Background Serotonin 1A receptors (5-HT1A) are implicated in major depressive disorder (MDD). We previously reported higher 5-HT1A binding potential (BPF=Bavail/KD) in antidepressant naïve MDD subjects compared to controls while other studies report lower BPND(BPND=fNDBavail/KD). Discrepancies can be related to differences in study population or methodology. We sought to replicate our findings in a novel cohort and determine whether choice of reference region and outcome measure could explain discrepancies. Methods Nine new controls and 22 new not recently medicated (4 years, NRM) MDD subjects underwent positron emission tomography with [11C]WAY100635. BPF and BPND were determined using a metabolite and free fraction corrected arterial input function. BPND was also determined using cerebellar gray matter (CGM) and cerebellar white matter (CWM) reference regions as input functions. Results BPF is higher in the new NRM cohort (p=0.037) compared to new controls, which is comparable to the effect in the previous cohort (p=0.04). We combined the cohorts to examine the effects of the reference region and outcome measure. In the combined cohort, BPF is higher in the NRM compared to controls (p=0.0001). Neither BPND using CWM (p=0.86) nor VT (p=0.374) differs between groups. When CGM is used, the NRM group has lower 5HT1A BPND compared with controls (p=0.03). CGM VT is higher in NRM compared to controls (p=0.007). Conclusions Choice of reference region and outcome measure can produce different 5-HT1A findings in MDD. Higher 5-HT1A BPF in MDD was found with the method with fewest assumptions about nonspecific binding and a reference region without receptors.

Amyloid load in the brain using 11C-PIB PET and cerebral glucose metabolism using 18F-FDG PET were evaluated in patients with mild Alzheimer’s disease (AD, n=18), mild cognitive impairment (MCI, n=24) and controls (CTR, n=18). 11C-PIB binding potential (BPND) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI, and in prefrontal cortex for MCI compared to CTR. For 18F-FDG, rCMRGlu was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI-CTR differences. For the AD-CTR comparison, precuneus BPND area under the ROC curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination AUC was 0.989. 11C-PIB PET BPND clearly distinguished diagnostic groups, and combined with 18F-FDG PET rCMRGlu this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies.

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