title: Robust graft survival and normalized dopaminergic innervation do not obligate recovery in a Parkinson disease patient.
abstract: OBJECTIVE
  The main goal of dopamine cell replacement therapy in Parkinson disease (PD) is to provide clinical benefit mediated by graft survival with nigrostriatal reinnervation. We report a dichotomy between graft structure and clinical function in a patient dying 16 years following fetal nigral grafting.
  
  
  METHODS
  A 55-year-old levodopa-responsive woman with PD received bilateral putaminal fetal mesencephalic grafts as part of an NIH-sponsored double-blind sham-controlled trial. The patient never experienced clinical benefit, and her course was complicated by the development of graft-related dyskinesias. Fluorodopa positron emission tomography demonstrated significant increases postgrafting bilaterally. She experienced worsening of parkinsonism with severe dyskinesias, and underwent subthalamic nucleus deep brain stimulation 8 years after grafting. She died 16 years after transplantation.
  
  
  RESULTS
  Postmortem analyses confirmed the diagnosis of PD and demonstrated >300,000 tyrosine hydroxylase (TH)-positive grafted cells per side with normalized striatal TH-immunoreactive fiber innervation and bidirectional synaptic connectivity. Twenty-seven percent and 17% of grafted neurons were serine 129-phosphorylated α-synuclein positive in the left and right putamen, respectively.
  
  
  CONCLUSIONS
  These findings represent the largest number of surviving dopamine neurons and the densest and most widespread graft-mediated striatal dopamine reinnervation following a transplant procedure reported to date. Despite this, clinical recovery was not observed. Furthermore, the grafts were associated with a form of dyskinesias that resembled diphasic dyskinesia and persisted in the off-medication state. We hypothesize that the grafted cells produced a low level of dopamine sufficient to cause a levodopa-independent continuous form of diphasic dyskinesias, but insufficient to provide an antiparkinsonian benefit. ANN NEUROL 2017;81:46-57.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.|Van Andel Institute, Grand Rapids, MI.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kordower
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Goetz
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Neuroscience Research Australia and Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nicholson
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
authors.forename: Timothy F
authors.identifier: http://orcid.org/0000-0003-0533-7967
authors.initials: TF
authors.lastname: Musial
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
authors.forename: David J
authors.initials: DJ
authors.lastname: Marmion
authors.affiliation: Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: A Jon
authors.initials: AJ
authors.lastname: Stoessl
authors.affiliation: Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Vesna
authors.initials: V
authors.lastname: Sossi
authors.affiliation: Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Freeman
authors.affiliation: Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY.
authors.forename: C Warren
authors.initials: CW
authors.lastname: Olanow
mesh_terms: D016380:Brain Tissue Transplantation; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D006085:Graft Survival; D006801:Humans; D008636:Mesencephalon / Q000637:transplantation*; D008875:Middle Aged; D010300:Parkinson Disease / Q000601:surgery*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase