Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study

Report of three cases

View More View Less
  • 1 Departments of Surgery (Neurosurgery), Medicine (Neurology), Anaesthesia and Gynaecology, Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax; Neural Transplantation Laboratory, Department of Anatomy and Neurobiology, Dalhousie University, Halifax; McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; and Departments of Community Health and Epidemiology, and Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

✓ The main neural transplantation strategy in Parkinson disease (PD) has been focused on reinnervating the striatum. The clinical results reported in patients who receive transplants have been limited and do not justify the use of neural transplantation as a routine therapeutic procedure for PD. Identifying the optimal target for transplantation may be one of the critical factors for optimizing clinical outcomes. Evidence from preclinical studies indicates that simultaneous intrastriatal and intranigral grafts (double grafts) may produce a more complete functional recovery. The authors report the clinical and positron emission tomography (PET) scanning results in three patients enrolled in a safety and feasibility pilot study who received double grafts and who have been followed for up to 13 months posttransplantation.

Patients included in the study had idiopathic PD. All patients underwent detailed assessments before and after surgery, in accordance with the Core Assessment Program for Intracerebral Transplantation. The patients received implants of fetal mesencephalic cell suspensions in the putamen and substantia nigra (SN) bilaterally. There were no intraoperative or perioperative complications. Follow-up PET scans demonstrated an increase in the mean fluorodopa uptake constant values in the putamen and SN 12 months postsurgery. Improvements were also noted in the total Unified Parkinson′s Disease Rating Scale, Hoehn and Yahr, Schwab and England, and pronation/supination scores after transplantation. The authors demonstrate the feasibility of reinnervating the SN and striatum by using a double transplant strategy in humans.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Address reprint requests to: Ivar Mendez, M.D., Division of Neurosurgery, QEII Health Sciences Centre, New Halifax Infirmary, 1796 Summer Street, Room #3806, Halifax, Nova Scotia, Canada B3H 3A7. email: mendez@is.dal.ca.
  • 1.

    Apostolides C, , Sanford E, & Hong M, et al: Glial cell line-derived neurotrophic factor improves intrastriatal graft survival of stored dopaminergic cells. Neuroscience 83:363372, 1998 Apostolides C, Sanford E, Hong M, et al: Glial cell line-derived neurotrophic factor improves intrastriatal graft survival of stored dopaminergic cells. Neuroscience 83:363–372, 1998

    • Search Google Scholar
    • Export Citation
  • 2.

    Baker KA, , Sadi D, & Hong M, et al: Simultaneous intrastriatal and intranigral dopaminergic grafts in the parkinsonian rat model: role of the intranigral graft. J Comp Neurol 426:106116, 2000 Baker KA, Sadi D, Hong M, et al: Simultaneous intrastriatal and intranigral dopaminergic grafts in the parkinsonian rat model: role of the intranigral graft. J Comp Neurol 426:106–116, 2000

    • Search Google Scholar
    • Export Citation
  • 3.

    Brundin P, , Pogarell O, & Hagell P, et al: Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease. Brain 123:13801390, 2000 Brundin P, Pogarell O, Hagell P, et al: Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease. Brain 123:1380–1390, 2000

    • Search Google Scholar
    • Export Citation
  • 4.

    Cheramy A, , Leviel V, & Glowinski J: Dendritic release of dopamine in the substantia nigra. Nature 289:537542, 1981 Cheramy A, Leviel V, Glowinski J: Dendritic release of dopamine in the substantia nigra. Nature 289:537–542, 1981

    • Search Google Scholar
    • Export Citation
  • 5.

    Cheramy A, , Nieoullon A, & Glowinski J: In vivo evidence for a dendritic release of dopamine in cat substantia nigra. Appl Neurophysiol 42:5759, 1979 Cheramy A, Nieoullon A, Glowinski J: In vivo evidence for a dendritic release of dopamine in cat substantia nigra. Appl Neurophysiol 42:57–59, 1979

    • Search Google Scholar
    • Export Citation
  • 6.

    Collins DL, , Neelin P, & Peters TM, et al: Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J Comput Assist Tomogr 18:192205, 1994 Collins DL, Neelin P, Peters TM, et al: Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J Comput Assist Tomogr 18:192–205, 1994

    • Search Google Scholar
    • Export Citation
  • 7.

    Cytel Software Corporation: StateXact 4 for Windows. Statistical Software for Exact Nonparametric Inference. User Manual. Cambridge, MA: Cytel Software, 1999 Cytel Software Corporation: StateXact 4 for Windows. Statistical Software for Exact Nonparametric Inference. User Manual. Cambridge, MA: Cytel Software, 1999

    • Search Google Scholar
    • Export Citation
  • 8.

    Evans AC, , Marrett S, & Torrescorzo J, et al: MRI-PET correlation in three dimensions using a volume-of-interest (VOI) atlas. J Cereb Blood Flow Metab 11:A69A78, 1991 Evans AC, Marrett S, Torrescorzo J, et al: MRI-PET correlation in three dimensions using a volume-of-interest (VOI) atlas. J Cereb Blood Flow Metab 11:A69–A78, 1991

    • Search Google Scholar
    • Export Citation
  • 9.

    Fahn S, & Elton RL, Members of the UPDRS Development Committee: Unified Parkinson's Disease Rating Scale, in Fahn S, , Marsden CD, & Goldstein M, et al (eds): Recent Developments in Parkinson's Disease, ed 2. New York: Macmillian, 1987, pp 153 163, pp 293–304 Fahn S, Elton RL, Members of the UPDRS Development Committee: Unified Parkinson's Disease Rating Scale, in Fahn S, Marsden CD, Goldstein M, et al (eds): Recent Developments in Parkinson's Disease, ed 2. New York: Macmillian, 1987, pp 153–163, pp 293–304

    • Search Google Scholar
    • Export Citation
  • 10.

    Freed CR, , Breeze RE, & Rosenberg NL, et al: Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med 327:15491555, 1992 Freed CR, Breeze RE, Rosenberg NL, et al: Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med 327:1549–1555, 1992

    • Search Google Scholar
    • Export Citation
  • 11.

    Freed CR, , Greene PE, & Breeze RE, et al: Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 344:710719, 2001 Freed CR, Greene PE, Breeze RE, et al: Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 344:710–719, 2001

    • Search Google Scholar
    • Export Citation
  • 12.

    Freeman TB: From transplants to gene therapy for Parkinson's disease. Exp Neurol 144:4750, 1997 Freeman TB: From transplants to gene therapy for Parkinson's disease. Exp Neurol 144:47–50, 1997

    • Search Google Scholar
    • Export Citation
  • 13.

    Freeman TB, , Olanow CW, & Hauser RA, et al: Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease. Ann Neurol 38:379388, 1995 Freeman TB, Olanow CW, Hauser RA, et al: Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease. Ann Neurol 38:379–388, 1995

    • Search Google Scholar
    • Export Citation
  • 14.

    Gauchy C, , Kemel ML, & Desban M, et al: The role of dopamine released from distal and proximal dendrites of nigrostriatal dopaminergic neurons in the control of GABA transmission in the thalamic nucleus ventralis medialis in the cat. Neuroscience 22:935946, 1987 Gauchy C, Kemel ML, Desban M, et al: The role of dopamine released from distal and proximal dendrites of nigrostriatal dopaminergic neurons in the control of GABA transmission in the thalamic nucleus ventralis medialis in the cat. Neuroscience 22:935–946, 1987

    • Search Google Scholar
    • Export Citation
  • 15.

    Hagell P, , Schrag A, & Piccini P, et al: Sequential bilateral transplantation in Parkinson's disease: effects of the second graft. Brain 122:11211132, 1999 Hagell P, Schrag A, Piccini P, et al: Sequential bilateral transplantation in Parkinson's disease: effects of the second graft. Brain 122:1121–1132, 1999

    • Search Google Scholar
    • Export Citation
  • 16.

    Hauser RA, , Freeman TB, & Snow BJ, et al: Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch Neurol 56:179187, 1999 Hauser RA, Freeman TB, Snow BJ, et al: Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch Neurol 56:179–187, 1999

    • Search Google Scholar
    • Export Citation
  • 17.

    Hoehn MM, & Yahr MD: Parkinsonism: onset, progression and mortality. Neurology 17:427442, 1967 Hoehn MM, Yahr MD: Parkinsonism: onset, progression and mortality. Neurology 17:427–442, 1967

    • Search Google Scholar
    • Export Citation
  • 18.

    Jackson EA, & Kelly PH: Role of nigral dopamine in amphetamine-induced locomotor activity. Brain Res 278:366369, 1983 Jackson EA, Kelly PH: Role of nigral dopamine in amphetamine-induced locomotor activity. Brain Res 278:366–369, 1983

    • Search Google Scholar
    • Export Citation
  • 19.

    Kordower JH, , Freeman TB, & Olanow CW: Neuropathology of fetal nigral grafts in patients with Parkinson's disease. Mov Disord 13 (Suppl 1):8895, 1998 Kordower JH, Freeman TB, Olanow CW: Neuropathology of fetal nigral grafts in patients with Parkinson's disease. Mov Disord 13 (Suppl 1):88–95, 1998

    • Search Google Scholar
    • Export Citation
  • 20.

    Kordower JH, , Freeman TB, & Snow BJ, et al: Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N Engl J Med 332:11181124, 1995 Kordower JH, Freeman TB, Snow BJ, et al: Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N Engl J Med 332:1118–1124, 1995

    • Search Google Scholar
    • Export Citation
  • 21.

    Langston JW, , Widner H, & Goetz CG, et al: Core assessment program for intracerebral transplantations (CAPIT). Move Disord 7:213, 1992 Langston JW, Widner H, Goetz CG, et al: Core assessment program for intracerebral transplantations (CAPIT). Move Disord 7:2–13, 1992

    • Search Google Scholar
    • Export Citation
  • 22.

    Leenders KL, , Salmon EP, & Tyrrell P, et al: The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease. Arch Neurol 47:12901298, 1990 Leenders KL, Salmon EP, Tyrrell P, et al: The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease. Arch Neurol 47:1290–1298, 1990

    • Search Google Scholar
    • Export Citation
  • 23.

    Lindvall O: Neural transplantation: can we improve the symptomatic relief? Adv Neurol 80:635640, 1999 Lindvall O: Neural transplantation: can we improve the symptomatic relief? Adv Neurol 80:635–640, 1999

    • Search Google Scholar
    • Export Citation
  • 24.

    Lindvall O, , Brundin P, & Widner H, et al: Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 247:574577, 1990 Lindvall O, Brundin P, Widner H, et al: Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 247:574–577, 1990

    • Search Google Scholar
    • Export Citation
  • 25.

    Lindvall O, , Sawle G, & Widner H, et al: Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease. Ann Neurol 35:172180, 1994 Lindvall O, Sawle G, Widner H, et al: Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease. Ann Neurol 35:172–180, 1994

    • Search Google Scholar
    • Export Citation
  • 26.

    Mehta V, , Hong M, & Spears J, et al: Enhancement of graft survival and sensorimotor behavioral recovery in rats undergoing transplantation with dopaminergic cells exposed to glial cell line-derived neurotrophic factor. J Neurosurg 88:10881095, 1998 Mehta V, Hong M, Spears J, et al: Enhancement of graft survival and sensorimotor behavioral recovery in rats undergoing transplantation with dopaminergic cells exposed to glial cell line-derived neurotrophic factor. J Neurosurg 88:1088–1095, 1998

    • Search Google Scholar
    • Export Citation
  • 27.

    Mehta V, , Spears J, & Mendez I: Neural transplantation in Parkinson's disease. Can J Neurol Sci 24:292301, 1997 Mehta V, Spears J, Mendez I: Neural transplantation in Parkinson's disease. Can J Neurol Sci 24:292–301, 1997

    • Search Google Scholar
    • Export Citation
  • 28.

    Mendez I, , Baker KA, & Hong M: Simultaneous intrastriatal and intranigral grafting (double grafts) in the rat model of Parkinson's disease. Brain Res Brain Res Rev 32:328339, 2000 Mendez I, Baker KA, Hong M: Simultaneous intrastriatal and intranigral grafting (double grafts) in the rat model of Parkinson's disease. Brain Res Brain Res Rev 32:328–339, 2000

    • Search Google Scholar
    • Export Citation
  • 29.

    Mendez I, , Dagher A, & Hong, M, et al: Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line—derived neurotrophic factor in patients with Parkinson's disease. J Neurosurg 92:863869, 2000 Mendez I, Dagher A, Hong, M, et al: Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line—derived neurotrophic factor in patients with Parkinson's disease. J Neurosurg 92:863–869, 2000

    • Search Google Scholar
    • Export Citation
  • 30.

    Mendez I, & Hong M: Reconstruction of the striato-nigro-striatal circuitry by simultaneous double dopaminergic grafts: a tracer study using fluorogold and horseradish peroxidase. Brain Res 778:194205, 1997 Mendez I, Hong M: Reconstruction of the striato-nigro-striatal circuitry by simultaneous double dopaminergic grafts: a tracer study using fluorogold and horseradish peroxidase. Brain Res 778:194–205, 1997

    • Search Google Scholar
    • Export Citation
  • 31.

    Mendez I, , Hong M, & Smith S, et al: Neural transplantation cannula and microinjector system: experimental and clinical experience. Technical note. J Neurosurg 92:493499, 2000 Mendez I, Hong M, Smith S, et al: Neural transplantation cannula and microinjector system: experimental and clinical experience. Technical note. J Neurosurg 92:493–499, 2000

    • Search Google Scholar
    • Export Citation
  • 32.

    Mendez I, , Sadi D, & Hong M: Reconstruction of the nigrostriatal pathway by simultaneous intrastriatal and intranigral dopaminergic transplants. J Neurosci 16:72167227, 1996 Mendez I, Sadi D, Hong M: Reconstruction of the nigrostriatal pathway by simultaneous intrastriatal and intranigral dopaminergic transplants. J Neurosci 16:7216–7227, 1996

    • Search Google Scholar
    • Export Citation
  • 33.

    Nikkhah G, , Bentlage C, & Cunningham MG, et al: Intranigral fetal dopamine grafts induce behavioral compensation in the rat Parkinson model. J Neurosci 14:34493461, 1994 Nikkhah G, Bentlage C, Cunningham MG, et al: Intranigral fetal dopamine grafts induce behavioral compensation in the rat Parkinson model. J Neurosci 14:3449–3461, 1994

    • Search Google Scholar
    • Export Citation
  • 34.

    Olanow CW, , Kordower JH, & Freeman TB: Fetal nigral transplantation as a therapy for Parkinson's disease. Trends Neurosci 19:102109, 1996 Olanow CW, Kordower JH, Freeman TB: Fetal nigral transplantation as a therapy for Parkinson's disease. Trends Neurosci 19:102–109, 1996

    • Search Google Scholar
    • Export Citation
  • 35.

    Olsson M, , Nikkhah G, & Bentlage C, et al: Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J Neurosci 15:38633875, 1995 Olsson M, Nikkhah G, Bentlage C, et al: Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J Neurosci 15:3863–3875, 1995

    • Search Google Scholar
    • Export Citation
  • 36.

    Patlak CS, & Blasberg RG: Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 5:584590, 1985 Patlak CS, Blasberg RG: Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 5:584–590, 1985

    • Search Google Scholar
    • Export Citation
  • 37.

    Peschanski M, , Defer G, & N'Guyen JP, et al: Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson's disease following intrastriatal transplantation of foetal ventral mesencephalon. Brain 117:487499, 1994 Peschanski M, Defer G, N'Guyen JP, et al: Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson's disease following intrastriatal transplantation of foetal ventral mesencephalon. Brain 117:487–499, 1994

    • Search Google Scholar
    • Export Citation
  • 38.

    Piccini P, , Brooke DJ, & Bjorklund A, et al: Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient. Nat Neurosci 2:11371140, 1999 Piccini P, Brooke DJ, Bjorklund A, et al: Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient. Nat Neurosci 2:1137–1140, 1999

    • Search Google Scholar
    • Export Citation
  • 39.

    Robertson GS, & Robertson HA: Evidence that L-dopa-induced rotational behavior is dependent on both striatal and nigral mechanisms. J Neurosci 9:33263331, 1989 Robertson GS, Robertson HA: Evidence that L-dopa-induced rotational behavior is dependent on both striatal and nigral mechanisms. J Neurosci 9:3326–3331, 1989

    • Search Google Scholar
    • Export Citation
  • 40.

    Robertson HA: Dopamine receptor interactions: some implications for the treatment of Parkinson's disease. Trends Neurosci 15:201206, 1992 Robertson HA: Dopamine receptor interactions: some implications for the treatment of Parkinson's disease. Trends Neurosci 15:201–206, 1992

    • Search Google Scholar
    • Export Citation
  • 41.

    Schwab R, & England AC Jr: Projection technique for evaluating surgery in Parkinson's disease, in Gillingham FJ, & Donaldson IML (eds): Third Symposium on Parkinson's Disease. Edinburgh: E & S Livingstone, 1969, pp 152157 Schwab R, England AC Jr: Projection technique for evaluating surgery in Parkinson's disease, in Gillingham FJ, Donaldson IML (eds): Third Symposium on Parkinson's Disease. Edinburgh: E & S Livingstone, 1969, pp 152–157

    • Search Google Scholar
    • Export Citation
  • 42.

    Starr PA, , Wichmann T, & van Horne C, et al: Intranigral transplantation of fetal substantia nigra allograft in the hemiparkinsonian rhesus monkey. Cell Transplant 8:3745, 1999 Starr PA, Wichmann T, van Horne C, et al: Intranigral transplantation of fetal substantia nigra allograft in the hemiparkinsonian rhesus monkey. Cell Transplant 8:37–45, 1999

    • Search Google Scholar
    • Export Citation
  • 43.

    Vingerhoets FJG, , Schulzer M, & Snow BJ: Reproducibility of the fluorodopa positron emission tomography indices in Parkinson's disease. Mov Disord 9 (Suppl 1):119, 1994 (Abstract) Vingerhoets FJG, Schulzer M, Snow BJ: Reproducibility of the fluorodopa positron emission tomography indices in Parkinson's disease. Mov Disord 9 (Suppl 1):119, 1994 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 44.

    Widner H, , Tetrud J, & Rehncrona S, et al: Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. N Engl J Med 327:15561563, 1992 Widner H, Tetrud J, Rehncrona S, et al: Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. N Engl J Med 327:1556–1563, 1992

    • Search Google Scholar
    • Export Citation
  • 45.

    Winkler C, , Bentlage C, & Nikkhah G, et al: Intranigral transplants of GABA-rich striatal tissue induce behavioral recovery in the rat Parkinson model and promote the effects obtained by intrastriatal dopaminergic transplants. Exp Neurol 155:165186, 1999 Winkler C, Bentlage C, Nikkhah G, et al: Intranigral transplants of GABA-rich striatal tissue induce behavioral recovery in the rat Parkinson model and promote the effects obtained by intrastriatal dopaminergic transplants. Exp Neurol 155:165–186, 1999

    • Search Google Scholar
    • Export Citation
  • 46.

    Yurek DM: Intranigral transplants of fetal ventral mesencephalic tissue attenuate D1-agonist-induced rotational behavior. Exp Neurol 143:19, 1997 Yurek DM: Intranigral transplants of fetal ventral mesencephalic tissue attenuate D1-agonist-induced rotational behavior. Exp Neurol 143:1–9, 1997

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 1083 293 18
Full Text Views 486 199 16
PDF Downloads 58 11 0
EPUB Downloads 0 0 0