The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow
The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow
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DOI：
10.1093/brain/aws174
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发表时间：
2012-08-01
期刊：
影响因子：
14.5
通讯作者：
Berman, Karen F.
中科院分区：
文献类型：
--
作者：
Goker-Alpan, Ozlem;Masdeu, Joseph C.;Berman, Karen F.
编码葡萄糖脑苷酶的基因GBA突变是帕金森病的常见危险因素，因为帕金森病患者携带GBA突变的可能性是健康对照者的五倍以上。与没有GBA突变的患者相比，GBA突变患者通常有更早的帕金森病发病和更多的认知障碍。我们研究了GBA突变是否会改变帕金森病的神经生物学，研究了107名受试者（38名女性，69名男性）的脑多巴胺合成和静息区域脑血流量。我们用f -18-氟多巴正电子发射断层扫描测量多巴胺合成，用(H2O)- o -15正电子发射断层扫描测量静息状态下四个研究组的静息区域脑血流量：(i)帕金森病和戈谢病患者（n = 7，平均年龄= 56.6±9.2岁）；（ii）无GBA突变的帕金森病患者（n = 11, 62.1±7.1岁）；（iii）患有戈谢病但无帕金森病，但有帕金森病家族史的患者（n = 14, 52.6±12.4年）；（iv）有帕金森病家族史的健康gba突变携带者（n = 7, 50.1±18岁）。我们将每个研究组与匹配的对照组进行比较。使用感兴趣区域和基于体素的方法对数据进行分析。两组帕金森病患者的病程、帕金森病功能和分期评分相似，纹状体多巴胺合成也相似：尾状体的损失最大（壳核Ki损失分别为44%和42%），尾状体的减少较少（20%和18%）。然而，同时患有帕金森病和戈谢病的组在侧顶枕联合皮层和双侧楔前叶的静息区域脑血流量减少。此外，两名无帕金森表现的戈谢病患者纹状体多巴胺减少。总之，帕金森和戈谢病患者多巴胺丢失的模式与散发性帕金森病相似，表明中脑神经元的损伤相似。然而，(H2O)-O-15正电子发射断层扫描研究表明，这些受试者在弥漫性路易体病的模式下具有静息活动下降的特征。这些发现为gba相关帕金森病的病理生理学提供了见解。
Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with F-18-fluorodopa positron emission tomography, and resting regional cerebral blood flow with (H2O)-O-15 positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 +/- 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 +/- 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 +/- 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 +/- 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the pattern of dopamine loss in patients with both Parkinson and Gaucher disease was similar to sporadic Parkinson disease, indicating comparable damage in midbrain neurons. However, (H2O)-O-15 positron emission tomography studies indicated that these subjects have decreased resting activity in a pattern characteristic of diffuse Lewy body disease. These findings provide insight into the pathophysiology of GBA-associated parkinsonism.