Early DBS Protects Cognition in Genetic Parkinson’s

Summary:

A multi-center international study reveals that the timing of Deep Brain Stimulation (DBS) surgery is the deciding factor in preserving cognitive function for Parkinson’s disease patients carrying a GBA1 mutation. Published in Movement Disorders, researchers analyzed 343 patients across 10 medical centers and identified a critical 7- to 8-year surgical window post-diagnosis. Intervening before this cutoff allowed GBA1 carriers to secure substantial motor relief while delaying severe cognitive decline, whereas late-stage surgery led to accelerated mental deterioration.

Key Facts:

• The GBA1 Timing Window: Parkinson’s patients with the GBA1 mutation who underwent DBS within 7 to 8 years of diagnosis retained cognitive abilities significantly longer than those who received surgery at later stages.
• Genetics-Specific Vulnerability: The surgical timing effect was unique to GBA1 carriers; patients without the genetic mutation showed no difference in post-surgical cognitive outcomes based on when DBS was performed.
• Argument for Early Genetic Screening: Possessing a GBA1 variant should not disqualify patients from DBS; instead, early genetic testing is essential to map the optimal timeline for surgery before the window closes.

Source: Hackensack Meridian Health

Deep Brain Stimulation (DBS) has reshaped modern Parkinson’s disease treatment. By implanting thin electrodes into precise motor hubs and delivering mild electrical pulses from a subcutaneous neurostimulator, DBS acts like a pacemaker for the brain. The rhythmic stimulation overrides chaotic neural firing, offering profound relief from disabling tremors, rigidity, and dyskinesias when standard dopaminergic drugs become inconsistent.

However, clinical decision-making becomes exceedingly fraught when treating patients carrying mutations in the GBA1 gene, the most common known genetic risk factor for Parkinson’s.

Individuals with GBA1-associated Parkinson’s often develop aggressive motor symptoms at a younger age, making them prime candidates for surgical intervention. Yet they are also biologically predisposed to earlier and more severe executive dysfunction and dementia.

This dual profile has fueled an intense clinical controversy: Does DBS surgery accelerate cognitive decline in GBA1 carriers, or is progressive dementia merely an unavoidable natural feature of the genetic mutation itself?

Now, a collaborative study co-led by the Hackensack Meridian Neuroscience Institute at JFK University Medical Center and the Hackensack Meridian School of Medicine provides a definitive answer: The surgery itself does not inherently accelerate cognitive decline, but the surgical timing is paramount.

Published in Movement Disorders, the peer-reviewed journal of the International Parkinson and Movement Disorder Society, the study establishes that performing DBS within a critical early therapeutic window preserves mental faculties while delivering vital motor relief.

“We may be approaching a turning point in how we use deep brain stimulation for Parkinson’s disease,” said co-lead author Gian Pal, M.D., Chief of Neurology and Director of the Movement Disorders Program at Hackensack Meridian Neuroscience Institute at JFK University Medical Center. “For decades, DBS decisions have largely been based on a patient’s symptoms and clinical characteristics. Our research suggests that a patient’s genetics—and importantly, the timing of surgery—may also matter. The future of DBS may not simply be deciding who should receive it, but identifying the right window to intervene for each individual patient. That moves us closer to truly personalized treatment for Parkinson’s disease.”

Tracking Long-Term Outcomes Across 10 Medical Centers

To resolve the timing debate, Dr. Pal and an international team of neuroscientists and neurosurgeons pooled longitudinal clinical and cognitive data from 343 Parkinson’s patients treated across 10 major academic medical centers in the United States and Europe.

The investigators stratified patients by their GBA1 carrier status and categorized them based on whether they underwent DBS surgery early or late in the course of their disease trajectory.

The longitudinal data revealed a clear divergence:

• Late-Stage DBS in GBA1 Carriers: Patients with the GBA1 mutation who delayed DBS until late in disease progression experienced a significantly faster and steeper post-operative decline in memory and executive function.
• Early-Stage DBS in GBA1 Carriers: Patients with the GBA1 mutation who underwent surgery early maintained their cognitive faculties, successfully delaying the onset of significant cognitive impairment while gaining long-term motor control.
• Non-Carriers (Sporadic Parkinson’s): In patients lacking the GBA1 variant, the surgical timing had no measurable impact on long-term cognitive outcomes, confirming that the vulnerability to late-stage surgical timing is specifically driven by the GBA1 genotype.

The 7-to-8-Year Window: Timing Outweighs Mutation Severity

The investigation identified an actionable clinical threshold: intervening within the first seven to eight years following an initial Parkinson’s diagnosis constitutes the critical therapeutic window for GBA1 carriers.

Crucially, the statistical analysis demonstrated that the specific severity of the GBA1 variant (mild versus severe enzymatic loss) did not alter this outcome—surgical timing emerged as the overriding factor dictating cognitive preservation.

The authors caution that a positive GBA1 test should never be used as a reason to exclude a patient from receiving the life-altering benefits of DBS. Instead, it serves as a clinical signal to act decisively.

The findings establish an urgent imperative for universal, early genetic testing across all newly diagnosed Parkinson’s patients. Identifying GBA1 status at onset allows clinical care teams to map a proactive surgical timeline, ensuring patients receive the benefits of neuromodulation before irreversible cognitive pathways take hold.

Funding agency: This work was supported by a grant from the Italian Ministry of Health in the Next Generation EU Program—Piano Nazionale di Ripresa e Resilienza (PNRR)—Mission 6C2–2.1 “Valorizzazione e potenziamento della ricerca biomedica del SSN”—PNRR-MAD-2022-12,376,496, “Neurobiological fingerprinting of Parkinson’s disease to identify trajectories and personalised therapeutic targets from prodromal to advanced disease stages: a clinical, genetic, biochemical and MRI study.” Moreover, this research was supported by the Parkinson Disease Foundation and the National Institute of Neurological Disorders and Stroke K23-NS097625-05. Collection from Mount Sinai was supported by U01-NS094148-01 and U01-NS107016-01A1. The French collection was supported by the program “Investissements d’Avenir” ANR-10-IAIHU-06. Data from the NIH Parkinson’s Clinic were supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Editorial Notes:

• This article was edited by a Neuroscience News editor.
• Journal paper reviewed in full.
• Additional context added by our staff.

About this Neurology and Neuropharmacology Research:

• Media Contact: Seth Augenstein
• Source: Hackensack Meridian Health
• Image Credit: Image credited to Neuroscience News
• Original Research is Open Access: Movement Disorders (Oct 1, 2026). “Timing of Deep Brain Stimulation and Cognitive Trajectories in GBA1-Associated Parkinson’s Disease.” Authors: Evridiki Asimakidou MD, MSc, Micol Avenali MD, PhD, Jan O. Aasly MD, Mitra Afshari MD, MPH, Roy N. Alcalay MD, MS, Sharlet Anderson PhD, Carlo Alberto Artusi MD, Bryan Bernard PhD, Marco Bozzali MD, Susan Bressman MD, Giovanna Calandra-Buonaura MD, Francesco Cavallieri MD, Roberto Cilia MD, Jean-Christoph Corvol MD, PhD, Antoniangela Cocco MD, Rob M.A. de Bie MD, PhD, Debra Ehrlich MD, Roberto Eleopra MD, Thomas Foltynie MD, PhD, Alessio Di Fonzo MD, Giulia Giannini MD, Christopher Goetz MD, Deborah Hall MD, PhD, Joohi Jimenez-Shahed MD, Leonardo Lopiano MD, Vanessa Lythe BM BCh, MSc, Maria Chiara Malaguti MD, Francesca Mameli PsyD, Graziella Mangone MD, PhD, Karen Marder MD, MPH, M. Maral Mouradian MD, Augusto Rini MD, Luisa Sambati MD, Rachel Saunders-Pullman MD, Vicki Lynn Shanker MD, Francesca Spagnolo MD, Marie-Laure Welter MD, PhD, Roberta Zangaglia MD, Gian Pal MD, MS, Enza Maria Valente MD, PhD, PARKNET Study Group.
• DOI: 10.1002/mds.70520

Abstract

Timing of Deep Brain Stimulation and Cognitive Trajectories in GBA1-Associated Parkinson’s Disease

Background

Individuals with Parkinson’s disease (PD) carrying GBA1 variants often develop advanced motor complications that prompt evaluation for deep brain stimulation (DBS). However, concerns about accelerated cognitive decline after DBS in GBA1 carriers complicate clinical decision making. A critical aspect that is increasingly gaining attention is the time at which DBS is performed.

Objective

The objective is to determine how the timing of DBS in relation to PD onset impacts cognitive trajectories across different GBA1 variant classes and in individuals without GBA1 variants.

Methods

A multicenter cohort study across 10 study sites in Europe and the USA was conducted. The study population comprised subjects with (GBA1-Associated Parkinson’s Disease [GBA-PD]) and without GBA1 variants (nonGBA-PD), who were subjected to bilateral subthalamic nucleus (STN)-DBS. The main outcome measure was the Mattis Dementia Rating Scale (MDRS).

Results

A total of 343 individuals (91 GBA-PD and 252 nonGBA-PD) were included in this study. Percentile-based stratification into early and late STN-DBS treatment groups and linear mixed model analyses revealed that GBA-PD patients in the late DBS group had a significantly faster rate of cognitive decline independent of age, with sensitivity analyses identifying the 7- and 8-year cutoffs as the time points with a significant difference between early and late STN-DBS groups in GBA-PD. A negative correlation between MDRS scores and time from disease onset to STN-DBS was observed in GBA-PD, and was not present in nonGBA-PD. Cognitive trajectories were markedly worse in GBA-PD compared to nonGBA-PD, and this pattern was not influenced by the variant type.

Conclusions

In GBA-PD, STN-DBS treatment at later stages is associated with greater risk of cognitive decline. Earlier STN-DBS intervention in GBA-PD may extend the period of improved motor function before the onset of significant cognitive decline. These findings highlight the potential importance of early genetic testing and disease duration when considering STN-DBS in genetically defined PD populations.