MEASUREMENT OF TRANSITION METALS IN THE RODENT BRAIN USING X-RAY FLUORESCENCE AND NEUTRON ACTIVATION ANALYSIS

Abstract

<p>Transition metals, such as iron, manganese, and copper are essential in the development and function of biological systems. However, disrupted levels of transition metals are highly cytotoxic, and metal homeostasis is strictly maintained in cells under normal conditions. The neuropathology of several brain disorders, such as Alzheimer’s disease and Parkinson’s disease has been linked to altered metal levels. This work focused on the measurement of iron, manganese, and copper, with the aim of better elucidating their role in brain disease.</p> <p>Two experiments were carried out in C57Bl/6 mice looking at metal homeostasis: <em>1.</em> following manganese injections typically administered in manganese-enhanced MRI animal studies, and <em>2.</em> following copper deficiency in a cuprizone model of demyelination. Metal measurements were made in the brain and visceral organs using X-ray fluorescence to measure iron and copper concentrations, and neutron activation analysis to measure manganese concentrations.</p> <p>In the MEMRI study in this work, in addition to the expected manganese concentration increases in brain regions, a statistically significant decrease in iron concentration in the thalamus was found. This change in iron levels in the thalamus following manganese injections should serve as a caution that care should be taken when interpreting signal changes in brain regions.</p> <p>The cuprizone study in this thesis confirmed that copper levels are reduced following cuprizone administration. Surprisingly, manganese concentrations were significantly higher in several brain regions that have demyelination in this model, but not iron or copper. The mechanism of cuprizone toxicity was related to manganese neurotoxicity that may contribute to demyelination.</p>