Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson's disease following intrastriatal transplantation of foetal ventral mesencephalon

Abstract

Several recent reports have suggested that foetal ventral mesencephalic transplants could alleviate motor symptoms in patients with Parkinson's disease. Expectations of future success must be clarified by precise analysis of the extent and limitation of recovery associated with an assessment of function of the graft using [18F]fluorodopa (18F-dopa) PET. Two patients with idiopathic Parkinson's disease, severely impaired despite optimal medication, have been followed 10 and 17 months after stereotaxic unilateral intrastriatal transplantation of neural cells dissociated from human foetal ventral mesencephalon. Analysis of the clinical evolution complied with the protocol established in the 'Core Assessment Program for Intracerebral Transplantation'. Both patients have benefited from the transplantation in their daily activities and in motor timed tests, although they still exhibit parkinsonian symptoms and require L-dopa therapy. This is associated with a gradual increase in 18F-dopa uptake at the site of grafting. There are two major clinical changes: (i) a bilateral motor improvement for the speed of movements (the quality of movements improved almost exclusively on the side contralateral to the graft); (ii) a change in the outcome of the L-dopa treatment as exemplified by a postoperative transient period of heavy dyskinesias and subsequent additive actions of the two treatments. These results confirm that neural transplantation may be useful for patients with Parkinson's disease. The improvement recorded on the side ipsilateral to the graft does not match that observed on the contralateral side and it is proposed that bilateral transplantation may be necessary. The existence of a transient postoperative period of heavy dyskinesias suggests that the patients may benefit from a controlled decrease of L-dopa intake after grafting.

Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques

“…Successful results were first reported in studies using macaques in the late 1980s (22)(23)(24). Subsequent open-label trials in patients with PD also showed that engrafted fetal neurons can survive, appropriately differentiate, and provide striatal dopamine release as measured by PET and showed clinical improvements (34)(35)(36), with only one exception (37). Although later double-blind placebo-controlled trials reported no significant clinical benefits (38,39), successful cell replacement therapy in PD would probably be achieved with more sophisticated cell preparation, surgical and patient selection procedures (2,3).…”

Influence of cell preparation and target location on the behavioral recovery after striatal transplantation of fetal dopaminergic neurons in a primate model of Parkinson’s disease

“…(Freed et al, 1992;Freed et al, 2001;Freeman et al, 1995;Hagell et al, 1999;Levivier et al, 1997;Lindvall et al, 1990;Lindvall et al, 1992;Lopez-Lozano et al, 1997b;Mendez et al, 2002;Mendez et al, 2005;Molina et al, 1994;Olanow et al, 2003;Peschanski et al, 1994;Piccini et al, 1999;Piccini et al, 2000;Spencer et al, 1992). In many cases patients showed significant clinical improvements and in several cases, they were able to eliminate their dopamine medication altogether (Lindvall et al, 1994).…”

The Functional Impact of the Intrastriatal Dopamine Neuron Grafts in Parkinsonian Rats Is Reduced with Advancing Disease

“…Clinical trials using transplants of human embryonic mesencephalic tissue in PD patients have revealed that grafted DA neurons can survive, appropriately differentiate and reinnervate the striatum, release DA, and become functionally integrated into the host neural circuitries (Lindvall et al, 1990;Kordower et al, 1995;Piccini et al, 1999;Mendez et al, 2005). However, the magnitude of transplant-induced functional outcome has been variable with some patients displaying major improvements and others no or only minor clinical response (Peschanski et al, 1994;Hagell et al, 1999;Hauser et al, 1999;Brundin et al, 2000;Mendez et al, 2000;Freed et al, 2001;Cochen et al, 2003;Olanow et al, 2003) [for detailed review of the literature, see Winkler et al (2005)]. Importantly, the extent of DA neurodegeneration and the preoperative distribution and magnitude of loss of DA innervation in the forebrain have not been so far taken into consideration, neither in the selection of patients for grafting nor in the design of the transplant procedure.…”