title: Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cilia
authors.affiliation: Department of Translational Medicine, Unit of Medical Statistics and Cancer Epidemiology, University of Piemonte Orientale, Novara, Italy.|Center for Cancer Epidemiology and Prevention (CPO), University Hospital "Città della Salute e della Scienza di Torino", Turin, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Tunesi
authors.affiliation: Nuclear Medicine Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Marotta
authors.affiliation: Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cereda
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Siri
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Tesei
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Zecchinelli
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Canesi
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Claudio B
authors.initials: CB
authors.lastname: Mariani
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Meucci
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sacilotto
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Zini
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Barichella
authors.affiliation: Department of Translational Medicine, Unit of Medical Statistics and Cancer Epidemiology, University of Piemonte Orientale, Novara, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Magnani
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy; and Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy; and Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.affiliation: Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy; and Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Soldà
authors.affiliation: Molecular Genetics Laboratory, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Seresini
authors.affiliation: Molecular Genetics Laboratory, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Seia
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.affiliation: Parkinson Institute, ASST "Gaetano Pini-CTO", Milan, Italy.
authors.forename: Stefano
authors.identifier: http://orcid.org/0000-0002-1651-567X
authors.initials: S
authors.lastname: Goldwurm
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D003430:Cross-Sectional Studies; D003704:Dementia / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005962:Glucosylceramidase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D020961:Lewy Body Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D005962:Glucosylceramidase