Poorer aging trajectories are associated with elevated serotonin synthesis capacity

Abstract

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [¹⁸F]Fluoro-m-tyrosine ([¹⁸F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [¹⁸F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and β-amyloid (Aβ) pathology using cross-sectional [¹⁸F]Flortaucipir and [¹¹C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [¹⁸F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.

Figure 1:. Timeline and Age-group differences in [¹⁸F]FMT Ki:

(A) Timeline of older adult data (n = 49), including longitudinal MRI scans, longitudinal depression symptom testing sessions, [¹¹C]PiB PET, and [¹⁸F]Flortaucipir PET relative to the [¹⁸F]FMT PET scan shown at time 0 for each participant. (B) Tukey boxplot, with means shown as white diamonds. Older adults (red) show significantly higher [¹⁸F]FMT Ki than younger adults (blue) in the dorsal raphe nucleus (p < .001***). (C) A whole-brain voxel-wise two-sample t-test comparing older adult [¹⁸F]FMT Ki to young adult [¹⁸F]FMT Ki showed regions of significantly higher [¹⁸F]FMT Ki in older adults overlapping with the DRN (outlined in blue) region of interest (t-map overlay displayed at p < 2.5 x 10⁻⁶).

Figure 2:. Relationships among cortical thickness changes, DRN [¹⁸F]FMT, and depression symptom changes:

(A) Whole-brain vertex-wise regressions of dorsal raphe nucleus (DRN) [¹⁸F]FMT Ki showed negative associations (cool colors) such that higher DRN [¹⁸F]FMT Ki was associated with decreasing cortical thickness in the left temporal cortex. (B) Whole-brain vertexwise regression of depression symptom changes over time demonstrated that worsening depression symptoms were associated with decreasing cortical thickness. Color bars show significance using a −log(10) p-value scale. All analyses include Monte Carlo correction for multiple comparisons (p < .05).

Figure 3:. DRN [¹⁸F]FMT Ki modulates relationships with depression symptom change:

(A) Moderation analyses involving cortical thickness measured change in cortical thickness within the region outlined in white (left banks of the superior temporal sulcus, BanksSTS), which represents the region of overlap for both vertex-wise regression analyses displayed in Figure 2A,B. (B) Graphical representation of the conditional effects of dorsal raphe nucleus (DRN) [¹⁸F]FMT Ki levels on atrophy and depression symptoms. Individuals with high levels of DRN [¹⁸F]FMT Ki, defined as one standard deviation over the mean, show worsening depression symptoms with decreasing cortical thickness. (C) A significant sex by entorhinal cortex [¹⁸F]Flortaucipir SUVR interaction predicting changes in depression symptoms, where females showed a significant positive relationship of higher tau burden and worsening depression symptoms over time. (D) Graphical representation of the moderating effects of DRN [¹⁸F]FMT Ki on entorhinal cortex [¹⁸F]Flortaucipir SUVR and depression symptoms. Individuals with high levels of DRN [¹⁸F]FMT Ki show worsening depression symptoms with higher levels of entorhinal cortex [¹⁸F]Flortaucipir SUVR.