Brain Advance Access published online on February 11, 2004
Brain, doi:10.1093/brain/awh102
© 2004 by Guarantors of Brain
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Article
1 Pacific Parkinson’s Research Centre, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Division of Neurology, Hospital Arquitecto Marcide, 15405 Ferrol (A Coruña), Spain
* Corresponding author. E-mail: rfuente{at}medynet.com.
Received 12 January 2003
; revised 29 September 2003
; accepted 12 December 2003
Levodopa-treated Parkinson’s disease is often complicated by the occurrence of motor fluctuations, which can be predictable (‘wearing-off’) or unpredictable (‘on-off’). In contrast, untreated dopa-responsive dystonia (DRD) is usually characterized by predictable diurnal fluctuation. The pathogenesis of motor fluctuations in treated Parkinson’s disease and diurnal fluctuation in untreated DRD is poorly understood. We have developed a mathematical model indicating that all these fluctuations in motor function can be explained by presynaptic mechanisms. The model is predicated upon the release of dopamine being subject to probabilistic variations in the quantity of dopamine released by exocytosis of vesicles. Specifically, we propose that the concentration of intravesicular dopamine undergoes dynamic changes according to a log-normal distribution that is associated with different probabilities of release failure. Changes in two parameters, (i) the proportion of vesicles that undergo exocytosis per unit of time and (ii) the proportion of dopamine subject to re-uptake from the synapse, allowed us to model different curves of levodopa response, for the same degree of nigrostriatal damage in Parkinson’s disease. The model predicts the following periods of levodopa clinical benefit: 4 h for stable responders, 3 h for wearing-off fluctuators, and 1.5 h for on-off fluctuators. The model also predicts that diurnal fluctuation in untreated DRD should occur some 8 h after getting up in the morning. All these results fit well with clinical observations. Additionally, we calculated the probability of obtaining a second ON period after a single dose of levodopa in Parkinson’s disease (the ‘yo-yoing’ phenomenon). The model shows that the yo-yoing phenomenon depends on how fast the curve crosses the threshold that separates ON and OFF states, which explains why this phenomenon is virtually exclusive to patients with on-off fluctuations. The model supports the idea that presynaptic mechanisms play a key role in both short-duration and long-duration responses encountered in Parkinson’s disease. Dyskinesias may also be explained by the same mechanisms.
Keywords: dopamine release; vesicle; probability; motor fluctuations; Parkinson’s disease
Presynaptic mechanisms of motor fluctuations in Parkinson’s disease: a probabilistic model
2 Pacific Parkinson’s Research Centre, University of British Columbia, Vancouver, BC V6T 2B5, Canada
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Carlsson, M. Carta, A. Munoz, B. Mattsson, C. Winkler, D. Kirik, and A. Bjorklund Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration Brain, February 1, 2009; 132(2): 319 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Munoz, Q. Li, F. Gardoni, E. Marcello, C. Qin, T. Carlsson, D. Kirik, M. Di Luca, A. Bjorklund, E. Bezard, et al. Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia Brain, December 1, 2008; 131(12): 3380 - 3394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Tarsy, D. K. Simon, and J. Eric Ahlskog BEATING A DEAD HORSE: DOPAMINE AND PARKINSON DISEASE Neurology, November 11, 2008; 71(20): 1651 - 1652. [Full Text] [PDF]
|
|
|
|
|
|
J. Lee, W.-M. Zhu, D. Stanic, D. I. Finkelstein, M. H. Horne, J. Henderson, A. J. Lawrence, L. O'Connor, D. Tomas, J. Drago, et al. Sprouting of dopamine terminals and altered dopamine release and uptake in Parkinsonian dyskinaesia Brain, June 1, 2008; 131(6): 1574 - 1587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. Rommelfanger, G. L. Edwards, K. G. Freeman, L. C. Liles, G. W. Miller, and D. Weinshenker Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice PNAS, August 21, 2007; 104(34): 13804 - 13809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Carta, T. Carlsson, D. Kirik, and A. Bjorklund Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats Brain, July 1, 2007; 130(7): 1819 - 1833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Linazasoro Pathophysiology of Motor Complications in Parkinson Disease: Postsynaptic Mechanisms Are Crucial Arch Neurol, January 1, 2007; 64(1): 137 - 140. [Full Text] [PDF]
|
|
|
|
|
|
R. de la Fuente-Fernandez Presynaptic Mechanisms of Motor Complications in Parkinson Disease Arch Neurol, January 1, 2007; 64(1): 141 - 143. [Full Text] [PDF]
|
|
|
|
|
|
V. Sossi, R. de la Fuente-Fernandez, M. Schulzer, J. Adams, and J. Stoessl Age-related differences in levodopa dynamics in Parkinson's: implications for motor complications Brain, April 1, 2006; 129(4): 1050 - 1058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. de la Fuente-Fernandez, V. Sossi, Z. Huang, S. Furtado, J.-Q. Lu, D. B. Calne, T. J. Ruth, and A. J. Stoessl Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias Brain, December 1, 2004; 127(12): 2747 - 2754. [Abstract] [Full Text] [PDF]
|
|