Robust graft survival and normalized dopaminergic innervation do not obligate recovery in a Parkinson disease patient.

Autor: Kordower JH; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.; Van Andel Institute, Grand Rapids, MI., Goetz CG; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL., Chu Y; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL., Halliday GM; Neuroscience Research Australia and Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia., Nicholson DA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL., Musial TF; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL., Marmion DJ; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL., Stoessl AJ; Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, British Columbia, Canada., Sossi V; Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, British Columbia, Canada., Freeman TB; Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL., Olanow CW; Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY.
Jazyk: angličtina
Zdroj: Annals of neurology [Ann Neurol] 2017 Jan; Vol. 81 (1), pp. 46-57. Date of Electronic Publication: 2017 Jan 06.
DOI: 10.1002/ana.24820
Abstrakt: 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.
Interpretation: 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.
(© 2017 American Neurological Association.)
Databáze: MEDLINE
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