Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease

Abstract

We have previously demonstrated that fetal nigral grafts can survive, reinnervate the striatum, and mediate clinically relevant recovery in a patient with Parkinson's disease (PD). Most previous autopsy cases have failed to identify meaningful numbers of viable grafted cells suggesting that differences in critical transplant variables determine graft viability. The present study evaluated the structural and functional correlates of fetal nigral transplantation in a second PD patient who received fetal nigral grafts according to our previously published transplant protocol. A 61-year-old woman with severe PD received bilateral fetal nigral grafts to the postcommissural putamen from seven donor fetuses (four right side and three left side) aged 6.5-9 weeks postconception. This patient died 19 months after surgery from a cause unrelated to the transplant surgery. Her postoperative clinical course was characterized by improved motor and activities of daily living scores during "off time," reduced "off time," and increased "on" time without dyskinesia. Positron emission tomography (PET) scans revealed a bilateral and progressive increase in fluorodopa (FD) uptake within the grafted putamen. Postmortem examination of the right hemisphere revealed large oval-shaped grafts containing more than 138,000 tyrosine-hydroxylase-immunoreactive (TH-ir) neurons. Grafted cells formed a seamless border with the host and provided dense TH-ir innervation to 78% of the host postcommissural putamen. Graft-mediated sprouting of host fibers was not observed. These data provide essential confirmation that, under appropriate transplant conditions, grafted nigral neurons can survive, reinnervate the host striatum, and provide clinical benefit to PD patients. These findings also support the concept that improved motor function and striatal FD uptake on PET after nigral grafting in PD are the result of the viability of grafted neurons and graft-derived reinnervation of the host striatum.