DESCRIPTION: (modified from abstract) This is a two-center study of transplantation of fetal mesencephalic neurons in patients with Parkinsonism. The PI is at U CO Health Sciences; the second center is the Movement Disorders Unit at Columbia Presbyterian Medical Center in NY (Stanley Fahn). The PI initially completed an open study of this therapy in 26 PD patients. Thereafter he undertook the present study of 40 patients with Parkinson's disease, using a double-blind, placebo controlled trial of implantation of embryonic (7-8 weeks post-conception), human mesencephalic cells. Patients were under 75 and had PD of at least 7 years duration. Transplanted patients received cultured mesencephalic tissue from four embryos along four 30 to 40 mm needle tracts bilaterally in the putamen. Control patients had burr holes but no actual implantations. No patients were immunosuppressed. 21 men and 19 women enrolled in the study. 39 (19 transplant, 20 placebo) completed 12 months of double blind follow-up. By January, 1999, 39 patients had received either an implant or a sham procedure and been followed for one year with blinded evaluations and then had the blind revealed. The primary endpoint in the study was a subjective Global Rating Scale; this was not significantly different in treated and untreated groups. However, the transplanted patients had significant improvement in several objective measurements of PD, including UPDRS motor "off" (34%), Schwab and England "off" (20% in toto, 30% in young), and 19F-fluorodopa uptake (20%). Placebo surgery patients showed no improvement in these measures. The beneficial effects stratified predominantly to patients under 60 years of age. In longer-term follow-up of up to three years, there has been progressive improvement in UPDRS motor "off" and Schwab and England "off" scores. Drug doses have also been reduced, typically by up to 50% in patients follow-up up to 30-36 months. Some of the transplanted patients develop dyskinesias (abnormal, excess movements) even off agonist therapy, starting typically more than one year after surgery. Of 20 patients in the sham group, 14 elected to have cell implantations. Follow-up analysis of this unblinded, formerly sham treated but now implanted group shows a time-course of improvement of the UPDRS motor "off" scores that is parallel to that seen in patients transplanted on the double blind protocol. Two patients died of causes unrelated to the transplant. Both showed substantial survival of transplanted dopamine neurons as assessed by counts of hydroxylase positive neurons in the striatum. These studies were performed with Dr. J. Trojanowski as a neuropath collaborator. In addition to hydroxylase chemistry, the tissue was processed for H+E staining, and quantitation of CD3, CD4 and CD8 lymphocytes. The present proposal is to follow these patients for another five years, taking the follow-up in the treated patients out for 5 to 10 years. On the basis of uncontrolled reports of small numbers of patients, the group postulates that the patients will have progressive clinical improvement for 3 - 4 years followed by a plateau and possibly a decline 6 - 8 years after transplant. The intention is to address five questions: 1) Do implanted patients show clinical improvement over periods of years? 2) Does fluorodopa uptake on PET scans increase progressively? Correlate with clinical change? 3) Do transplants in the open trial have the same clinical course as those in the blind trial? 4) Do transplant effects plateau and then decline? and 5) At autopsy, does the survival of dopamine cells and accompanying neurite outgrowth correlate with clinical and PET scan observations? In the proposed funding period, the PI will continue to evaluate all subjects enrolled in this study. This now includes 38 surviving subjects of whom 32 have received tissue (18 in the double blind phase, 14 originally untreated controls who opted to be implanted after the double blind was lifted. The intention is to perform three comparisons: 1) status of patients who received cells in the unblinded vs. the blinded protocol; 2) status of patients with implantations relative to themselves prior to implantation; and 3) Fluorodopa PET scans in all implanted patients. All patients will have follow-up once a year in Denver (Drs. Freed and Breeze) and twice a year at the Clinical Research Center at CPMC (Dr. Fahn). For patients treated originally in the double-blind study (Group A), follow-up at the Irving Clinical Center at Columbia will be every 6 months post-implantation x 1 year, then at 1 year and subsequently every 2 years. For patients implanted in the open trial (Group B), the scans will be done every 4 months for the first year, then at two-year intervals. This will require travelling to NY to meet Dr. Fahn and to visit the North Shore Hospital for the scans (Dr. David Eidelberg). For patients treated in the original blinded protocol (Group A), 19F-fluorodopa scans will be performed at years 1 and 2 after implant and then every 2 years thereafter. Group B patients had 19FF-fluorodopa scans at baseline and 1 year after sham surgery. They will have follow-up scans at 1 and 2 years post-implant and then every 2 years. The full battery of tests every six months at CPMC will include out-patient and in-patient components. The out-patient component consists of: (1) a diary; each will be scored by a clinical coordinator at Colorado. Group B patients will keep diaries for one week every 4 months x 1 year and then every 6 months. Group A patients will keep diaries for 1 week every 6 months. All patients will also keep a diary for 2 weeks prior to being admitted to the CPMC for follow-up. (2) self-administered home UPDRS testing with self-video performed 1 hour before and 1 hour after the first drug dose, and done daily for 14 days before the CPMC visits. The clinical coordinator in CO will rate these from -4 (severely off, cannot do the task) to +4 (severely dyskinetic); the squares of the scores are used to rate the degree of normality. The patient diaries also apparently self-rate status from -4 to +4. From these diary score, the team will calculate a good "on" time as the area under the curve between -1 and +1 (mild to absent Parkinson symptoms), averaged over 14 days. Also, dyskinesias will be estimated at the area under the curve for score above +1 over 14 days. These will be compared to the post-surgical period (?? not the baseline). Analogously, severe "off" time will be measured as the area of curves below -1. A series of in-patient tests will include: (1) global rating scales, (2) a neuropsychological test battery; (3) quantitative and qualitative speech analysis; (4) quality of life assessment; (5) drug-response testing; and (6) recording of adverse events. The primary outcome variable for the open-label phase is the UPDRS "practically define off" scores obtained during the in-patient evaluation. Secondary endpoints will be the Schwab and England "off" and "on" scores and the UPDRS "on" scores. The team will analyze both the individual time course data as well as the group data. Analysis of the longitudinal data (repeated measures) will be performed by applying Generalized Estimating Equations (GEE) to regression models with repeated measures. Autopsies will be obtained whenever possible. The PI estimates 1 death per year. Brains will be retrieved through a commercial service (Medilegal Services) and sent to Dr. John Trojanowski. The post-mortem brains will undergo MRIs to determine the orientation of the needle tracks for brain blocking. Brains will be stained with H+E and immunostained for tyrosine hydroxylase and B and T cell markers. Stereologically corrected counts of TH-positive neurons will be determined.