Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, Inage-ku, Chiba, Japan.
Department of Psychiatry, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Schizophr Bull. 2023 May 3;49(3):688-696. doi: 10.1093/schbul/sbac181.
Phosphodiesterase 10A (PDE10A) is a highly expressed enzyme in the basal ganglia, where cortical glutamatergic and midbrain dopaminergic inputs are integrated. Therapeutic PDE10A inhibition effects on schizophrenia have been reported previously, but the status of this molecule in the living patients with schizophrenia remains elusive. Therefore, this study aimed to investigate the central PDE10A status in patients with schizophrenia and examine its relationship with psychopathology, cognition, and corticostriatal glutamate levels.
This study included 27 patients with schizophrenia, with 5 antipsychotic-free cases, and 27 healthy controls. Positron emission tomography with [18F]MNI-659, a specific PDE10A radioligand, was employed to quantify PDE10A availability by measuring non-displaceable binding potential (BPND) of the ligand in the limbic, executive, and sensorimotor striatal functional subregions, and in the pallidum. BPND estimates were compared between patients and controls while controlling for age and gender. BPND correlations were examined with behavioral and clinical measures, along with regional glutamate levels quantified by the magnetic resonance spectroscopy.
Multivariate analysis of covariance demonstrated a significant main effect of diagnosis on BPND (p = .03). A posthoc test showed a trend-level higher sensorimotor striatal BPND in patients, although it did not survive multiple comparison corrections. BPND in controls in this subregion was significantly and negatively correlated with the Tower of London scores, a cognitive subtest. Striatal or dorsolateral prefrontal glutamate levels did not correlate significantly with BPND in either group.
The results suggest altered striatal PDE10A availability and associated local neural dysfunctions in patients with schizophrenia.
磷酸二酯酶 10A（PDE10A）在基底神经节中高度表达，而皮质谷氨酸能和中脑多巴胺能输入在此处整合。先前已有报道称 PDE10A 抑制作用对精神分裂症具有治疗效果，但这种分子在患有精神分裂症的活体患者中的状态仍难以捉摸。因此，本研究旨在调查精神分裂症患者中枢 PDE10A 的状态，并研究其与精神病理学、认知和皮质纹状体谷氨酸水平的关系。
本研究纳入了 27 例精神分裂症患者，其中 5 例未使用抗精神病药物，27 例健康对照者。采用正电子发射断层扫描（PET）技术，使用[18F]MNI-659（一种特异性 PDE10A 放射性配体），通过测量配体在边缘、执行和感觉运动纹状体功能亚区以及苍白球中的非置换性结合潜能（BPND），来量化 PDE10A 的可用性。在控制年龄和性别后，比较患者和对照组之间的 BPND 估计值。同时，还检查了 BPND 与行为和临床测量指标以及通过磁共振波谱定量的区域谷氨酸水平之间的相关性。
多变量协方差分析显示，诊断对 BPND 有显著的主效应（p =.03）。事后检验显示，患者的感觉运动纹状体 BPND 呈上升趋势，但未通过多重比较校正。对照组中，该亚区的 BPND 与塔沃尔斯测试（一种认知亚测试）的分数显著负相关。两组中，纹状体或背外侧前额叶的谷氨酸水平与 BPND 均无显著相关性。
研究结果表明，精神分裂症患者的纹状体 PDE10A 可用性发生改变，与之相关的局部神经功能障碍。
