Alterations in Metal Homeostasis Occur Prior to Canonical Markers in Huntington Disease

Objective: The importance of metal biology in neurodegenerative diseases such as Huntingtin Disease is well documented with evidence of direct interactions between metals such as copper, zinc, iron and manganese and mutant Huntingtin pathobiology. To date, it is unclear whether these interactions are observed in humans, how this impacts other metals, and how mutant Huntington alters homeostatic mechanisms governing levels of copper, zinc, iron and manganese in cerebrospinal fluid and blood in HD patients.Methods: Plasma and cerebrospinal fluid from control, pre-manifest, manifest and late manifest HD participants were collected as part of HD-Clarity. Levels of cerebrospinal fluid and plasma copper, zinc, iron and manganese were measured as well as levels of mutant Huntingtin and neurofilament in a sub-set of cerebrospinal fluid samples.Results: We find that elevations in cerebrospinal fluid copper, manganese and zinc levels are altered early in disease prior to alterations in canonical biomarkers of HD although these changes are not present in plasma. We also evidence that CSF iron is elevated in manifest patients. The relationships between plasma and cerebrospinal fluid metal are altered based on disease stage.Interpretation: These findings demonstrate that there are alterations in metal biology selectively in the CSF which occur prior to changes in known canonical biomarkers of disease. Our work indicates that there are pathological changes related to alterations in metal biology in individuals without elevations in neurofilament and mutant Huntingtin.

Serum Copper Level and Polycystic Ovarian Syndrome: A Meta-Analysis

<b><i>Introduction:</i></b> The association of serum copper with polycystic ovarian syndrome (PCOS) has been studied for years, but no definite conclusion is drawn. Therefore, we conducted a meta-analysis to investigate serum copper concentrations in PCOS subjects compared with healthy controls. <b><i>Methods:</i></b> Electronic search was performed in PubMed, Google Scholar, and Scopus up to June 30, 2020, without any restriction. Standardized mean differences (SMDs) with corresponding 95% CIs in serum copper levels were employed with random-effects model. <i>I</i>² was applied to evaluate heterogeneity among studies. <b><i>Results:</i></b> Nine studies, measuring plasma copper levels in 1,168 PCOS patients and 1,106 controls, were included. Pooled effect size suggested serum copper level was significantly higher in women with PCOS (SMD = 0.51 μg/mL, 95% CI = [0.30, 0.72], <i>p</i> &#x3c; 0.0001). The overall heterogeneity was not connected with subgroups of the country, but derived from the opposite result of 1 study. <b><i>Conclusion:</i></b> Our research generally indicated circulating copper level in PCOS sufferers was significantly higher than normal controls. Large-scale studies are still needed to elucidate the clear relation between copper status and etiology of PCOS.

Association of Copper-to Zinc Ratio with Sperm Concentration among Males Investigated for Infertility

Background: The importance of copper and zinc in the fertility potential of males are well understood. The close relationship and the antagonistic interactions between copper and zinc requires further investigation especially because of conflicting reports in literature on the association of the trace elements with sperm quantity and quality. This study evaluates seminal plasma copper and zinc concentrations, copper-to-zinc ratio and their associations with sperm concentration in infertile males. Methods: This is a cross-sectional study of 400 males investigated for infertility and 100 male control subjects. Seminal plasma copper and zinc were determined using atomic absorption spectrophotometry technique (Buck Scientific Model VGP-210, Germany). The subjects were grouped based on sperm count; normozoospermia(>15 x 106cells/mL), oligozoospermia (<15x106cells/mL) and azoospermia (no sperm cell). The levels of copper, zinc and Cu/Zn ratio were compared using unpaired Students-t-test and analysis of variance while Pearson correlation coefficient was used to assess the correlation between measured variables and sperm count. Results: Seminal plasma zinc was significantly lower (p<0.001) while copper and Cu/Zn ratio were significantly higher (p<0.001) in infertile than fertile males. The Cu/Zn ratio was significantly higher (p<0.001) among infertile males than controls. Seminal plasma levels of copper and Cu/Zn ratio increased with decreasing concentrations of sperm cells while zinc levels increase with increasing concentration of sperm cells.

U-Shaped Association Between Plasma Cobalt Levels and Type 2 Diabetes

Objectives The aim of this study was to investigate the association of plasma cobalt with newly diagnosed T2D. The potential interactions of plasma cobalt with copper and metallothioneins (MTs) polymorphisms were further evaluated. Methods A large case-control study including 4564 participants: 2282 newly diagnosed T2D cases and 2282 controls with normal glucose tolerance (NGT). Plasma cobalt and copper concentrations were measured with inductively coupled plasma mass spectrometry (ICPMS). In addition, MTs polymorphisms were genotyped in a random subset of participants (827 T2D and 827 NGT) by Agena MassArray System. Results The medians of the plasma cobalt concentrations were 1.88 μg/dL for NGT and 2.22 μg/L for T2D. A U-shaped association was observed between plasma cobalt and T2D. From the lowest to the highest quartiles of plasma cobalt, the multivariable adjusted ORs of T2D were 1.29 (1.07–1.56), 1.20 (0.99–1.45), 1.00 (reference) and 1.62 (1.34–1.96), respectively. The U-shaped association was consistently indicated in subgroups and in spline analysis with the lowest odds of T2D at the cobalt concentration of 2.00 μg/dL. There was a statistically significant interaction between plasma cobalt and copper (P &lt; 0.01), and cobalt showed a positive association of T2D in those with the lowest tertile of plasma copper. Conclusions Both low and high levels of plasma cobalt were associated with higher odds of T2D, and the association could be modified by plasma copper concentrations. Funding Sources This work was funded by the National Key Research and Development Program of China, the Major International (Regional) Joint Research Project, the National Natural Science Foundation of China, the Young Scientists Fund of the National Natural Science Foundation of China and the China Postdoctoral Science Foundation.

Nutritional Factors Modulating Alu Methylation in an Italian Sample from The Mark-Age Study Including Offspring of Healthy Nonagenarians

Alu hypomethylation promotes genomic instability and is associated with aging and age-related diseases. Dietary factors affect global DNA methylation, leading to changes in genomic stability and gene expression with an impact on longevity and the risk of disease. This preliminary study aims to investigate the relationship between nutritional factors, such as circulating trace elements, lipids and antioxidants, and Alu methylation in elderly subjects and offspring of healthy nonagenarians. Alu DNA methylation was analyzed in sixty RASIG (randomly recruited age-stratified individuals from the general population) and thirty-two GO (GeHA offspring) enrolled in Italy in the framework of the MARK-AGE project. Factor analysis revealed a different clustering between Alu CpG1 and the other CpG sites. RASIG over 65 years showed lower Alu CpG1 methylation than those of GO subjects in the same age class. Moreover, Alu CpG1 methylation was associated with fruit and whole-grain bread consumption, LDL2-Cholesterol and plasma copper. The preserved Alu methylation status in GO, suggests Alu epigenetic changes as a potential marker of aging. Our preliminary investigation shows that Alu methylation may be affected by food rich in fibers and antioxidants, or circulating LDL subfractions and plasma copper.

Greater Circulating Copper Concentrations and Copper/Zinc Ratios are Associated with Lower Psychological Distress, But Not Cognitive Performance, in a Sample of Australian Older Adults

Dyshomeostasis of copper and zinc is linked to neurodegeneration. This study investigated the relationship between circulating copper and zinc and copper/zinc ratios and cognitive function, symptoms of depression and anxiety, and neurotrophic factors in older Australian adults. In this cross-sectional study (n = 139), plasma copper, serum zinc, and neurotrophic factors (brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor, and insulin-like growth factor-1) were assessed. Cognition was assessed using the Cogstate battery and the Behavior Rating Inventory (BRI) of Executive Function (Adult version). Symptoms of anxiety and depression were assessed with the Hospital Anxiety and Depression Scale. Copper (β = −0.024; 95% CI = −0.044, −0.004; p = 0.019) and copper/zinc ratio (β = −1.99; 95% CI = −3.41, −0.57; p = 0.006) were associated with lower depressive symptoms, but not cognition. Plasma copper had a modest positive association with BDNF (β = −0.004; 95% CI = 0.000, 0.007; p = 0.021). Zinc was not associated with any of the outcomes. In conclusion, greater circulating copper concentrations and higher copper/zinc ratios were associated with lower depressive symptoms (but not cognition), with copper also positively associated with BDNF concentration, in a sample of community-dwelling older adults.

Circulating Multiple Metals and Incident Stroke in Chinese Adults

Background and Purpose— Circulating metals synchronously reflect multiple metal exposures from both natural and anthropogenic sources, which may be linked with the risk of stroke. However, there is a lack of prospective studies investigating the associations of multiple metal exposures with incident stroke. Methods— We performed a nested case-control study within the ongoing Dongfeng-Tongji cohort launched in 2008. A total of 1304 incident stroke cases (1035 ischemic strokes and 269 hemorrhagic strokes) were prospectively identified by December 31, 2016, and matched to incident identity sampled controls according to age (within 1 year), sex, and blood sampling date (within 1 month). We determined the concentrations of 24 plasma metals and assessed the associations of plasma multiple metal concentrations with incident stroke using conditional logistic regression and elastic net model. Results— The average follow-up was 6.1 years. After adjusting for established risk confounders, copper, molybdenum, and titanium were significantly associated with higher risk of ischemic stroke (odds ratios according to per interquartile range increase, 1.29 [95% CI, 1.13–1.46], 1.19 [95% CI, 1.05–1.35], and 1.30 [95% CI, 1.07–1.59]), whereas rubidium and selenium were associated with lower risk of hemorrhagic stroke (odds ratios according to per interquartile range increase, 0.66 [95% CI, 0.50–0.87] and 0.68 [95% CI, 0.51–0.91]). The predictive plasma metal scores based on multiple metal exposures were significantly associated with higher risk of ischemic and hemorrhagic stroke (adjusted odds ratios according to per interquartile range increase, 1.37 [95% CI, 1.20–1.56] and 1.53 [95% CI, 1.16–2.01]). Conclusions— Plasma copper, molybdenum, and titanium were associated with higher risk of ischemic stroke, whereas plasma rubidium and selenium were associated with lower risk of hemorrhagic stroke. These findings may have important public health implications given the ever-increasing burden of stroke worldwide.