Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida, USA.
Mov Disord. 2017 Nov;32(11):1584-1593. doi: 10.1002/mds.27184. Epub 2017 Sep 26.
A number of genetic loci are associated with risk for Parkinson's disease (PD) based on genome-wide association studies; however, the relationship between genetic variants and nigrostriatal degeneration, which is the structural correlate of parkinsonism, has not been reported.
We quantified nigrostriatal dopaminergic integrity with image analysis of putaminal tyrosine hydroxylase immunoreactivity in 492 brains with Lewy body disease and used this pathologic endophenotype to explore possible association with PD genetic variants.
The study cases had Lewy-related pathology and variable degrees of nigrostriatal degeneration. They were assigned to one of the following clinical subgroups according to their predominant clinical syndrome: parkinsonism-predominant, parkinsonism+dementia, and dementia-predominant. In addition to putaminal tyrosine hydroxylase immunoreactivity, semiquantitative scoring was used to assess substantia nigra neuronal loss. A total of 29 PD genetic risk variants were genotyped on each case.
When compared with controls, tyrosine hydroxylase immunoreactivity was reduced in Lewy body cases in the dorsolateral (79%) and ventromedial (57%) putamen. The dorsolateral region was better preserved in dementia-predominant cases than in cases with parkinsonism. Dorsolateral putaminal tyrosine hydroxylase immunoreactivity correlated with neuronal loss in the ventrolateral substantia nigra. Genetic analyses showed no significant association of PD risk variants with putaminal tyrosine hydroxylase immunoreactivity.
The results confirm regional differences in putaminal dopaminergic degeneration and vulnerability of nigrostriatal pathway in Lewy body disorders with parkinsonism. The lack of association with PD genetic risk variants suggests that they may not be associated with quantitative endophenotypes of nigrostriatal degeneration, but more likely related to the risk of disease per se. © 2017 International Parkinson and Movement Disorder Society.
基于全基因组关联研究，已有多个遗传位点与帕金森病（PD）的风险相关；然而，遗传变异与黑质纹状体变性（帕金森病的结构相关物）之间的关系尚未报道。
我们通过对 492 例路易体病患者的壳核酪氨酸羟化酶免疫反应进行图像分析，量化了黑质纹状体多巴胺能神经完整性，并利用这种病理内表型来探索与 PD 遗传变异的可能关联。
研究病例具有与路易体相关的病理学和不同程度的黑质纹状体变性。根据其主要临床综合征，将其分为以下临床亚组之一：帕金森病为主型、帕金森病伴痴呆型和痴呆为主型。除壳核酪氨酸羟化酶免疫反应外，还使用半定量评分来评估黑质神经元丢失。对每个病例进行了 29 个 PD 遗传风险变异的基因分型。
与对照组相比，路易体病患者的壳核背外侧（79%）和腹内侧（57%）酪氨酸羟化酶免疫反应降低。在痴呆为主型病例中，背外侧区域比帕金森病病例保留得更好。壳核背外侧酪氨酸羟化酶免疫反应与腹侧黑质中神经元丢失相关。遗传分析显示 PD 风险变异与壳核酪氨酸羟化酶免疫反应无显著相关性。
这些结果证实了帕金森病伴路易体病患者壳核多巴胺能变性和黑质纹状体通路易损性存在区域差异。与 PD 遗传风险变异无关联表明，它们可能与黑质纹状体变性的定量内表型无关，而更可能与疾病本身的风险有关。
