Quantitative MRI measures of multiexponential T 2 relaxation and magnetization transfer were acquired from six samples of excised and fixed rat spinal cord and compared with quantitative histology. MRI and histology data were analyzed from six white matter tracts, each of which possessed unique microanatomic characteristics (axon diameter and myelin thickness, in particular) but a relatively constant volume fraction of myelin. The results indicated that multiexponential T 2 relaxation characteristics varied substantially with variation of microanatomy, while the magnetization transfer characteristics remained close to constant. The most-often-cited multiexponential T 2 relaxation metric, myelin water fraction, varied by almost a factor of 2 between two regions with myelin volume fractions that differed by only % 12%. Based on the quantitative histology, the proposed explanation for this variation was intercompartmental water exchange, which caused the underestimation of myelin water fraction and T 2 values and is, presumably, a greater factor in white matter regions where axons are small and myelin is thin. In contrast to the multiexponential T 2 relaxation observations, magnetization transfer metrics were relatively constant across white matter tracts and concluded to be relatively insensitive to intercompartmental water exchange. Magn Reson Med 63:902-909, 2010. V C 2010 Wiley-Liss, Inc.Key words: MRI; multiexponential T 2 ; magnetization transfer; histology; myelin Multiexponential T 2 (MET 2 ) and quantitative magnetization transfer (qMT) have been proposed as potential MRI-derived reporters of myelin content in white matter (WM) and nerve. With MET 2 , the relative size of shortlived T 2 component (typically, T 2 ¼ 8-50 ms, depending on the amplitude of static field) has been defined as the myelin water fraction (MWF) and interpreted as a direct measure of myelin content (1,2). Similarly, in WM, the macromolecular protons that exchange magnetization with water protons are thought to be substantially constituents of myelin (3,4). That is, the qMT measure of this macromolecular pool size relative to the total water signal, sometimes called the pool-size-ratio (PSR) (5), is believed to be a measure of relative myelin content. While both MWF and PSR have been found to correlate with myelin content when comparing normal myelinated tissue with demyelinated or dysmyelinated tissue (6-11 and many others), the exact relationship between these measures and myelin content is not well understood.The interpretation of MWF as a measure of myelin content is predicated on the assumption of slow exchange between myelin water and water in the intraand interaxonal spaces, referred to herein as other water. If the rate of exchange between myelin water and other water is dependent upon the dimensions of these compartments (i.e., axon diameter [AxD], myelin thickness [MyTh], interaxonal distance), then the slow exchange model may be more suitable in some myelinated tissues than others. For example, peripheral nerve tends to have...

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Previous studies have demonstrated the ability of the dithiocarbamate, disulfiram, to produce a peripheral neuropathy in humans and experimental animals and have also provided evidence that N,N-diethyldithiocarbamate (DEDC) is a proximate toxic species of disulfiram. The ability of DEDC to elevate copper levels in the brain suggests that it may also elevate levels of copper in peripheral nerve, possibly leading to oxidative stress and lipid peroxidation from redox cycling of copper. The study presented here investigates the potential of DEDC to promote copper accumulation and lipid peroxidation in peripheral nerve. Rats were administered either DEDC or deionized water by ip osmotic pumps and fed a normal diet or diet containing elevated copper, and the levels of metals, isoprostanes, and the severity of lesions in peripheral nerve and brain were assessed by ICP-AES/AAS, GC/MS, and light microscopy, respectively. Copper was the only metal that demonstrated any significant compound-related elevations relative to controls, and total copper was increased in both brain and peripheral nerve in animals administered DEDC on both diets. In contrast, lesions and elevated F2-isoprostanes were significantly increased only in peripheral nerve for the rats administered DEDC on both diets. Autometallography staining of peripheral nerve was consistent with increased metal content along the myelin sheath, but in brain, focal densities were observed, and a periportal distribution occurred in liver. These data are consistent with the peripheral nervous system being more sensitive to DEDC-mediated demyelination and demonstrate the ability of DEDC to elevate copper levels in peripheral nerve. Additionally lipid peroxidation appears to either be a contributing event in the development of demyelination, possibly through an increase of redox active copper, or a consequence of the myelin injury.

Selenoprotein P is an abundant extracellular protein that is expressed in liver, brain, and other tissues. Studies in mice with the selenoprotein P gene deleted (Sepp-/- mice) have implicated the protein in maintaining brain selenium. Sepp-/- mice fed a normal or low selenium diet develop severe motor impairment and die, but Sepp-/- mice fed a high selenium diet remain clinically unimpaired. As an initial step to evaluate the effect of selenoprotein P deletion on central nervous system architecture, the brains and cervical spinal cords of Sepp-/- and Sepp+/+ mice fed low or high selenium diets were examined by light and electron microscopy. Brains of Sepp-/- mice demonstrated no gross abnormalities. At the light microscopic level, however, Sepp-/- mice fed either the selenium deficient diet or the high selenium diet had enlarged dystrophic axons and degenerated axons in their brainstems and cervical spinal cords. No axonal lesions were observed in the Sepp+/+ mice fed either diet. Electron microscopy demonstrated that the enlarged axons in the Sepp-/- mice were packed with organelles, suggesting a deficit in fast axonal transport. The similar severity of axonal lesions observed in Sepp-/- mice fed the 2 diets suggests that axonal dystrophy is a common phenotype for deletion of selenoprotein P regardless of selenium intake and that additional studies will be required to determine the pathogenesis of the neurological signs and mortality observed in Sepp-/- mice fed a low selenium diet.

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