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John R. Sladek Jr. and Don Marshall Gash

✓ The successful utilization of fetal nerve-cell grafts as therapeutic tools in animal models of neurodegenerative disease has prompted the first clinical attempts in parkinsonian patients in at least three countries. The extensive scientific data in rodents coupled with the first successful fetal neural grafts in monkeys with experimental parkinsonism suggest that consideration might now be given to clinical applications. Attention is also directed to the various types of donor cells that might be utilized in clinical trials for the treatment of parkinsonism, including potential benefits, risks, and limitations associated with each type of donor material. This review highlights major developments in this field as they relate to basic principles of neural grafting and discusses potential applications in humans.

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Robert J. Plunkett, Stephen C. Saris, Krzysztof S. Bankiewicz, Barbara Ikejiri and Richard J. Weber

. Photomicrograph of the needle track showing minimal tissue disruption and a small number of the injected cells (arrow) . H & E, × 100. Discussion Implantation of cells into the brain is often used to correct focal abnormalities which are expressed behaviorally. To confirm a successful outcome is much more difficult than the relatively straightforward assessment of a parameter such as survival after cardiac transplantation. Although successful cell implantation has been performed in rodent models of neurodegenerative diseases, 3, 9 these brains are

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Victor W. Henderson and Caleb E. Finch

: Cytoskeletal protein abnormalities in neurodegenerative diseases. Ann Neurol 19 : 209 – 223 , 1986 Goldman JE, Yen SH: Cytoskeletal protein abnormalities in neurodegenerative diseases. Ann Neurol 19: 209–223, 1986 93. Goudsmit J , Morrow CH , Asher DM , et al : Evidence for and against the transmissibility of Alzheimer disease. Neurology 30 : 945 – 950 , 1980 Goudsmit J, Morrow CH, Asher DM, et al: Evidence for and against the transmissibility of Alzheimer disease. Neurology 30: 945–950, 1980 94

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David M. Frim, M. Priscilla Short, William S. Rosenberg, Joseph Simpson, Xandra O. Breakefield and Ole Isacson

receiving an NGF-secreting graft. † Difference significant to p < 0.01. Discussion We have confirmed that striatal lesions produced by quinolinic acid, an excitotoxin that causes axon-sparing lesions similar to those found in human neurodegenerative disease, 5, 31 can be reduced in size up to 80% by locally implanted NGF-secreting fibroblasts. 30 Furthermore, NGF-producing fibroblast implants placed at a distance from the quinolinate infusion (in this study in the contralateral corpus callosum) do not significantly affect lesion size or

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David Barba, Joseph Hardin, Jasodhara Ray and Fred H. Gage

be successful. The selective killing by genetically modified cells in the brain has other potential uses in the CNS in addition to the treatment of brain tumors. Animal models of neurodegenerative diseases such as Alzheimer's disease have been improved by the transplantation of cells modified to produce neurotrophic factors such as nerve growth factor. 5 A safety concern regarding the use of such genetically modified cells has been control in the unlikely event of their formation into a tumorous growth. If these modified cells were also modified with the HSV

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Jason A. Brodkey, Eric D. Laywell, Thomas F. O'Brien, Andreas Faissner, Kari Stefansson, H. Ulrich Dörries, Melitta Schachner and Dennis A. Steindler

survival times, respectively. We also compared these samples with brain sections from patients with various stages (0, 2, and 3) of Huntington's disease, as well as control brain tissue from another ongoing study of astrocytes and ECM in human neurodegenerative diseases. * 30 Finally, sections from an anaplastic astrocytoma were used as a positive control for the tenascin immunocytochemical and in situ hybridization studies. 2, 12 The focus of this report is a 28-year-old man who was brought to the Elvis Presley Memorial Regional Trauma Center in Memphis, Tennessee

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Michael A. Weitzner, Christina A. Meyers and Kevin Byrne

share some attributes with other cancer patients in that they have a form of cancer and undergo radiotherapy and chemotherapy. Yet, this population also resembles the chronic illness population because they have a progressive neurodegenerative disease and will continue to have some dysfunction after treatment. Therefore, assessing this population with well-validated multidimensional QOL instruments is an important step in understanding the impact of brain tumors on specific aspects of QOL. The FP-QLI and PAIS-SR, as shown in this study, assess domains of function in

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Gordon Tang and E. Antonio Chiocca

Gene transfer offers the potential to explore basic physiological processes and to intervene in human disease. The central nervous system (CNS) presents a fertile field in which to develop novel therapeutic modalities to treat intractable and pervasive malignant tumors and neurodegenerative disease. The extension of gene therapy to the CNS, however, faces the delivery obstacles of a target population that is postmitotic and isolated behind a blood-brain barrier (BBB). Approaches to this problem have included grafting of genetically modified cells to deliver novel proteins or introducing genes by viral or synthetic vectors geared toward the CNS cell population. Direct inoculation and bulk flow, as well as osmotic and pharmacological disruption, have been used to circumvent the BBB's exclusionary role. Once the gene is delivered, myriad strategies have been used to affect a therapeutic result. Genes activating prodrugs are the most common antitumor approach. Other approaches focus on activating immune responses, targeting angiogenesis, and influencing apoptosis and tumor suppression. At this time, therapy directed at neurodegenerative diseases has centered on ex vivo gene therapy for supply of trophic factors to promote neuronal survival, axonal outgrowth, and target tissue function. Despite early promise, gene therapy for CNS disorders will require advancements in methods for delivery and long-term expression before becoming feasible for human disease.

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Jae Y. Lim, Antonio A. F. de Salles, Jeff Bronstein, Donna L. Masterman and Jeffrey L. Saver

P arkinson's disease (PD) is a common neurodegenerative disease with a prevalence of 85 to 187 cases per 100,000 population. 5, 15 Stereotactic radio-frequency (RF) pallidotomy is effective in alleviating the symptoms of idiopathic (I)PD, but the long-term efficacy as well as the safety of this procedure remain to be fully determined. Radiofrequency has long been favored as the technique of choice for functional lesion making in pallidotomies. It consistently generates well-circumscribed lesions and allows electrical stimulation for localization and

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Colin Watts and Stephen B. Dunnett

H untington's disease is a chronic progressive neurodegenerative disease inherited in an autosomal dominant manner. It is characterized pathologically by the loss of intrinsic medium-sized spiny neurons from the basal ganglia with subsequent neuronal loss in various output structures including the thalamus and cerebral cortex. 24, 25, 51, 54, 62 These pathological changes manifest clinically in midlife as a triad of cognitive decline, psychiatric disturbance, and impairment of motor function. 37 This devastating hereditary disease is currently incurable. The