Vano Luke James, McCutcheon Robert Ali, Sedlacik Jan, Kaar Stephen John, Rutigliano Grazia, Nordio Giovanna, Finelli Valeria, Townsend Leigh, Berry Alaine, Statton Ben, Fazlollahi Amir, Veronese Mattia, Hopkins Seth Cabot, Koblan Kenneth Stephen, Everall Ian Paul, Howes Oliver David
Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London.
Psychiatric Imaging Group, MRC Laboratory of Medical Sciences, Hammersmith Hospital, London.
Am J Psychiatry. 2025 Sep 1;182(9):830-839. doi: 10.1176/appi.ajp.20240512.
OBJECTIVE: Neuroimaging studies have independently associated schizophrenia with low iron and elevated dopamine synthesis. While preclinical research demonstrates that midbrain iron deficiency leads to striatal hyperdopaminergia, this relationship has not been studied in schizophrenia. The authors conducted a case-control study to examine differences in tissue magnetic susceptibility, a marker of brain iron, and correlated these with striatal dopamine synthesis capacity. METHODS: Magnetic susceptibility in the substantia nigra and ventral tegmental area (SN-VTA) was measured using quantitative susceptibility mapping (QSM) MRI in 159 participants (control subjects, N=80; early-course schizophrenia, N=79, including patients who were antipsychotic-naïve or antipsychotic-free). Because magnetic susceptibility is increased by neuromelanin and reduced by myelin, neuromelanin-sensitive MRI (NM-MRI) and diffusion tensor imaging (DTI) were employed to investigate the influence of neuromelanin and myelin on the QSM findings in 99 participants (control subjects, N=38; schizophrenia patients, N=61). Dopamine synthesis capacity (K ) was then assessed with [F]-DOPA positron emission tomography in 40 people from the schizophrenia group to test whether low SN-VTA magnetic susceptibility was related to high striatal K . RESULTS: SN-VTA magnetic susceptibility was lower in patients with schizophrenia than in control subjects (d=-0.66, 95% CI=-0.98, -0.34). This difference remained significant in analyses controlling for mean diffusivity (a DTI measure inversely correlating with myelin concentration) and NM-MRI contrast-to-noise ratios. SN-VTA magnetic susceptibility was significantly inversely correlated with striatal K , independent of mean diffusivity and NM-MRI contrast-to-noise ratios (r=-0.44). In both analyses, the strongest effects were observed in the ventral SN-VTA. CONCLUSIONS: These findings suggest that lower levels of non-neuromelanin-bound iron in the SN-VTA contribute to striatal hyperdopaminergia in schizophrenia. Further investigation is warranted to understand the role of low iron in schizophrenia and its potential as a treatment target.
目的：神经影像学研究已分别将精神分裂症与铁含量低和多巴胺合成增加联系起来。虽然临床前研究表明中脑缺铁会导致纹状体多巴胺能亢进，但这种关系在精神分裂症中尚未得到研究。作者进行了一项病例对照研究，以检查组织磁化率（一种脑铁标志物）的差异，并将这些差异与纹状体多巴胺合成能力相关联。 方法：在159名参与者（对照组，N = 80；早期精神分裂症患者，N = 79，包括未使用过抗精神病药物或未服用抗精神病药物的患者）中，使用定量磁化率成像（QSM）MRI测量黑质和腹侧被盖区（SN-VTA）的磁化率。由于神经黑色素会增加磁化率，而髓磷脂会降低磁化率，因此在99名参与者（对照组，N = 38；精神分裂症患者，N = 61）中采用神经黑色素敏感MRI（NM-MRI）和扩散张量成像（DTI）来研究神经黑色素和髓磷脂对QSM结果的影响。然后，在精神分裂症组的40人中，用[F]-多巴正电子发射断层扫描评估多巴胺合成能力（K），以测试低SN-VTA磁化率是否与高纹状体K相关联。 结果：精神分裂症患者的SN-VTA磁化率低于对照组（d = -0.66，95%CI = -0.98，-0.34）。在控制平均扩散率（一种与髓磷脂浓度呈负相关的DTI测量值）和NM-MRI对比噪声比的分析中，这种差异仍然显著。SN-VTA磁化率与纹状体K呈显著负相关，与平均扩散率和NM-MRI对比噪声比无关（r = -0.44）。在两项分析中，在腹侧SN-VTA观察到的效应最强。 结论：这些发现表明，SN-VTA中与神经黑色素结合的铁含量较低导致了精神分裂症患者纹状体多巴胺能亢进。有必要进行进一步研究，以了解铁含量低在精神分裂症中的作用及其作为治疗靶点的潜力。
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