Evaluation of an fMRI USPIO-based assay in healthy human volunteers.

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.

Additive effects of a cholinesterase inhibitor and a histamine inverse agonist on scopolamine deficits in humans.

RATIONALE: Enhancement of histaminergic neurotransmission or histaminergic plus cholinergic neurotransmission may represent novel strategies for improving cognition in Alzheimer's disease. OBJECTIVE: To evaluate the effects of a novel histamine H3 receptor inverse agonist (MK-3134), an acetylcholinesterase inhibitor (donepezil), and their combination in attenuating the cognitive impairment associated with scopolamine. METHODS: Thirty-one subjects were randomized, and 28 completed this double-blind, placebo-controlled, five-period crossover study. Cognition was assessed using the Groton Maze Learning Task (GMLT) as the primary outcome measure. The two primary hypotheses were that donepezil 10 mg and MK-3134 25 mg, respectively, would attenuate scopolamine (0.5 mg)-induced impairment as measured by the GMLT over the first 12 h after scopolamine administration (AUC(1-12) (h)). A secondary hypothesis was that the combination of donepezil and MK-3134 would attenuate scopolamine-induced cognitive impairment to a greater extent than either agent alone as measured by the GMLT AUC(1-12 h). RESULTS: The primary and secondary hypotheses were not met. Upon examining the time course of the scopolamine effects (an exploratory objective), peak effects were generally observed around 2 h after scopolamine administration. Administration of MK-3134 or donepezil improved performance on the GMLT at the 2-h time point, rather than AUC(1-12 h), compared with scopolamine alone. Moreover, it appeared that the combination of MK-3134 and donepezil blunted the scopolamine effect to a greater extent than either drug alone. CONCLUSIONS: Exploratory analyses provide evidence for cognitive improvement through inverse agonism of the H3 histamine receptor and for cooperation between human cholinergic and histaminergic neurotransmitter systems. (ClinicalTrials.gov trial registration number: NCT01181310).