Survival and dementia in GBA-associated Parkinson Disease: The mutation matters

This is really interesting isn't? I know that patients with GBA related PD tend to have a more severe form of Parkinson's and that dementia is common. I had assumed that the dementia was an important reason for shorter survival. The only concern I have is whether it is appropriate to adjust for dementia in the analysis... the problem is that although dementia is associated with the exposure (GBA status) and the outcome (death), it may be on the causal pathway between GBA status and death (which means that it ought not to be considered a confounding factor). I would be interested to see survival presented on two levels (dementia and non-dementia) rather than adjusted analysis....

Ann Neurol. 2016 Sep 15. doi: 10.1002/ana.24777. [Epub ahead of print]

Cilia R, Tunesi S, Marotta G, Cereda E, Siri PsyD C, Tesei S, Zecchinelli A, Canesi M, Mariani CB, Meucci N, Sacilotto G, Zini M, Barichella M, Magnani C, Duga S, Asselta R, Soldà G, Seresini A, Seia M, Pezzoli G, Goldwurm S.

http://onlinelibrary.wiley.com/doi/10.1002/ana.24777/full

Abstract

Objective 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 2764 unrelated consecutive PD patients: 123 GBA-carriers (67 mild-p.N370S, 56 severe mainly p.L444P) and 2641 non-carriers. Brain perfusion and dopamine transporter imaging was analyzed, including Dementia with Lewy Bodies (DLB) as additional control group. Results Multivariable analysis adjusted by gender, age at onset and disease duration attributed to GBA-carriers a greater risk for dementia (HR=3.16, p<0.001) and death (HR=1.85, p=0.002) than non-carriers. When dementia was introduced in the model as 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 non-dopaminergic 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 non-carriers. Neuroimaging features of carriers of mild mutations overlapped with PD non-carriers, while carriers of severe mutations were closer to DLB. Interpretation Survival is reduced in GBA-carriers compared to non-carriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by the 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.