Population-based input function and image-derived input function for [¹¹C](R)-rolipram PET imaging: Methodology, validation and application to the study of major depressive disorder

Quantitative PET studies of neuroreceptor tracers typically require that arterial input function be measured. The aim of this study was to explore the use of a population-based input function (PBIF) and an image-derived input function (IDIF) for [¹¹C](R)-rolipram kinetic analysis, with the goal of reducing - and possibly eliminating - the number of arterial blood samples needed to measure parent radioligand concentrations. Methods: A PBIF was first generated using [¹¹C](R)-rolipram parent time-activity curves from 12 healthy volunteers (Group 1). Both invasive (blood samples) and non-invasive (body weight, body surface area, and lean body mass) scaling methods for PBIF were tested. The scaling method that gave the best estimate of the Logan-V_T values was then used to determine the test-retest variability of PBIF in Group 1 and then prospectively applied to another population of 25 healthy subjects (Group 2), as well as to a population of 26 patients with major depressive disorder (Group 3). Results were also compared to those obtained with an image-derived input function (IDIF) from the internal carotid artery. In some subjects, we measured arteriovenous differences in [¹¹C](R)-rolipram concentration to see whether venous samples could be used instead of arterial samples. Finally, we assessed the ability of IDIF and PBIF to discriminate depressed patients (MDD) and healthy subjects. Results: Arterial blood-scaled PBIF gave better results than any non-invasive scaling technique. Excellent results were obtained when the blood-scaled PBIF was prospectively applied to the subjects in Group 2 (V_T ratio 1.02±0.05; mean±SD) and Group 3 (V_T ratio 1.03±0.04). Equally accurate results were obtained for two subpopulations of subjects drawn from Groups 2 and 3 who had very differently shaped (i.e. "flatter" or "steeper") input functions compared to PBIF (V_T ratio 1.07±0.04 and 0.99±0.04, respectively).Results obtained via PBIF were equivalent to those obtained via IDIF (V_T ratio 0.99±0.05 and 1.00±0.04 for healthy subjects and MDD patients, respectively). Retest variability of PBIF was equivalent to that obtained with full input function and IDIF (14.5%, 15.2%, and 14.1%, respectively). Due to [¹¹C](R)-rolipram arteriovenous differences, venous samples could not be substituted for arterial samples. With both IDIF and PBIF, depressed patients had a 20% reduction in [¹¹C](R)-rolipram binding as compared to control (two-way ANOVA: p=0.008 and 0.005, respectively). These results were almost equivalent to those obtained using 23 arterial samples. Conclusion: Although some arterial samples are still necessary, both PBIF and IDIF are accurate and precise alternatives to full arterial input function for [¹¹C](R)-rolipram PET studies. Both techniques give accurate results with low variability, even for clinically different groups of subjects and those with very differently shaped input functions.