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Survival and dementia in GBA ‐associated Parkinson's disease: T he mutation matters
Objective The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene ( GBA ). Methods We included 2,764 unrelated consecutive PD patients: 123 GBA carri...
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| Published in: | Annals of neurology 2016-11, Vol.80 (5), p.662-673 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Language: | English |
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| container_title | Annals of neurology |
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| creator | Cilia, Roberto Tunesi, Sara Marotta, Giorgio Cereda, Emanuele Siri, Chiara Tesei, Silvana Zecchinelli, Anna L. Canesi, Margherita Mariani, Claudio B. Meucci, Nicoletta Sacilotto, Giorgio Zini, Michela Barichella, Michela Magnani, Corrado Duga, Stefano Asselta, Rosanna Soldà, Giulia Seresini, Agostino Seia, Manuela Pezzoli, Gianni Goldwurm, Stefano |
| description | Objective
The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (
GBA
).
Methods
We included 2,764 unrelated consecutive PD patients: 123
GBA
carriers (67 mild‐p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group.
Results
Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to
GBA
carriers a greater risk for dementia (hazard ratio [HR] = 3.16;
p
|
| doi_str_mv | 10.1002/ana.24777 |
| format | article |
| fullrecord | <record><control><sourceid>crossref</sourceid><recordid>TN_cdi_crossref_primary_10_1002_ana_24777</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>10_1002_ana_24777</sourcerecordid><originalsourceid>FETCH-LOGICAL-c747-a552b68a70b46a8ff43a70fb30ce4aec0ab96769cae14c4a3158363ad982beec3</originalsourceid><addsrcrecordid>eNot0L1OwzAUhmELgUQpDNyBN8SQchw7dsJWKihIlUAizNGJcyIMjYNstxIbl8A1ciWUn-l7p294GDsVMBMA-QV6nOXKGLPHJqKQIitzVe2zCUitskJIdciOYnwBgEoLmLCnx03Yui2uOfqOdzSQTw6583x5NedfH58Y42gdJur4A4ZX5-PozyLvXCSMdMlr_kx82CRMbvR8wJQoxGN20OM60sn_Tll9c10vbrPV_fJuMV9l1iiTYVHkrS7RQKs0ln2v5K77VoIlhWQB20obXVkkoaxCKYpSaoldVeYtkZVTdv53a8MYY6C-eQtuwPDeCGh-OJodR_PLIb8BNWxUQQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Survival and dementia in GBA ‐associated Parkinson's disease: T he mutation matters</title><source>Wiley</source><creator>Cilia, Roberto ; Tunesi, Sara ; Marotta, Giorgio ; Cereda, Emanuele ; Siri, Chiara ; Tesei, Silvana ; Zecchinelli, Anna L. ; Canesi, Margherita ; Mariani, Claudio B. ; Meucci, Nicoletta ; Sacilotto, Giorgio ; Zini, Michela ; Barichella, Michela ; Magnani, Corrado ; Duga, Stefano ; Asselta, Rosanna ; Soldà, Giulia ; Seresini, Agostino ; Seia, Manuela ; Pezzoli, Gianni ; Goldwurm, Stefano</creator><creatorcontrib>Cilia, Roberto ; Tunesi, Sara ; Marotta, Giorgio ; Cereda, Emanuele ; Siri, Chiara ; Tesei, Silvana ; Zecchinelli, Anna L. ; Canesi, Margherita ; Mariani, Claudio B. ; Meucci, Nicoletta ; Sacilotto, Giorgio ; Zini, Michela ; Barichella, Michela ; Magnani, Corrado ; Duga, Stefano ; Asselta, Rosanna ; Soldà, Giulia ; Seresini, Agostino ; Seia, Manuela ; Pezzoli, Gianni ; Goldwurm, Stefano</creatorcontrib><description>Objective
The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (
GBA
).
Methods
We included 2,764 unrelated consecutive PD patients: 123
GBA
carriers (67 mild‐p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group.
Results
Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to
GBA
carriers a greater risk for dementia (hazard ratio [HR] = 3.16;
p
< 0.001) and death (HR = 1.85;
p
= 0.002) than noncarriers. When dementia was introduced in the model as a time‐dependent covariate, the mortality risk remained greater in carriers (HR = 1.65;
p
= 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination,
GBA
carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (
p
< 0.001), but similar mortality risk. Consistent with clinical data,
GBA
carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB.
Interpretation
Survival is reduced in
GBA
carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with
GBA
mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662–673</description><identifier>ISSN: 0364-5134</identifier><identifier>EISSN: 1531-8249</identifier><identifier>DOI: 10.1002/ana.24777</identifier><language>eng</language><ispartof>Annals of neurology, 2016-11, Vol.80 (5), p.662-673</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c747-a552b68a70b46a8ff43a70fb30ce4aec0ab96769cae14c4a3158363ad982beec3</citedby><cites>FETCH-LOGICAL-c747-a552b68a70b46a8ff43a70fb30ce4aec0ab96769cae14c4a3158363ad982beec3</cites><orcidid>0000-0002-1651-567X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids></links><search><creatorcontrib>Cilia, Roberto</creatorcontrib><creatorcontrib>Tunesi, Sara</creatorcontrib><creatorcontrib>Marotta, Giorgio</creatorcontrib><creatorcontrib>Cereda, Emanuele</creatorcontrib><creatorcontrib>Siri, Chiara</creatorcontrib><creatorcontrib>Tesei, Silvana</creatorcontrib><creatorcontrib>Zecchinelli, Anna L.</creatorcontrib><creatorcontrib>Canesi, Margherita</creatorcontrib><creatorcontrib>Mariani, Claudio B.</creatorcontrib><creatorcontrib>Meucci, Nicoletta</creatorcontrib><creatorcontrib>Sacilotto, Giorgio</creatorcontrib><creatorcontrib>Zini, Michela</creatorcontrib><creatorcontrib>Barichella, Michela</creatorcontrib><creatorcontrib>Magnani, Corrado</creatorcontrib><creatorcontrib>Duga, Stefano</creatorcontrib><creatorcontrib>Asselta, Rosanna</creatorcontrib><creatorcontrib>Soldà, Giulia</creatorcontrib><creatorcontrib>Seresini, Agostino</creatorcontrib><creatorcontrib>Seia, Manuela</creatorcontrib><creatorcontrib>Pezzoli, Gianni</creatorcontrib><creatorcontrib>Goldwurm, Stefano</creatorcontrib><title>Survival and dementia in GBA ‐associated Parkinson's disease: T he mutation matters</title><title>Annals of neurology</title><description>Objective
The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (
GBA
).
Methods
We included 2,764 unrelated consecutive PD patients: 123
GBA
carriers (67 mild‐p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group.
Results
Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to
GBA
carriers a greater risk for dementia (hazard ratio [HR] = 3.16;
p
< 0.001) and death (HR = 1.85;
p
= 0.002) than noncarriers. When dementia was introduced in the model as a time‐dependent covariate, the mortality risk remained greater in carriers (HR = 1.65;
p
= 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination,
GBA
carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (
p
< 0.001), but similar mortality risk. Consistent with clinical data,
GBA
carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB.
Interpretation
Survival is reduced in
GBA
carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with
GBA
mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662–673</description><issn>0364-5134</issn><issn>1531-8249</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNot0L1OwzAUhmELgUQpDNyBN8SQchw7dsJWKihIlUAizNGJcyIMjYNstxIbl8A1ciWUn-l7p294GDsVMBMA-QV6nOXKGLPHJqKQIitzVe2zCUitskJIdciOYnwBgEoLmLCnx03Yui2uOfqOdzSQTw6583x5NedfH58Y42gdJur4A4ZX5-PozyLvXCSMdMlr_kx82CRMbvR8wJQoxGN20OM60sn_Tll9c10vbrPV_fJuMV9l1iiTYVHkrS7RQKs0ln2v5K77VoIlhWQB20obXVkkoaxCKYpSaoldVeYtkZVTdv53a8MYY6C-eQtuwPDeCGh-OJodR_PLIb8BNWxUQQ</recordid><startdate>201611</startdate><enddate>201611</enddate><creator>Cilia, Roberto</creator><creator>Tunesi, Sara</creator><creator>Marotta, Giorgio</creator><creator>Cereda, Emanuele</creator><creator>Siri, Chiara</creator><creator>Tesei, Silvana</creator><creator>Zecchinelli, Anna L.</creator><creator>Canesi, Margherita</creator><creator>Mariani, Claudio B.</creator><creator>Meucci, Nicoletta</creator><creator>Sacilotto, Giorgio</creator><creator>Zini, Michela</creator><creator>Barichella, Michela</creator><creator>Magnani, Corrado</creator><creator>Duga, Stefano</creator><creator>Asselta, Rosanna</creator><creator>Soldà, Giulia</creator><creator>Seresini, Agostino</creator><creator>Seia, Manuela</creator><creator>Pezzoli, Gianni</creator><creator>Goldwurm, Stefano</creator><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0002-1651-567X</orcidid></search><sort><creationdate>201611</creationdate><title>Survival and dementia in GBA ‐associated Parkinson's disease: T he mutation matters</title><author>Cilia, Roberto ; Tunesi, Sara ; Marotta, Giorgio ; Cereda, Emanuele ; Siri, Chiara ; Tesei, Silvana ; Zecchinelli, Anna L. ; Canesi, Margherita ; Mariani, Claudio B. ; Meucci, Nicoletta ; Sacilotto, Giorgio ; Zini, Michela ; Barichella, Michela ; Magnani, Corrado ; Duga, Stefano ; Asselta, Rosanna ; Soldà, Giulia ; Seresini, Agostino ; Seia, Manuela ; Pezzoli, Gianni ; Goldwurm, Stefano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c747-a552b68a70b46a8ff43a70fb30ce4aec0ab96769cae14c4a3158363ad982beec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cilia, Roberto</creatorcontrib><creatorcontrib>Tunesi, Sara</creatorcontrib><creatorcontrib>Marotta, Giorgio</creatorcontrib><creatorcontrib>Cereda, Emanuele</creatorcontrib><creatorcontrib>Siri, Chiara</creatorcontrib><creatorcontrib>Tesei, Silvana</creatorcontrib><creatorcontrib>Zecchinelli, Anna L.</creatorcontrib><creatorcontrib>Canesi, Margherita</creatorcontrib><creatorcontrib>Mariani, Claudio B.</creatorcontrib><creatorcontrib>Meucci, Nicoletta</creatorcontrib><creatorcontrib>Sacilotto, Giorgio</creatorcontrib><creatorcontrib>Zini, Michela</creatorcontrib><creatorcontrib>Barichella, Michela</creatorcontrib><creatorcontrib>Magnani, Corrado</creatorcontrib><creatorcontrib>Duga, Stefano</creatorcontrib><creatorcontrib>Asselta, Rosanna</creatorcontrib><creatorcontrib>Soldà, Giulia</creatorcontrib><creatorcontrib>Seresini, Agostino</creatorcontrib><creatorcontrib>Seia, Manuela</creatorcontrib><creatorcontrib>Pezzoli, Gianni</creatorcontrib><creatorcontrib>Goldwurm, Stefano</creatorcontrib><collection>CrossRef</collection><jtitle>Annals of neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cilia, Roberto</au><au>Tunesi, Sara</au><au>Marotta, Giorgio</au><au>Cereda, Emanuele</au><au>Siri, Chiara</au><au>Tesei, Silvana</au><au>Zecchinelli, Anna L.</au><au>Canesi, Margherita</au><au>Mariani, Claudio B.</au><au>Meucci, Nicoletta</au><au>Sacilotto, Giorgio</au><au>Zini, Michela</au><au>Barichella, Michela</au><au>Magnani, Corrado</au><au>Duga, Stefano</au><au>Asselta, Rosanna</au><au>Soldà, Giulia</au><au>Seresini, Agostino</au><au>Seia, Manuela</au><au>Pezzoli, Gianni</au><au>Goldwurm, Stefano</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Survival and dementia in GBA ‐associated Parkinson's disease: T he mutation matters</atitle><jtitle>Annals of neurology</jtitle><date>2016-11</date><risdate>2016</risdate><volume>80</volume><issue>5</issue><spage>662</spage><epage>673</epage><pages>662-673</pages><issn>0364-5134</issn><eissn>1531-8249</eissn><abstract>Objective
The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (
GBA
).
Methods
We included 2,764 unrelated consecutive PD patients: 123
GBA
carriers (67 mild‐p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group.
Results
Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to
GBA
carriers a greater risk for dementia (hazard ratio [HR] = 3.16;
p
< 0.001) and death (HR = 1.85;
p
= 0.002) than noncarriers. When dementia was introduced in the model as a time‐dependent covariate, the mortality risk remained greater in carriers (HR = 1.65;
p
= 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination,
GBA
carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (
p
< 0.001), but similar mortality risk. Consistent with clinical data,
GBA
carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB.
Interpretation
Survival is reduced in
GBA
carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with
GBA
mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662–673</abstract><doi>10.1002/ana.24777</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-1651-567X</orcidid></addata></record> |
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| source | Wiley |
| title | Survival and dementia in GBA ‐associated Parkinson's disease: T he mutation matters |
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