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Positive Potential of Fetal Nigral Implants for Parkinson Disease (Editorial) by Roger N. Rosenberg Archives of Neurology. 2004;61:837-838. Abstract of article, "Reaction time and movement time after embryonic cell implantation in Parkinson disease." follows "In 2001, Freed et al1 reported that human embryonic dopamine-neuron transplants survive in patients with severe Parkinson disease (PD) and do result in some clinical benefit in younger but not in older patients, those older than 60 years. In a similar study in 2003 with bilateral human embryonic dopamine-neuron implants in the putamen in patients with PD, Olanow et al2concluded that transplantation offered no significant improvement and could not be recommended. Both studies were unable to achieve their primary objective of major clinical improvement despite increased striatal F-18 fluorodopa uptake with positron emission tomography and data showing maintenance of transplanted neurons at postmortem examination.1-2 Freed et al1 did find improved motor function in a subset of patients younger than 60 years; Olanow et al did not find similar evidence but did note improvement in patients with milder disease at baseline. Of note, both studies reported disabling dyskinesia while not receiving medication in patients who received a transplant. In this issue of the ARCHIVES, Gordon et al3 provide an update from the original Freed et al1 cohort of patients who were initially described in 2001. They have quantitatively analyzed patients who received either sham or embryonic nigral implants for their combined reaction time (RT) and movement time (MT) to measure motor performance. Reaction time is a measure of premovement central neural processing. Movement time is a physiologic correlate of movement and is prolonged in bradykinesia.1, 3 Forty patients with levodopa-responsive Hoehn and Yahr scale stage 3 or greater PD were randomized to receive implants or placebo (sham) surgery. All patients underwent RT + MT measurements preoperatively and at 4 and 12 months postoperatively while not taking medication. Of considerable interest, the difference in mean RT + MT between the sham and the implant groups was statistically significant (P = .005) and was greatest in those older than 60 years (P = .003). They found that there was significant deterioration in the sham surgery group at 12 months, which was thought to be the result of worsening in patients older than 60 years (P = .003). Their findings are of significance even though they may be clinically modest. I concur with Gordon et al that these observations show that comprehensive analyses of different RT paradigms can document subtle changes in motor performance across time. These documented changes of physiologic benefit recorded in their article do indicate that there are objective markers of motor behavior that were altered for the better with embryonic tissue implantation in patients with PD. We are at the beginning of our understanding of the neurobiological and neurotherapeutic basis of stem cell and embryonic cell transplantation for neurological diseases. The human genome was first sequenced and analyzed in 2001, and of the 30 000 to 35 000 genes now known, only about 5% have been identified as to their gene product and function in the mammalian brain. An entire issue of the Archives of Neurology was devoted to Genomic Neurology in November 2001, and one can see in that review issue that the era of genomic neurology has really just begun. The therapeutic rewards from a complete analysis of the genomic and proteomic microarrays from normal and PD brain tissue will provide important insights as to the specificity of altered gene expression in PD caused by inherited genetic polymorphisms or the consequence of environmental factors and toxins. We should be very encouraged by the studies of Freed et al,1 Olanow et al,2 and Gordon et al3 related to the margins of improvement in embryonic neuronal implant therapy for PD. Embryonic neuronal implants and stem cell implants provide many potential therapeutic factors besides dopamine. These tissue implants secrete trophic factors, cytokines, interleukins, and even potential toxic inflammatory products. The issue now is to define the specific factors needed to reestablish the normal nigral-striatal, nigral-pallidal, nigral-subthalamic, and nigral-reticular connections that the stem cell or embryonic neuronal implant can provide. The specific genes that synthesize these factors (gene products) responsible for forming these circuits need to be identified from ongoing neurogenomic studies and induced in association with the neural or stem cell implants to reestablish a normal extrapyramidal motor circuitry to reverse the degenerative pathologic process of PD. It is clear now that these genes that underlie the formation of motor circuits in embryogenesis will be found and will provide the instructions to reproduce these events again. The current information provided by present studies1-3 provide an important beginning and basis to design new genomic approaches. Gordon et al3 in this issue of the ARCHIVES build on the prior observations of Freed et al1 and Olanow et al2 in showing that small but definite improvements do occur with embryonic neural implants. The challenge now is to build on these nascent findings through genetic and genomic studies. I believe these will provide important insights into neural circuit patterning and formation and will lead to highly specific and effective new genomic-based therapies. The golden age of neurology is just beginning! AUTHOR INFORMATION Corresponding author: Roger N. Rosenberg, MD, Archives of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9108 (e-mail: [log in to unmask]). REFERENCES 1. Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson disease. N Engl J Med. 2001;344:710-719. ABSTRACT/FULL TEXT 2. Olanow CW, Goetz CG, Kordower JH, et al. Double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson disease. Ann Neurol. 2003;54:403-414. CrossRef | ISI | MEDLINE 3. Gordon PH, Yu Q, Qualls C, et al. Reaction time and movement time after embryonic cell implantation in Parkinson disease. Arch Neurol. 2004;61:858-861. ABSTRACT/FULL TEXT Abstract: Reaction Time and Movement Time After Embryonic Cell Implantation in Parkinson Disease Paul H. Gordon, Qiping Yu, Clifford Qualls, Hal Winfield, Sandra Dillon, Paul E. Greene, Stanley Fahn, Robert E. Breeze, Curt R. Freed, and Seth L. Pullman Arch Neurol. 2004;61:858-861. Background : Embryonic nigral cell implants are a novel treatment for Parkinson disease (PD). Reaction time (RT) and movement time (MT) analysis, validated quantitative measures of premovement neural processing and motor execution, can be used as objective physiological markers of motor performance in PD. Objectives To gauge the change in motor performance in patients with PD who received implants, and to determine whether the physiological findings correlate with clinical outcome measures after transplantation. Design: Double-blind, placebo-controlled trial. Patients Forty patients with levodopa-responsive, Hoehn and Yahr stage III or greater PD. Interventions: Random assignment to embryonic tissue implants or placebo (sham) operation. Main Outcome Measures Combined RT + MT scores measured preoperatively and at 4 and 12 months postoperatively in the “off” state. Results: The difference in mean RT + MT scores between the sham and implant groups was statistically significant (P = .005) and was greatest in those 60 years or older (P = .003). Changes correlated with Unified Parkinson’s Disease Rating Scale off scores at 4 (r = 0.87, P = .001) and 12 (r = 0.75, P = .01) months in those younger than 60 years. There was a significant deterioration in the sham surgery group at 12 months (P = .03) that was thought to be due to worsening in subjects 60 years and older (P<.001). Conclusions: The physiological measures detected significant changes in patients undergoing embryonic nigral cell implants and correlated directly with clinical outcome measures. Comprehensive analyses of RT paradigms can document subtle changes in motor performance over time, making them useful outcome measures in therapeutic trials of PD. These findings support further research into nigral cell implantation for PD. From the Department of Neurology and Clinical Motor Physiology Laboratory, Columbia-Presbyterian Medical Center, New York, NY (Drs Gordon, Yu, Greene, Fahn and Pullman; Mr Winfield; and Ms Dillon); Department of Biostatistics, University of New Mexico, Albuquerque (Dr Qualls); and Departments of Neurosurgery (Dr Breeze), Medicine (Dr Freed), and Pharmacology (Dr Freed), University of Colorado, Denver (Drs Breeze and Freed). RELATED ARTICLES IN ARCHIVES OF NEUROLOGY ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn