Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
C.J. Gorter MRI Center, Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands.
Neuroimage Clin. 2023;39:103450. doi: 10.1016/j.nicl.2023.103450. Epub 2023 Jun 8.
Strong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington's disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures.
This is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites' level and diffusion. Age and sex matched healthy subjects are included as a control group.
Results from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other.
有强有力的证据表明，铁在大脑中的积累除了亨廷顿病（HD）众所周知的神经退行性方面之外，还起着重要作用。铁与 HD 发病机制相关的潜在机制有很多，包括氧化应激、铁死亡和神经炎症。然而，以前在神经退行性疾病中没有研究将 MRI 测量的脑铁积累增加与铁积累的既定脑脊液（CSF）和血液生物标志物联系起来，也没有与神经炎症等相关过程联系起来。本研究旨在将从 HD 患者 7T MRI 获得的铁水平和神经炎症代谢物的定量数据，与特定的、众所周知的 CSF 和血液生物标志物联系起来，这些标志物可用于铁积累、神经退行性变和神经炎症。生物流体标志物将提供铁积累、神经退行性变和神经炎症的定量测量，而另一方面，MRI 测量将提供脑病理学、神经炎症和脑铁积累的定量空间信息，这些信息将与临床结果测量相关联。
这是一项在 HD 基因扩增携带者和健康对照者中进行的观察性横断面研究，IMAGINE-HD。我们纳入了前显型 HD 基因扩增携带者和处于早期或中度阶段的显型 HD 患者。该研究包括大脑的 7T MRI 扫描、临床评估、运动、功能和神经心理学评估，以及 CSF 和血液样本的采集，以检测铁、神经退行性和炎症标志物。定量磁化率图将使用 T2*加权图像重建，以量化脑铁水平，磁共振波谱将用于通过测量细胞特异性细胞内代谢物的水平和扩散来获取神经炎症信息。将年龄和性别匹配的健康受试者纳入对照组。
这项研究的结果将为评估脑铁水平和神经炎症代谢物作为 HD 疾病分期的影像学生物标志物及其与疾病相关的重要发病机制的关系提供重要依据，另一方面，与临床结果也有关系。
