A study paradigm allowing comparison of multiple high-resolution rCBV-maps for the examination of drug effects.
Owing to the neuro-vascular coupling, measurement of changes in regional cerebral blood flow and blood volume (rCBV) can be used as surrogates reflecting the effects of central nervous system active drugs on neural transmission. As most such drugs are administered orally or intramuscularly and, in many cases, beneficial effects due to drug treatment can be observed only after chronic administration for days or weeks, the evaluation of drug efficacy requires the development of acquisition and analysis tools that allow for comparison of imaging data sets obtained in multiple sessions and for multiple subjects. In the present study, high-resolution susceptibility contrast MR perfusion imaging using a super-paramagnetic contrast agent (CA) was applied to study the effect of a single oral administration of the acetylcholine-esterase inhibitor rivastigmine (Exelon) on rCBV in rats. rCBV maps were calculated from two T2-weighted three-dimensional fast-spin-echo scans recorded before and after the injection of the CA, respectively. All MRI data sets were mapped to a reference data set obtained from a normal male Sprague-Dawley rat using an automated co-registration procedure prior to the analysis for drug effects. Rivastigmine was orally administered at doses of 2, 4 or 8 mg/kg 1 h prior to the rCBV measurement. Rivastigmine increased rCBV in several brain areas including cortex, caudate putamen and hippocampus. The observed effects were dose-dependent and the changes reached the order of 5-12% as compared with baseline levels. Vehicle-treated animals showed no significant alterations of blood volume, demonstrating the reproducibility and stability of rCBV measurements.
Rausch
M
M
Novartis Institutes for Biomedical Research, Discovery Technologies, Analytical and Imaging Sciences, WSJ-386.3.01, CH-4002 Basel, Switzerland. martin.rausch@pharma.novartis.com
Gentsch
C
C
Enz
A
A
Baumann
D
D
Rudin
M
M
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007089:Image Enhancement / Q000379:methods; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D021621:Imaging, Three-Dimensional / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D048448:Phenylcarbamates / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D000068836:Rivastigmine; D013382:Subtraction Technique
D048448:Phenylcarbamates; D000068836:Rivastigmine