Multicomponent T2 analysis of dithiocarbamate-mediated peripheral nerve demyelination

Abstract

Standard light microscope histological evaluation of peripheral nerve lesions has been used routinely to assess peripheral nerve demyelination; however, the development of magnetic resonance (MR) methodology for assessing peripheral nerve may provide complementary information, with less expense and in less time than nerve histology methods. In this study, the utility of multicomponent NMR T(2) relaxation analysis for assessing myelin injury in toxicology studies was examined using two dithiocarbamates, N,N-diethyldithiocarbamate (DEDC) and pyrrolidine dithiocarbamate (PDTC), known to produce myelin injury and elevate copper in the nervous system. T(2) analysis was used in conjunction with standard histological methods to assess myelin injury and determine if dithiocarbamate-mediated copper accumulation in peripheral nerve was associated with more severe myelin lesions. Male Sprague-Dawley rats were administered i.p. DEDC for 8 weeks and maintained on either a diet containing normal (13 ppm) or elevated (200 ppm) copper. Another group of male Sprague-Dawley rats was administered oral PDTC and a 200 ppm copper diet, with controls given only the 200 ppm copper diet, for 47 weeks. Following exposures, the morphology of sciatic nerve was evaluated using light microscopy and multicomponent T(2) analysis of excised fixed nerves; and copper levels in sciatic nerve were determined using ICP-AES. Light microscopy demonstrated the presence of a primary myelinopathy in dithiocarbamate-exposed rats characterized by intramyelinic edema, demyelination, and secondary axonal degeneration. Both the nerve copper level and number of degenerated axons, as ascertained by ICP-AES and microscopy, respectively, were augmented by dietary copper supplementation in conjunction with administration of DEDC or PDTC. T(2) analysis revealed a decreased contribution from the shortest T(2) component in multicomponent T(2) spectra obtained from animals administered DEDC or PDTC, consistent with decreased myelin content; and the decrease of the myelin water component was inversely correlated to the levels of nerve copper and myelin lesion counts. Also, the T(2) analysis showed reduced variability compared to histological assessment. These studies support multicomponent T(2) analysis as a complementary method to light microscopic evaluations that may also be applicable to in vivo assessments.

In vivo multi-slice mapping of myelin water content using T2* decay

“…One approach commonly used to quantify myelin is based on analyses of T 2 relaxation times. It has been reported that the T 2 spectrum of healthy brain tissue and several myelinated tissue samples consists of three components (MacKay et al, 1994;Whittall et al, 1997;Does and Gore, 2002;Wachowicz and Snyder, 2002;Lancaster et al, 2003;Andrews et al, 2005;Valentine et al, 2007). Because the water trapped in the myelin sheath has the shortest T 2 relaxation time among those three components, the myelin water fraction (MWF), defined as the ratio of the signal intensity of the shortest T 2 component to the total, can represent the myelin content in WM.…”

“…MWF is commonly calculated by fitting the T 2 decay signal from multi-echo acquisition data. A regularized non-negative least-squares (NNLS) algorithm (Whittall and MacKay, 1989;Whittall et al, 1997;MacKay et al, 1994;Laule et al, 2004;Does and Gore, 2002;Wachowicz and Snyder, 2002;Valentine et al, 2007;Moore et al, 2000;Laule et al, 2006;Oh et al, 2006) and a three-pool model (Lancaster et al, 2003;Andrews et al, 2005) have been used for multi-exponential fitting of the multi-echo data. The regularized NNLS algorithm does not require any prior knowledge of the T 2 spectrum except for a smoothing constraint.…”

Copper accumulation and lipid oxidation precede inflammation and myelin lesions in N,N-diethyldithiocarbamate peripheral myelinopathy

“…However, the molecular processes underlying the myelinopathy are not well defined. Previous studies have reported increased levels of copper and lipid oxidation to be associated with dithiocarbamate induced neurotoxicity (Calviello, 2005;Delmaestro, 1995;Tonkin, 2004) and correlative data have shown a relationship between copper levels in peripheral nerve and the severity of myelin injury produced by pyrrolidine dithiocarbamate and N,Ndiethyldithiocarbamate (DEDC) in rodent models (Valentine et al, 2006;Valentine et al, 2007). Additionally, proteomic analysis of sciatic nerve proteins using this animal model has demonstrated significant elevations in expression levels of glutathione transferase isozymes within Schwann cells consistent with activation of the antioxidant response element pathways subsequent to DEDC exposure (Viquez et al, 2007).…”

Improved myelin water quantification using spatially regularized non‐negative least squares algorithm

“…A technique that provides specific and sensitive information about the myelin content was developed based on an analysis of T 2 relaxation times (5,6). It has been reported that the T 2 spectrum of WM and several myelinated tissue samples consists of multiple components (7)(8)(9)(10)(11)(12)(13) and that the short component with T 2 between 10 ms and 50 ms corresponds to the water pool within the myelin sheath (2)(3)(4)(5)(6). Myelin content can therefore be quantitated using the fraction of this short T 2 component.…”