Brain Advance Access originally published online on May 4, 2005
Brain 2005 128(7):1498-1510; doi:10.1093/brain/awh510
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Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease
1 Dalhousie University and Queen Elizabeth II Health Science Center, Division of Neurosurgery and Neuroscience, Halifax, 2 McGill University and Montreal Neurological Institute, McConnel Brain Imaging Centre, Montreal, Canada and 3 Harvard University and McLean Hospital, NINDS Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA
Correspondence to: Professor Ole Isacson, Neuroregeneration Laboratory, Harvard Medical School, McLean Hospital, MRC 130, 115 Mill St, Belmont, MA 02478, USA E-mail: isacson{at}hms.harvard.edu
We report the first post-mortem analysis of two patients with Parkinson's disease who received fetal midbrain transplants as a cell suspension in the striatum, and in one case also in the substantia nigra. These patients had a favourable clinical evolution and positive 18F-fluorodopa PET scans and did not develop motor complications. The surviving transplanted dopamine neurons were positively identified with phenotypic markers of normal control human substantia nigra (n = 3), such as tyrosine hydroxylase, G-protein-coupled inward rectifying current potassium channel type 2 (Girk2) and calbindin. The grafts restored the cell type that provides specific dopaminergic innervation to the most affected striatal regions in the parkinsonian brain. Such transplants were able to densely reinnervate the host putamen with new dopamine fibres. The patients received only 6 months of standard immune suppression, yet by post-mortem analysis 3–4 years after surgery the transplants appeared only mildly immunogenic to the host brain, by analysis of microglial CD45 and CD68 markers. This study demonstrates that, using these methods, dopamine neuronal replacement cell therapy can be beneficial for patients with advanced disease, and that changing technical approaches could have a favourable impact on efficacy and adverse events following neural transplantation.
Key Words: transplantation; dopamine neuron; Parkinson's disease
Abbreviations: 18F-DOPA = 18F-fluorodopa; GDNF = glial-derived neurotrophic factor; GFAP = glial fibrillary acidic protein; Girk2 = G-protein-coupled inward rectifying current potassium channel type 2; PBS = phosphate buffered saline; SN = substantia nigra; SNc = substantia nigra pars compacta; TH = tyrosine hydroxylase; UPDRS = Unified Parkinson's Disease Rating Scale
Received August 4, 2004. Revised November 12, 2004. Second revision on February 9, 2005. Third revision on March 11, 2005. Accepted March 14, 2005.
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