Objective: To investigate the cognitive outcomes of Deep Brain Stimulation (DBS) in conjunction with the genetic profile of Parkinson´s disease (PD) patients.

Background: There are still many questions with regard to the cognitive impact of DBS in PD patients that remain unanswered.  Thus far, cognitive deterioration after DBS is generally considered to be mild and comprises mainly deficits in verbal fluency, executive functions, attention and information processing speed (1,2). Albeit not conclusive, recent evidence points to a link between glucocerebrosidase (GBA) mutations and a more prominent cognitive decline following DBS (3,4).

Method: Data from 19 studies reporting cognitive outcomes in patients with genetic PD after DBS was pooled within the framework of a meta-analysis using the R and JASP software. Cognitive function was evaluated with the Mattis Dementia Rating Scale (MDRS), Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) scores.

Results: GBA and a-synuclein (SNCA) carriers had worse cognitive outcomes, whereas leucine-rich repeat kinase 2 (LRRK2) carriers exhibited better cognitive functioning compared to other genetic mutations. Yet, cognitive outcomes differed across carriers of distinct variants of the same gene and were influenced by the simultaneous presence of mutations in other genes. Importantly, within the GBA sub-group, the severe variant GBA L444P was associated with the worst cognitive outcome, while the concomitant LRRK2 G2019S mutation mitigated cognitive impairment in GBA carriers.

Conclusion: Genetic status information can assist in clinical decision-making and predict cognitive function following DBS. However, a multidisciplinary assessment on a case-by-case basis is of paramount importance. Identification of genetic variants that are present alongside with polygenic risk scores can contribute to a more reliable risk-stratification.

References: 1. Rački V, Hero M, Rožmarić G, Papić E, Raguž M, Chudy D, Vuletić V. Cognitive Impact of Deep Brain Stimulation in Parkinson’s Disease Patients: A Systematic Review. Front Hum Neurosci. 2022 May 13;16:867055.
2. Bucur M, Papagno C. Deep Brain Stimulation in Parkinson Disease: A Meta-analysis of the Long-term Neuropsychological Outcomes. Neuropsychol Rev. 2023 Jun;33(2):307-346.
3. 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 Mar;91(3):424-435.
4. 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; PARKNET Study Group. 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 Oct 25:jnnp-2023-332387.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cognitive-function-of-patients-with-parkinsons-disease-after-deep-brain-stimulation-a-gene-and-variant-based-approach/