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Survival and dementia in GBA ‐associated Parkinson's disease: T he mutation matters
Author(s) -
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
Publication year - 2016
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24777
Subject(s) - dementia , dementia with lewy bodies , glucocerebrosidase , hazard ratio , parkinson's disease , medicine , genotype , oncology , disease , psychology , genetics , biology , gene , confidence interval
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