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

Ignacio F Mata^{1

2}, James B Leverenz³, Daniel Weintraub^{4

5

6}, John Q Trojanowski^{7

8}, Alice Chen-Plotkin⁴, Vivianna M Van Deerlin⁷, Beate Ritz^{9

10

11}, Rebecca Rausch¹¹, Stewart A Factor¹², Cathy Wood-Siverio¹², Joseph F Quinn^{13

14}, Kathryn A Chung^{13

14}, Amie L Peterson-Hiller^{13

14}, Jennifer G Goldman¹⁵, Glenn T Stebbins¹⁵, Bryan Bernard¹⁵, Alberto J Espay¹⁶, Fredy J Revilla^{16

17}, Johnna Devoto¹⁶, Liana S Rosenthal¹⁸, Ted M Dawson^{18

19

20}, Marilyn S Albert¹⁸, Debby Tsuang^{1

21}, Haley Huston^{1

2}, Dora Yearout^{1

2}, Shu-Ching Hu^{1

2}, Brenna A Cholerton^{1

21}, Thomas J Montine²², Karen L Edwards²³, Cyrus P Zabetian^{1

2}

Affiliations

¹ Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
² Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
³ Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁴ Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵ Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶ Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.
⁷ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, California, USA.
¹⁰ Department of Environmental Health Sciences, School of Public Health, University of California Los Angeles, Los Angeles, California, USA.
¹¹ Department of Neurology, University of California Los Angeles, Los Angeles, California, USA.
¹² Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
¹³ Portland Veterans Affairs Medical Center, Portland, Oregon, USA.
¹⁴ Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
¹⁵ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
¹⁶ Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁷ Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
¹⁸ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁰ Solomon H. Snyder Department of Neuroscience and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²¹ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
²² Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
²³ Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, California, USA.

PMID: 26296077
PMCID: PMC4724255
DOI: 10.1002/mds.26359

Multicenter Study

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

Ignacio F Mata et al. Mov Disord. 2016 Jan.

. 2016 Jan;31(1):95-102.

doi: 10.1002/mds.26359. Epub 2015 Aug 21.

Authors

Affiliations

¹ Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
² Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
³ Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁴ Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵ Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶ Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.
⁷ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Department of Epidemiology, School of Public Health, University of California Los Angeles, Los Angeles, California, USA.
¹⁰ Department of Environmental Health Sciences, School of Public Health, University of California Los Angeles, Los Angeles, California, USA.
¹¹ Department of Neurology, University of California Los Angeles, Los Angeles, California, USA.
¹² Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
¹³ Portland Veterans Affairs Medical Center, Portland, Oregon, USA.
¹⁴ Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
¹⁵ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
¹⁶ Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁷ Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
¹⁸ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁰ Solomon H. Snyder Department of Neuroscience and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²¹ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
²² Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
²³ Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, California, USA.

PMID: 26296077
PMCID: PMC4724255
DOI: 10.1002/mds.26359

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: GBA; cognition; neuropsychological tests; visuospatial; working memory.

PubMed Disclaimer

Conflict of interest statement

Financial Disclosure/Conflict of Interest concerning the research related to the manuscript: None

References

1. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson's disease: a population-based, prospective study. J Am Geriatr Soc. 2000;48:938–942. - PubMed
1. Klepac N, Trkulja V, Relja M, Babic T. Is quality of life in non-demented Parkinson's disease patients related to cognitive performance? A clinic-based cross-sectional study. Eur J Neurol. 2008;15:128–133. - PubMed
1. Levy G, Tang MX, Louis ED, et al. The association of incident dementia with mortality in PD. Neurology. 2002;59:1708–1713. - PubMed
1. Aarsland D, Bronnick K, Larsen JP, Tysnes OB, Alves G. Norwegian ParkWest Study G. Cognitive impairment in incident, untreated Parkinson disease: the Norwegian ParkWest study. Neurology. 2009;72:1121–1126. - PubMed
1. Muslimovic D, Post B, Speelman JD, Schmand B. Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology. 2005;65:1239–1245. - PubMed

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical