title: Evaluation of an fMRI USPIO-based assay in healthy human volunteers.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  1 J. MAGN. RESON. IMAGING 2017;46:124-133.
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Richard
authors: R
authors: Baumgartner
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: William
authors: W
authors: Cho
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Alexandre
authors: A
authors: Coimbra
authors: Memory Aging & Cognition Centre at National University Health System, Singapore.
authors: Christopher
authors: C
authors: Chen
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Zaiqi
authors: Z
authors: Wang
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Arie
authors: A
authors: Struyk
authors: Memory Aging & Cognition Centre at National University Health System, Singapore.
authors: Narayanaswamy
authors: N
authors: Venketasubramanian
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: May
authors: M
authors: Low
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Cindy
authors: C
authors: Gargano
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Fuqiang
authors: F
authors: Zhao
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Donald
authors: D
authors: Williams
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Torsten
authors: T
authors: Reese
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Stephanie
authors: S
authors: Seah
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Dai
authors: D
authors: Feng
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Sonya
authors: S
authors: Apreleva
authors: Department of Diagnostic Radiology, National University Singapore.
authors: Esben
authors: E
authors: Petersen
authors: Merck & Co. Inc, Kenilworth, New Jersey, USA.
authors: Jeffrey L
authors: JL
authors: Evelhoch
mesh_terms: D001783:Blood Flow Velocity / Q000502:physiology*; D001810:Blood Volume; D001811:Blood Volume Determination / Q000379:methods; D001931:Brain Mapping / Q000379:methods; D002560:Cerebrovascular Circulation; D003287:Contrast Media / Q000008:administration & dosage; D003911:Dextrans / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005074:Evoked Potentials, Visual / Q000502:physiology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles / Q000008:administration & dosage*; D008297:Male; D012016:Reference Values; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014793:Visual Cortex / Q000502:physiology*; D014796:Visual Perception / Q000502:physiology*
chemical_list: D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; C097921:ferumoxtran-10
keywords: cerebral blood volume; drug development; fMRI; ferumoxytol; visual stimulation