Objective: Our study aims to investigate the influence of GBA gene mutations in the outcomes of DBS in PD through the assessment of motor and nonmotor phenotypes after DBS in a cohort of GBA-PD Portuguese patients.

Background: Mutations in the Glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson’s Disease (PD). PD related with GBA gene mutations (GBA-PD) is associated with a younger age of onset and a more severe motor and cognitive progression. Deep brain stimulation (DBS) is one of the key treatment approaches for PD, nevertheless it is associated with a faster cognitive decline and its impact on GBA-PD patients is not clear.

Method: To investigate post-DBS motor and non-motor phenotypes in our Lisbon Cohort of GBA-PD, we performed a cross sectional and retrospective study comparing GBA-PD vs patients without known mutations (iPD). Patients from both groups had pre- and post-DBS evaluations including MDS-UPDRSIII and MMSE. Post DBS MDS-UPDRS was performed in 4 different treatment conditions concerning ON/OFF medication and  ON/OFF stimulation, in order to better characterize the impact of DBS in the motor phenotype of GBA-PD.

Results: 18 patients were included (8 GBA-PD vs 10 iPD). We identified significantly higher post-DBS MDS-UPDRS III scores in GBA-PD vs iPD (GBA-PD 40.1±9.1 vs iPD 28.8±11.2 (p=0.050)) in StimON/MedON. Nonetheless, DBS was efective in GBA-PD, showing significant motor benefit when comparing StimOFF/MedOFF vs StimON/MedOFF conditions post-DBS (p=0.0260). In post-DBS, there was no significant difference in the MMSE score between GBA-PD and iPD patients. Importantly, 5 out of the 8 (62,5%) of GBA-PD patients presented a post-DBS MMSE ˃27. Our study does not support excluding GBA-PD patients from DBS.

Conclusion: These are preliminary data, and we are currently still assessing further patients, but our current data does not support the exclusion of GBA-PD patients from a therapeutic approach using DBS.

References: Domingo, A., & Klein, C. (2018). Chapter 14 – Genetics of Parkinson disease. In D. H. Geschwind, H. L. Paulson, & C. B. T.-H. of C. N. Klein (Eds.), Neurogenetics, Part I (Vol. 147, pp. 211–227). Elsevier. https://doi.org/https://doi.org/10.1016/B978-0- 444-63233-3.00014-2
Kalia, L. V, & Lang, A. E. (2015). Parkinson’s disease. The Lancet, 386(9996), 896–912. https://doi.org/10.1016/S0140-6736(14)61393-3
Brockmann, K., Srulijes, K., Pflederer, S., Hauser, A.-K., Schulte, C., Maetzler, W., Gasser, T., & Berg, D. (2015). GBA-associated Parkinson’s disease: Reduced survival and more rapid progression in a prospective longitudinal study. Movement Disorders, 30(3), 407–411. https://doi.org/https://doi.org/10.1002/mds.26071
Sidransky, E., Nalls, M. A., Aasly, J. O., Aharon-Peretz, J., Annesi, G., Barbosa, E. R., Bar- Shira, A., Berg, D., Bras, J., Brice, A., Chen, C.-M., Clark, L. N., Condroyer, C., De Marco, E. V, Dürr, A., Eblan, M. J., Fahn, S., Farrer, M. J., Fung, H.-C., … Ziegler, S. G. (2009). Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson’s Disease. New England Journal of Medicine, 361(17), 1651–1661. https://doi.org/10.1056/NEJMoa0901281

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-gba-mutations-in-the-outcomes-of-deep-brain-stimulation-in-parkinsons/