Reference values for trace element levels in the human brain: A systematic review of the literature

Some trace elements (TE) are eminently toxic for humans (e.g., Al, Pb, Hg, Cd) and its presence in the central nervous system has been linked to the etiology of neurodegenerative diseases (ND). More recently, the focus has shifted to the potential role of the imbalances on essential TE levels (e.g., Fe, Cu, Zn, Se) within the brain tissue, and they have also been identified as potentially responsible for the cognitive decline associated with normal ageing and the development of some ND, although their definite role remains unclear. Accurately, well-defined reference values for TE levels in human body fluids and tissues are indispensable to identify possible disturbances in individual cases. Moreover, since the brain is a highly heterogeneous organ, with anatomically and physiologically very different areas, a detailed mapping of TE distribution across the brain tissue of normal individuals, with an in-depth analysis of TE levels in the different brain regions, is a mandatory prior work so that the results obtained from patients suffering from ND and other brain diseases can be interpreted. This review aims to compile and summarize the available data regarding TE levels in the different human brain regions of "normal" (non-diseased) individuals in order to contribute to the establishment of robust reference values. Fifty-four studies, published since 1960, were considered. The results showed a great variability between different studies. The potential sources of this variability are discussed. The need for increased harmonization of experimental strategies is highlighted in order to improve the comparability of the data obtained.