Date

7-2014

Document Type

Dissertation

Degree Name

Ph.D.

Department

Department of Behavioral Neuroscience

Institution

Oregon Health & Science University

Abstract

Introduction: Methamphetamine (MA) abuse produces long term changes to the dopamine system that likely contribute to the psychiatric and cognitive symptoms that are seen in MA users. Emerging evidence from preclinical studies suggests that brain iron accumulation plays a role in MA toxicity, both as a biomarker of damage and a potential source of oxidative stress; however, this relationship has not yet been characterized in human MA users. The goal of this study was to utilize in vivo magnetic resonance imaging (MRI) techniques to measure brain iron levels in human subjects with a history of MA dependence and determine if these measurements represent functionally significant biomarkers of MA toxicity. Iron is paramagnetic, and its presence increases the transverse relaxation rate constant (R2) of nearby water protons causing a loss of signal intensity on T2-weighted images. Measuring this effect using quantitative MRI techniques allows for in vivo investigation of the effects of MA on the distribution of brain iron. Methods: MRI datasets were acquired from 27 currently abstinent MA users and 27 aged matched healthy control subjects. Series used in this study included a high-resolution, T1-weighted MPRAGE, T2-weighted TRSE, Turbo Spin Echo TSE) sequences acquired with three different echo times and a 3D proton density (PD) sequence. R2 (≡1/T2) maps were calculated at each voxel using a monoexponential decay function. Maps of the fractional macromolecular (fM) content were created by normalizing PD images intensities to the peak intensity values of voxels within the cerebrospinal fluid. Parametric maps of the distribution of iron content were then calculated using a relaxometry model incorporating the combined effects of fM and iron content. These parametric iron maps were registered to a common brain space. The effect of MA on regional iron distribution was assessed using both region of interest analysis and oxelwise linear models. Additional analyses were also conducted using the R2 and fM maps, as well as T2-weighted signal intensity measurements.

Results: Using quantitative relaxometry measures that are specific for iron, I was unable to detect any differences in regional iron content in former MA users when compared to aged-matched healthy control subjects. These measures yielded values for iron and fM that were in substantial agreement with literature values. These measures also detected strong age associated increases in iron content within basal ganglia regions consistent with previous reports providing a positive control for these methods. While no group differences in iron accumulation were found, the MA group had significantly reduced fM values in the thalamus, uggesting increased tissue water content in this region.

Discussion: Contrary to the proposed hypothesis, this study found no evidence of altered iron accumulation in abstinent MA users, suggesting that iron accumulation is not a useful biomarker of MA toxicity. This finding is in marked contrast to a study in nonhuman primates which demonstrated an MA induced increase in iron accumulation that was similar to the effects of advanced aging. The discrepancy between these findings is likely due to interspecies differences in brain iron accumulation.

Identifier

doi:10.6083/M4028Q7C

School

School of Medicine

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