Association between ageing, brain chemistry and white matter volume revealed with complementary MRI and FTIR brain imaging.

Magnetic resonance imaging (MRI) is the gold standard method to study brain anatomy in vivo. Using MRI, subtle alterations to white matter structures in the brain are observed prior to cognitive decline associated with the ageing process, and neurodegenerative diseases such as Alzheimer's disease. Detection of such alterations provides hope for early clinical diagnosis. While MRI is essential to detect subtle alterations to brain structure in vivo, the technique is less suited to study and image the distribution of biochemical markers within specific brain structures. Consequently, the chemical changes that drive, or are associated with MRI-detectable alterations to white matter are not well understood. Herein, we describe (to the best of our knowledge) the first application of a complementary imaging approach that incorporates in vivo MRI with ex vivo Fourier transform infrared (FTIR) spectroscopic imaging on the same brain tissue. The combined workflow is used to detect and associate markers of altered biochemistry (FTIR) with anatomical changes to brain white matter (MRI). We have applied this combination of techniques to the senescence accelerated murine prone strain 8 (SAMP8) mouse model (n = 6 animals in each group, analysed across two ageing time points, 6 and 12 months). The results have demonstrated alterations to lipid composition and markers of disturbed metabolism during ageing are associated with loss of white matter volume.

A review of the "metallome" within neurons and glia, as revealed by elemental mapping of brain tissue.

It is now well established that transition metals, such as Iron (Fe), Copper (Cu), and Zinc (Zn) are necessary for healthy brain function. Although Fe, Cu, and Zn are essential to the brain, imbalances in the amount, distribution, or chemical form ("metallome") of these metals is linked to the pathology of numerous brain diseases or disorders. Despite the known importance of metal ions for both brain health and disease, the metallome that exists within specific types of brain cells is yet to be fully characterised. The aim of this mini-review is to present an overview of the current knowledge of the metallome found within specific brain cells (oligodendrocytes, astrocytes, microglia, and neurons), as revealed by direct elemental mapping techniques. It is hoped this review will foster continued research using direct elemental mapping techniques to fully characterise the brain cell metallome.

[Mapping the Metallo-maze to Memory Loss: Does Neuronal Metal Ion Deficiency Contribute to Dementia?]

Dementia has no cure and is an international health crisis. In addition to the immeasurable loss of QOL caused by dementia, the global economic cost is predicted to reach $2 trillion (USD) by 2030. Although much remains unknown about the biochemical pathways driving cognitive decline and memory loss during dementia, metals have been implicated in neurodegenerative disease. For example, total levels of Fe and Cu increase, which has been proposed to drive oxidative stress; and Fe, Cu, and Zn can bind amyloid-ß, catalysing aggregation and formation of amyloid plaques. Unfortunately, despite these known facets through which metal ions may induce pathology, studies in greater detail have been hampered by a lack of microscopy methods to directly visualise metal ions, and their chemical form, within brain cells. Herein we report the use of synchrotron X-ray fluorescence microscopy to simultaneously image Fe, Cu, and Zn within neurons in ex vivo brain tissue sections. Using animal models of dementia, we now demonstrate for the first time that despite global increases in brain metal content and metal ion accumulation within amyloid plaques, key brain regions may also become metal ion deficient. Such deficiency could contribute to cognitive decline because of the essential roles metal ions play in neurotransmitter synthesis and energy metabolism. These recent findings are discussed in the context of memory loss, and the impact that metal ion dis-homeostasis may have on diagnostic and therapeutic development.

Revealing differences in the chemical form of zinc in brain tissue using K-edge X-ray absorption near-edge structure spectroscopy.

Zinc is a prominent trace metal required for normal memory function. Memory loss and cognitive decline during natural ageing and neurodegenerative disease have been associated with altered brain-Zn homeostasis. Yet, the exact chemical pathways through which Zn influences memory function during health, natural ageing, or neurodegenerative disease remain unknown. The gap in the literature may in part be due to the difficulty to simultaneously image, and therefore, study the different chemical forms of Zn within the brain (or biological samples in general). To this extent, we have begun developing and optimising protocols that incorporate X-ray absorption near-edge structure (XANES) spectroscopic analysis of tissue at the Zn K-edge as an analytical tool to study Zn speciation in the brain. XANES is ideally suited for this task as all chemical forms of Zn are detected, the technique requires minimal sample preparation that may otherwise redistribute or alter the chemical form of Zn, and the Zn K-edge has known sensitivity to coordination geometry and ligand type. Herein, we report our initial results where we fit K-edge spectra collected from micro-dissected flash-frozen brain tissue, to a spectral library prepared from standard solutions, to demonstrate differences in the chemical form of Zn that exist between two brain regions, the hippocampus and cerebellum. Lastly, we have used an X-ray microprobe to demonstrate differences in Zn speciation within sub-regions of thin air-dried sections of the murine hippocampus; but, the corresponding results highlight that the chemical form of Zn is easily perturbed by sample preparation such as tissue sectioning or air-drying, which must be a critical consideration for future work.