This is the second resubmission of an R01 application. We recently measured dopamine transporter (DAT) binding in adults with ADHD, using single photon emission computed tomography (SPECT) with the highly selective radiopharmaceutical, altropane.[9] DAT binding in was 70% greater Jn adults with ADHD. Our findings were partially replicated by Krause et al., (17% increase) but not replicated by van Dyck et al. (no increase), both using less specific radioligands. Positron emission tomography (PET) with 11C- altropane is ideal to measure DAT. It produces higher resolution, improved signal-to-noise ratio and less artifact than SPECT over a shorter acquisition time and permits kinetic modeling and estimates of affinity and density. To date, 6 adults and 6 controls have been imaged at MGH using [11C]altropane and PET which revealed a 34% increase in DAT binding. Moreover, Cook and others have demonstrated an association between ADHD and the 480-bp allele of the dopamine transporter gone. To this end, the primary goal of this molecular imaging proposal is to firmly establish the magnitude of increased DAT binding in adult ADHD with expert diagnostic methodology, a much larger N (66), a technically superior ligand (11C- altropane) and state-of-the-art imaging (PET). In addition, we seek to extend the previous findings to examine density (B'max) and affinity (Kd). The proposed work should move the field of ADHD research into a new direction in which molecular genetic and imaging studies are combined.
Our specific aims are the following: 1. To examine DAT receptor bindinq in adults with ADHD usinq PET scanninq with 11C altropane as the li.qand. We hypothesize that compared to adults without ADHD, adults with ADHD will have greater DAT binding that will not be accounted for by psychiatric comorbidity, gender or age. Furthermore, we will separately examine density of DAT sites and affinity. 2. To examine the relationship of DAT binding to clinical features of ADHD. We hypothesize that DAT binding will be positively correlated with a) severity of ADHD symptoms; and b) neuropsychological and interpersonal dysfunction. 3. To examine the relationship between DAT bindinq and .qenetic risk factors, a) We hypothesize that DAT binding will be associated with the 480 allele of the 40-bp VNTR in the 3'-untranslated region of the dopamine transporter gene.
