The first studies of transplantation in humans utilized autologous adrenomedullary cells implanted into the caudate nucleus. Dramatic benefits were reported in a small group of patients (Madrazo et al., 1987), but these were not confirmed in subsequent studies (Lindvall et al., 1987; Goetz et al., 1989; Olanow et al., 1990) and few if any surviving cells were detected at autopsy (Peterson et al., 1989). The procedure was associated with substantial morbidity and this treatment approach has been abandoned.
Transplantation using fetal nigral dopamine cells derived from human ventral mesencephalon provides superior results in the laboratory (Dunnett and Annett, 1991; Olanow et al., 1996). In the clinic, several open label studies reported benefit following fetal nigral transplantation (Lindvall et al., 1990; 1992; Freed et al., 1992; Peschanski et al., 1994; Freeman et al., 1995; Bjorklund et al., 2003). Improvement was observed in a variety of measures of motor function including motor score on the unified Parkinson's disease rating scale (UPDRS) performed in the practically defined off state (approximately 12 h after the last evening dose of levodopa) and in percent on time without dyskinesia based on home diary assessments. Benefits have been reported to be long-lasting (Lindvall et al., 1994; Hauser et al., 1999), and some transplanted patients no longer required levodopa. On the other hand, some patients did not improve following transplant, possibly reflecting differences in patient selection and the transplant variables employed (reviewed in Olanow et al., 1996). Variables that must be considered in developing a transplant protocol include method of tissue storage prior to surgery, donor age (ontogeny studies suggest age 6.5-9 weeks post conception is the optimal time), number of donors implanted (most studies have chosen 1-4 donors per side), site of transplantation (putamen, caudate, or both), type of transplant (cell suspension or solid graft), and the use of immunosuppression. The rationale for considering these various transplant variables is discussed in detail in reference (Olanow et al., 1996).
Clinical improvement in PD features following fetal nigral transplantation has been associated with a significant and progressive increase in striatal flu-orodopa (FD) uptake on positron emission tomography (PET) in some studies (Lindvall et al., 1994; Kordower et al., 1995; Remy et al., 1995). FD-PET is a surrogate biomarker of dopamine terminal function, and increased striatal FD uptake has been interpreted to represent an index of the survival of transplanted dopamine neurons (Lindvall et al., 1994). Post-mortem studies on transplanted patients have shown healthy appearing graft deposit with survival of more than 100,000 transplanted cells per side (Kordower et al., 1995; 1996; Mendez et al., 2005). In these studies, individual implanted cells express a normal dopamine phenotype; TH positive processes extended from the graft into the striatum providing continuous dopamine innervation between graft deposits with a patch-matrix pattern; grafted regions stained positively for cytochrome oxidase indicating increased metabolism, and expressed TH mRNA consistent with functional activity; no host-derived sprouting was observed; electron microscopy demonstrated normal appearing synaptic connections; and no overt graft rejection was detected, although there was increased expression of immune markers in grafted regions (Kordower et al., 1997).
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