Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers

Gian Pal; Graziella Mangone; Emily J. Hill; Bichun Ouyang; Yuanqing Liu; Vanessa Lythe; Debra Ehrlich; Rachel Saunders-Pullman; Vicki Shanker; Susan Bressman; Roy N. Alcalay; Priscilla Garcia; Karen S. Marder; Jan Aasly; M. Maral Mouradian; Samantha Link; Marc Rosenbaum; Sharlet Anderson; Bryan Bernard; Robert Wilson; Glenn Stebbins; William C. Nichols; Marie Laure Welter; Sepehr Sani; Mitra Afshari; Leo Verhagen; Rob M.A. de Bie; Tom Foltynie; Deborah Hall; Jean Christophe Corvol; Christopher G. Goetz

doi:10.1002/ana.26302

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers

Gian Pal^*, Graziella Mangone, Emily J. Hill, Bichun Ouyang, Yuanqing Liu, Vanessa Lythe, Debra Ehrlich, Rachel Saunders-Pullman, Vicki Shanker, Susan Bressman, Roy N. Alcalay, Priscilla Garcia, Karen S. Marder, Jan Aasly, M. Maral Mouradian, Samantha Link, Marc Rosenbaum, Sharlet Anderson, Bryan Bernard, Robert WilsonGlenn Stebbins, William C. Nichols, Marie Laure Welter, Sepehr Sani, Mitra Afshari, Leo Verhagen, Rob M.A. de Bie, Tom Foltynie, Deborah Hall, Jean Christophe Corvol, Christopher G. Goetz

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

Objective: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. Methods: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. Results: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = −1.80 to −1.18). Interpretation: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435.

Original language	English (US)
Pages (from-to)	424-435
Number of pages	12
Journal	Annals of neurology
Volume	91
Issue number	3
DOIs	https://doi.org/10.1002/ana.26302
State	Published - Mar 2022

Funding

We thank our patients, who inspire us daily and have contributed to this research. 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 NIH, National Institute of Neurological Disorders and Stroke. R.M.A.d.B. received research grants from Medtronic and Lysosomal Therapeutics, paid to the institution. Data used in the preparation of this article were obtained from the Accelerating Medicine Partnership® (AMP®) Parkinson’s Disease (AMP PD) Knowledge Platform. For up‐to‐date information on the study, visit https://www.amp-pd.org . The AMP® PD program is a public‐private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson's (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol‐Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson's Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences. ACCELERATING MEDICINES PARTNERSHIP and AMP are registered service marks of the U.S. Department of Health and Human Services. We thank our patients, who inspire us daily and have contributed to this research. 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 NIH, National Institute of Neurological Disorders and Stroke. R.M.A.d.B. received research grants from Medtronic and Lysosomal Therapeutics, paid to the institution. Data used in the preparation of this article were obtained from the Accelerating Medicine Partnership® (AMP®) Parkinson’s Disease (AMP PD) Knowledge Platform. For up-to-date information on the study, visit https://www.amp-pd.org. The AMP® PD program is a public-private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson's (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol-Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson's Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences. ACCELERATING MEDICINES PARTNERSHIP and AMP are registered service marks of the U.S. Department of Health and Human Services. Parkinson’s Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/policy . The PDBP Investigators have not participated in reviewing the data analysis or content of the manuscript. The LRRK2 Cohort Consortium is coordinated and funded by The Michael J. Fox Foundation for Parkinson’s Research. Data used in preparation of this article were obtained from the MJFF‐sponsored LRRK2 Cohort Consortium (LCC). The LCC Investigators have not participated in reviewing the data analysis or content of the manuscript. For up‐to‐date information on the study, visit https://www.michaeljfox.org/biospecimens .

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/ana.26302

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Pal, G., Mangone, G., Hill, E. J., Ouyang, B., Liu, Y., Lythe, V., Ehrlich, D., Saunders-Pullman, R., Shanker, V., Bressman, S., Alcalay, R. N., Garcia, P., Marder, K. S., Aasly, J., Mouradian, M. M., Link, S., Rosenbaum, M., Anderson, S., Bernard, B., ... Goetz, C. G. (2022). Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers. Annals of neurology, 91(3), 424-435. https://doi.org/10.1002/ana.26302

@article{7aae00cf17f941039cc323e5cd242604,

title = "Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers",

abstract = "Objective: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. Methods: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. Results: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = −1.80 to −1.18). Interpretation: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435.",

author = "Gian Pal and Graziella Mangone and Hill, {Emily J.} and Bichun Ouyang and Yuanqing Liu and Vanessa Lythe and Debra Ehrlich and Rachel Saunders-Pullman and Vicki Shanker and Susan Bressman and Alcalay, {Roy N.} and Priscilla Garcia and Marder, {Karen S.} and Jan Aasly and Mouradian, {M. Maral} and Samantha Link and Marc Rosenbaum and Sharlet Anderson and Bryan Bernard and Robert Wilson and Glenn Stebbins and Nichols, {William C.} and Welter, {Marie Laure} and Sepehr Sani and Mitra Afshari and Leo Verhagen and {de Bie}, {Rob M.A.} and Tom Foltynie and Deborah Hall and Corvol, {Jean Christophe} and Goetz, {Christopher G.}",

note = "Publisher Copyright: {\textcopyright} 2022 American Neurological Association.",

year = "2022",

month = mar,

doi = "10.1002/ana.26302",

language = "English (US)",

volume = "91",

pages = "424--435",

journal = "Annals of neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "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 2022, 'Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers', Annals of neurology, vol. 91, no. 3, pp. 424-435. https://doi.org/10.1002/ana.26302

TY - JOUR

T1 - Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation

T2 - Cognitive Effects in GBA Mutation Carriers

AU - Pal, Gian

AU - Mangone, Graziella

AU - Hill, Emily J.

AU - Ouyang, Bichun

AU - Liu, Yuanqing

AU - Lythe, Vanessa

AU - Ehrlich, Debra

AU - Saunders-Pullman, Rachel

AU - Shanker, Vicki

AU - Bressman, Susan

AU - Alcalay, Roy N.

AU - Garcia, Priscilla

AU - Marder, Karen S.

AU - Aasly, Jan

AU - Mouradian, M. Maral

AU - Link, Samantha

AU - Rosenbaum, Marc

AU - Anderson, Sharlet

AU - Bernard, Bryan

AU - Wilson, Robert

AU - Stebbins, Glenn

AU - Nichols, William C.

AU - Welter, Marie Laure

AU - Sani, Sepehr

AU - Afshari, Mitra

AU - Verhagen, Leo

AU - de Bie, Rob M.A.

AU - Foltynie, Tom

AU - Hall, Deborah

AU - Corvol, Jean Christophe

AU - Goetz, Christopher G.

PY - 2022/3

Y1 - 2022/3

N2 - Objective: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. Methods: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. Results: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = −1.80 to −1.18). Interpretation: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435.

AB - Objective: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. Methods: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. Results: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = −1.80 to −1.18). Interpretation: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435.

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Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers

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