Early cognitive decline after bilateral subthalamic deep brain stimulation in Parkinson's disease patients with GBA mutations
Introduction
Deep brain stimulation of the subthalamic nucleus (STN-DBS) is indicated in advanced Parkinson's disease (PD) at the stage of motor fluctuations and dyskinesia. Although STN-DBS has demonstrated its efficacy on quality of life by improving motor complications in these patients, it does not change the course of the disease, and cognitive decline may occur after surgery questioning its benefit/risk ratio in some patients. Follow-up of PD patients treated with STN-DBS treated has revealed levels of 25–31% of dementia after 3–5 years [1,2]. Older age, longer disease duration, and preoperative cognitive impairment have been shown to be risk factors for developing dementia after DBS. Patients with these profiles are thus not recommended for surgery [3]. However, the determinants of cognitive decline post-surgery are not fully understood. The heterogeneity of its progression may also depend on environmental factors, other medical conditions, or different progression profiles related to genetic forms or genetic modifiers of the disease.
Although commonly sporadic, mutations in several genes have been found to cause monogenic forms of PD [4], particularly in the younger population more likely to be offered DBS surgery. The most common mutations responsible for autosomal dominant forms of PD are found in the Leucine-Rich Repeat serine/threonine-protein Kinase 2 (LRRK2) coding gene, whereas mutations in the gene encoding Parkin (PRKN) are the most frequent in autosomal recessive juvenile forms of the disease. Heterozygous mutations in the glucocerebrosidase (GBA) gene have been shown to be the most important genetic risk factor for PD, and GBA mutation is associated with a higher risk of cognitive decline [5,6]. Considering DBS, the motor response was reported to be similar across genotypes and sporadic PD, but only a few case series evaluated long term cognitive outcomes suggesting differences among genotypes [7]. On the other hand, genetic polymorphisms have been associated with different cognitive profiles in PD, such as the Apolipoprotein E-ε4 (ApoE-ε4), Val66Met polymorphisms in the Brain Derived Neurotrophic Factor (BDNF) gene, and H1/H2 haplotype in the Microtubule-Associated Protein Tau (MAPT) gene [8]. However, large cohorts of PD patients undergoing DBS with systematic cognitive assessment and genetic testing are lacking.
The objective of this retrospective study was to investigate the role of genetic factors on early cognitive outcome after STN-DBS in a large cohort of PD patients screened for GBA, LRRK2 and PRKN, PINK1 and DJ-1 mutations, and for Apo-ε4, Val66Met BDNF, and H1/H2 MAPT polymorphisms.
Section snippets
Patients
For this analysis, we used the data from a clinical database collected from all PD patients who consecutively underwent STN-DBS at the Pitié-Salpêtrière Hospital (Paris, France) between April 1997 and April 2009. During this period, all patients underwent a standardized clinical and neuropsychological evaluation before, and one year post surgery. Following our clinical routine guidelines, patients were considered suitable for surgery according to the following criteria: (1) age below 70 years;
Patient population and genotyping
From the 387 patients with PD who underwent preoperative evaluation at the Pitié-Salpêtrière Hospital (Paris, France) from April 1997 to April 2009, 309 received STN-DBS surgery and DNA was available from 246 patients (Supplementary Figure 1). These patients were screened for mutations in LRRK2, GBA, PRKN, PINK1, DJ-1 genes as described in the methods. We found 22 patients (9%) with LRRK2 mutations, and 22 patients (9%) with at least 1 mutation of the GBA gene, two of the latter also had a
Discussion
In our study, cognition was evaluated 12 months after STN-DBS in 208 PD patients including 25 GBA, 22 LRRK2, and 18 PRKN mutation carriers, and 143 patients without mutation. GBA mutation status was the only genetic factor associated with cognitive decline at 12 months, in addition to age at PD onset and baseline MDRS scores. This result is consistent with previous smaller case series with longer follow-up showing a higher risk of dementia in GBA PD patients after DBS [7,18,19]. We show here
Funding
The research leading to these results received funding from the French government program “Investissements d’Avenir” ANR-10-IAIHU-06, the France Parkinson Association, the Fondation de France (FDF), and the Fédération pour la Recherche sur le Cerveau (FRC).
Author's disclosures
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Graziella Mangone reports no disclosures.
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Samir Bekadar reports no disclosures.
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Florence Cormier-Dequaire reports no disclosures.
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Khadija Tahiri reports no disclosures.
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Arlette Welaratne reports no disclosures.
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Virginie Czernecki reports no disclosures.
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Fanny Pineau reports no disclosures.
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Carine Karachi reports speaking honoraria from Medtronic and Boston Scientific and research grants from the Agence Nationale de la Recherche, Michael J Fox Foundation, and Boston Scientific outside of this work.
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Anna
Acknowledgements
The research leading to these results received funding from the French government program “Investissements d’Avenir” ANR-10 - IAIHU-06, the France Parkinson Association, the Fondation de France, the Fédération pour la Recherche sur le Cerveau (FRC). The authors gratefully acknowledge all patients who participated in this study and the DNA and Cell Bank of the ICM for sample preparation.
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2022, Progress in Brain ResearchCitation Excerpt :As deep brain stimulation (DBS) options for PD become increasibly ubiquitous and patients express interet in pursuing surgical options at earlier stages of disease, studies which stratify DBS outcomes with regard to underlying genetic influences and mechanisms will be needed. Mangone et al. (2020) retrospectively analyzed 25 GBA, 18 LRRK2, 22 PRKN, and 143 PD patients without mutations who had undergone STN-DBS. Twelve months following DBS implantation, only the GBA mutation group had experienced a statistically significant change in MDRS scores from a baseline of normal cognitive function when sex, age at onset, disease duration until DBS, ethnicity, and baseline MDRS score were adjusted for (Mangone et al., 2020).
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2022, NeuropharmacologyCitation Excerpt :A meta-analysis reported a higher occurrence of wearing-off and faster motor progression compared to non-carriers (Zhang et al., 2018). Moreover, recent studies suggested increased rate of cognitive decline in GBA-PD patients after deep brain stimulation (Lythe et al., 2017; Mangone et al., 2020). Classification of GBA variants can be taken from GD, where severe variants (e.g. p.L444P, c.84GG, p.V394L) lead to the neuronopathic forms of GD (types 2 and 3) and mild variants (e.g. p.N370S, p.R496H) lead to the non-neuronopathic form of GD (type 1).