Presynaptic mechanisms of motor fluctuations in Parkinson's disease: a probabilistic model.
Identifieur interne : 001283 ( PubMed/Checkpoint ); précédent : 001282; suivant : 001284Presynaptic mechanisms of motor fluctuations in Parkinson's disease: a probabilistic model.
Auteurs : Raúl De La Fuente-Fernández [Canada] ; Michael Schulzer ; Edwin Mak ; Donald B. Calne ; A Jon StoesslSource :
- Brain : a journal of neurology [ 0006-8950 ] ; 2004.
English descriptors
- KwdEn :
- Antiparkinson Agents (adverse effects), Biological Clocks, Circadian Rhythm, Dopamine (metabolism), Dopamine Agents (adverse effects), Dyskinesia, Drug-Induced (etiology), Dyskinesia, Drug-Induced (physiopathology), Dystonia (etiology), Dystonia (physiopathology), Humans, Levodopa (adverse effects), Models, Statistical, Parkinson Disease (complications), Parkinson Disease (drug therapy), Parkinson Disease (physiopathology), Presynaptic Terminals (physiology), Synaptic Vesicles (metabolism).
- MESH :
- chemical , adverse effects : Antiparkinson Agents, Dopamine Agents, Levodopa.
- chemical , metabolism : Dopamine.
- complications : Parkinson Disease.
- drug therapy : Parkinson Disease.
- etiology : Dyskinesia, Drug-Induced, Dystonia.
- metabolism : Synaptic Vesicles.
- physiology : Presynaptic Terminals.
- physiopathology : Dyskinesia, Drug-Induced, Dystonia, Parkinson Disease.
- Biological Clocks, Circadian Rhythm, Humans, Models, Statistical.
Abstract
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.
DOI: 10.1093/brain/awh102
PubMed: 14960500
Affiliations:
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Calne</name></author><author><name sortKey="Stoessl, A Jon" sort="Stoessl, A Jon" uniqKey="Stoessl A" first="A Jon" last="Stoessl">A Jon Stoessl</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2004">2004</date><idno type="RBID">pubmed:14960500</idno><idno type="pmid">14960500</idno><idno type="doi">10.1093/brain/awh102</idno><idno type="wicri:Area/PubMed/Corpus">001355</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001355</idno><idno type="wicri:Area/PubMed/Curation">001355</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001355</idno><idno type="wicri:Area/PubMed/Checkpoint">001355</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001355</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Presynaptic mechanisms of motor fluctuations in Parkinson's disease: a probabilistic model.</title><author><name sortKey="De La Fuente Fernandez, Raul" sort="De La Fuente Fernandez, Raul" uniqKey="De La Fuente Fernandez R" first="Raúl" last="De La Fuente-Fernández">Raúl De La Fuente-Fernández</name><affiliation wicri:level="1"><nlm:affiliation>Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC V6T 2B5, Canada. rfuente@medynet.com</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC V6T 2B5</wicri:regionArea><wicri:noRegion>BC V6T 2B5</wicri:noRegion></affiliation></author><author><name sortKey="Schulzer, Michael" sort="Schulzer, Michael" uniqKey="Schulzer M" first="Michael" last="Schulzer">Michael Schulzer</name></author><author><name sortKey="Mak, Edwin" sort="Mak, Edwin" uniqKey="Mak E" first="Edwin" last="Mak">Edwin Mak</name></author><author><name sortKey="Calne, Donald B" sort="Calne, Donald B" uniqKey="Calne D" first="Donald B" last="Calne">Donald B. Calne</name></author><author><name sortKey="Stoessl, A Jon" sort="Stoessl, A Jon" uniqKey="Stoessl A" first="A Jon" last="Stoessl">A Jon Stoessl</name></author></analytic><series><title level="j">Brain : a journal of neurology</title><idno type="ISSN">0006-8950</idno><imprint><date when="2004" type="published">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiparkinson Agents (adverse effects)</term><term>Biological Clocks</term><term>Circadian Rhythm</term><term>Dopamine (metabolism)</term><term>Dopamine Agents (adverse effects)</term><term>Dyskinesia, Drug-Induced (etiology)</term><term>Dyskinesia, Drug-Induced (physiopathology)</term><term>Dystonia (etiology)</term><term>Dystonia (physiopathology)</term><term>Humans</term><term>Levodopa (adverse effects)</term><term>Models, Statistical</term><term>Parkinson Disease (complications)</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson Disease (physiopathology)</term><term>Presynaptic Terminals (physiology)</term><term>Synaptic Vesicles (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Antiparkinson Agents</term><term>Dopamine Agents</term><term>Levodopa</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dopamine</term></keywords><keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>Dystonia</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Synaptic Vesicles</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Presynaptic Terminals</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>Dystonia</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Biological Clocks</term><term>Circadian Rhythm</term><term>Humans</term><term>Models, Statistical</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">14960500</PMID><DateCreated><Year>2004</Year><Month>03</Month><Day>26</Day></DateCreated><DateCompleted><Year>2004</Year><Month>05</Month><Day>20</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">0006-8950</ISSN><JournalIssue CitedMedium="Print"><Volume>127</Volume><Issue>Pt 4</Issue><PubDate><Year>2004</Year><Month>Apr</Month></PubDate></JournalIssue><Title>Brain : a journal of neurology</Title><ISOAbbreviation>Brain</ISOAbbreviation></Journal><ArticleTitle>Presynaptic mechanisms of motor fluctuations in Parkinson's disease: a probabilistic model.</ArticleTitle><Pagination><MedlinePgn>888-99</MedlinePgn></Pagination><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>de la Fuente-Fernández</LastName><ForeName>Raúl</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC V6T 2B5, Canada. rfuente@medynet.com</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schulzer</LastName><ForeName>Michael</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Mak</LastName><ForeName>Edwin</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Calne</LastName><ForeName>Donald B</ForeName><Initials>DB</Initials></Author><Author ValidYN="Y"><LastName>Stoessl</LastName><ForeName>A Jon</ForeName><Initials>AJ</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, 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Terminals</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013572" MajorTopicYN="N">Synaptic Vesicles</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>2</Month><Day>13</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2004</Year><Month>5</Month><Day>21</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>2</Month><Day>13</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">14960500</ArticleId><ArticleId IdType="doi">10.1093/brain/awh102</ArticleId><ArticleId IdType="pii">awh102</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Calne, Donald B" sort="Calne, Donald B" uniqKey="Calne D" first="Donald B" last="Calne">Donald B. Calne</name><name sortKey="Mak, Edwin" sort="Mak, Edwin" uniqKey="Mak E" first="Edwin" last="Mak">Edwin Mak</name><name sortKey="Schulzer, Michael" sort="Schulzer, Michael" uniqKey="Schulzer M" first="Michael" last="Schulzer">Michael Schulzer</name><name sortKey="Stoessl, A Jon" sort="Stoessl, A Jon" uniqKey="Stoessl A" first="A Jon" last="Stoessl">A Jon Stoessl</name></noCountry><country name="Canada"><noRegion><name sortKey="De La Fuente Fernandez, Raul" sort="De La Fuente Fernandez, Raul" uniqKey="De La Fuente Fernandez R" first="Raúl" last="De La Fuente-Fernández">Raúl De La Fuente-Fernández</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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