Copper Isotope Compositions Measured Using a Sapphire Dual Path MC-ICPMS with a Collision/Reaction Cell.

We present a new approach to Cu isotopic measurements using a state-of-the-art Nu Sapphire multicollector inductively coupled plasma source mass spectrometer equipped with a collision/reaction cell (CRC-MC-ICPMS). We investigate the effects of Na doping and Cu concentration mismatch between bracketing standard and unknown samples and demonstrate the efficacy of introducing a He-H2 gas mix into the CRC to efficiently eliminate the sample matrix-based 40Ar23Na+ isobaric interference on 63Cu+. This capability is crucial when measuring samples with high Na/Cu ratios, such as some biological samples, which have significantly different chemical compositions compared to most geological samples. Moreover, considering the necessity of obtaining large data sets for biological samples to ensure reliable interpretations, the implementation of a CRC for mitigating the 40Ar23Na+ interference offers the advantage of minimizing the requirement for extensive Cu chemical separation procedure prior to Cu isotopic measurements. Our results demonstrate that the accurate determination of the δ65Cu values is achievable for samples with Na/Cu concentration ratios of up to ∼65, even when measuring 100 ppb Cu solutions (equivalent to a signal of ∼3.5-4 V total Cu). Furthermore, our results showcase a good short-term repeatability on δ65Cu for pure Cu standard solutions (NIST SRM 976 and Cu-IPGP), typically of 0.05‰ (2 SD) when measuring >50 ppb Cu solutions. Our long-term external reproducibility stands at approximately 0.07‰ (2 SD). This value accounts for the variable Cu concentrations analyzed across the different analytical sequences (from 10 to 100 ppb Cu solutions). To validate the robustness of our analytical method, we first conduct a comparison between data sets from mice brains processed twice through column chemistry using a Thermo Finnigan Neptune MC-ICPMS and a Nu Sapphire CRC-MC-ICPMS in CRC mode. This comparison serves to verify the reliability of our method for measuring Cu isotopic composition using the CRC on samples with a low Na/Cu ratio after traditional chemical processing. Then, we compare the data sets obtained for biological standards (tuna fish ERM-CE 464 (IRMM) and human serum Seronorm Trace Elements Serum L-1) processed either once, or twice, through column chemistry and demonstrate that the CRC allows accurate Cu isotopic measurements of the samples processed only once and therefore with a higher Na/Cu ratio.

Impact of aging on copper isotopic composition in the murine brain.

Aging is the main risk factor for Alzheimer's disease (AD). AD is linked to alterations in metal homeostasis and changes in stable metal isotopic composition can occur, possibly allowing the latter to serve as relevant biomarkers for potential AD diagnosis. Copper stable isotopes are used to investigate changes in Cu homeostasis associated with various diseases. Prior work has shown that in AD mouse models, the accumulation of 63Cu in the brain is associated with the disease's progression. However, our understanding of how the normal aging process influences the brain's isotopic composition of copper remains limited. In order to determine the utility and predictive power of Cu isotopes in AD diagnostics, we aim-in this study-to develop a baseline trajectory of Cu isotopic composition in the normally aging mouse brain. We determined the copper concentration and isotopic composition in brains of 30 healthy mice (WT) ranging in age from 6 to 12 mo, and further incorporate prior data obtained for 3-mo-old healthy mice; this range approximately equates to 20-50 yr in human equivalency. A significant 65Cu enrichment has been observed in the 12-mo-old mice compared to the youngest group, concomitant with an increase in Cu concentration with age. Meanwhile, literature data for brains of AD mice display an enrichment in 63Cu isotope compared to WT. It is acutely important that this baseline enrichment in 65Cu is fully constrained and normalized against if any coherent diagnostic observations regarding 63Cu enrichment as a biomarker for AD are to be developed.

Copper and zinc isotopic excursions in the human brain affected by Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is neuropathologically marked by amyloid beta (Aß) plaques and neurofibrillary tangles. Little is known about isotopic compositions of human AD brains. Here we study this in comparison with control subjects for copper and zinc. Methods: We use mass-spectrometry methods, developed to study extraterrestrial materials, to compare the copper and zinc isotopic composition of 10 AD and 10 control brains. Results: Copper and zinc natural isotopic compositions of AD brains are statistically different compared to controls, and correlate with Braak stages. Discussion: The distribution of natural copper and zinc isotopes in AD is not affected by the diet, but is a consequence of Aß plaques and tau fibril accumulation. This is well predicted by the changes of the chemical bonding environment caused by the development of Aß lesions and accumulation of tau proteins. Future work will involve testing whether these changes affect brain functions and are propagated to body fluids.