A method of creating an image difference overlay comprises identifying a loop of reference images of a subject and identifying a loop of data images of the subject. The loop of image data can be identified after an event, such as the administration of contrast agent to the subject. A reference loop image frame is compared to one or more data loop image frames and the reference loop frame is associated with a data loop image frame which closely resembles the data loop image frame. Each of the associated frames can then be processed and used to create an image difference overlay frame.