While there has been some resistance to the use of double-blind placebo-controlled trials to assess new surgical therapies, we believe that it is essential to employ this study design in evaluating the safety and efficacy of cell-based therapies for PD (Freeman et al., 1999). Placebo and bias effects can be powerful and seriously distort the results of a trial (McRae et al., 2004). Placebo therapy can also be associated with dopamine release with possible clinical conse-quences (de la Fuente-Fernandez et al., 2001). There are numerous examples of surgical procedures that were adopted into general practice based on
anecdotal observations that were discarded after negative results in more formal clinical trials (Freeman et al., 1999). In PD, we have recently seen that positive results in open label trials of human fetal nigral transplantation, porcine fetal nigral transplantation, and GDNF infusion were not con-firmed in double-blind trials. Transplantation thera-pies in PD are particularly appropriate for evaluation in double-blind trials as the intervention is relatively standardized and the treatment has much in com-mon with drug therapies; issues such as dose, distri-bution, metabolism/degeneration, delayed response, and immune reactivity must all be considered (Olanow, 2005). Indeed, a recent survey showed that 97% of PD investigators would insist on a double-blind placebo-controlled trial before accepting that a cell-based or gene therapy procedure was effica-cious, despite the need for a sham control (Kim et al., 2005). While a sham procedure is not fully without risk, the alternative is to expose patients to a procedure that might not work, and whose safety and efficacy profile has not been fully defined.
6.13 Conclusion
The future of mesencephalic cell transplantation for PD is uncertain at this time. Laboratory studies have demonstrated that transplanted dopamine cells can survive, release dopamine, reinnervate the striatum and provide benefit in animal models of PD. Open label studies of fetal nigral transplantation showed positive clinical benefits associated with increased striatal FD uptake on PET. Post-mortem studies reveal histologic evidence of robust graft survival with extensive and organotypic striatal reinnerva-tion. However, two double-blind studies failed to demonstrate that transplanted patients were superior to placebo with respect to their primary endpoints. Further, transplantation of fetal mesen-cephalic dopamine neurons was associated with a potentially disabling off-medication dyskinesia. Thus, fetal nigral transplantation can not be currently recommended as a treatment for PD. It is still possi-ble that transplantation using different transplant
protocols or different dopaminergic cells will prove helpful for PD patients. Post hoc analyses in the dou-ble-blind transplant studies suggest that improved clinical results might be obtained with protocols that employ younger patients with milder disease and long-term use of immunosuppression. It remains to be determined if transplantation of larger numbers of cells or co-administration of agents that enhance cell survival will influence outcome. It is also possible that enhanced benefit can be derived by transplantation of other dopaminergic cell types such as stem cells.
It is also important to question whether transplan-tation of dopaminergic cells can provide benefits any greater than can be achieved with levodopa (Lang and Obeso, 2004b). Levodopa does not improve potentially disabling features of PD such as sleep disturbances, autonomic dysfunction, freezing of gait, postural instability, and dementia presumably because they result from degeneration of non-dopaminergic neurons. It is not clear that trans-planted dopamine cells will provide better results.
Indeed, Lindvall et al. report the best results in patients whose clinical features can be best con-trolled with levodopa, and suggest that these are the optimal candidates for a transplant procedure. It is possible that early replacement of dopaminergic tone will have downstream effects that prevent dam-age to non-dopaminergic regions. For example, it has been postulated that dopamine depletion-induced increased firing of glutamatergic neurons in the STN could cause excitotoxic damage in target neurons such as the globus pallidus, substantia nigra pars reticulata, the pedunculopontine nucleus, as well as the SNc (Rodriguez et al., 1998). Early restoration of dopamine might prevent these non-dopaminergic consequences. It is also possible that degeneration of dopaminergic pathways to cerebral cortex and other brain regions might contribute to the gait, auto-nomic, and cognitive dysfunction that occurs in PD.
It is by no means clear, however, that transplantation of dopamine neurons into the striatum will have any effect on these non-dopaminergic systems and that these types of disability that occur in PD will persist despite complete restoration of the nigrostri-atal dopamine system. For additional discussion of
transplantation therapies in Parkinson’s and other neurodegenerative disease, see Volume I, Chapter 34.
R E F E R E N C E S
Deep Brain stimulation study group. (2001). Deep-brain stimu-lation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. New Engl J Med, 345, 956–963.
Agrawal, A.K., Chaturvedi, R.K., Shukla, S., Seth, K., Chauhan, S., Ahmad, A. and Seth, P.K. (2004). Restorative potential of dopaminergic grafts in presence of antioxidants in rat model of Parkinson’s disease. J Chem Neuroanat, 28, 253–264.
Ahlskog, J.E. and Muenter, M.D. (2001). Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord, 16, 448–458.
Altar, C.A., Boylan, C.B., Fritsche, M., Jones, B.E., Jackson, C., Wiegand, S.J., Lindsay, R.M. and Hyman, C. (1994). Efficacy of brain-derived neurotrophic factor and neurotrophin-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions. J Neurochem, 63, 1021–1032.
Arjona, V., Minguez-Castellanos, A., Montoro, R.J., Ortega, A., Escamilla, F., Toledo-Aral, J.J., Pardal, R., Mendez-Ferrer, S., Martin, J.M., Perez, M., Katati, M.J., Valencia, E., Garcia, T.
and Lopez-Barneo, J. (2003). Autotransplantation of human carotid body cell aggregates for treatment of Parkinson’s disease. Neurosurgery, 53, 321–328, discussion 328–330.
Baker, K.A., Sadi, D., Hong, M. and Mendez, I. (2000). Simultaneous intrastriatal and intranigral dopaminergic grafts in the Parkinsonian rat model: role of the intranigral graft. J Comp Neurol, 426, 106–116.
Baker-Cairns, B.J., Sloan, D.J., Broadwell, R.D., Puklavec, M. and Charlton, H.M. (1996). Contributions of donor and host blood vessels in CNS allografts. Exp Neurol, 142, 36–46.
Barker, R.A., Dunnett, S.B., Faissner, A. and Fawcett, J.W. (1996).
The time course of loss of dopaminergic neurons and the gliotic reaction surrounding grafts of embryonic mesen-cephalon to the striatum. Exp Neurol, 141, 79–93.
Bensadoun, J.C., Deglon, N., Tseng, J.L., Ridet, J.L., Zurn, A.D.
and Aebischer, P. (2000). Lentiviral vectors as a gene deliv-ery system in the mouse midbrain: cellular and behavioral improvements in a 6-OHDA model of Parkinson’s disease using GDNF. Exp Neurol, 164, 15–24.
Bjorklund, A. and Stenevi, U. (1971). Growth of central cate-cholamine neurones into smooth muscle grafts in the rat mesencephalon. Brain Res, 31, 1–20.
Bjorklund, A., Dunnett, S.B., Brundin, P., Stoessl, A.J., Freed, C.R., Breeze, R.E., Levivier, M., Peschanski, M., Studer, L. and
Barker, R. (2003). Neural transplantation for the treatment of Parkinson’s disease. Lancet Neurol, 2, 437–445.
Bjorklund, L.M., Sanchez-Pernaute, R., Chung, S., Andersson, T., Chen, I.Y., McNaught, K.S., Brownell, A.L., Jenkins, B.G., Wahlestedt, C., Kim, K.S. and Isacson, O. (2002). Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA, 99, 2344–2349.
Bohn, M.C., Goldstein, M. and Black, I.B. (1982). Expression of phenylethanolamine N-methyltransferase in rat sympa-thetic ganglia and extra-adrenal chromaffin tissue. Dev Biol, 89, 299–308.
Boll, J.B., Geist, M.A., Kaminski Schierle, G.S., Petersen, K., Leist, M. and Vaudano, E. (2004). Improvement of embry-onic dopaminergic neurone survival in culture and after grafting into the striatum of hemiparkinsonian rats by CEP-1347. J Neurochem, 88, 698–707.
Brundin, P., Nilsson, O.G., Strecker, R.E., Lindvall, O., Astedt, B.
and Bjorklund, A. (1986). Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson’s dis-ease. Exp Brain Res, 65, 235–240.
Brundin, P., Strecker, R.E., Widner, H., Clarke, D.J., Nilsson, O.G., Astedt, B., Lindvall, O. and Bjorklund, A. (1988). Human fetal dopamine neurons grafted in a rat model of Parkinson’s dis-ease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release. Exp Brain Res, 70, 192–208.
Brundin, P., Karlsson, J., Emgard, M., Schierle, G.S., Hansson, O., Petersen, A. and Castilho, R.F. (2000a). Improving the sur-vival of grafted dopaminergic neurons: a review over current approaches. Cell Transplant, 9, 179–195.
Brundin, P., Pogarell, O., Hagell, P., Piccini, P., Widner, H., Schrag, A., Kupsch, A., Crabb, L., Odin, P., Gustavii, B., Bjorklund, A., Brooks, D.J., Marsden, C.D., Oertel, W.H., Quinn, N.P., Rehncrona, S. and Lindvall, O. (2000b). Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson’s disease. Brain, 123(Part 7), 1380–1390.
Burnstein, R.M., Foltynie, T., He, X., Menon, D.K., Svendsen, C.N.
and Caldwell, M.A. (2004). Differentiation and migration of long term expanded human neural progenitors in a partial lesion model of Parkinson’s disease. Int J Biochem Cell Biol, 36, 702–713.
Carvey, P.M., Ling, Z.D., Sortwell, C.E., Pitzer, M.R., McGuire, S.O., Storch, A. and Collier, T.J. (2001). A clonal line of mesen-cephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplanta-tion in Parkinson’s disease. Exp Neurol, 171, 98–108.
Chun, H.S., Gibson, G.E., Degiorgio, L.A., Zhang, H., Kidd, V.J.
and Son, J.H. (2001). Dopaminergic cell death induced by
MPP(), oxidant and specific neurotoxicants shares the com-mon molecular mechanism. J Neurochem, 76, 1010–1021.
Cohen, J. (1994). New fight over fetal tissue grafts. Science, 263, 600–601.
Collier, T.J., Sortwell, C.E., Elsworth, J.D., Taylor, J.R., Roth, R.H., Sladek Jr., J.R. and Redmond Jr., D.E. (2002). Embryonic ventral mesencephalic grafts to the substantia nigra of MPTP-treated monkeys: feasibility relevant to multiple-target grafting as a therapy for Parkinson’s disease. J Comp Neurol, 442, 320–330.
de la Fuente-Fernandez, R., Ruth, T.J., Sossi, V., Schulzer, M., Calne, D.B. and Stoessl, A.J. (2001). Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s dis-ease. Science, 293, 1164–1166.
Deacon, T., Schumacher, J., Dinsmore, J., Thomas, C., Palmer, P., Kott, S., Edge, A., Penney, D., Kassissieh, S., Dempsey, P. and Isacson, O. (1997). Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson’s disease. Nat Med, 3, 350–353.
Dezawa, M., Kanno, H., Hoshino, M., Cho, H., Matsumoto, N., Itokazu, Y., Tajima, N., Yamada, H., Sawada, H., Ishikawa, H., Mimura, T., Kitada, M., Suzuki, Y. and Ide, C. (2004). Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest, 113, 1701–1710.
Drucker-Colin, R. and Verdugo-Diaz, L. (2004). Cell transplanta-tion for Parkinson’s disease: present status. Cell Mol Neurobiol, 24, 301–316.
Duan, W.M., Widner, H., Bjorklund, A. and Brundin, P. (1993).
Sequential intrastriatal grafting of allogeneic embryonic dopamine-rich neuronal tissue in adult rats: will the second graft be rejected? Neuroscience, 57, 261–274.
Dunnett, S.B. and Annett, L.E. (1991). Nigral transplants in primate models of parkinsonism. In: Intracerebral Trans-plantation in Movement Disorders (eds Lindvall, O., Bjorklund, A. and Widermer, H.R.), Elsevier Science Publishers, New York.
Dunnett, S.B., Bjorklund, A., Schmidt, R.H., Stenevi, U. and Iversen, S.D. (1983). Intracerebral grafting of neuronal cell suspensions. IV. Behavioural recovery in rats with unilateral 6-OHDA lesions following implantation of nigral cell sus-pensions in different forebrain sites. Acta Physiol Scand Suppl, 522, 29–37.
Dunnett, S.B., Hernandez, T.D., Summerfield, A., Jones, G.H.
and Arbuthnott, G. (1988). Graft-derived recovery from 6-OHDA lesions: specificity of ventral mesencephalic graft tissues. Exp Brain Res, 71, 411–424.
Espejo, E.F., Gonzalez-Albo, M.C., Moraes, J.P., El Banoua, F., Flores, J.A. and Caraballo, I. (2001). Functional regeneration in a rat Parkinson’s model after intrastriatal grafts of glial cell line-derived neurotrophic factor and transforming
growth factor beta1-expressing extra-adrenal chromaffin cells of the Zuckerkandl’s organ. J Neurosci, 21, 9888–9895.
Fahn, S., Oakes, D., Shoulson, I., Kieburtz, K., Rudolph, A., Lang, A., Olanow, C.W., Tanner, C. and Marek, K. (2004). Levodopa and the progression of Parkinson’s disease. New Engl J Med, 351, 2498–2508.
Fawcett, J.W., Barker, R.A. and Dunnett, S.B. (1995). Dopaminergic neuronal survival and the effects of bFGF in explant, three dimensional and monolayer cultures of embryonic rat ventral mesencephalon. Exp Brain Res, 106, 275–282.
Fisher, L.J. and Gage, F.H. (1993). Grafting in the mammalian central nervous system. Physiol Rev, 73, 583–616.
Freed, C.R., Breeze, R.E., Rosenberg, N.L., Schneck, S.A., Kriek, E., Qi, J.X., Lone, T., Zhang, Y.B., Snyder, J.A., Wells, T.H., et al.
(1992). Survival of implanted fetal dopamine cells and neu-rologic improvement 12 to 46 months after transplantation for Parkinson’s disease. New Engl J Med, 327, 1549–1555.
Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W.Y., Dumouchel, W., Kao, R., Dillon, S., Winfield, H., Culver, S., Trojanowski, J.Q., Eidelberg, D. and Fahn, S. (2001). Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. New Engl J Med, 344, 710–719.
Freed, C.R., Breeze, R.E., Fahn, S. and Eidelberg, D. (2004).
Preoperative response to levodopa is the best predictor of transplant outcome. Ann Neurol, 55, 896, author reply 896–897.
Freeman, T.B., Olanow, C.W., Hauser, R.A., Nauert, G.M., Smith, D.A., Borlongan, C.V., Sanberg, P.R., Holt, D.A., Kordower, J.H., Vingerhoets, F.J., et al. (1995). Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson’s disease. Ann Neurol, 38, 379–388.
Freeman, T.B., Vawter, D.E., Leaverton, P.E., Godbold, J.H., Hauser, R.A., Goetz, C.G. and Olanow, C.W. (1999). Use of placebo surgery in controlled trials of a cellular-based ther-apy for Parkinson’s disease. N Engl J Med, 341, 988–992.
Gage, F.H. (2000). Mammalian neural stem cells. Science, 287, 1433–1438.
Gash, D.M., Zhang, Z., Cass, W.A., Ovadia, A., Simmerman, L., Martin, D., Russell, D., Collins, F., Hoffer, B.J. and Gerhardt, G.A. (1995). Morphological and functional effects of intranigrally administered GDNF in normal rhesus mon-keys. J Comp Neurol, 363, 345–358.
Gash, D.M., Zhang, Z., Ovadia, A., Cass, W.A., Yi, A., Simmerman, L., Russell, D., Martin, D., Lapchak, P.A., Collins, F., Hoffer, B.J.
and Gerhardt, G.A. (1996). Functional recovery in parkin-sonian monkeys treated with GDNF. Nature, 380, 252–255.
Gearan, T., Castillo, O.A. and Schwarzschild, M.A. (2001). The parkinsonian neurotoxin, MPP induces phosphorylated c-Jun in dopaminergric neurons of mesencephalic cultures.
Parkinsonism Relat Disord, 8, 19–22.
Goetz, C.G., Olanow, C.W., Koller, W.C., Penn, R.D., Cahill, D., Morantz, R., Stebbins, G., Tanner, C.M., Klawans, H.L. and Shannon, K.M. (1989). Multicenter study of autologous adrenal medullary transplantation to the corpus striatum in patients with advanced Parkinson’s disease. New Engl J Med, 320, 337–341.
Gordon, P.H., Yu, Q., Qualls, C., Winfield, H., Dillon, S., Greene, P.E., Fahn, S., Breeze, R.E., Freed, C.R. and Pullman, S.L. (2004).
Reaction time and movement time after embryonic cell implantation in Parkinson disease. Arch Neurol, 61, 858–861.
Granholm, A.C., Mott, J.L., Bowenkamp, K., Eken, S., Henry, S., Hoffer, B.J., Lapchak, P.A., Palmer, M.R., Van Horne, C. and Gerhardt, G.A. (1997). Glial cell line-derived neurotrophic factor improves survival of ventral mesencephalic grafts to the 6-hydroxydopamine lesioned striatum. Exp Brain Res, 116, 29–38.
Hagell, P., Schrag, A., Piccini, P., Jahanshahi, M., Brown, R., Rehncrona, S., Widner, H., Brundin, P., Rothwell, J.C., Odin, P., Wenning, G.K., Morrish, P., Gustavii, B., Bjorklund, A., Brooks, D.J., Marsden, C.D., Quinn, N.P. and Lindvall, O.
(1999). Sequential bilateral transplantation in Parkinson’s dis-ease: effects of the second graft. Brain, 122(Pt 6), 1121–1132.
Hagell, P., Piccini, P., Bjorklund, A., Brundin, P., Rehncrona, S., Widner, H., Crabb, L., Pavese, N., Oertel, W.H., Quinn, N., Brooks, D.J. and Lindvall, O. (2002). Dyskinesias following neural transplantation in Parkinson’s disease. Nat Neurosci, 5, 627–628.
Harris, C.A., Deshmukh, M., Tsui-Pierchala, B., Maroney, A.C.
and Johnson Jr., E.M. (2002). Inhibition of the c-Jun N-terminal kinase signaling pathway by the mixed lineage kinase inhibitor CEP-1347 (KT7515) preserves metabolism and growth of trophic factor-deprived neurons. J Neurosci, 22, 103–113.
Hauser, R.A., Freeman, T.B., Snow, B.J., Nauert, M., Gauger, L., Kordower, J.H. and Olanow, C.W. (1999). Long-term evalua-tion of bilateral fetal nigral transplantaevalua-tion in Parkinson disease. Arch Neurol, 56, 179–187.
Itakura, T., Uematsu, Y., Nakao, N., Nakai, E. and Nakai, K.
(1997). Transplantation of autologous sympathetic gan-glion into the brain with Parkinson’s disease. Long-term follow-up of 35 cases. Stereotact Funct Neurosurg, 69, 112–115.
Kim, S.Y.H., Frank, S., Holloway, R., Zimmerman, C., Wilson, R. and Kierburtz, K. (2005). Science and ethics of sham surgery: a survey of Parkinson’s disease clinical researchers. Arch Neurol, 62, 1357–1360.
Kim, T.E., Lee, H.S., Lee, Y.B., Hong, S.H., Lee, Y.S., Ichinose, H., Kim, S.U. and Lee, M.A. (2003). Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurr1-overexpressing neural stem cell. Biochem Biophys Res Commun, 305, 1040–1048.
Kirik, D., Winkler, C. and Bjorklund, A. (2001). Growth and func-tional efficacy of intrastriatal nigral transplants depend on the extent of nigrostriatal degeneration. J Neurosci, 21, 2889–2896.
Kordower, J.H., Freeman, T.B., Snow, B.J., Vingerhoets, F.J., Mufson, E.J., Sanberg, P.R., Hauser, R.A., Smith, D.A., Nauert, G.M., Perl, D.P., et al. (1995). Neuropathological evi-dence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. New Engl J Med, 332, 1118–1124.
Kordower, J.H., Rosenstein, J.M., Collier, T.J., Burke, M.A., Chen, E.Y., Li, J.M., Martel, L., Levey, A.E., Mufson, E.J., Freeman, T.B. and Olanow, C.W. (1996). Functional fetal nigral grafts in a patient with Parkinson’s disease:
chemoanatomic, ultrastructural, and metabolic studies. J Comp Neurol, 370, 203–230.
Kordower, J.H., Styren, S., Clarke, M., Dekosky, S.T., Olanow, C.W.
and Freeman, T.B. (1997). Fetal grafting for Parkinson’s dis-ease: expression of immune markers in two patients with functional fetal nigral implants. Cell Transplant, 6, 213–219.
Kordower, J.H., Freeman, T.B., Chen, E.Y., Mufson, E.J., Sanberg, P.R., Hauser, R.A., Snow, B. and Olanow, C.W. (1998).
Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson’s disease. Mov Disord, 13, 383–393.
Kordower, J.H., Emborg, M.E., Bloch, J., Ma, S.Y., Chu, Y., Leventhal, L., McBride, J., Chen, E.Y., Palfi, S., Roitberg, B.Z., Brown, W.D., Holden, J.E., Pyzalski, R., Taylor, M.D., Carvey, P., Ling, Z., Trono, D., Hantraye, P., Deglon, N. and Aebischer, P.
(2000). Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease.
Science, 290, 767–773.
Lang, A.E. and Lozano, A.M. (1998). Parkinson’s disease. First of two parts. New Engl J Med, 339, 1044–1053.
Lang, A.E. and Obeso, J.A. (2004a). Challenges in Parkinson’s disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol, 3, 309–316.
Lang, A.E. and Obeso, J.A. (2004b). Time to move beyond nigrostriatal dopamine deficiency in Parkinson’s disease.
Ann Neurol, 55, 761–765.
Lee, C.S., Cenci, M.A., Schulzer, M. and Bjorklund, A. (2000).
Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson’s disease.
Brain, 123(Pt 7), 1365–1379.
Lin, L.F., Doherty, D.H., Lile, J.D., Bektesh, S. and Collins, F.
(1993). GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science, 260, 1130–1132.
Lindvall, O., Backlund, E.O., Farde, L., Sedvall, G., Freedman, R., Hoffer, B., Nobin, A., Seiger, A. and Olson, L. (1987).
Transplantation in Parkinson’s disease: two cases of adrenal medullary grafts to the putamen. Ann Neurol, 22, 457–468.
Lindvall, O., Brundin, P., Widner, H., Rehncrona, S., Gustavii, B., Frackowiak, R., Leenders, K.L., Sawle, G., Rothwell, J.C., Marsden, C.D., et al. (1990). Grafts of fetal dopamine neu-rons survive and improve motor function in Parkinson’s disease. Science, 247, 574–577.
Lindvall, O., Widner, H., Rehncrona, S., Brundin, P., Odin, P., Gustavii, B., Frackowiak, R., Leenders, K.L., Sawle, G., Rothwell, J.C., et al. (1992). Transplantation of fetal dopamine neurons in Parkinson’s disease: one-year clinical and neuro-physiological observations in two patients with putaminal implants. Ann Neurol, 31, 155–165.
Lindvall, O., Sawle, G., Widner, H., Rothwell, J.C., Bjorklund, A., Brooks, D., Brundin, P., Frackowiak, R., Marsden, C.D., Odin, P., et al. (1994). Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Ann Neurol, 35, 172–180.
Luquin, M.R., Montoro, R.J., Guillen, J., Saldise, L., Insausti, R., Del Rio, J. and Lopez-Barneo, J. (1999). Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen. Neuron, 22, 743–750.
Ma, Y., Feigin, A., Dhawan, V., Fukuda, M., Shi, Q., Greene, P., Breeze, R., Fahn, S., Freed, C. and Eidelberg, D. (2002).
Dyskinesia after fetal cell transplantation for parkinsonism:
a PET study. Ann Neurol, 52, 628–634.
Macklin, R. (1999). The ethical problems with sham surgery in clinical research. New Engl J Med, 341, 992–996.
Madrazo, I., Drucker-Colin, R., Diaz, V., Martinez-Mata, J., Torres, C. and Becerril, J.J. (1987). Open microsurgical auto-graft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. New Engl J Med, 316, 831–834.
Magavi, S.S. and Macklis, J.D. (2001). Manipulation of neural precursors in situ: induction of neurogenesis in the neocor-tex of adult mice. Neuropsychopharmacology, 25, 816–835.
Marsden, C.D. and Parkes, J.D. (1976). “On-off” effects in patients with Parkinson’s disease on chronic levodopa ther-apy. Lancet, 1, 292–296.
McRae, C., Cherin, E., YAmazaki, T.G., Diem, G., Vo, A.H., Russell, D., Ellgring, J.H., Fahn, S., Greene, P., Dillon, S., Winfield, H., Bjugstad, K.B. and Freed, C.R. (2004). Effects of perceived treatment on quality of life and medical out-comes in a double-blind placebo surgery trial. Arch Gen Psychiatry, 61, 412–420.
Mendez, I., Dagher, A., Hong, M., Gaudet, P., Weerasinghe, S., McAlister, V., King, D., Desrosiers, J., Darvesh, S., Acorn, T.
and Robertson, H. (2002). Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases.
J Neurosurg, 96, 589–596.
Mendez, I., Sanchez-Pernaute, R., Cooper, O., Vinuela, A., Ferrari, D., Bjorklund, L., Dagher, A. and Isacson, O. (2005).
Cell type analysis of functional fetal dopamine cell suspen-sion transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain, 128, 1498–1510.
Meyer, M., Widmer, H.R., Wagner, B., Guzman, R., Evtouchenko, L., Seiler, R.W. and Spenger, C. (1998). Comparison of mesen-cephalic free-floating tissue culture grafts and cell suspen-sion grafts in the 6-hydroxydopamine-lesuspen-sioned rat. Exp Brain Res, 119, 345–355.
Murakata, C., Kaneko, M., Gessner, G., Angeles, T.S., Ator, M.A., O’Kane, T.M., McKenna, B.A., Thomas, B.A., Mathiasen, J.R., Saporito, M.S., Bozyczko-Coyne, D. and Hudkins, R.L.
(2002). Mixed lineage kinase activity of indolocarbazole analogues. Bioorg Med Chem Lett, 12, 147–150.
Nakao, N., Kakishita, K., Uematsu, Y., Yoshimasu, T., Bessho, T., Nakai, K., Naito, Y. and Itakura, T. (2001). Enhancement of the response to levodopa therapy after intrastriatal trans-plantation of autologous sympathetic neurons in patients with Parkinson disease. J Neurosurg, 95, 275–284.
Nikkhah, G., Odin, P., Smits, A., Tingstrom, A., Othberg, A., Brundin, P., Funa, K. and Lindvall, O. (1993). Platelet-derived growth factor promotes survival of rat and human mesencephalic dopaminergic neurons in culture. Exp Brain Res, 92, 516–523.
Nikkhah, G., Cunningham, M.G., Jodicke, A., Knappe, U. and Bjorklund, A. (1994). Improved graft survival and striatal reinnervation by microtransplantation of fetal nigral cell sus-pensions in the rat Parkinson model. Brain Res, 633, 133–143.
Obeso, J.A., Rodriguez-Oroz, M.C., Rodriguez, M., Lanciego, J.L., Artieda, J., Gonzalo, N. and Olanow, C.W. (2000). Pathophysio-logy of the basal ganglia in Parkinson’s disease. Trends Neurosci, 23, S8–S19.
Olanow, C.W. (2003). Present and future directions in the man-agement of motor complications in patients with advanced PD. Neurology, 61, S24–S33.
Olanow, C.W. (2004). The scientific basis for the current treat-ment of Parkinson’s disease. Annu Rev Med, 55, 41–60.
Olanow, C.W. (2005). Double-blind, placebo-controlled trials for surgical interventions in Parkinson’s disease. Arch Neurol, 62, 1343–1344.
Olanow, C.W., Koller, W., Goetz, C.G., Stebbins, G.T., Cahill, D.W., Gauger, L.L., Morantz, R., Penn, R.D., Tanner, C.M., Klawans, H.L., et al. (1990). Autologous transplantation of adrenal medulla in Parkinson’s disease. 18-month results.
Arch Neurol, 47, 1286–1289.
Olanow, C.W., Kordower, J.H. and Freeman, T.B. (1996). Fetal nigral transplantation as a therapy for Parkinson’s disease.
Trends Neurosci, 19, 102–109.
Olanow, C.W., Watts, R.L. and Koller, W.C. (2001). An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology, 56, S1–S88.
Olanow, C.W., Goetz, C.G., Kordower, J.H., Stoessl, A.J., Sossi, V.,
Olanow, C.W., Goetz, C.G., Kordower, J.H., Stoessl, A.J., Sossi, V.,