Increased Serotonin Synthesis Capacity is Associated with Longitudinal Cortical Atrophy and Worsening Depressive Symptoms

Background Serotonin‐producing raphe nuclei are sites of age and Alzheimer’s disease‐related alterations in structure and function. Method We used [ 18 F]Fluoro‐m‐tyrosine ([ 18 F]FMT) positron emission tomography (PET) to measure serotonin synthesis capacity in younger (mean age = 22.08, n = 62) and older adults (mean age = 77.8, n = 49). [ 18 F]FMT net tracer influx (Ki) was higher in older adults in both the dorsal and median raphe nuclei (both p < 0.001). To examine the functional relevance of higher raphe [ 18 F]FMT Ki in older adults, we tested relationships with β‐amyloid status as defined by [ 11 C]Pittburgh compound B ([ 11 C]PiB) PET, retrospective longitudinal declines in cortical thickness, and retrospective longitudinal changes in depression symptoms measured using the geriatric depression scale (GDS). Result [ 11 C]PiB positive (n=14) older adults showed trend‐level elevation in dorsal and median raphe [ 18 F]FMT Ki relative to [ 11 C]PiB negative older adults (n = 35; both p < 0.09). Higher dorsal raphe [ 18 F]FMT Ki was associated with decreasing cortical thickness over time in the banks of the superior temporal sulcus (BanksSTS) (Monte Carlo, p < 0.05, r = ‐0.513), consistent with the interpretation that serotonin synthesis may be upregulated in response to neural losses. Decreasing cortical thickness was also associated with increasing GDS. We did not find evidence that higher dorsal raphe [ 18 F]FMT Ki had a beneficial impact on affective function. Instead, interaction analyses revealed relationships between atrophy and increasing GDS were strongest in individuals with highest dorsal raphe [ 18 F]FMT Ki (t = ‐2.056, p = 0.049; adjusting for age, sex, and [ 11 C]PiB status). Conclusion Together, these findings suggest serotonin synthesis capacity increases with age, and appears to signal poor aging trajectories. Most elevated serotonin synthesis capacity was associated with greatest cortical atrophy and drove relationships between atrophy and worsening depressive symptoms over time.