Validation of cerebral blood perfusion imaging as a modality for quantitative pharmacological MRI in rats.
The aim of this study was to validate continuous arterial spin labeling (CASL) as a quantitative imaging modality for pharmacological MRI (phMRI) based on local cerebral blood perfusion. Specifically, the capability of CASL to assess brain-activity signatures of pharmacological interventions in animal models was evaluated with respect to drug discovery in diseases of the central nervous system (CNS). Perfusion as a surrogate for neuronal activity was measured in various brain areas of the rat. The validation approach was threefold. First, perfusion was shown to reliably reflect differential effects of anesthesia on striatal activation. Different baseline levels and different temporal response profiles after amphetamine challenges under isoflurane, propofol, ketamine, and alpha-chloralose anesthesia were consistent with known properties of these anesthetics. Second, remarkable consistency of multi-area baseline perfusion patterns between independent groups of animals confirmed the notion that CASL is highly reproducible and thus particularly suitable for long-term longitudinal studies. Third, administration of the well-characterized psychotomimetic compounds amphetamine and phencyclidine (PCP) elicited dose-dependent activation patterns that were related to the drugs' particular interactions with the dopaminergic and glutamatergic systems, respectively. In conclusion, perfusion-based phMRI is a robust, reliable and valid quantitative technique suitable for evaluating brain-activation patterns in animal models of CNS diseases.
F. Hoffmann-La Roche Pharmaceuticals Ltd., Basel, Switzerland.
Andreas
A
Bruns
Basil
B
Künnecke
Céline
C
Risterucci
Jean-Luc
JL
Moreau
Markus
M
von Kienlin
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D018810:Magnetic Resonance Angiography / Q000379:methods* / Q000662:veterinary*; D008297:Male; D055420:Perfusion Imaging / Q000379:methods* / Q000662:veterinary*; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D000661:Amphetamine