Synchrotron X-ray Fluorescence Reveals Abnormal Metal Distributions in Brain and Spinal Cord in Spinocerebellar Ataxia: A Case Report

Abstract

For the first time, synchrotron rapid-scanning X-ray fluorescence (RS-XRF) was used to simultaneously localize and quantify iron, copper, and zinc in spinal cord and brain in a case of spinocerebellar ataxia (SCA). In the normal medulla, a previously undescribed copper enrichment was seen associated with spinocerebellar fibers and amiculum olivae. This region was virtually devoid of all metals in the SCA case. Regions with neuronal loss and gliosis in the cerebellar cortex, inferior olivary, and dentate nuclei and areas showing loss of myelinated fibers were also low in all metals in SCA compared to control. In contrast, the ventral columns of the spinal cord that exhibited only moderate myelin pallor had increased metal levels. Iron and zinc were also elevated in the globus pallidus pars externa in SCA relative to control. We hypothesize that metals increase as part of the initial neurodegenerative process, but once degeneration is advanced, the metal levels drop. This implies a role for multiple metals in SCA neurodegeneration, but further study is required to establish a causative role. We suggest that if these findings are generally true of at least some cases of SCA, not only iron but also copper and zinc should be considered as possible therapeutic targets.

Neurochemical and Structural Organization of the Principal Nucleus of the Inferior Olive in the Human

“…Cerebellar or brainstem damage, specifically to the central tegmental tract, results in a specific type of degeneration in the olive, ''hypertrophic olivary degeneration,'' (Weber, 1942;Gautier and Blackwood, 1961;Goto et al, 1988;Braak et al, 2003;Rü b et al, 2005;Aladdin et al, 2008;Valente et al, 2008). There is also degeneration of IO neurons in several neurological disorders, for example spinocerebellar ataxias and Joubert syndrome (Braak et al, 2003;Rü b et al, 2005;Valente et al, 2008;Popescu et al, 2009). …”

Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions

“…Each method employs a different chemical reaction, and therefore cannot be used on the same tissue section. X-ray fluorescence imaging (XFI) is element-specific, quantitatively detects all chemical forms of any metal and simultaneously maps multiple metals, therefore addressing the limitations of histochemistry [45, 46, 48, 49, 52]. This is the first systematic synchrotron X-ray fluorescence study to compare the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing white matter (normal appearing WM) and periplaque white matter (periplaque WM) from a given patient, and to assess the involvement of these metals in MS lesion pathogenesis.…”

The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light

“…As Popescu et al (2009a) observe, the escape depth is element-dependent, so although under most conditions they can obtain relative metal ion distribution maps across a sample area, the penetration depth for each map will differ as a function of the element mapped. Their approach, utilizing thick tissue slices and rapid SXRF scanning, has enabled transition metal maps to be generated for selected regions of the central nervous system in cases of PD, spinocerebellar ataxia, and healthy control (Popescu et al, 2009a,b,c). This is an advance on histochemical staining in that the elemental maps are achieved simultaneously from a given sample, and there is excellent specificity (if spectra are fitted, rather than simply gated), for elements in addition to iron such as copper and zinc, so long as the element-specific differences in sampling depth are not critical to the experiment design.…”