Magnesium Serum Concentrations in Patients with Dementia Vs . Controls ; A Systematic Review and Meta-Analysis

Background: The role of magnesium in the pathogenesis of dementia and other degenerative disorders has focused attention in recent years. There have been several studies reporting favorable effects of magnesium in the treatment of various degenerative illnesses. In contrast, other research found that both low and high serum magnesium levels were associated with an increased risk of Alzheimer’s disease and mixed dementia. These contrasting results render the role of magnesium levels in dementia unclear. Our objective was to investigate the possible association between dementia and hypomagnesaemia. Methods: We conducted a systematic review and meta-analysis of all articles, in any language, reporting on serum magnesium concentrations either in plasma or serum of patients with dementia, compared to patients without dementia. Studies reporting on proportion of hypomagnesaemia patients and not mean levels were excluded. Results: Seven studies were accepted for the meta-analysis, reporting on 2932 dementia cases and 42920 controls. All types of dementia were reported. There was a significant heterogeneity in the results, and the difference in Mg2+ concentrations between patients with dementia and controls was not significant (mean difference -10.68 micromole/L (95% confidence interval -30.62 and +9.27). There were no significant differences in the measured levels of the different types of dementia. Conclusions: Our study, based on large numbers of dementia patients and controls, suggests that low serum magnesium concentrations are not associated with increased risk of dementia. This may be explained by poor correlation between serum and tissue distribution of magnesium and by the fact that less than one percent of total body magnesium circulates in the blood. [3]. Low magnesium levels were found to be decreased in various tissues of patients with Alzheimer’s disease in clinical, experimental, and autopsy studies [4]. A reduction in the frequency of intracellular magnesium deposits in neurons of Alzheimer’s patients was reported. Decrease in magnesium and glutamic acid have been shown in the hippocampal tissue of Alzheimer’s disease patients [5]. There is evidence that glutamate release and intake are chronically disturbed in Alzheimer’s disease, and glutamate levels are possibly increased in the synaptic cleft, with resultant calcium influx to postsynaptic neurons and activation of the calcium related enzyme system. This leads to production of free radicals, protein destruction, lipid peroxidation, and neuron death with DNA destruction [4]. Increasing volume of research has explored the connection between magnesium and the role of NMDA receptors in degenerative brain disorders. NMDA receptors have a critical role the central nervous system, including neuronal development, plasticity and neurodegeneration [1, 3]. These receptors lead to channels which are permeable to calcium, sodium and potassium ions and voltagegated channels blocked by magnesium ions. Transient glutamate release from the presynaptic region occurs during normal learning and memory process. This release causes depolarization on the postsynaptic membrane, after which ionized magnesium (Mg2+) leaves voltage gated channels on NMDARs, and Ca2+ influx inside the neuron occurs. Increase in Ca2+ levels inside the neuron initiates a signal transmission process and this facilitates memory and learning. At the end of stimulation, Mg2+ stops Ca2+ influx inside the neuron by closing channels on the NMDA receptors [1, 3]. There have been several studies suggesting favorable effects of magnesium in the treatment of various degenerative illnesses. Improvement in memory was reported with nutritional magnesium support in patients with dementia [6-7]. Similarly, higher selfreported dietary intake of magnesium was found to be associated with a decreased risk of dementia [7]. Moreover, the risk for the development of vascular dementia was decreased with hazard ratio of 0.26 (95% CI 0.11–0.61) for the highest quartiles of magnesium intake [7]. In contrast, other research found that both low and high serum magnesium levels were associated with an increased risk Introduction The role of magnesium in the pathogenesis of dementia and other degenerative disorders has focused increased attention in recent years [1-2]. There have been two main hypotheses for the role of magnesium in dementia: 1) A direct effect of neuronal magnesium on regulation of the ionotropic glutamatergic receptor N-methyl-D-aspartate (NMDA). It has been demonstrated that ionized magnesium leads to closure of cation channels which have been opened by glutamate on NMDA receptors [3]. 2) Magnesium deficiency leads to oxidative stress which stimulates secretion of inflammatory mediators such as interleukins, tumor necrosis factors, and nitric oxide. These mediators are thought to stimulate atherosclerosis and thereby increase the risk of dementia Journal of Parkinson’s Disease & Alzheimer’s Disease August 2021 Vol.:8, Issue:1 © All rights are reserved by Ben-Zaken S et al. Avens Publishing Group Inviting Innovations Citation: Ben-Zaken S, Kaplan Y, Koren G. Magnesium Serum Concentrations in Patients with Dementia Vs. Controls; A Systematic Review and MetaAnalysis. J Parkinson’s Dis Alzheimer’s Dis. 2021;8(1): 3. J Parkinson’s Dis Alzheimer’s Dis 8(1): 3 (2021) Page 2 ISSN: 2330-2178 of Alzheimer’s disease and mixed dementia [8]. These contrasting results render the role of magnesium levels in dementia unclear. For that end, our objective was to conduct a systematic review and meta-analysis in order to verify whether dementia and Alzheimer disease are associated with lower serum magnesium concentrations. Materials and Methods We conducted a search for all articles, in any language, reporting on serum magnesium concentrations in patients with dementia, compared to control groups of patients without dementia. We searched PubMed, Medline, Embase, Google and Google Scholar from inception to August 1, 2020. We included original papers and excluded case reports, letters to the editor, reviews and animal studies, or any paper where there was no comparison of magnesium levels to control group of subjects without dementia. We reviewed the papers for demographics and details on diagnosis and measured magnesium levels. We included papers that reported means of magnesium levels. Papers that reported only proportions of patients with hypomagnesemia but without specific mean levels were excluded. Data were extracted from eligible studies which reported mean and SD of magnesium levels in patients with dementia and their respective control groups. Data were combined by using a random effects model with RevMan 3.3 (Review Manager 5.3; Cochrane Collaboration, Oxford, UK) and the effect size was represented by the mean difference (MD) since the unit of the outcome was similar in all included trials [9]. Heterogeneity was assessed utilizing the Q and I-square statistic. An I square value between 25%-50% signifies low heterogeneity, between 50%-75% moderate and >75% signifies high heterogeneity. A funnel plot was not used to evaluate publication bias since the number of included studies was below 10, which yields a low power detecting asymmetry with good accuracy [10]

Results: Seven studies were accepted for the meta-analysis, reporting on 2932 dementia cases and 42920 controls. All types of dementia were reported. There was a significant heterogeneity in the results, and the difference in Mg2+ concentrations between patients with dementia and controls was not significant (mean difference -10.68 micromole/L (95% confidence interval -30.62 and +9.27). There were no significant differences in the measured levels of the different types of dementia.

Conclusions:
Our study, based on large numbers of dementia patients and controls, suggests that low serum magnesium concentrations are not associated with increased risk of dementia. This may be explained by poor correlation between serum and tissue distribution of magnesium and by the fact that less than one percent of total body magnesium circulates in the blood. [3]. Low magnesium levels were found to be decreased in various tissues of patients with Alzheimer's disease in clinical, experimental, and autopsy studies [4]. A reduction in the frequency of intracellular magnesium deposits in neurons of Alzheimer's patients was reported. Decrease in magnesium and glutamic acid have been shown in the hippocampal tissue of Alzheimer's disease patients [5]. There is evidence that glutamate release and intake are chronically disturbed in Alzheimer's disease, and glutamate levels are possibly increased in the synaptic cleft, with resultant calcium influx to postsynaptic neurons and activation of the calcium -related enzyme system. This leads to production of free radicals, protein destruction, lipid peroxidation, and neuron death with DNA destruction [4].
Increasing volume of research has explored the connection between magnesium and the role of NMDA receptors in degenerative brain disorders. NMDA receptors have a critical role the central nervous system, including neuronal development, plasticity and neurodegeneration [1,3]. These receptors lead to channels which are permeable to calcium, sodium and potassium ions and voltagegated channels blocked by magnesium ions. Transient glutamate release from the presynaptic region occurs during normal learning and memory process. This release causes depolarization on the postsynaptic membrane, after which ionized magnesium (Mg2+) leaves voltage gated channels on NMDARs, and Ca2+ influx inside the neuron occurs. Increase in Ca2+ levels inside the neuron initiates a signal transmission process and this facilitates memory and learning. At the end of stimulation, Mg2+ stops Ca2+ influx inside the neuron by closing channels on the NMDA receptors [1,3].
There have been several studies suggesting favorable effects of magnesium in the treatment of various degenerative illnesses. Improvement in memory was reported with nutritional magnesium support in patients with dementia [6][7]. Similarly, higher selfreported dietary intake of magnesium was found to be associated with a decreased risk of dementia [7]. Moreover, the risk for the development of vascular dementia was decreased with hazard ratio of 0.26 (95% CI 0.11-0.61) for the highest quartiles of magnesium intake [7]. In contrast, other research found that both low and high serum magnesium levels were associated with an increased risk

Introduction
The role of magnesium in the pathogenesis of dementia and other degenerative disorders has focused increased attention in recent years [1][2]. There have been two main hypotheses for the role of magnesium in dementia: 1) A direct effect of neuronal magnesium on regulation of the ionotropic glutamatergic receptor N-methyl-D-aspartate (NMDA). It has been demonstrated that ionized magnesium leads to closure of cation channels which have been opened by glutamate on NMDA receptors [3].
2) Magnesium deficiency leads to oxidative stress which stimulates secretion of inflammatory mediators such as interleukins, tumor necrosis factors, and nitric oxide. These mediators are thought to stimulate atherosclerosis and thereby increase the risk of dementia of Alzheimer's disease and mixed dementia [8]. These contrasting results render the role of magnesium levels in dementia unclear.
For that end, our objective was to conduct a systematic review and meta-analysis in order to verify whether dementia and Alzheimer disease are associated with lower serum magnesium concentrations.

Materials and Methods
We conducted a search for all articles, in any language, reporting on serum magnesium concentrations in patients with dementia, compared to control groups of patients without dementia. We searched PubMed, Medline, Embase, Google and Google Scholar from inception to August 1, 2020. We included original papers and excluded case reports, letters to the editor, reviews and animal studies, or any paper where there was no comparison of magnesium levels to control group of subjects without dementia.
We reviewed the papers for demographics and details on diagnosis and measured magnesium levels. We included papers that reported means of magnesium levels. Papers that reported only proportions of patients with hypomagnesemia but without specific mean levels were excluded. Data were extracted from eligible studies which reported mean and SD of magnesium levels in patients with dementia and their respective control groups. Data were combined by using a random effects model with RevMan 3.3 (Review Manager 5.3; Cochrane Collaboration, Oxford, UK) and the effect size was represented by the mean difference (MD) since the unit of the outcome was similar in all included trials [9]. Heterogeneity was assessed utilizing the Q and I-square statistic. An I square value between 25%-50% signifies low heterogeneity, between 50%-75% moderate and >75% signifies high heterogeneity. A funnel plot was not used to evaluate publication bias since the number of included studies was below 10, which yields a low power detecting asymmetry with good accuracy [10]

Results
We identified 214 potentially eligible titles. During title and abstract review 12 full text studies were reviewed, and 7 studies described in 6 peer review papers were accepted for the meta-analysis [11][12][13][14][15] as Vural et al described 2 separate populations in a single paper [14] (Table 1). All types of dementia were included (Alzheimer's, Vascular, Mixed). The determinations of Mg2+ levels were made mostly after a period of hospitalization. Dietary supplement with magnesium was not detailed in most studies.
The studies (n=7), conducted between 1990 and 2020, compared serum or plasma magnesium levels between patients with dementia and controls. They included 2932 dementia patients and 42900 controls. Ratio between women and men was 1.278. There were no differences in mean magnesium levels related to patient age. There was a significant heterogeneity in the results, and the difference in Mg2+ concentrations between patients with dementia and controls was not significant (mean difference -10.68 micromole/L (95% confidence interval -30.62 +9.27). (Table 1). Most studies did not report on medications received by the patient, that may affect magnesium levels.
In 5 of the studies we could compare magnesium levels among Alzheimer patients versus controls. The results were heterogenous.
In a previous systematic review Verones and colleagues identified an additional paper comparing magnesium levels in CSF, as well as hair magnesium [18]. In their review they included four articles comparing serum magnesium in 190 Alzheimer patients and 189 controls, not showing significant differences. It was possible that this lack of difference might have been the result of small sample size and a resultant limited statistical power. Our present analysis has identified 7 reports with tenfold more dementia subjects and 220fold more controls. Our results, failing to show significant changes in serum magnesium with very large numbers of subjects and controls corroborate the much smaller sample size in Veronese study.
Of potential importance, Veronese' study also compared small numbers of studies comparing cerebrospinal fluid levels (n=2) and hair concentrations (n=2) showing significantly lower levels in Alzheimer patients vs. controls [18].
Using serum magnesium as a biological marker of magnesium status has inherent shortcomings, as it does not reflect intracellular or total body magnesium status [19][20]. Indeed, Veronese et al did find lower levels of magnesium in CSF and hair of dementia patients [18], and brain levels do not appear to be lower [16].
In contrast to these observational studies, there is evidence that higher self-reported dietary intake of magnesium had been associated with a decreased risk of dementia [7].
Several limitations of this study must be acknowledged. For obvious reasons serum magnesium is much more available than tissue magnesium; however the lack of strong correlation between serum magnesium and tissue magnesium makes it difficult to interpret serum magnesium. The heterogeneity of the reported serum magnesium among the different studies may reflect inconsistencies in time of measurement of magnesium (e.g. upon admission to hospital vs. in the community, in dietary supplementation and inclusion/ exclusion of drugs affecting magnesium levels.
Our study, based on large numbers of dementia patients and controls, suggests that low serum magnesium concentrations are not associated with increased likelihood of dementia. Hence, serum magnesium should be used with caution to predict the status and activity of dementia in patients. More studies are needed in order to identify biological markers of magnesium disposition in dementia, particularly on the direct comparison of different types of dementia.