Publications by authors named "Brandon Mahan"

5 Publications

  • Page 1 of 1

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

Alzheimers Dement (Amst) 2020 19;12(1):e12112. Epub 2020 Oct 19.

Centre de Neurologie Cognitive Hopital Lariboisière Fernand-Widal GHU Nord APHP Université de Paris, and Inserm Paris France.

Introduction: Alzheimer's disease (AD) is neuropathologically marked by amyloid beta (Aβ) 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 Aβ plaques and tau fibril accumulation. This is well predicted by the changes of the chemical bonding environment caused by the development of Aβ lesions and accumulation of tau proteins. Future work will involve testing whether these changes affect brain functions and are propagated to body fluids.
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http://dx.doi.org/10.1002/dad2.12112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571480PMC
October 2020

Longitudinal biometal accumulation and Ca isotope composition of the Göttingen minipig brain.

Metallomics 2020 10;12(10):1585-1598

Université de Paris, Institut de Physique du Globe de Paris, CNRS, 75238 Paris, France.

Biometals play a critical role in both the healthy and diseased brain's functioning. They accumulate in the normal aging brain, and are inherent to neurodegenerative disorders and their associated pathologies. A prominent example of this is the brain accumulation of metals such as Ca, Fe and Cu (and more ambiguously, Zn) associated with Alzheimer's disease (AD). The natural stable isotope compositions of such metals have also shown utility in constraining biological mechanisms, and in differentiating between healthy and diseased states, sometimes prior to conventional methods. Here we have detailed the distribution of the biologically relevant elements Mg, P, K, Ca, Fe, Cu and Zn in brain regions of Göttingen minipigs ranging in age from three months to nearly six years, including control animals and both a single- and double-transgenic model of AD (PS1, APP/PS1). Moreover, we have characterized the Ca isotope composition of the brain for the first time. Concentration data track rises in brain biometals with age, namely for Fe and Cu, as observed in the normal ageing brain and in AD, and biometal data point to increased soluble amyloid beta (Aβ) load prior to AD plaque identification via brain imaging. Calcium isotope results define the brain as the isotopically lightest permanent reservoir in the body, indicating that brain Ca dyshomeostasis may induce measurable isotopic disturbances in accessible downstream reservoirs such as biofluids.
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http://dx.doi.org/10.1039/d0mt00134aDOI Listing
October 2020

Isotope metallomics approaches for medical research.

Cell Mol Life Sci 2020 Sep 4;77(17):3293-3309. Epub 2020 Mar 4.

Thermo Fisher Isotope Development Hub, Department of Earth and Environmental Sciences, Macquarie University, Sydney, NSW, 2109, Australia.

Metallomics is a rapidly evolving field of bio-metal research that integrates techniques and perspectives from other "-omics" sciences (e.g. genomics, proteomics) and from research vocations further afield. Perhaps the most esoteric of this latter category has been the recent coupling of biomedicine with element and isotope geochemistry, commonly referred to as isotope metallomics. Over the course of less than two decades, isotope metallomics has produced numerous benchmark studies highlighting the use of stable metal isotope distribution in developing disease diagnostics-e.g. cancer, neurodegeneration, osteoporosis-as well as their utility in deciphering the underlying mechanisms of such diseases. These pioneering works indicate an enormous wealth of potential and provide a call to action for researchers to combine and leverage expertise and resources to create a clear and meaningful path forward. Doing so with efficacy and impact will require not only building on existing research, but also broadening collaborative networks, bolstering and deepening cross-disciplinary channels, and establishing unified and realizable objectives. The aim of this review is to briefly summarize the field and its underpinnings, provide a directory of the state of the art, outline the most encouraging paths forward, including their limitations, outlook and speculative upcoming breakthroughs, and finally to offer a vision of how to cultivate isotope metallomics for an impactful future.
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http://dx.doi.org/10.1007/s00018-020-03484-0DOI Listing
September 2020

Examining the homeostatic distribution of metals and Zn isotopes in Göttingen minipigs.

Metallomics 2018 09;10(9):1264-1281

Institut de Physique du Globe de Paris, Université Paris Diderot, Sorbonne Paris Cité, CNRS UMR 7154, 1 rue Jussieu, 75238 Paris Cedex 05, France.

The role of metals in biologic systems is manifold, and understanding their behaviour in bodily processes, especially those relating to neurodegenerative diseases, is at the forefront of medical science. The function(s) of metals - such as the transition metals - and their utility in both the diagnosis and treatment of diseases in human beings, is often examined via the characterization of their distribution in animal models, with porcine models considered exceptional proxies for human physiology. To this end, we have investigated the homeostatic distribution of numerous metals (Mg, K, Ca, Mn, Fe, Cu, Zn, Rb and Mo), the non-metal P, and Zn isotopes in the organs and blood (red blood cells, plasma) of Göttingen minipigs. These results represent the first set of data outlining the homeostatic distribution of metals and Zn isotopes in Göttingen minipigs, and indicate a relatively homogeneous distribution of alkali/alkaline earth metals and P among the organs, with generally lower levels in the blood, while indicating more heterogeneous and systematic abundance patterns for transition metals. In general, the distribution of all elements analysed is similar to that found in humans. Our elemental abundance data, together with data reported for humans in the literature, suggest that element-to-element ratios, e.g. Cu/Mg, show potential as simple diagnostics for diseases such as Alzheimer's. Isotopic data indicate a heterogeneous distribution of Zn isotopes among the organs and blood, with the liver, heart and brain being the most depleted in heavy Zn isotopes, and the blood the most enriched, consistent with observations in other animal models and humans. The Zn isotopic composition of Göttingen minipigs displays a systematic offset towards lighter δ66Zn values relative to mice and sheep models, suggesting physiology that is more closely aligned with that of humans. Cumulatively, these observations strongly suggest that Göttingen minipigs are an excellent animal model for translational research involving metals, and these data provide a strong foundation for future research.
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http://dx.doi.org/10.1039/c8mt00179kDOI Listing
September 2018

Volatile element evolution of chondrules through time.

Proc Natl Acad Sci U S A 2018 08 6;115(34):8547-8552. Epub 2018 Aug 6.

Institut de Physique du Globe de Paris, Université Paris Diderot, Sorbonne Paris Cité, CNRS UMR 7154, 75238 Paris Cedex 05, France.

Chondrites and their main components, chondrules, are our guides into the evolution of the Solar System. Investigating the history of chondrules, including their volatile element history and the prevailing conditions of their formation, has implications not only for the understanding of chondrule formation and evolution but for that of larger bodies such as the terrestrial planets. Here we have determined the bulk chemical composition-rare earth, refractory, main group, and volatile element contents-of a suite of chondrules previously dated using the Pb-Pb system. The volatile element contents of chondrules increase with time from ∼1 My after Solar System formation, likely the result of mixing with a volatile-enriched component during chondrule recycling. Variations in the Mn/Na ratios signify changes in redox conditions over time, suggestive of decoupled oxygen and volatile element fugacities, and indicating a decrease in oxygen fugacity and a relative increase in the fugacities of in-fluxing volatiles with time. Within the context of terrestrial planet formation via pebble accretion, these observations corroborate the early formation of Mars under relatively oxidizing conditions and the protracted growth of Earth under more reducing conditions, and further suggest that water and volatile elements in the inner Solar System may not have arrived pairwise.
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http://dx.doi.org/10.1073/pnas.1807263115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112700PMC
August 2018