Factors affecting the clinical outcome after neural transplantation in Parkinson's disease
Factors affecting the clinical outcome after neural transplantation in Parkinson's disease
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DOI：
10.1093/brain/awh649
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发表时间：
2005-12-01
期刊：
影响因子：
14.5
通讯作者：
Lindvall, O
中科院分区：
文献类型：
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作者：
Piccini, P;Pavese, N;Lindvall, O
胚胎中脑组织的纹状体内移植物可以在帕金森病患者的大脑中存活，但症状缓解的程度差异很大，有些病例会出现麻烦的运动障碍。在这里，我们利用临床评估和 (18)F-多巴和 (11)C-雷氯必利 PET 探索可能影响移植后功能结果的因素。我们观察到移植的壳核中的 (18)F-多巴摄取增加，这意味着移植的多巴胺能神经元持续存活，同时整个患者组的非移植区域中的 (18)F-多巴摄取逐渐减少。移植后具有最佳功能结果的患者在术前或术后1年或2年时在移植区域以外的区域没有表现出多巴胺能去神经支配。相比之下，没有或适度临床获益的患者在移植之前或之后表现出腹侧纹状体中的(18)F-多巴减少，这可能限制了移植物诱导的改善。我们没有获得任何证据表明运动障碍是由移植物异常释放多巴胺（DA）引起的。正如对内在多巴胺能神经元所观察到的那样，在含有移植物的壳核中，(18)F-多巴摄取与甲基苯丙胺诱导的(11)C-雷氯必利结合变化（作为 DA 释放的量度）之间存在显着相关性。此外，我们观察到在基础条件下或甲基苯丙胺后前部、后部或整个壳核中的 (11)C-雷氯必利结合与身体对侧运动障碍严重程度评分之间没有相关性。移植后 29 个月停止免疫抑制不会导致 (18)F-多巴摄取减少或 UPDRS 运动评分恶化，表明移植物持续存活和功能。然而，患者表现出运动障碍评分增加，这可能是由于移植物生长或移植物周围低度炎症恶化引起的。这些发现表明，移植后的不良结果与移植物外部区域进行性多巴胺能去神经支配有关，这一过程可能在手术前就已经开始了。此外，移植后运动障碍的发生与移植物过度释放 DA 无关。最后，我们的数据提供的证据表明，可以撤消长期免疫抑制，而不会干扰移植物存活或移植引起的运动恢复。
Intrastriatal grafts of embryonic mesencephalic tissue can survive in the brains of patients with Parkinson's disease, but the degree of symptomatic relief is highly variable and some cases develop troublesome dyskinesias. Here we explored, using clinical assessment and (18)F-dopa and (11)C-raclopride PET, factors which may influence the functional outcome after transplantation. We observed increased (18)F-dopa uptake in the grafted putamen, signifying continued survival of the transplanted dopaminergic neurons, in parallel with a progressive reduction of (18)F-dopa uptake in non-grafted regions for the whole patient group. The patients with the best functional outcome after transplantation exhibited no dopaminergic denervation in areas outside the grafted areas either preoperatively or at 1 or 2 years post-operatively. In contrast, patients with no or modest clinical benefit showed reduction of (18)F-dopa in ventral striatum prior to or following transplantation, which may have limited graft-induced improvement. We obtained no evidence that dyskinesias were caused by abnormal dopamine (DA) release from the grafts. As has been observed for intrinsic dopaminergic neurons, there was a significant correlation between (18)F-dopa uptake and methamphetamine-induced change of (11)C-raclopride binding (as a measure of DA release) in the putamen containing the graft. Furthermore, we observed no correlation between (11)C-raclopride binding in anterior, posterior or entire putamen under basal conditions or after methamphetamine, and dyskinesia severity scores in the contralateral side of the body. Withdrawal of immunosuppression at 29 months after transplantation caused no reduction of (18)F-dopa uptake or worsening of UPDRS motor score, indicating continued survival and function of the graft. However, patients showed increased dyskinesia scores, which might have been caused either by growth of the graft or worsening of a low-grade inflammation around the graft. These findings indicate that poor outcome after transplantation is associated with progressive dopaminergic denervation in areas outside the grafts, a process which may have started already before surgery. Also, that the development of dyskinesias after transplantation is not associated with excessive DA release from the grafts. Finally, our data provide evidence that long-term immunosuppression can be withdrawn without interfering with graft survival or the motor recovery induced by transplantation.