GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease

Ignacio F. Mata, James B. Leverenz, Daniel Weintraub, John Q. Trojanowski, Alice Chen-Plotkin, Vivianna M. Van Deerlin, Beate Ritz, Rebecca Rausch, Stewart A. Factor, Cathy Wood-Siverio, Joseph F. Quinn, Kathryn A. Chung, Amie L. Peterson-Hiller, Jennifer G. Goldman, Glenn T. Stebbins, Bryan Bernard, Alberto J. Espay, Fredy J. Revilla, Johnna Devoto, Liana Isa Shapiro RosenthalTed M Dawson, Marilyn Albert, Debby Tsuang, Haley Huston, Dora Yearout, Shu Ching Hu, Brenna A. Cholerton, Thomas J. Montine, Karen L. Edwards, Cyrus P. Zabetian

Research output: Contribution to journalArticle

Abstract

Background: Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. Methods: We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections. Results: Mutation carriers (n=60; 4.4%) and E326K carriers (n=65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio=5.1; P=9.7×10-6; E326K, odds ratio=6.4; P=5.7×10-7) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc]=9.0×10-4; E326K, Pc=0.036), Trail Making B-A (mutations, Pc=0.018; E326K, Pc=0.018), and Benton Judgment of Line Orientation (mutations, Pc=0.0045; E326K, Pc=0.0013). Conclusions: Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.

Original languageEnglish (US)
Pages (from-to)95-102
Number of pages8
JournalMovement disorders : official journal of the Movement Disorder Society
Volume31
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Parkinson Disease
Mutation
Aptitude
Executive Function
Short-Term Memory
Odds Ratio
Trail Making Test
Verbal Learning
Semantics
Cognition
Dementia
Linear Models
Language
Genotype
Learning
Genes

Keywords

  • Cognition
  • GBA
  • Neuropsychological tests
  • Visuospatial
  • Working memory

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Mata, I. F., Leverenz, J. B., Weintraub, D., Trojanowski, J. Q., Chen-Plotkin, A., Van Deerlin, V. M., ... Zabetian, C. P. (2016). GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society, 31(1), 95-102. https://doi.org/10.1002/mds.26359

GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. / Mata, Ignacio F.; Leverenz, James B.; Weintraub, Daniel; Trojanowski, John Q.; Chen-Plotkin, Alice; Van Deerlin, Vivianna M.; Ritz, Beate; Rausch, Rebecca; Factor, Stewart A.; Wood-Siverio, Cathy; Quinn, Joseph F.; Chung, Kathryn A.; Peterson-Hiller, Amie L.; Goldman, Jennifer G.; Stebbins, Glenn T.; Bernard, Bryan; Espay, Alberto J.; Revilla, Fredy J.; Devoto, Johnna; Rosenthal, Liana Isa Shapiro; Dawson, Ted M; Albert, Marilyn; Tsuang, Debby; Huston, Haley; Yearout, Dora; Hu, Shu Ching; Cholerton, Brenna A.; Montine, Thomas J.; Edwards, Karen L.; Zabetian, Cyrus P.

In: Movement disorders : official journal of the Movement Disorder Society, Vol. 31, No. 1, 01.01.2016, p. 95-102.

Research output: Contribution to journalArticle

Mata, IF, Leverenz, JB, Weintraub, D, Trojanowski, JQ, Chen-Plotkin, A, Van Deerlin, VM, Ritz, B, Rausch, R, Factor, SA, Wood-Siverio, C, Quinn, JF, Chung, KA, Peterson-Hiller, AL, Goldman, JG, Stebbins, GT, Bernard, B, Espay, AJ, Revilla, FJ, Devoto, J, Rosenthal, LIS, Dawson, TM, Albert, M, Tsuang, D, Huston, H, Yearout, D, Hu, SC, Cholerton, BA, Montine, TJ, Edwards, KL & Zabetian, CP 2016, 'GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease', Movement disorders : official journal of the Movement Disorder Society, vol. 31, no. 1, pp. 95-102. https://doi.org/10.1002/mds.26359
Mata, Ignacio F. ; Leverenz, James B. ; Weintraub, Daniel ; Trojanowski, John Q. ; Chen-Plotkin, Alice ; Van Deerlin, Vivianna M. ; Ritz, Beate ; Rausch, Rebecca ; Factor, Stewart A. ; Wood-Siverio, Cathy ; Quinn, Joseph F. ; Chung, Kathryn A. ; Peterson-Hiller, Amie L. ; Goldman, Jennifer G. ; Stebbins, Glenn T. ; Bernard, Bryan ; Espay, Alberto J. ; Revilla, Fredy J. ; Devoto, Johnna ; Rosenthal, Liana Isa Shapiro ; Dawson, Ted M ; Albert, Marilyn ; Tsuang, Debby ; Huston, Haley ; Yearout, Dora ; Hu, Shu Ching ; Cholerton, Brenna A. ; Montine, Thomas J. ; Edwards, Karen L. ; Zabetian, Cyrus P. / GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. In: Movement disorders : official journal of the Movement Disorder Society. 2016 ; Vol. 31, No. 1. pp. 95-102.
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abstract = "Background: Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. Methods: We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections. Results: Mutation carriers (n=60; 4.4{\%}) and E326K carriers (n=65; 4.7{\%}) had a higher prevalence of dementia (mutations, odds ratio=5.1; P=9.7×10-6; E326K, odds ratio=6.4; P=5.7×10-7) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc]=9.0×10-4; E326K, Pc=0.036), Trail Making B-A (mutations, Pc=0.018; E326K, Pc=0.018), and Benton Judgment of Line Orientation (mutations, Pc=0.0045; E326K, Pc=0.0013). Conclusions: Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.",
keywords = "Cognition, GBA, Neuropsychological tests, Visuospatial, Working memory",
author = "Mata, {Ignacio F.} and Leverenz, {James B.} and Daniel Weintraub and Trojanowski, {John Q.} and Alice Chen-Plotkin and {Van Deerlin}, {Vivianna M.} and Beate Ritz and Rebecca Rausch and Factor, {Stewart A.} and Cathy Wood-Siverio and Quinn, {Joseph F.} and Chung, {Kathryn A.} and Peterson-Hiller, {Amie L.} and Goldman, {Jennifer G.} and Stebbins, {Glenn T.} and Bryan Bernard and Espay, {Alberto J.} and Revilla, {Fredy J.} and Johnna Devoto and Rosenthal, {Liana Isa Shapiro} and Dawson, {Ted M} and Marilyn Albert and Debby Tsuang and Haley Huston and Dora Yearout and Hu, {Shu Ching} and Cholerton, {Brenna A.} and Montine, {Thomas J.} and Edwards, {Karen L.} and Zabetian, {Cyrus P.}",
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T1 - GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease

AU - Mata, Ignacio F.

AU - Leverenz, James B.

AU - Weintraub, Daniel

AU - Trojanowski, John Q.

AU - Chen-Plotkin, Alice

AU - Van Deerlin, Vivianna M.

AU - Ritz, Beate

AU - Rausch, Rebecca

AU - Factor, Stewart A.

AU - Wood-Siverio, Cathy

AU - Quinn, Joseph F.

AU - Chung, Kathryn A.

AU - Peterson-Hiller, Amie L.

AU - Goldman, Jennifer G.

AU - Stebbins, Glenn T.

AU - Bernard, Bryan

AU - Espay, Alberto J.

AU - Revilla, Fredy J.

AU - Devoto, Johnna

AU - Rosenthal, Liana Isa Shapiro

AU - Dawson, Ted M

AU - Albert, Marilyn

AU - Tsuang, Debby

AU - Huston, Haley

AU - Yearout, Dora

AU - Hu, Shu Ching

AU - Cholerton, Brenna A.

AU - Montine, Thomas J.

AU - Edwards, Karen L.

AU - Zabetian, Cyrus P.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Background: Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. Methods: We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections. Results: Mutation carriers (n=60; 4.4%) and E326K carriers (n=65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio=5.1; P=9.7×10-6; E326K, odds ratio=6.4; P=5.7×10-7) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc]=9.0×10-4; E326K, Pc=0.036), Trail Making B-A (mutations, Pc=0.018; E326K, Pc=0.018), and Benton Judgment of Line Orientation (mutations, Pc=0.0045; E326K, Pc=0.0013). Conclusions: Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.

AB - Background: Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. Methods: We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at eight sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised), working memory/executive function (Letter-Number Sequencing Test and Trail Making Test A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (MoCA). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni's corrections. Results: Mutation carriers (n=60; 4.4%) and E326K carriers (n=65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio=5.1; P=9.7×10-6; E326K, odds ratio=6.4; P=5.7×10-7) and lower performance on Letter-Number Sequencing (mutations, corrected P[Pc]=9.0×10-4; E326K, Pc=0.036), Trail Making B-A (mutations, Pc=0.018; E326K, Pc=0.018), and Benton Judgment of Line Orientation (mutations, Pc=0.0045; E326K, Pc=0.0013). Conclusions: Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.

KW - Cognition

KW - GBA

KW - Neuropsychological tests

KW - Visuospatial

KW - Working memory

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