Brandeis University, Waltham, MA, 02453, USA.
Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, 94720, USA.
Mol Psychiatry. 2023 Oct;28(10):4390-4398. doi: 10.1038/s41380-023-02177-x. Epub 2023 Jul 17.
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 [F]Fluoro-m-tyrosine ([F]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 [F]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 [F]Flortaucipir and [C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [F]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.
中缝背核（DRN）是阿尔茨海默病相关 tau 病理学最早的靶点之一，也是大脑 5-羟色胺的主要来源。我们使用 [F]氟代 m-酪氨酸 ([F]FMT) PET 成像来测量 111 名健康成年人（18-85 岁）DRN 中的 5-羟色胺合成能力。与儿茶酚胺系统的报告类似，我们发现与年轻人相比，老年人的 5-羟色胺合成能力升高。为了确定在衰老过程中 5-羟色胺合成能力升高的结构和功能背景，我们使用磁共振成像检查了 DRN [F]FMT 净示踪剂流入 (Ki) 与皮质厚度的纵向变化之间的关系，使用横断面 [F]Flortaucipir 和 [C]匹兹堡化合物 B PET 分别检查了与 AD 相关的 tau 和 β-淀粉样蛋白 (Aβ) 病理学与自我报告的抑郁症状的纵向变化之间的关系。总的来说，我们的研究结果表明，DRN [F]FMT Ki 的升高是衰老轨迹较差的标志物。5-羟色胺合成能力最高的老年人表现出最大的颞叶皮质萎缩。皮质萎缩与随时间推移抑郁症状的增加有关，这些影响在 5-羟色胺合成能力最高的个体中似乎最强。我们没有发现 5-羟色胺合成能力与 AD 相关病理学之间的直接关系。探索性分析揭示了老年组内性别之间的细微影响。老年女性表现出最高的 DRN 合成能力，并表现出与内嗅皮层 tau 病理学和抑郁症状随时间增加之间最强的关系。这些发现共同揭示了对 5-羟色胺系统的 PET 测量是与 AD 和老年时的情感变化相关的衰老轨迹的有前途的标志物。
