Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94103-0555, USA.
Neuroimage. 2011 Jan;54 Suppl 1:S189-95. doi: 10.1016/j.neuroimage.2010.01.023. Epub 2010 Jan 18.
Recently, we developed an MRI-based method that enables tracking of parenchymal infusions of therapeutic agents by inclusion of a contrast reagent in the infusate. We show that both liposomal Gadoteridol (GDL) and free Gadoteridol (Gd) can be used for MRI-monitored infusions into the non-human primate (NHP) putamen to predict the distribution of GDNF protein after convection-enhanced delivery (CED). GDNF and both MRI tracers showed good co-distribution within the putamen and other brain regions. Although the CED infusion technique can distribute GDNF protein over large brain regions, continuous administration of GDNF could cause undesired effects that could counteract the benefits of CED as demonstrated in this study when large volumes of GDNF were delivered that lead to GDNF leakage into CSF. These limitations can be addressed by employing an intermittent CED schedule that permits consistent target coverage without GDNF leakage into CSF or white matter. We present an approach intracranial GDNF infusions that can be optimized by means of real-time monitoring via MRI. Adoption of this new standard, along with advanced, reflux-resistant cannulae, may permit reconsideration of direct GDNF infusion into parenchyma as a clinical strategy, since previous clinical studies involving chronic infusion of recombinant glial cell line-derived neurotrophic factor (GDNF) to the putamen for the treatment of Parkinson's disease have yielded mixed results, a state of affairs that may in part be attributed to suboptimal infusion parameters.
最近，我们开发了一种基于 MRI 的方法，通过在输注液中包含对比试剂，实现对实质内治疗剂输注的追踪。我们表明，脂质体钆特醇（GDL）和游离钆特醇（Gd）都可用于 MRI 监测的非人灵长类动物（NHP）壳核输注，以预测 GDNF 蛋白在对流增强递送（CED）后的分布。GDNF 和两种 MRI 示踪剂在壳核和其他脑区均有良好的共分布。尽管 CED 输注技术可以将 GDNF 蛋白分布在大脑的大区域，但连续给予 GDNF 可能会产生不良影响，这在本研究中得到了证实，当大量 GDNF 被递送到导致 GDNF 泄漏到 CSF 中时，就会出现这种情况。这些局限性可以通过采用间歇性 CED 方案来解决，该方案可以在不发生 GDNF 泄漏到 CSF 或白质的情况下，保持目标的持续覆盖。我们提出了一种颅内 GDNF 输注方法，可以通过 MRI 实时监测进行优化。采用这种新标准和先进的、抗反流的套管，可能会重新考虑将 GDNF 直接输注到实质作为一种临床策略，因为之前涉及将重组胶质细胞系源性神经营养因子（GDNF）慢性输注到壳核以治疗帕金森病的临床研究结果喜忧参半，这种情况部分可能归因于输注参数不理想。
