ABSTRACT
BACKGROUND: Aberrant accumulation of transition metals in the brain may have an early and important role in the pathogenesis of several neurodegenerative disorders, including Huntington disease (HD). OBJECTIVE: To comprehensively evaluate and validate the distribution of metal deposition in the brain using advanced magnetic resonance imaging methods from the premanifest through symptomatic stages of HD. DESIGN: Observational study. SETTING: University imaging center. PARTICIPANTS: Twenty-eight HD expanded gene carriers, 34 patients with symptomatic HD, and 56 age- and sex-matched healthy control subjects were included in the study. INTERVENTIONS: Participants underwent magnetic resonance imaging for the quantification of the phase evolution of susceptibility-weighted images. MAIN OUTCOME MEASURES: To verify the identity of the metals responsible for the changes in the phase evolution of the susceptibility signal in the brain and to assess correlations with systemic levels. Inductively coupled plasma mass spectrometry was used to measure transition metal concentrations in postmortem brains. RESULTS: In the basal ganglia, progressive increases in the phase evolution were found in HD, beginning in premanifest individuals who were far from expected onset and increasing with proximity to expected onset and thereafter. Increases in the cerebral cortex were regionally selective and present only in symptomatic HD. Increases were verified by excessive deposition of brain iron, but a complex alteration in other transition metals was found. CONCLUSION: An important and early role of altered metal homeostasis is suggested in the pathogenesis of HD.
Subject(s)
Brain/metabolism , Huntington Disease/metabolism , Huntington Disease/pathology , Iron/metabolism , Adult , Brain Mapping , Case-Control Studies , Disease Progression , Female , Humans , Huntington Disease/genetics , Imaging, Three-Dimensional , Magnetic Resonance Imaging , Male , Middle Aged , Observation , Severity of Illness IndexABSTRACT
Iron oxide contrast agents have been employed extensively in anesthetized rodents to enhance fMRI sensitivity and to study the physiology of cerebral blood volume (CBV) in relation to blood oxygen level-dependent (BOLD) signal following neuronal activation. This study quantified the advantages of exogenous agent for repeated neuroimaging in awake, nonhuman primates using a clinical 3 Tesla scanner. A monocrystalline iron oxide nanoparticle (MION) solution was injected at iron doses of 8 to 10 mg/kg in two macaque monkeys. Adverse behavioral effects due to contrast agent were not observed in either monkey using cumulative doses in excess of 60 mg/kg. Relative to BOLD imaging at 3 Tesla, MION increased functional sensitivity by an average factor of 3 across the brain for a stimulus of long duration. Rapid stimulus presentation attenuated MION signal changes more than BOLD signal changes, due to the slower time constant of the blood volume response relative to BOLD signal. Overall, the contrast agent produced a dramatic improvement in functional brain imaging results in the awake, behaving primate at this field strength. (c) 2002 Elsevier Science (USA).
