Department of Neuroscience, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 3K7, Canada; Western Institute for Neuroscience, Western University, London, Ontario N6A 3K7, Canada.
Robarts Research Institute, Western University, London, Ontario N6A 3K7, Canada; Department of Medical Biophysics, Western University, London, Ontario N6A 3K7, Canada.
Neuroimage Clin. 2024;41:103577. doi: 10.1016/j.nicl.2024.103577. Epub 2024 Feb 17.
Degeneration in the substantia nigra (SN) pars compacta (SNc) underlies motor symptoms in Parkinson's disease (PD). Currently, there are no neuroimaging biomarkers that are sufficiently sensitive, specific, reproducible, and accessible for routine diagnosis or staging of PD. Although iron is essential for cellular processes, it also mediates neurodegeneration. MRI can localize and quantify brain iron using magnetic susceptibility, which could potentially provide biomarkers of PD. We measured iron in the SNc, SN pars reticulata (SNr), total SN, and ventral tegmental area (VTA), using quantitative susceptibility mapping (QSM) and R2* relaxometry, in PD patients and age-matched healthy controls (HCs). PD patients, diagnosed within five years of participation and HCs were scanned at 3T (22 PD and 23 HCs) and 7T (17 PD and 21 HCs) MRI. Midbrain nuclei were segmented using a probabilistic subcortical atlas. QSM and R2* values were measured in midbrain subregions. For each measure, groups were contrasted, with Age and Sex as covariates, and receiver operating characteristic (ROC) curve analyses were performed with repeated k-fold cross-validation to test the potential of our measures to classify PD patients and HCs. Statistical differences of area under the curves (AUCs) were compared using the Hanley-MacNeil method (QSM versus R2*; 3T versus 7T MRI). PD patients had higher QSM values in the SNc at both 3T (p = 0.001) and 7T (p = 0.01), but not in SNr, total SN, or VTA, at either field strength. No significant group differences were revealed using R2* in any midbrain region at 3T, though increased R2* values in SNc at 7T MRI were marginally significant in PDs compared to HCs (p = 0.052). ROC curve analyses showed that SNc iron measured with QSM, distinguished early PD patients from HCs at the single-subject level with good diagnostic accuracy, using 3T (mean AUC = 0.83, 95 % CI = 0.82-0.84) and 7T (mean AUC = 0.80, 95 % CI = 0.79-0.81) MRI. Mean AUCs reported here are from averages of tests in the hold-out fold of cross-validated samples. The Hanley-MacNeil method demonstrated that QSM outperforms R2* in discriminating PD patients from HCs at 3T, but not 7T. There were no significant differences between 3T and 7T in diagnostic accuracy of QSM values in SNc. This study highlights the importance of segmenting midbrain subregions, performed here using a standardized atlas, and demonstrates high accuracy of SNc iron measured with QSM at 3T MRI in identifying early PD patients. QSM measures of SNc show potential for inclusion in neuroimaging diagnostic biomarkers of early PD. An MRI diagnostic biomarker of PD would represent a significant clinical advance.
黑质致密部（SNc）的退变是帕金森病（PD）运动症状的基础。目前，尚无足够敏感、特异、可重复和易于常规诊断或分期的神经影像学生物标志物。尽管铁是细胞过程所必需的，但它也介导神经退行性变。MRI 可以使用磁化率定位和定量脑铁，这可能为 PD 提供生物标志物。我们使用定量磁化率图（QSM）和 R2弛豫率测量了 PD 患者和年龄匹配的健康对照者（HC）的 SNc、SN 网状部（SNr）、总 SN 和腹侧被盖区（VTA）中的铁。PD 患者在参加研究后的五年内被诊断出来，在 3T（22 名 PD 和 23 名 HC）和 7T（17 名 PD 和 21 名 HC）MRI 上进行扫描。使用概率性皮质下图谱对中脑核进行分割。在中脑亚区测量 QSM 和 R2值。对于每个测量值，都进行了组间对比，以年龄和性别为协变量，并使用重复 k 折交叉验证进行了接收器工作特征（ROC）曲线分析，以测试我们的测量值对 PD 患者和 HCs 进行分类的潜力。使用 Hanley-MacNeil 方法比较曲线下面积（AUC）的统计学差异（QSM 与 R2*；3T 与 7T MRI）。在这两种场强下，PD 患者的 SNc 的 QSM 值均较高（3T：p=0.001；7T：p=0.01），但在 SNr、总 SN 或 VTA 中没有这种差异。在 3T 时，在任何中脑区域使用 R2都没有显示出显著的组间差异，但在 PD 患者中，7T MRI 中 SNc 的 R2值稍高，与 HCs 相比具有边缘显著性（p=0.052）。ROC 曲线分析表明，使用 QSM 测量的 SNc 铁可以在单个受试者水平上以良好的诊断准确性区分早期 PD 患者和 HCs，使用 3T（平均 AUC=0.83，95%CI=0.82-0.84）和 7T（平均 AUC=0.80，95%CI=0.79-0.81）MRI。这里报告的平均 AUC 是从交叉验证样本的保留折叠测试平均值。Hanley-MacNeil 方法表明，在 3T 时，QSM 比 R2*在区分 PD 患者和 HCs 方面表现更好，但在 7T 时并非如此。在 SNc 的 QSM 值的诊断准确性方面，3T 和 7T 之间没有显著差异。本研究强调了对中脑亚区进行分割的重要性，这里使用标准化图谱进行了分割，并证明了在 3T MRI 上使用 QSM 测量 SNc 铁在识别早期 PD 患者方面具有很高的准确性。SNc 的 QSM 测量值有可能被纳入早期 PD 的神经影像学诊断生物标志物。PD 的 MRI 诊断生物标志物将是一个重大的临床进展。
