Genetic Testing in Deep Brain Stimulation for Parkinson’s Disease – A New Era of Personalized Therapy
Date: May 2025
Prepared by SIC Members: Gian Pal, MD, MS, and Michele Matarazzo, MD
Authors: David Arkadir, MD, PhD, Saar Anis, MD
Editors: Lorraine Kalia, MD, PhD; Daniela Berg, MD, PhD; and Jeffery H. Kordower, PhD
Introduction
Parkinson’s disease (PD) is as heterogeneous as the patients it affects. Today’s standard of care involves tailoring treatment plans based on a comprehensive clinical evaluation—age, lifestyle, cognitive function, symptom profile, and medication response all play vital roles. Yet as medicine moves toward precision approaches, genetic factors are emerging as important variables that could refine, and potentially redefine, how we select and manage patients for advanced therapies, such as deep brain stimulation (DBS).
The discussion below delves into the potential role of genetics—especially GBA1 and LRRK2 variants—in DBS decision-making for PD patients.
Until now, clinicians have largely remained agnostic to genetic data when recommending DBS.
Individuals with PD carrying pathogenic variants in the GBA1 gene (GBA1-PD) typically experience substantial motor benefit and reduced medication burden after DBS1, 2. However, questions remain about long-term cognitive outcomes. Recent studies have suggested that cognitive outcomes of subthalamic nucleus DBS (STN-DBS) may be suboptimal in people with GBA1-PD2-6. This finding is significant, as carriers of GBA1 mutations—particularly those with severe or homozygous variants—may experience a more aggressive disease course with earlier onset, faster motor decline, more frequent neuropsychiatric complications, and potentially reduced survival.
This discussion below takes a critical look at whether GBA1 status should be integrated into the selection process for DBS, and if so, how. The discussion also contrasts the evidence for LRRK2 mutation carriers, who may fare better with DBS6, 7 and exhibit slower disease progression overall. Ethical questions, the limitations of current evidence, and the pressing need for longitudinal, multicenter studies all take center stage.
As genetic testing is offered to more people with PD, this blog sheds light on the complex but necessary task of incorporating genetic information into DBS decisions—especially in a landscape where therapeutic innovation and patient expectations are rapidly evolving.
1. What do we currently know about the relevance of genetics and genetic testing to DBS for Parkinson’s disease?
Dr. David Arkadir
Recent studies indicate that up to 10% of Parkinson’s disease (PD) patients carry mutations in the GBA1 gene and about 3% in the LRRK2 gene. These mutations are more prevalent in specific populations, such as Ashkenazi Jews, and are often overrepresented among candidates for advanced therapies like DBS. GBA1 mutations, on average, are associated with a more aggressive disease course—greater neuropsychiatric and cognitive complications, faster progression, and increased medication needs. In contrast, LRRK2 mutations are generally associated with a slower progression on average. While short-term outcomes of DBS are positive across genotypes, the concern is whether DBS, particularly in the subthalamic nucleus (STN), could accelerate cognitive decline in GBA1 mutation carriers—a question that remains unresolved.
2. What is the current evidence on DBS outcomes in GBA1 carriers?
Dr. Saar Anis
GBA1 mutation carriers experience similar motor benefits from DBS as non-carriers, including reductions in dyskinesias, motor fluctuations, and medication burden. However, research, including studies by Avenali, Valente, Gian Pal, and Christopher Goetz, shows that these patients tend to have faster cognitive decline post-DBS compared with PD patients without GBA1 mutations. The extent of this decline appears to depend on the severity of the GBA1 variant, with severe or neuronopathic variants associated with greater impairment. GBA1 carriers are also more prone to post-operative complications like orthostatic hypotension and psychosis. Despite these concerns, it is still unclear whether the cognitive decline is caused by DBS or is simply part of the natural disease course, especially due to a lack of randomized controlled trials and well-matched non-DBS comparison groups.
3. Do you routinely test for GBA1 mutations before recommending DBS?
Dr. David Arkadir
Currently, genetic testing for GBA1 is not routinely performed in clinical practice prior to DBS. One reason is the lack of clear actionability—it is uncertain how a positive result should alter the DBS decision if the patient meets traditional criteria such as motor fluctuations and preserved cognition. Nonetheless, in borderline cases—older patients or those with marginal cognitive status—GBA1 status may be considered, as its presence could signal increased risk of post-DBS cognitive decline. LRRK2 positivity, conversely, is more reassuring given its better prognosis. While clinical use remains limited, genetic testing is vital in research to help generate the evidence base needed for future decision-making.
4. Do different GBA1 variants (mild, severe, risk) influence DBS outcomes?
Dr. Saar Anis
This is a pressing but insufficiently explored question. Research should focus more on how variant type influences DBS outcomes. For instance, what are the outcomes for severe variants that may be associated with a more aggressive form of PD? On the other hand, risk variants, while increasing PD risk, may behave differently. While limited, work by Gian Pal has already shown outcome differences between variants, suggesting the need for finer stratification in research. Understanding these distinctions could help personalize DBS recommendations more effectively.
Dr. David Arkadir
There is growing recognition that not all GBA1 variants carry the same clinical impact. Severe variants generally predict worse outcomes, though there are exceptions—such as the E326K variant, which is mild but associated with cognitive issues. However, we are still in the early stages of determining how specific GBA1 mutations should influence DBS decisions, and routine clinical stratification by variant type is not yet feasible.
5. What is known about DBS outcomes in LRRK2 mutation carriers?
Dr. Saar Anis
Current evidence suggests that patients with LRRK2-related PD benefit from DBS similarly to those with idiopathic PD, with strong responses to both DBS and dopaminergic medications. Unlike GBA1, LRRK2 mutations are not associated with increased cognitive or psychiatric complications post-DBS. Some studies even suggest that disease progression is slower than in idiopathic PD, which may translate into longer-term benefit from DBS. However, there is a need for more research, as there are currently no randomized trials in LRRK2 pertaining to DBS, to confirm these findings and identify any variant-specific nuances.
Dr. David Arkadir
I agree that LRRK2 mutation carriers generally have a more straightforward and predictable disease course. The evidence, while not methodologically perfect, supports DBS use in this group. These patients typically enjoy longer-lasting benefits, and the presence of a LRRK2 mutation can be viewed as a reassuring factor when considering DBS.
6. What are the ethical and clinical challenges of integrating genetic testing into DBS decision-making?
Dr. David Arkadir
One of the main ethical challenges is the uncertainty surrounding how to act on genetic findings, particularly GBA1. Physicians face a dilemma—should they test for a gene when they cannot confidently explain the implications to the patient? As clinicians, we must provide a recommendation, even amidst uncertainty, based on our experience and understanding of disease progression. I personally discuss the genetic risks, particularly the potential cognitive concerns in GBA1, but still advise DBS for ideal candidates.
Dr. Saar Anis
I believe the biggest challenge is whether we, as clinicians, are prepared to effectively communicate the significance of genetic findings. Delivering complex genetic information during such a pivotal stage in a patient's care requires both clarity and compassion. It also highlights the need to educate providers to ensure ethical, informed conversations. This is especially important in underserved populations, where access to testing and follow-up may be limited. We must not only discuss the science but also consider how we ethically share this evolving knowledge.
7. What are the most promising research directions in genetics and DBS for PD?
Dr. David Arkadir
Even after decades of DBS use, the long-term strategy for maximizing mobility and preserving cognition remains unclear. The recent introduction of new therapies like continuous levodopa/carbidopa makes it more critical to understand how best to tailor advanced therapies. Long-term, multicenter, methodologically sound studies are needed—for patients with GBA1 mutations, LRRK2 mutations, and other genes—to evaluate therapy options over decades. Only by building a structured, collaborative research framework can we begin to answer these pressing questions.
Dr. Saar Anis
In addition to cohort studies, I see great potential in using AI-driven models to integrate genetic, clinical, and biomarker data to identify patterns we might otherwise miss. This approach could help personalize DBS decisions more accurately. Another exciting area is polygenic risk scores, which may better reflect a patient’s overall risk than any single variant. The interaction between multiple mutations, such as GBA1 and LRRK2, also deserves exploration. The future lies in evaluating the patient as a whole—genetically, clinically, and biologically—to guide truly personalized therapy.
References
1. Artusi CA, Dwivedi AK, Romagnolo A, Pal G, Kauffman M, Mata I, Patel D, Vizcarra JA, Duker A, Marsili L, Cheeran B, Woo D, Contarino MF, Verhagen L, Lopiano L, Espay AJ, Fasano A, Merola A. Association of Subthalamic Deep Brain Stimulation With Motor, Functional, and Pharmacologic Outcomes in Patients With Monogenic Parkinson Disease: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019;2(2):e187800. Epub 2019/02/02. doi: 10.1001/jamanetworkopen.2018.7800. PubMed PMID: 30707228; PMCID: PMC6484599.
2. Angeli A, Mencacci NE, Duran R, Aviles-Olmos I, Kefalopoulou Z, Candelario J, Rusbridge S, Foley J, Pradhan P, Jahanshahi M, Zrinzo L, Hariz M, Wood NW, Hardy J, Limousin P, Foltynie T. Genotype and phenotype in Parkinson's disease: lessons in heterogeneity from deep brain stimulation. Mov Disord. 2013;28(10):1370-5. Epub 2013/07/03. doi: 10.1002/mds.25535. PubMed PMID: 23818421; PMCID: PMC3886301.
3. Avenali M, Zangaglia R, Cuconato G, Palmieri I, Albanese A, Artusi CA, Bozzali M, Calandra-Buonaura G, Cavallieri F, Cilia R, Cocco A, Cogiamanian F, Colucci F, Cortelli P, Di Fonzo A, Eleopra R, Giannini G, Imarisio A, Imbalzano G, Ledda C, Lopiano L, Malaguti MC, Mameli F, Minardi R, Mitrotti P, Monfrini E, Spagnolo F, Tassorelli C, Valentino F, Valzania F, Pacchetti C, Valente EM. Are patients with GBA-Parkinson disease good candidates for deep brain stimulation? A longitudinal multicentric study on a large Italian cohort. J Neurol Neurosurg Psychiatry. 2023. Epub 20231025. doi: 10.1136/jnnp-2023-332387. PubMed PMID: 37879897.
4. Lythe V, Athauda D, Foley J, Mencacci NE, Jahanshahi M, Cipolotti L, Hyam J, Zrinzo L, Hariz M, Hardy J, Limousin P, Foltynie T. GBA-Associated Parkinson's Disease: Progression in a Deep Brain Stimulation Cohort. J Parkinsons Dis. 2017;7(4):635-44. Epub 2017/08/05. doi: 10.3233/JPD-171172. PubMed PMID: 28777757.
5. Pal G, Mangone G, Hill EJ, Ouyang B, Liu Y, Lythe V, Ehrlich D, Saunders-Pullman R, Shanker V, Bressman S, Alcalay RN, Garcia P, Marder KS, Aasly J, Mouradian MM, Link S, Rosenbaum M, Anderson S, Bernard B, Wilson R, Stebbins G, Nichols WC, Welter ML, Sani S, Afshari M, Verhagen L, de Bie RMA, Foltynie T, Hall D, Corvol JC, Goetz CG. Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers. Ann Neurol. 2022;91(3):424-35. Epub 20220125. doi: 10.1002/ana.26302. PubMed PMID: 34984729; PMCID: PMC8857042.
6. Mangone G, Bekadar S, Cormier-Dequaire F, Tahiri K, Welaratne A, Czernecki V, Pineau F, Karachi C, Castrioto A, Durif F, Tranchant C, Devos D, Thobois S, Meissner WG, Navarro MS, Cornu P, Lesage S, Brice A, Welter ML, Corvol JC, contributors/investigators. Early cognitive decline after bilateral subthalamic deep brain stimulation in Parkinson's disease patients with GBA mutations. Parkinsonism Relat Disord. 2020;76:56-62. Epub 2020/09/01. doi: 10.1016/j.parkreldis.2020.04.002. PubMed PMID: 32866938.
7. Rizzone MG, Martone T, Balestrino R, Lopiano L. Genetic background and outcome of Deep Brain Stimulation in Parkinson's disease. Parkinsonism Relat Disord. 2019;64:8-19. Epub 2018/08/20. doi: 10.1016/j.parkreldis.2018.08.006. PubMed PMID: 30121162.