Evaluation of an fMRI USPIO-based Assay in Healthy Human Volunteers

J Magn Reson Imaging. 2017 Jul;46(1):124-133. doi: 10.1002/jmri.25499. Epub 2016 Oct 24.

Abstract

Purpose: To present the testretest and contrast dose effect results of cerebral blood volume (CBV) functional MRI (fMRI) in healthy human volunteers using ferumoxytol (Feraheme), an ultrasmall-superparamagnetic iron oxide (USPIO) nanoparticle.

Materials and methods: This was an open-label, two-period, fixed-sequence study in healthy young volunteers. In eight subjects, using a 3 Tesla field strength system, blood oxygen level dependent (BOLD) and CBV fMRI were acquired in response to a visual black-and-white checkboard stimulation paradigm using an escalating ferumoxytol dose design (250, 350, and 510 mg iron). Multiple outcome measures were analyzed including absolute percent signal change (|PSC|, primary endpoint), its contrast-to-noise ratio (CNR) and corresponding z-score, percent CBV change (ΔCBV) and respective CNR, concentration of Fe, and baseline CBV.

Results: The |PSC| in the visual cortex increased with ferumoxytol dose and was up to 3 × higher than BOLD fMRI. Test-retest reliability was comparable for BOLD and CBV fMRI. Intraclass correlation coefficients (ICCs) for |PSC| were 0.3 (one-sided 95% lower confidence limit = 0.00), 0.81 (0.47), 0.48 (0.00), and 0.3 (0.00) for BOLD and the 250-, 350-, and 510-mg doses of ferumoxytol, respectively. For ΔCBV, ICCs were 0.77 (0.37), 0.48 (0.00), and 0.49 (0.00) for 250 mg, 350 mg, and 510 mg, respectively.

Conclusion: This work demonstrates that CBV fMRI techniques and endpoints are dose dependent, robust and have good test-retest repeatability. It also confirms previous findings that USPIO enhances sensitivity of fMRI stimulus-response endpoints.

Level of evidence: 1 J. MAGN. RESON. IMAGING 2017;46:124-133.

Keywords: cerebral blood volume; drug development; fMRI; ferumoxytol; visual stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Flow Velocity / physiology*
  • Blood Volume
  • Blood Volume Determination / methods
  • Brain Mapping / methods
  • Cerebrovascular Circulation*
  • Contrast Media / administration & dosage
  • Dextrans / administration & dosage*
  • Dose-Response Relationship, Drug
  • Evoked Potentials, Visual / physiology
  • Female
  • Humans
  • Magnetic Resonance Imaging / methods*
  • Magnetite Nanoparticles / administration & dosage*
  • Male
  • Reference Values
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Visual Cortex / physiology*
  • Visual Perception / physiology*

Substances

  • Contrast Media
  • Dextrans
  • Magnetite Nanoparticles
  • ferumoxtran-10