Decoding the effects of neural transplantation in patients with Parkinson's disease: a multimodal imaging study

帕金森氏病（Parkinson's disease，PD）是一种常见的神经系统退行性疾病，临床表现为运动迟缓、强直和震颤。这些临床特征与从黑质到纹状体的多巴胺能输入的进行性损失有关。因此，PD的管理最初可以使用多巴胺能药物非常成功，然而这些药物不能重新建立正常的紧张性/阶段性信号传导，并且随着时间的推移导致禁用副作用，例如“开-关”波动和不可控的不自主运动（运动障碍）。这些副作用不仅与多巴胺（DA）的非生理性递送有关，而且与脱靶的药物作用有关。解决这些问题的一种方法是使用基于靶向DA细胞的疗法，将其置于壳核中，壳核是PD中DA损失最大的大脑部位。当移植的组织来源于发育中的人类腹侧中脑时，这已经取得了最大的成功。在过去的25年里，已经表明（包括我们的小组）这种方法可以导致细胞的长期存活，生理DA释放和相关皮质运动区的重新激活。然而，虽然一些患者对这种干预反应非常好，症状显著缓解，以至于他们可以停止使用抗PD药物，但其他患者仅显示出适度的临床改善，而一些患者出现了严重的非状态移植物诱导的运动障碍（GID）。尽管如此，这种疗法提供相当大益处的潜力是显而易见的，并导致国际专家聚集一堂，研究可变结果背后的原因。这导致了在欧盟的成功申请，以及一项新的试验（Transeuro），其中重新评估和优化了患者选择、免疫抑制方案、移植方法和组织切割（包括新的临床前研究），以提高成功率。该项目现在已经发展到这样一个地步，到今年年底，150名患者的观察队列中将有15名患者接受移植，这些患者在移植前进行了广泛的成像。从2015年11月至今，我们已经完成了13例手术，我们的目标是到2016年12月完成15例手术。我们现在希望使用我们在移植前已经采用的同样广泛的多模式神经影像学技术来随访这一独特的移植患者队列。我们现在提出的这项研究将：1。准确量化DA代谢和转运的任何变化，特别是在移植部位的壳核中。2.检查移植的组织是否含有重要的5-羟色胺神经元，这些神经元在过去与GIDS的发展有关。确定哪些大脑改变在预测移植后的积极临床结果方面最重要，以及与任何副作用（如GID）相关的改变。4.确定皮质运动区功能激活恢复的程度，以及受移植影响的特定额纹状体回路是否有改善。将联合收割机成像分析与广泛的运动、认知、神经心理和生活质量数据相结合，以确定大脑与行为之间的直接联系.定义移植前和移植后的成像参数，以最好地预测对多巴胺细胞移植的临床反应。虽然人类胎儿中脑组织移植永远不会成为PD的主流治疗方法，因为它们会产生后勤和伦理问题，但它们将为下一代干细胞衍生的多巴胺治疗PD奠定基础。STEM-PD目前处于临床前开发的最后阶段，预计2019年将首次进行人体试验。因此，这项研究的结果将告诉我们如何为这项首次人体干细胞临床试验提供最佳成像方案。

Parkinson's disease (PD) is a common incurable neurodegenerative disease, clinically characterised by the development of bradykinesia, rigidity and tremor. These clinical features are linked to progressive loss of the dopaminergic input from the substantia nigra to the striatum. Thus the management of PD can initially be highly successful using dopaminergic drugs, however these agents do not re-establish normal tonic /phasic signalling, and with time lead to disabling side-effects, such as "ON-OFF" fluctuations and uncontrollable involuntary movements (dyskinesias). These side effects relate not only to the non physiological delivery of dopamine (DA), but also to drug actions that are off target. One way to combat these problems is using targeted DA cell based therapies placed in the putamen, the site of the brain with greatest DA loss in PD. This has been done with greatest success when the grafted tissue is derived from the developing human ventral mesencephalon. Over the last 25 years it has been shown (including by our group) that this approach can lead to long term survival of cells, with physiological DA release and re-activation of relevant cortical motor areas. However, while some patients have responded extremely well to this intervention with significant relief of symptoms to the extent that they could come off their anti-PD medications, others showed only modest clinical improvements while some developed severe, off-state graft-induced dyskinesias (GID). Nonetheless, the potential for this therapy to provide considerable benefit is clear and led to a gathering of international experts to examine the reasons behind the variable outcomes. This resulted in a successful application to the EU, and a new trial (Transeuro) in which patient selection, immunosuppressive regime, method of transplant and tissue dissection were re-appraised and optimized (including new pre-clinical studies) to increase the rate of success. This project has now evolved to the point that by the end of this year 15 patients will have been grafted out of an observational cohort of 150 patients, who have had extensive imaging pre transplantation. From November 2015 to date we have performed 13 surgeries, and we aim to complete 15 patients by December 2016. We now wish to follow up this unique cohort of grafted patients using the same extensive multimodal battery of neuroimaging techniques that we have already employed pre transplantation. This study that we are now proposing will: 1. Accurately quantify any changes to the metabolism and transport of DA, particularly in the putamen at the graft site. 2. Examine whether the grafted tissue contains significant serotonin neurons which in the past have been linked to the development of GIDs.3. Identify which brain alterations are most important at predicting a positive clinical outcome post grafting, as well as those associated with any side effects such as GIDs. 4. Define the degree to which functional activation in cortical motor regions is restored, and whether there are improvements in specific frontostriatal circuits which are impacted on by the transplant.5. Combine imaging analysis with the extensive motor, cognitive, neuropsychological and quality of life data, in order to ascertain the direct links between brain and behaviour.6. Define those imaging parameters pre and post grafting that best predict clinical response to dopamine cell transplants.While human fetal mesencephalic tissue transplants will never become a mainline therapy for PD given the logistical and ethical problems that they engender, they will lay the foundations for the next generation of stem cell derived dopamine therapies for PD. STEM-PD is currently is in the final stages of pre clinical development, with a projected time to a first in human trial in 2019. As such the outcome of this study will inform us as to how to deliver the best imaging protocol for this first in human clinical trial with stem cells.