Robust Graft Survival and Normalized Dopaminergic Innervation Do Not Obligate Recovery in a Parkinson Disease Patient
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Objective: The main goal of dopamine cell replacement therapy in Parkinson disease (PD) is to provide clinical benefit mediated by graft survival with nigrostriatal reinnervation. We report a dichotomy between graft structure and clinical function in a patient dying 16 years following fetal nigral grafting.
Methods: A 55-year-old levodopa-responsive woman with PD received bilateral putaminal fetal mesencephalic grafts as part of an NIH-sponsored double-blind sham-controlled trial. The patient never experienced clinical benefit, and her course was complicated by the development of graft-related dyskinesias. Fluorodopa positron emission tomography demonstrated significant increases postgrafting bilaterally. She experienced worsening of parkinsonism with severe dyskinesias, and underwent subthalamic nucleus deep brain stimulation 8 years after grafting. She died 16 years after transplantation.
Results: Postmortem analyses confirmed the diagnosis of PD and demonstrated >300,000 tyrosine hydroxylase (TH)-positive grafted cells per side with normalized striatal TH-immunoreactive fiber innervation and bidirectional synaptic connectivity. Twenty-seven percent and 17% of grafted neurons were serine 129-phosphorylated α-synuclein positive in the left and right putamen, respectively.
Interpretation: These findings represent the largest number of surviving dopamine neurons and the densest and most widespread graft-mediated striatal dopamine reinnervation following a transplant procedure reported to date. Despite this, clinical recovery was not observed. Furthermore, the grafts were associated with a form of dyskinesias that resembled diphasic dyskinesia and persisted in the off-medication state. We hypothesize that the grafted cells produced a low level of dopamine sufficient to cause a levodopa-independent continuous form of diphasic dyskinesias, but insufficient to provide an antiparkinsonian benefit. ANN NEUROL 2017;81:46–57
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Citation / Publisher Attribution
Annals of Neurology, v. 81, issue 1, p. 46-57
Scholar Commons Citation
Kordower, Jeffrey H.; Goetz, Christopher G.; Chu, Yaping; Halliday, Glenda M.; Nicholson, Daniel A.; Musial, Timothy F.; Marmion, David J.; Stoessl, A. Jon; Sossi, Vesna; Freeman, Thomas B.; and Olanow, C. Warren, "Robust Graft Survival and Normalized Dopaminergic Innervation Do Not Obligate Recovery in a Parkinson Disease Patient" (2017). Neurosurgery and Brain Repair Faculty Publications. 54.