PDF(Pubmed)
Abstract：
Substantia nigra pars compacta (SNc) and locus coeruleus (LC) are neuromelanin-rich nuclei implicated in diverse cognitive and motor processes in normal brain function and disease. However, their roles in aging and neurodegenerative disease mechanisms have remained unclear due to a lack of tools to study them in vivo. Preclinical and post-mortem human investigations indicate that the relationship between tissue neuromelanin content and neurodegeneration is complex. Neuromelanin exhibits both neuroprotective and cytotoxic characteristics, and tissue neuromelanin content varies across the lifespan, exhibiting an inverted U-shaped relationship with age. Neuromelanin-sensitive MRI (NM-MRI) is an emerging modality that allows measurement of neuromelanin-associated contrast in SNc and LC in humans. NM-MRI robustly detects disease effects in these structures in neurodegenerative conditions, including Parkinson\'s disease (PD). Previous NM-MRI studies of PD have largely focused on detecting disease group effects, but few studies have reported NM-MRI correlations with phenotype. Because neuromelanin dynamics are complex, we hypothesize that they are best interpreted in the context of both disease stage and aging, with neuromelanin loss correlating with symptoms most clearly in advanced stages where neuromelanin loss and neurodegeneration are coupled. We tested this hypothesis using NM-MRI to measure SNc and LC volumes in healthy older adult control individuals and in PD patients with and without freezing of gait (FOG), a severe and disabling PD symptom. We assessed for group differences and correlations between NM-MRI measures and aging, cognition and motor deficits. SNc volume was significantly decreased in PD with FOG compared to controls. SNc volume correlated significantly with motor symptoms and cognitive measures in PD with FOG, but not in PD without FOG. SNc volume correlated significantly with aging in PD. When PD patients were stratified by disease duration, SNc volume correlated with aging, cognition, and motor deficits only in PD with disease duration >5 years. We conclude that in severe or advanced PD, identified by either FOG or disease duration >5 years, the observed correlations between SNc volume and aging, cognition, and motor function may reflect the coupling of neuromelanin loss with neurodegeneration and the associated emergence of a linear relationship between NM-MRI measures and phenotype.
摘要：
黑质致密体（SNc）和蓝斑（LC）是富含神经黑色素的核，涉及正常脑功能和疾病的多种认知和运动过程。然而,由于缺乏体内研究工具，它们在衰老和神经退行性疾病机制中的作用仍不清楚。临床前和死后的人类研究表明，组织神经黑色素含量与神经变性之间的关系是复杂的。神经黑色素表现出神经保护和细胞毒性特征，和组织神经黑色素的含量在整个生命周期中变化，与年龄呈倒U型关系。神经黑色素敏感性MRI（NM-MRI）是一种新兴的模式，可以测量人类SNc和LC中神经黑色素相关的对比度。NM-MRI在神经退行性疾病中强劲地检测到这些结构中的疾病影响，包括帕金森病（PD）。以前对PD的NM-MRI研究主要集中在检测疾病组的影响，但很少有研究报道NM-MRI与表型的相关性。因为神经黑色素的动力学很复杂,我们假设它们在疾病阶段和衰老的背景下都得到了最好的解释，在神经黑色素丢失和神经变性相关的晚期，神经黑色素丢失与症状最明显。我们使用NM-MRI测试了这一假设，以测量健康的老年人对照个体以及有和没有步态冻结（FOG）的PD患者的SNc和LC体积。严重和致残的PD症状。我们评估了NM-MRI测量值与衰老之间的组间差异和相关性，认知和运动缺陷。与对照相比,具有FOG的PD中的SNc体积显著降低。在伴有FOG的PD中，SNc体积与运动症状和认知测量值显着相关，但不是在没有雾的PD。SNc体积与PD的衰老显着相关。当PD患者按疾病持续时间分层时，SNc体积与衰老相关，认知，仅在疾病持续时间>5年的PD中出现运动缺陷。我们得出结论，在严重或晚期PD中，由FOG或疾病持续时间>5年确定，观察到的SNc体积与衰老之间的相关性，认知，和运动功能可能反映神经黑色素丢失与神经变性的耦合以及NM-MRI测量值与表型之间的线性关系的相关出现。
