Association of Selenium Levels with Neurodegenerative disease: A Systemic Review and Meta-analysis

doi:10.21203/rs.3.rs-2584949/v1

Background

Neurodegenerative diseases are debilitating and incurable disorders with a rapid-rising prevalence. Selenium, a trace element, works in anti-oxidant and anti-inflammatory aspects through selenoprotein biologically. Nowadays, it is in a great urgency to discover the intrinsic relationship between selenium and neurodegenerative diseases, and find more effective therapeutic strategies to combat these devastating diseases.

Method

Five public databases including PubMed, Web of Science, EMBASE, Cochrane, Clinical Trials were searched in our research. Random model effects were chosen, and Higgins inconsistency analyses (I²), Cochrane’s Q test, Tau2 were calculated to evaluate the heterogeneity.

Result

The association of selenium in neurodegenerative diseases patients including Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis, Amyotrophic lateral sclerosis and Huntington’s disease was studied. The strong relation was only found in AD patients, especially the erythrocytes in sub-group analysis of various tested tissue type.

Conclusion

Generally, this meta-analysis indicated that Alzheimer’s disease is strongly associated with lower selenium concentration, which may provide clinical reference in the future. However, more researches are in urgent need for further study and treatment for neurodegenerative diseases.

Selenium

Neurodegenerative disease

Selenoprotein

Systematic review

Meta- analysis

Neurodegenerative diseases(NDs), such as Alzheimer’s disease(AD), Parkinson’s disease(PD), Multiple sclerosis(MS), Amyotrophic lateral sclerosis(ALS), Huntington’s disease(HD) are debilitating and incurable disorders characterized by progressive loss of neurons in brain and spinal cord. The pathogenesis of NDs are complex and various, but with the same consequence, neuronal cell death. The number of people living with NDs is increasing worldwide, accompanied with diverse clinical manifestations, such as learning and cognition impairment, memory impairment, memory distortion, sleeping disorder.(Gitler, Dhillon and Shorter 2017)

It was found that the altered homeostasis of some mineral elements are strongly associated with the progression of NDs, such as copper,(Scheiber, Dringen and Mercer 2013) iron,(Ward et al. 2014) and zinc,(Mezzaroba et al. 2019) indicating the potential relation between elements and NDs. Selenium, a naturally nonmetallic element, which widely exists in minerals, soil and food, is essentially required by human body for normal physiological processes. It is considered as an irreplaceable element with key importance for keeping the body operational and healthy, including preventing from cancers and cardiovascular disease, regulating immune system.(Rayman 2000, Stuss, Michalska-Kasiczak and Sewerynek 2017) The biological functions of selenium are predominantly mediated by selenoproteins, a series of 25 selenium-containing proteins, acting as essential intracellular antioxidants in preventing oxidative injury. It has been demonstrated that the selenium supplementation plays a significant role in boosting up the internal antioxidative defense in recent studies.(Wang et al. 2017) Moreover, the defect of selenium and selenoproteins may cause malabsorption, cystic fibrosis, rheumatoid arthritis, neoplasia, and other diverse clinical disorders.(Lockitch 1989)

One of the mechanisms of NDs can be attributed to the deficiencies in antioxidant enzyme activity. Se has recently been demonstrated a significant role in several neurodegenerative disorders. It can influence the compounds with hormonal activity and neurotransmitters in human brain, regulate calcium ion channels and modulate neurogenesis(Whanger 2001, Öz and Çelik 2016) The increased Se level is associated with a higher GPX activity, an important antioxidant enzyme related with NDs.(Rita Cardoso et al. 2016) Moreover, Se can also work as an antioxidant, an antidote to toxicity of heavy metals.(Dexter et al. 1989) For example, selenium compounds can decrease the intracellular toxicity of the deranged tau and Aβ, as well as inhibiting the accumulation of advanced glycation end-products and the neurotoxicity of metal-induced in AD.(Aaseth et al. 2021) And selenoproteins play a vital part in antioxidant activity, which indicates a strong relationship between selenium and NDs.(Cardoso et al. 2015)

Nowadays, the precise association and possible relationship between Se and NDs still remain controversial. For instance, Huseyin Vural et al reported that the plasma in AD patients had lower levels of Se compared with healthy people, and found there was a strong relationship between selenium and GPx values.(Vural et al. 2010) However, some studies(Cornett et al. 1998, Meseguer et al. 1999) have shown no statistically significant difference of Se level between AD groups and control groups. It interests us that Sreeram Krishnan et al even points that blood selenium is not involved in regulating oxidative stress in AD.(Krishnan and Rani 2014) Some research suggested a protective mechanism of Se in PD patients.(Salaramoli, Joshaghani and Hashemy 2022, Zhang et al. 2019) While there also exists study reporting no relationship between Se and PD.(Mischley, Allen and Bradley 2012) Interestingly, another study implicated both reduced and excessive selenium related with NDs.(Mantle and Hargreaves 2022) And at present, no comprehensive overview or comparative analysis of NDs are available. Thus, this meta-analysis aims to study the association of selenium levels with NDs including AD, PD, MS, ALS, HD.

Protocol and Registration

The protocol for this research was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021286946) and was carried out based on the Pattern of Reporting Systematic Review and Meta-Analysis (PRISMA) guideline.

Literature searching strategy

Five databases including PubMed, Web of Science, EMBASE, Cochrane library and Clinical Trials were retrieved through Mesh terms get from National Center Biotechnology Information (NCBI). And the reference lists of eligible reports were also searched to identify potentially relevant literatures. The databases were searched through titles and abstracts, using the keywords “selenium”, “Alzheimer’s disease”, “Parkinson’s disease”, “Multiple sclerosis”, “Amyotrophic lateral sclerosis”, “Huntington’s disease”, and the Boolean operators “OR” and “AND”. Literature published between 1976 and 2021 were searched.

Inclusion and exclusion criteria

These criteria were formulated by all authors. Inclusion criteria: (I) studies with the tests of the selenium concentration in NDs patients; (II) the research should contain both NDs case group and healthy control group; (III) the studies should include standard and sufficient data; (IV) research data must be obtained independently by relative teams or organizations; (V) the publication language was English.

Exclusion criteria: (I) duplicate publications and data; (II) research data comes from public databases; (III) literature types are reviews, case reports, meeting abstracts, and basic experimental research literature; (IV) literature language is other than English.

Data Extraction and quality assessment

From each of the included literature, the following data were collected: author’s name, publication year, country or area, the number of patients, study design, NDs type, tissue type, mean value of selenium concentration, SD (standard deviation) value. These data were reported in standardized data extraction spreadsheet for further analysis. The quality assessment of eligible studies was done independently using the Newcastle–Ottawa scale. In addition, the funnel plots were used to evaluate the bias.

Statistical Analysis

The meta-analysis was performed through the Review Manager (RevMan) software version 5.4, and the obtained results were considered statistically significant when p < 0.05. Random model effects were analyzed, and heterogeneity was evaluated using Higgins inconsistency analyses (I²), Cochrane’s Q test, and Tau².

Study selection

The initial literature search identified 2188 reports, including 363 reports from the PubMed, 562 reports from the Web of Science, and 1064 reports from the EMBASE database, 53 from the Cochrane database, 146 from clinical trials. After removing duplicate reports, 652 literatures were considered to be potentially eligible. Finally, according to the above including and excluding criteria, 45 articles were selected, including 1050 patients. The study selection flowchart is shown in Fig. 1.

Baseline characteristics of included studies

The eligible studies included 4924 participants and 5 NDs types, Alzheimer’s disease(AD), Parkinson’s disease(PD), Multiple sclerosis(MS), Amyotrophic lateral sclerosis(ALS), Huntington’s disease(HD). The publication year was from 1976 to 2022, and the studies were performed in 17 different areas. Among all the research, 43 of them were utilized case-control study designs, while other studies belong to nested case-control study design. The detailed information was shown in table 1.

Analysis of selenium and AD

Forty-four research were chosen to perform the meta-analysis to observe the intrinsic association of selenium in AD patients. It was found that AD patients were negatively related to selenium concentration in tissue, compared with healthy people (SMD = − 0.42, 95% CI (− 0.64, -0.17), p = 0.001). (Fig. 2a) To observe more details, sub-group analysis was also performed, dividing AD patients into four sub-groups according to different tested tissue type, including serum/plasma, blood, cerebrospinal fluid(CSF), erythrocyte. And only the erythrocyte (SMD = − 1.54, 95% CI (− 2.97, -0.12), p = 0.03) showed strongly related with selenium in AD patients. (Fig. 3)

The relationship between selenium and PD

After performing the meta-analysis of PD patients, no obvious statistically significance was found about selenium level between PD patients and healthy control. (SMD = 0.30, 95% CI (− 0.31, 0.91), p = 0.34). (Fig. 2b)

Selenium in MS patients

To explore the potential association of selenium in MS patients, the meta-analysis was performed in seven literatures. However, still no statistically significance was found (SMD = − 0.28, 95% CI (− 1.01, 0.44), p = 0.44). (Fig. 2c)

Analysis of selenium and ALS

Nine studies were selected to compare the Se levels in ALS patients with healthy people.(Fig. 2d) The random-effects meta-analysis showed ALS patients had a higher tendency toward decreased serum SE levels, but without statistically significance (SMD = − 0.35, 95% CI (− 1.23, 0.54), p = 0.44).

Selenium in HD patients

In this meta-analysis, only one acceptable study was found (SMD = 2.56, 95% CI (1.65, 3.46)). (Fig. 2e)

Assessment of publication bias

The publication bias for this research was evaluated by funnel plots, which were collected and shown in Fig. 4. There was no obvious publication bias found in this research. Newcastle-Ottawa scale scores from 5 to 9, listed in table 1. The Heterogeneity value also indicated a low publication bias. (table 1)

Selenium is an essential element which is very important in human health and development, especially to maintain the brain function. Human brain is the most metabolically active organ in the body, with only 2% total mass but about 20% of the whole oxygen need and 25% glucose consumption of whole body.(Raichle and Mintun 2006) Compared with other organs, Se concentration in brain is low. However, it has the highest priority for the uptake and retention of Se when deficiency happens.(Behne and Wolters 1983) In our research, it was demonstrated that Se concentration in human is strongly negative associated in AD patients, compared with healthy people. Moreover, AD patients were shown to have a lower Se level especially in erythrocyte. While no statistical significance was observed in PD, MS, ALS and HD patients.

The biological functions of Se are mainly carried out through selenoprotein. Se is an indispensable element for the synthesis of selenoprotein including selenoprotein P (SelP), selenoprotein M (SelM), selenoprotein W (SelW), selenoprotein S (SelS), selenoprotein H (SelH), and it can also modulate the expression of selenoproteins. The antioxidant activity of selenoprotein in CNS has been confirmed. Decreased selenoprotein function and lower Se level will lead to impaired cognitive function and neurological disorders. SleP has been demonstrated to be able to combine with several heavy metals such as mercury(Yoneda and Suzuki 1997), zinc(Yan and Barrett 1998), nickel(Mostert, Lombeck and Abel 1998), cadmium and silver(Sasakura and Suzuki 1998). Recent studies also reported the function of SleP in delivery of selenium to the brain.(Hill et al. 2003) Also, it can protect from peroxynitrite-mediated oxidation and nitration in human plasma, which does harm to brain.(Arteel et al. 1998)

Glutathione peroxidases (GPxs), a selenoenzyme family capable of eliminating peroxides expressed in neurons and glia, can protect brain cells from ROS-induced damage. In animal experiments, mice deficient in cytoplasmic GPxs showed increased infarct size and more apoptosis.(Crack et al. 2001) SelP was shown to be the most efficient selenium donor with the ability to maintain selenium content and GPx activity.(Saito and Takahashi 2002) Some studies showed that SelM was strongly associated with promoting antioxidant enzymes in brain, and improving dietary supplementation of Se.(Chen et al. 2013, Yim et al. 2009, Reeves, Bellinger and Berry 2010) Furthermore, the major function of SelW include antioxidant activity, maintaining redox homeostasis and mediating synaptic function.(Raman et al. 2012) As for SelS, it can modulate the function of astrocytes, while overexpression of SelS will improve mitochondrial biogenesis and function (Wu et al. 2014) And SelH plays the role in protecting the cells against replicative senescence under chronic oxidative stress.

AD

Progressive loss of memory, and impairment of daily activities have become the main characteristics of AD patients. Oxidative stress is a significant part of AD pathogenesis, and ROS can adversely affect the mitochondrial biofunction, synaptic transmission, axonal transport, and stimulate neuroinflammation.(Swerdlow, Burns and Khan 2014, Picco et al. 2014, Haider et al. 2014) Glutathione peroxidase is a key point to protect the brain from free radicals acting, hydrogen peroxide and lipid peroxidation, which becomes a central defensive role in AD.(Cardoso et al. 2010) Selenium provides the protection to cellular tissue from ROS-induced cell damage with the proposed mechanisms invoking the functions of glutathione peroxidases (GPxs) and SleP.(Chen and Berry 2003) Compared with healthy people, we reported a declined Se level in AD patients (p = 0.004), which may also indicated a worse anti-oxidant ability and higher ROS attack for AD patients because of lower Se level. It has been demonstrated that plasma is considered as a marker of recent exposure, while erythrocytes tend to reflect longer-term Se level. And in our research, Se level was shown to be lower in erythrocyte of AD patients, while no statistically significance was found in serum/plasma, blood and CSF.

PD

Parkinson's disease (PD) is the neurodegenerative disorder, resulting primarily from the loss of dopaminergic neurons in substantia nigra, characterized with the presence of intraneuronal proteinaceous inclusions termed Lewy bodies. Current medications only treat on symptoms of PD rather than stopping the dopaminergic neuron degeneration. It was observed that the density of GPx-immunostained cells around the surviving dopaminergic neurons increased in PD patients, directly proportional to the extent of the severity in dopaminergic cell loss in the respective cell groups.(Dauer and Przedborski 2003) The research has found that, in patients with PD, the enzyme activity of GPx decreased about 20% in substantia nigra, external globus pallidus, putamen, and frontal cortex, compared with healthy people.(Kish, Morito and Hornykiewicz 1985) The value of Se is strongly associated with GPx, which may suggest several potential interactions.(Damier et al. 1993) While the association of Se in PD patients remains unclear. In similar research, there was no statistically significant difference was reported when cerebrospinal fluid and different brain regions were investigated.(Shahar et al. 2010) And in our research, after integrating the data, no significant relationship was found between Se and PD. (p = 0.25)

MS

Multiple sclerosis (MS) is a kind of progressive, inflammatory chronic disease affecting the function of CNS. The etiology of MS remains unclear, while it is believed to be associated with genetic and environmental interaction, abnormal immune response, oxidative stress.(Gandhi, Laroni and Weiner 2010) No significant relationship was observed between Se and MS in our study. (p = 0.45)

ALS

Amyotrophic lateral sclerosis (ALS), is a severe degenerative motor neuron disease with unknown etiology, although some cases reported the possible association with genetic origin. Vinceti et al. had described that the elevated level of selenite and selenised human serum albumin in CSF is related with the higher sporadic ALS risk, while a elevated CSF SePP level was found to be related to lower risk of this disease(Peters et al. 2021). However, this point remains controversial. Some studies showed that reduced Se level was observed in ALS patients compared with healthy people(Moriwaka et al. 1993). Nagata H et al. and his team reported a higher Se level in the red blood cells of patients with ALS.(Nagata et al. 1985) Meanwhile, several related studies have reported that no significant difference of the Se levels in body fluids was observed between ALS patients and healthy people.(Vinceti et al. 1997, De Benedetti et al. 2017) Thus, the association of Se levels and ALS was investigated in our research. ALS patients had a tendency toward decreased total Se levels compared with healthy, but no statistically significant difference was found (p = 0.64). Hence, the further investigations are necessary to address the association of Se levels in ALS individuals.,

HD

Huntington disease (HD), a dominantly inherited neurodegenerative disorder that results from expansion of the polyglutamine repeat in the huntingtin (HTT) gene(Munoz-Sanjuan and Bates 2011). In the population of HD, it was found that not only selenium inhibits lipid peroxidation by increasing specific glutathione peroxidases, but also GPx activity in the brain was significantly increased, especially GPx1 and GPx6.(Pillai, Uyehara-Lock and Bellinger 2014) Increased ROS production may result in a stress situation that activates several pathways to increase the expression of antioxidant enzymes.(Sorolla et al. 2008) Oxidative stress seems to be a key process to understand the pathogenesis of HD, but the intrinsic mechanism is still unclear. Thus, more studies are in need to explore the relationships of Se and HD.

Nevertheless, some limitations exist in the current research. Firstly, the heterogeneity of included research cannot be ignored. Various region and race, large span of publication year, the interaction between selenium and other food or drugs can result in high heterogeneity. In addition, although we recorded the baseline characters of the population and did the subgroup analysis, some of the included studies didn’t provide enough details, such as selenium treatment. And this study lacked the analysis of randomized controlled research with most of the eligible researches were retrospective study.

In conclusion, our research revealed that AD patient is strongly associated with lower selenium concentration compared with healthy people, especially in the erythrocyte, which may provide meaningful reference to clinic. While there is no statistically significant between selenium level and PD, MS, ALS and HD. Still, more researches are in need to find the concrete mechanism between selenium level and NDs and further improve the clinical treatment.

The data and materials (including Supplementary Material) used to support the findings in this research are available from the corresponding author upon request.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author Contributions

JX-Z and CQ-L conceived the idea. JX-Z, WF-Z and CQ-L wrote draft of the manuscript. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.

Fundings

This work was supported by the National Natural Science Foundation of China (No.81903294), and Medical Scientific Research Foundation of Guangdong Province of China (A2021123), and Guangzhou Basic and Applied Basic Research Foundation (202102020120).

Acknowledgments

Not applicable.

Aaseth, J., A. V. Skalny, P. M. Roos, J. Alexander, M. Aschner & A. A. Tinkov (2021) Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer's Disease. Int J Mol Sci, 22.
Arteel, G., V. Mostert, H. Oubrahim, K. Briviba, J. Abel & H. Sies (1998) Protection by selenoprotein P in human plasma against peroxynitrite-mediated oxidation and nitration. Biological chemistry, 379, 1201-1205.
Behne, D. & W. Wolters (1983) Distribution of selenium and glutathione peroxidase in the rat. The Journal of nutrition, 113, 456-461.
Cardoso, B. R., T. P. Ong, W. Jacob-Filho, O. Jaluul, M. I. Freitas & S. M. Cozzolino (2010) Nutritional status of selenium in Alzheimer's disease patients. Br J Nutr, 103, 803-6.
Cardoso, B. R., B. R. Roberts, A. I. Bush & D. J. Hare (2015) Selenium, selenoproteins and neurodegenerative diseases. Metallomics, 7, 1213-28.
Chen, J. & M. J. Berry (2003) Selenium and selenoproteins in the brain and brain diseases. J Neurochem, 86, 1-12.
Chen, P., R.-R. Wang, X.-J. Ma, Q. Liu & J.-Z. Ni (2013) Different forms of selenoprotein M differentially affect Aβ aggregation and ROS generation. International Journal of Molecular Sciences, 14, 4385-4399.
Cornett, C. R., W. D. Ehmann, D. R. Wekstein & W. R. Markesbery (1998) Trace elements in Alzheimer's disease pituitary glands. Biol Trace Elem Res, 62, 107-14.
Crack, P. J., J. M. Taylor, N. J. Flentjar, J. De Haan, P. Hertzog, R. C. Iannello & I. Kola (2001) Increased infarct size and exacerbated apoptosis in the glutathione peroxidase‐1 (Gpx‐1) knockout mouse brain in response to ischemia/reperfusion injury. Journal of neurochemistry, 78, 1389-1399.
Damier, P., E. Hirsch, P. Zhang, Y. Agid & F. Javoy-Agid (1993) Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience, 52, 1-6.
Dauer, W. & S. Przedborski (2003) Parkinson's Disease: Mechanisms and Models. Neuron, 39, 889-909.
De Benedetti, S., G. Lucchini, C. Del Bò, V. Deon, A. Marocchi, S. Penco, C. Lunetta, E. Gianazza, F. Bonomi & S. Iametti (2017) Blood trace metals in a sporadic amyotrophic lateral sclerosis geographical cluster. Biometals, 30, 355-365.
Dexter, D., C. Carter, F. Wells, F. Javoy‐Agid, Y. Agid, A. Lees, P. Jenner & C. D. Marsden (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. Journal of neurochemistry, 52, 381-389.
Gandhi, R., A. Laroni & H. L. Weiner (2010) Role of the innate immune system in the pathogenesis of multiple sclerosis. Journal of neuroimmunology, 221, 7-14.
Gitler, A. D., P. Dhillon & J. Shorter (2017) Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech, 10, 499-502.
Haider, S., S. Saleem, T. Perveen, S. Tabassum, Z. Batool, S. Sadir, L. Liaquat & S. Madiha (2014) Age-related learning and memory deficits in rats: role of altered brain neurotransmitters, acetylcholinesterase activity and changes in antioxidant defense system. Age (Dordr), 36, 9653.
Hill, K. E., J. Zhou, W. J. McMahan, A. K. Motley, J. F. Atkins, R. F. Gesteland & R. F. Burk (2003) Deletion of selenoprotein P alters distribution of selenium in the mouse. Journal of Biological Chemistry, 278, 13640-13646.
Kish, S. J., C. Morito & O. Hornykiewicz (1985) Glutathione peroxidase activity in Parkinson's disease brain. Neuroscience letters, 58, 343-346.
Krishnan, S. & P. Rani (2014) Evaluation of selenium, redox status and their association with plasma amyloid/tau in Alzheimer's disease. Biol Trace Elem Res, 158, 158-65.
Lockitch, G. (1989) Selenium: clinical significance and analytical concepts. Crit Rev Clin Lab Sci, 27, 483-541.
Mantle, D. & I. P. Hargreaves (2022) Mitochondrial Dysfunction and Neurodegenerative Disorders: Role of Nutritional Supplementation. Int J Mol Sci, 23.
Meseguer, I., J. A. Molina, F. J. Jiménez-Jiménez, M. V. Aguilar, C. J. Mateos-Vega, M. J. González-Muñoz, F. de Bustos, M. Ortí-Pareja, M. Zurdo, A. Berbel, E. Barrios & M. C. Martínez-Para (1999) Cerebrospinal fluid levels of selenium in patients with Alzheimer's disease. J Neural Transm (Vienna), 106, 309-15.
Mezzaroba, L., D. F. Alfieri, A. N. Colado Simão & E. M. Vissoci Reiche (2019) The role of zinc, copper, manganese and iron in neurodegenerative diseases. Neurotoxicology, 74, 230-241.
Mischley, L. K., J. Allen & R. Bradley (2012) Coenzyme Q10 deficiency in patients with Parkinson's disease. J Neurol Sci, 318, 72-5.
Moriwaka, F., H. Satoh, A. Ejima, C. Watanabe, K. Tashiro, T. Hamada, A. Matsumoto, K. Shima, T. Yanagihara & T. Fukazawa (1993) Mercury and selenium contents in amyotrophic lateral sclerosis in Hokkaido, the northernmost island of Japan. Journal of the neurological sciences, 118, 38-42.
Mostert, V., I. Lombeck & J. Abel (1998) A novel method for the purification of selenoprotein P from human plasma. Archives of biochemistry and biophysics, 357, 326-330.
Munoz-Sanjuan, I. & G. P. Bates (2011) The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease. The Journal of clinical investigation, 121, 476-483.
Nagata, H., S. Miyata, S. Nakamura, M. Kameyama & Y. Katsui (1985) Heavy metal concentrations in blood cells in patients with amyotrophic lateral sclerosis. Journal of the neurological sciences, 67, 173-178.
Öz, A. & Ö. Çelik (2016) Curcumin inhibits oxidative stress-induced TRPM2 channel activation, calcium ion entry and apoptosis values in SH-SY5Y neuroblastoma cells: Involvement of transfection procedure. Molecular membrane biology, 33, 76-88.
Peters, S., K. Broberg, V. Gallo, M. Levi, M. Kippler, P. Vineis, J. Veldink, L. van den Berg, L. Middleton & R. C. Travis (2021) Blood metal levels and amyotrophic lateral sclerosis risk: a prospective cohort. Annals of neurology, 89, 125-133.
Picco, A., M. C. Polidori, M. Ferrara, R. Cecchetti, D. Arnaldi, M. Baglioni, S. Morbelli, P. Bastiani, I. Bossert, G. Fiorucci, A. Brugnolo, M. E. Dottorini, F. Nobili & P. Mecocci (2014) Plasma antioxidants and brain glucose metabolism in elderly subjects with cognitive complaints. Eur J Nucl Med Mol Imaging, 41, 764-75.
Pillai, R., J. H. Uyehara‐Lock & F. P. Bellinger (2014) Selenium and selenoprotein function in brain disorders. IUBMB life, 66, 229-239.
Raichle, M. E. & M. A. Mintun (2006) Brain work and brain imaging. Annu. Rev. Neurosci., 29, 449-476.
Raman, A. V., M. W. Pitts, A. Seyedali, A. C. Hashimoto, L. A. Seale, F. P. Bellinger & M. J. Berry (2012) Absence of selenoprotein P but not selenocysteine lyase results in severe neurological dysfunction. Genes, Brain and Behavior, 11, 601-613.
Rayman, M. P. (2000) The importance of selenium to human health. The lancet, 356, 233-241.
Reeves, M. A., F. P. Bellinger & M. J. Berry (2010) The neuroprotective functions of selenoprotein M and its role in cytosolic calcium regulation. Antioxidants & redox signaling, 12, 809-818.
Rita Cardoso, B., D. Apolinário, V. da Silva Bandeira, A. L. Busse, R. M. Magaldi, W. Jacob-Filho & S. M. Cozzolino (2016) Effects of Brazil nut consumption on selenium status and cognitive performance in older adults with mild cognitive impairment: a randomized controlled pilot trial. Eur J Nutr, 55, 107-16.
Saito, Y. & K. Takahashi (2002) Characterization of selenoprotein P as a selenium supply protein. European Journal of Biochemistry, 269, 5746-5751.
Salaramoli, S., H. Joshaghani & S. I. Hashemy (2022) Selenium Effects on Oxidative Stress-Induced Calcium Signaling Pathways in Parkinson's Disease. Indian J Clin Biochem, 37, 257-266.
Sasakura, C. & K. T. Suzuki (1998) Biological interaction between transition metals (Ag, Cd and Hg), selenide/sulfide and selenoprotein P. Journal of inorganic biochemistry, 71, 159-162.
Scheiber, I., R. Dringen & J. F. Mercer (2013) Copper: effects of deficiency and overload. Met Ions Life Sci, 13, 359-87.
Shahar, A., K. V. Patel, R. D. Semba, S. Bandinelli, D. R. Shahar, L. Ferrucci & J. M. Guralnik (2010) Plasma selenium is positively related to performance in neurological tasks assessing coordination and motor speed. Mov Disord, 25, 1909-15.
Sorolla, M. A., G. Reverter-Branchat, J. Tamarit, I. Ferrer, J. Ros & E. Cabiscol (2008) Proteomic and oxidative stress analysis in human brain samples of Huntington disease. Free Radical Biology and Medicine, 45, 667-678.
Stuss, M., M. Michalska-Kasiczak & E. Sewerynek (2017) The role of selenium in thyroid gland pathophysiology. Endokrynol Pol, 68, 440-465.
Swerdlow, R. H., J. M. Burns & S. M. Khan (2014) The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta, 1842, 1219-31.
Vinceti, M., D. Guidetti, M. Bergomi, E. Caselgrandi, R. Vivoli, M. Olmi, L. Rinaldi, S. Rovesti & F. Solime (1997) Lead, cadmium, and selenium in the blood of patients with sporadic amyotrophic lateral sclerosis. The Italian Journal of Neurological Sciences, 18, 87-92.
Vural, H., H. Demirin, Y. Kara, I. Eren & N. Delibas (2010) Alterations of plasma magnesium, copper, zinc, iron and selenium concentrations and some related erythrocyte antioxidant enzyme activities in patients with Alzheimer's disease. J Trace Elem Med Biol, 24, 169-73.
Wang, N., H.-Y. Tan, S. Li, Y. Xu, W. Guo & Y. Feng (2017) Supplementation of Micronutrient Selenium in Metabolic Diseases: Its Role as an Antioxidant. Oxidative Medicine and Cellular Longevity, 2017, 7478523.
Ward, R. J., F. A. Zucca, J. H. Duyn, R. R. Crichton & L. Zecca (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol, 13, 1045-60.
Whanger, P. (2001) Selenium and the brain: a review. Nutritional neuroscience, 4, 81-97.
Wu, R. T., L. Cao, B. P. Chen & W.-H. Cheng (2014) Selenoprotein H suppresses cellular senescence through genome maintenance and redox regulation. Journal of Biological Chemistry, 289, 34378-34388.
Yan, J. & J. N. Barrett (1998) Purification from bovine serum of a survival-promoting factor for cultured central neurons and its identification as selenoprotein-P. Journal of Neuroscience, 18, 8682-8691.
Yim, S. Y., K. R. Chae, S. B. Shim, J. T. Hong, C. Y. Lee, H. J. Son & D. Y. Hwang (2009) ERK activation induced by selenium treatment significantly downregulates β/γ-secretase activity and Tau phosphorylation in the transgenic rat overexpressing human selenoprotein M. International journal of molecular medicine, 24, 91-96.
Yoneda, S. & K. T. Suzuki (1997) Equimolar Hg-Se complex binds to selenoprotein P. Biochemical and biophysical research communications, 231, 7-11.
Zhang, X., R. P. Liu, W. H. Cheng & J. H. Zhu (2019) Prioritized brain selenium retention and selenoprotein expression: Nutritional insights into Parkinson's disease. Mech Ageing Dev, 180, 89-96.

Table 1 basic characteristics of the studies included in the meta-analysis (n=45)

NK: not known

(AD)

Study	Year	Country	Tissue type	Patients		Healthy controls		Unit	Study type	NOS score
				No	Se level (Mean ± Sd.)	No	Se level (Mean ± Sd.)
Huseyin Vural	2010	Turkey	Plasma	23M	58.15±10.63	24M	67.84±9.69	ug/l	Case-control	8
Huseyin Vural	2010	Turkey	Plasma	27F	58.43±11.26	26F	68.70±12.58	ug/l	Case-control	8
Naibo Wang	2019	China	Urine and Blood	89	2.26±0.59	178	2.61±1.07	umol/ml	Nested case-control	6
I. Meseguer	1999	Spain	CSF	27	11.40±7.80	34	13.30±7.00	ng/ml	Case-control	5
I. Meseguer	1999	Spain	Serum	27	28.50±13.00	34	22.50±17.50	ng/ml	Case-control	5
R.González-Domínguez	2014	Spain	Serum	30	112.80±25.76	30	118.50±26.84	μg/L	Case-control	8
EMİNE RABİA KOÇ	2015	Turkey	Hair	37	0.50±0.10	31	0.60±0.10	µg/g	Case-control	7
EMİNE RABİA KOÇ	2015	Turkey	Serum	40	0.75±0.20	33	0.83±0.40	µg/mL	Case-control	7
Katarzyna Socha	2021	Poland	Serum	110	69.10±19.30	60	79.80±22.00	μg/L	Case-control	7
Giuseppe paglia	2016	Italy	Serum	34	70.36±19.28	40	82.62±23.40	μg/L	Case-control	6
Sreeram Krishnan	2014	India	Blood	30	173.63±31.01	40	187.53±48.73	ppb	Case-control	8
Bárbara Rita Cardoso	2012	Brazil	Plasma	20	31.44±21.42	21	54.87±23.54	μg/L	Case-control	7
Bárbara Rita Cardoso	2012	Brazil	Erythrocytes	20	40.25±17.74	20	87.75±51.24	μg/L	Case-control	7
Sabrina Giacoppo	2014	Italy	Blood	15	42.78±9.772	10	73.27±10.05	μg/L	Case-control	5
Azhaar Ashraf	2019	NK	plasma	44	0.106±0.067	44	0.112±0.049	mg/l	Case-control	6
IrÈneCeballos-Picot	1996	France	Plasma	40	54.10±12.90	34	49.70±9.60	ng/ml	Case-control	6
IrÈneCeballos-Picot	1996	France	Erythrocytes	40	0.286±0.048	34	0.291±0.0038	ng/ml	Case-control	6
B´arbara R. Cardoso	2017	Australia	Erythrocytes	36	68.36±5.09	39	92.17±6.59	μg/L	Case-control	6
			Serum	29	114.13±19.85	30	115.10±23.72
			CSF	10	1.09±0.16	31	1.69±1.00
Larry Baum	2010	China	Serum	44	1420±230	41	1390±240	nmol/L	Case-control	5
DavidWenstrup	1990	USA	Whole tissue	10	865±109	12	901±162	ng/g	Case-control	5
C. R. CORNET	1998	USA	Pituitary tissues	43	0.92±0.11	15	0.86±0.19	μg/g	Case-control	5
Ba´rbara Rita Cardoso	2010	Brazil	Plasma	28	32.59±21.99	29	50.99±21.07	μg/g	Case-control	7
			Erythrocytes	28	43.74±23.02	29	79.16±46.38
			Nails	28	0.3±0.14	29	0.4±0.13
Z. CHMATALOVA	2017	Czech Republic	plasma	11	76.07±18.45	12	90.72±17.56	μg/L	Case-control	6
Rau´l Gonza´lez-Domı´nguez	2014	NK	Serum	25	120.5±31.12	15	122.9±24.14	μg/L	Case-control	5
A. E. Panayi	2000	Netherlands	Superior frontal gyrus（dry mass）	16	0.133±0.044	8	0.128±0.029	μg/L	Case-control	6
			Superior parietal gyrus（dry mass）	14	0.143±0.037	9	0.128±0.015
			Superior temperol gyrus（dry mass）	12	0.129±0.040	9	0.104±0.036
BŕbaraR.Cardoso	2017	America	Membrane fraction of wet tissue	33	53.99±17.71	38	64.67±20.56	ng/g	Case-control	5
R. D. Lavanya	2021	India	Serum	30	422.2±41.0	18	314.4±47.8	ng/g	Case-control	5

(PD)

Study	Year	Country	Tissue type	Patients		Healthy controls		Unit	Study type	NOS score
				No	Se level (Mean ± Sd.)	No	Se level (Mean ± Sd.)
Fabian Maass	2020	Germany	CSF	75	2695±1358	68	2745±1848	ng/L	Case-control	6
Mohsen Hemmati-Dinarvand	2017	Iran	Serum	40	96.48±9.11	40	83.67±8.65	μg/L	Case-control	5
Hai-Wen Zhao	2013	china	Plasma	238	115±37	302	105±33	μg/L	Case-control	7
M. V. Aguilar	1998	Spain	CSF	28	17.9±12.3	43	13.5±8.2	ng/ml	Case-control	7
M. V. Aguilar	1998	Spain	Serum	28	29.8±16.9	43	22.5±17.5	ng/ml	Case-control	7
F J Jiménez-Jiménez	1995	Spain	Serum	29	34.60±2.35	30	45.20±3.83	μg/L	Case-control	6
F J Jiménez-Jiménez	1995	Spain	Urine	29	47.10±6.25	30	45.50±5.38	μg/24h	Case-control	6
Fabian Maass	2018	Germany	CSF	36	9.4±7.6	42	5.9±6.6	μg/L	Case-control	6
Shashikant Nikam	2009	India	Plasma	22	14.58±0.98	22	19.05±1.42	µ gm/dl	Case-control	7
Younes-Mhenni Samia	2013	tunisia	Plasma	48	98.5±17.6	36	95.8±14.4	μg/L	Case-control	6
G. A. Qureshi	2016	Sweden	CSF	17	19.7±1.9	21	14.2±1.8	μg/L	Case-control	5

(MS)

Study	Year	Country	Tissue type	Patients		Healthy controls		Unit	Study type	NOS score
				No	Se level (Mean ± Sd.)	No	Se level (Mean ± Sd.)
Seyed Sajjad Sharifmousavi	2020	Iran	Plasma	99	68.84±23.17	81	53.33±3.66	μg/L	Case-control	7
Katarzyna Socha	2014	Poland	Serum	101	55.2±16.2	63	79.2±20.6	μg/L	Case-control	6
SELENIUM	1976	Finland	Whole blood	15	56.0±14.5	18	61.8±15.5	ng/ml	Case-control	5
SELENIUM	1976	Finland	Serum	27	46.4±12.9	18	43.6±13.0	ng/ml	Case-control	5
Elisa Tamburo	2015	Italy	Hair	48	1.00±0.69	51	0.8±0.47	μg/g	Case-control	7
Masoud Mehrpour	2012	Iran	Serum	23	61±13	28	89±13	μg/L	Case-control	5
Sabrina Giacoppo	2014	Italy	Blood	41	68.60±19.02	23	71.10±18.09	μg/L	Case-control	5
Heikki Korpela	1989	Finland	Serum	12	123±17	11	120±18	μg/L	Nested Case-Control	5

(ALS)

Study	Year	Country	Tissue type	Patients		Healthy controls		Unit	Study type	NOS score
				No	Se level (Mean ± Sd.)	No	Se level (Mean ± Sd.)
Stefano De Benedetti	2017	Italy	Serum	6	100±12	5	90±8	μg/L	Case-control	7
Stefano De Benedetti	2017	Italy	whole blood	6	110 ± 18	5	121 ± 17	μg/L	Case-control	7
Vinceti M	1997	Italy	Serum	16	68.6±16.9	38	76.8±11.8	μg/L	Case-control	7
Dominique Bonnefont-Rousselot	2000	France	Plasma	167	1.21±0.21	62	1.18±0.18	μmol/l	Case-control	6
Susan Peters	2021	NK	Erythrocyte	107	115±1.25	319	117.70±1.31	ng/g	Nested Case-Control	6
Hélène Blasco	2021	France	Blood	9	108.75±17.14	10	106.40±13.82	μg/L	Case-control	6
F. Moriwaka	1993	Japan	Plasma	21	81.20±46.42	35	120.61±20.55	ng/g	Case-control	6
F. Moriwaka	1993	Japan	Blood cell	20	134.63±73.36	35	191.55±35.88	ng/g	Case-control	6
Hiroshi Nagata	1985	Japan	Blood cell	40	1.16±0.24	25	0.84±0.17	ng/mg	Case-control	5

(HD)

Study

Year

Country

Tissue type

Patients

Healthy controls

Unit

Study type

NOS score

No

Se level

(Mean ± Sd.)

No

Se level

(Mean ± Sd.)

Stefania Squadrone

2019

Italy

Blood

18

138±12

18

101±16

μg/L

Case-control

5

No competing interests reported.

Association of Selenium Levels with Neurodegenerative disease: A Systemic Review and Meta-analysis

Status:

Version 1

Abstract

Background

Method

Result

Conclusion

Figures

Introduction

Methods And Material

Protocol and Registration

Inclusion and exclusion criteria

Data Extraction and quality assessment

Statistical Analysis

Results

Study selection

Baseline characteristics of included studies

Analysis of selenium and AD

The relationship between selenium and PD

Selenium in MS patients

Analysis of selenium and ALS

Selenium in HD patients

Assessment of publication bias

Discussion

AD

PD

MS

ALS

HD

Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1