difference between hemorrhagic and ischemic stroke patients.
5. Conclusion
In conclusion, given that the general population is widely exposed to several metals, even a slight increase in the risk of stroke due to exposure to metals (especially copper) can have significant public health implications. Reducing exposure to multiple metals may help alleviate the risk of stroke.
References
- 1. Hsieh CY, Wu DP, Sung SF. Trends in vascular risk factors, stroke performance measures, and outcomes in patients with first-ever ischemic stroke in Taiwan between 2000 and 2012. J Neurol Sci. 2017;378:80–4. pmid:28566185
- 2. Mousavi-Mirzaei SM, Talebi A, Amirabadizadeh A, Nakhaee S, Azarkar G, Mehrpour O, et al. Increasing the risk of stroke by opium addiction. J Stroke Cerebrovasc Dis. 2019;28(7):1930–5. pmid:31000450
- 3. Mousavi-Mirzaei SM, Khorasani EY, Amirabadizadeh A, Nakhaee S, Baharshahi A, Rajabpour-Sanati A, et al. Comparison of blood lead concentrations in patients with acute ischemic stroke and healthy subjects. J Trace Elem Med Biol. 2020;61:126532. pmid:32361683
- 4.
Lindsay MP, Norrving B, Sacco RL, Brainin M, Hacke W, Martins S, et al. World Stroke Organization (WSO): global stroke fact sheet 2019. London, England: SAGE Publications Sage UK; 2019.
- 5. Guzik A, Bushnell C. Stroke epidemiology and risk factor management. Continuum (Minneap Minn). 2017;23(1):15–39. pmid:28157742
- 6. Feigin VL, Stark BA, Johnson CO, Roth GA, Bisignano C, Abady GG, et al. Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the global burden of disease study 2019. Lancet Neurology, 2021.20(10):795–820.
- 7. Saini V, Guada L, Yavagal DR. Global epidemiology of stroke and access to acute ischemic stroke interventions. Neurology. 2021;97(20 Suppl 2):S6–16. pmid:34785599
- 8. Feigin VL, Brainin M, Norrving B, Martins S, Sacco RL, Hacke W, et al.. World Stroke Organization (WSO): global stroke fact sheet 2022. Int J Stroke. 2022;17(1):18–29.
- 9. Kim YD, Jung YH, Saposnik G. Traditional risk factors for stroke in East Asia. J Stroke. 2016;18(3):273–85. pmid:27733028
- 10. Kim YN, Kim YA, Yang AR, Lee BH Relationship between blood mercury level and risk of cardiovascular diseases: results from the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV) 2008–2009. Prev Nutr Food Sci. 2014;19(4):333.
- 11. Houston MC. Role of mercury toxicity in hypertension, cardiovascular disease, and stroke. J Clin Hypertens. 2011;13(8):621–7.
- 12. Planel E, et al. Mercury and Alzheimer’s disease. Elev Int Congr. 2020;10:1–8.
- 13. Mattern L, Chen C, McClure LA, Brockman J, Cushman M, Judd S, et al. Serum zinc levels and incidence of ischemic stroke: the reasons for geographic and racial differences in stroke study. Stroke. 2021;52(12):3953–60. pmid:34412513
- 14. Skalny AV, Klimenko LL, Turna AA, Budanova MN, Baskakov IS, Savostina MS, et al. Serum trace elements are associated with hemostasis, lipid spectrum and inflammatory markers in men suffering from acute ischemic stroke. Metab Brain Dis. 2017;32(3):779–88. pmid:28220282
- 15. Karadas S, Sayın R, Aslan M, Gonullu H, Katı C, Dursun R, et al. Serum levels of trace elements and heavy metals in patients with acute hemorrhagic stroke. J Membr Biol. 2014;247(2):175–80. pmid:24346187
- 16. Gönüllü H, Karadaş S, Milanlioğlu A, Gönüllü E, Katı C, Demir H. Levels of serum trace elements in ischemic stroke patients. J Exper Clini Med. 2014;30(4):301–4.
- 17. Skalny AV, Klimenko LL, Turna AA, Budanova MN, Baskakov IS, Savostina MS, et al. Serum trace elements are associated with hemostasis, lipid spectrum and inflammatory markers in men suffering from acute ischemic stroke. Metab Brain Dis. 2017;32(3):779–88. pmid:28220282
- 18. Mitra J, Vasquez V, Hegde PM, Boldogh I, Mitra S, Kent TA, et al. Revisiting metal toxicity in neurodegenerative diseases and stroke: therapeutic potential. Neurol Res Therapy. 2014;1(2).
- 19. Lee C, Hu M. Parkinsonism in a patient with metal on metal total hip replacement related elevated serum heavy metal levels. Cureus. 2021;13(9):e17791. pmid:34522559
- 20. Farmani R, Mehrpour O, Kooshki A, Nakhaee S. Exploring the link between toxic metal exposure and ADHD: a systematic review of pb and hg. J Neurodev Disord. 2024;16(1):44. pmid:39090571
- 21. Kooshki A, Farmani R, Mehrpour O, Naghizadeh A, Amirabadizadeh A, Kavoosi S, et al. Alzheimer’s disease and circulatory imbalance of toxic heavy metals: a systematic review and meta-analysis of clinical studies. Biol Trace Elem Res. 2024.
- 22. Zamani N, Mehrpour O, Hassanian-Moghaddam H. A preliminary report on the largest ongoing outbreak of lead toxicity in Iran. J Env Health Sci Eng. 2020;10(1):11797.
- 23. Nguyen HD, Kim MS. In silico identification of molecular mechanisms for stroke risk caused by heavy metals and their mixtures: sponges and drugs involved. Neurotoxicology. 2023;96:222–39. pmid:37121440
- 24. Amirabadizadeh A, Nakhaee S, Mehrpour O. Risk assessment of elevated blood lead concentrations in the adult population using a decision tree approach. Drug Chem Toxicol. 2022;45(2):878–85. pmid:32588664
- 25. Prozialeck WC, Edwards JR, Nebert DW, Woods JM, Barchowsky A, Atchison WD. The vascular system as a target of metal toxicity. Toxicol Sci. 2008;102(2):207–18. pmid:17947343
- 26. Mlynek V, Skoczyńska A. The proinflammatory activity of cadmium. Adv Hyg and Exp Med. 2005;59.
- 27. (NTIS), N.T.I.S. Public health statement copper; 2004. Available from: www.atsdr.cdc.gov/
- 28. NIH. Copper; 2023. Available from: https://ods.od.nih.gov/factsheets/Copper-HealthProfessional/#en1
- 29.
Collins JF. Copper. In: Ross ACCB, Cousins RJ, Tucker KL, Ziegler TR, eds, Modern Nutrition in Health and Disease. Baltimore, MD: Lippincott Williams & Wilkins; 2014. p. 206–216.
- 30. Trocello JM, Girardot-Tinant N, Pelosse M, Lachaux A, Lloyd C. Wilson’s disease, 100 years later. Rev Neurol (Paris). 2013:169–936.
- 31. Leone N, Courbon D, Ducimetiere P, Zureik M. Zinc, copper, and magnesium and risks for all-cause, cancer, and cardiovascular mortality. Epidemiology. 2006;17(3):308–14. pmid:16570028
- 32. Eshak ES, Iso H, Yamagishi K, Maruyama K, Umesawa M, Tamakoshi A. Associations between copper and zinc intakes from diet and mortality from cardiovascular disease in a large population-based prospective cohort study. J Nutr Biochem. 2018;56:126–32. pmid:29529560
- 33. Zhang M, Li W, Wang Y, Wang T, Ma M, Tian C. Association between the change of serum copper and ischemic stroke: a systematic review and meta-analysis. J Mol Neurosci. 2020;70(3):475–80. pmid:31782058
- 34. Hu L, Bi C, Lin T, Liu L, Song Y, Wang P, et al. Association between plasma copper levels and first stroke: a community-based nested case-control study. Nutr Neurosci. 2022;25(7):1524–33. pmid:33535911
- 35. Patwa J, Flora SJS. Heavy metal-induced cerebral small vessel disease: insights into molecular mechanisms and possible reversal strategies. Int J Mol Sci. 2020;21(11):3862. pmid:32485831
- 36. Chen Z, Li YY, Liu X. Copper homeostasis and copper-induced cell death: Novel targeting for intervention in the pathogenesis of vascular aging. Biomed Pharmacother. 2023;169:115839. pmid:37976889
- 37. Abolbashari S, Darroudi S, Tayefi M, Khashyarmaneh Z, Zamani P, Haghighi HM, et al. Association between serum zinc and copper levels and antioxidant defense in subjects infected with human T-lymphotropic virus type 1. J Blood Med. 2018;10:29–35. pmid:30643476
- 38.
Huang M, Zhu L, Chen Y, Jin Y, Fang Z, Yao Y. Serum/plasma zinc is apparently increased in ischemic stroke: a meta-analysis. Biological Trace Element Research; 2022. p. 1–9.
- 39. Montazeri A, Akhlaghi M, Barahimi AR, Jahanbazi Jahan Abad A, Jabbari R. The role of metals in neurodegenerative diseases of the central nervous system. Neuroscience J Shefaye Khatam. 2020;8(2):130–46.
- 40. Munshi A, Babu S, Kaul S, Shafi G, Rajeshwar K, Alladi S, et al. Depletion of serum zinc in ischemic stroke patients. Methods Find Exp Clin Pharmacol. 2010;32(6):433–6. pmid:20852753
- 41. Bao QJ, Zhao K, Guo Y, Wu XT, Yang JC, Yang MF. Environmental toxic metal contaminants and risk of stroke: a systematic review and meta-analysis. Environ Sci Pollut Res Int. 2022;29(22):32545–65. pmid:35190994
- 42. Medina-Estévez F, Zumbado M, Luzardo OP, Rodríguez-Hernández Á, Boada LD, Fernández-Fuertes F, et al. Association between heavy metals and rare earth elements with acute ischemic stroke: a case-control study conducted in the canary Islands (Spain). Toxics. 2020;8(3):66. pmid:32887274
- 43. Wennberg M, Bergdahl IA, Hallmans G, Norberg M, Lundh T, Skerfving S, et al. Fish consumption and myocardial infarction: a second prospective biomarker study from northern Sweden. Am J Clin Nutr. 2011;93(1):27–36. pmid:21048056
- 44. Mousavi-Mirzaei SM, Khorasani EY, Amirabadizadeh A, Nakhaee S, Baharshahi A, Rajabpour-Sanati A, et al. Comparison of blood lead concentrations in patients with acute ischemic stroke and healthy subjects. J Trace Elem Med Biol. 2020;61:126532. pmid:32361683
- 45.
Li YV, Zhang JH. Metal ions in stroke pathophysiology. Metal ion in stroke; 2012. p. 1–12.
- 46. Alikunju M, Alikunju M, Misiriyyah N, Iqbal SS, Khan M. Manganese neurotoxicity as a stroke mimic: a case report. Cureus, 2023. 15(4).
- 47. Wen Y, Huang S, Zhang Y, Zhang H, Zhou L, Li D, et al. Associations of multiple plasma metals with the risk of ischemic stroke: a case-control study. Environ Int. 2019;125:125–34. pmid:30716572
- 48. Harischandra DS, Ghaisas S, Zenitsky G, Jin H, Kanthasamy A, Anantharam V, et al. Manganese-induced neurotoxicity: new insights into the triad of protein misfolding, mitochondrial impairment, and Neuroinflammation. Front Neurosci. 2019;13:654. pmid:31293375
- 49. Tinkov AA, Paoliello MMB, Mazilina AN, Skalny AV, Martins AC, Voskresenskaya ON, et al. Molecular targets of manganese-induced neurotoxicity: a five-year update. Int J Mol Sci. 2021;22(9):4646. pmid:33925013