Transplantation in Parkinson's disease: PET changes correlate with the amount of grafted tissue

Cochen, Valérie; Ribeiro, Maria-João; Nǵuyen, Jean-Paul; Gurruchaga, Jean‐Marc; Villafane, Gabriel; Loc’h, Christian; Defer, Gilles; Samson, Yves; Peschanski, Marc; Hantraye, Philippe; Césaro, P.; Rémy, Philippe

doi:10.1002/mds.10463

Cited by 60 publications

(39 citation statements)

References 24 publications

(39 reference statements)

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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Clinical trials involving intrastriatal transplants of human embryonic mesencephalic tissue have provided proof-of-principle that nigral dopamine (DA) neurons can survive and functionally integrate into the host neural circuitry. However, the degree of graft-induced symptomatic relief differs significantly between the patients. This variability has led to investigations aimed at identifying factors that could affect the clinical outcome. The extent and pattern of dopaminergic denervation in the brain may be one of the major determinants of the functional outcome after intrastriatal DA cell grafts. Here, we report that in animals subjected to an intrastriatal 6-hydroxydopamine lesion of the striatal dopaminergic afferent, the integrity of the host dopaminergic innervation outside the areas innervated by the graft is critical for optimal function of DA neurons placed in the striatum. Established graft-induced functional recovery, as assessed in the stepping and cylinder tests, was compromised in animals in which the dopaminergic lesion was extended to include also the medial and ventral striatum as well as the cortical and limbic DA projections. Poor clinical outcome after transplantation may, thus, at least in part, be caused by dopaminergic denervation in areas outside the graft-innervated territories, and similarly beneficial effects initially observed in patients may regress if the degeneration of the host extrastriatal DA projection systems proceeds with advancing disease. This would have two implications: first, patients with advanced disease involving the ventral striatum and/or nonstriatal DA projections would be unlikely to respond well to intrastriatal DA grafts and, second, to retain the full benefit of the grafts, progression of the disease should be avoided by, for example, combining cell therapy with a neuroprotective approach.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…Dopaminergic Grafts Can Survive and Become Morphologically Integrated in the PD Patient's Brain Following implantation of postmitotic DA neuroblasts from the ventral mesencephalon of 6-to 9-weekold human fetuses, positron emission tomography (PET) detected increases in 6-L-[ 18 F]-fluorodopa ( 18 F-dopa) uptake ( Fig. 1) [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], and histopathological studies have shown long-term, extensive synaptic reinnervation in the striatum [13,[20][21][22][23][24][25][26][27].…”

Section: Can Da Neurons Be Replaced and Neural Grafts Have Functionalmentioning

confidence: 99%

Cell Therapeutics in Parkinson's Disease

Lindvall

Björklund

2011

Neurotherapeutics

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The main pathology underlying motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process longterm after implantation. Mechanisms underlying graftinduced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

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“…Importantly, the recovery of dopamine function being was found to be dependant on the amount of fetal tissue implanted [107]. Recently, the graft's functionality has been investigated by Piccini and colleagues, where DA release from the fetal DA neurons was visualized using 11 C-labeled Raclopride [89].…”

Section: Applications Of Pet In Neurodegenerative Statesmentioning

confidence: 99%