Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in parkinson disease

Marie Y. Davis, Catherine O. Johnson, James B. Leverenz, Daniel Weintraub, John Q. Trojanowski, Alice Chen-Plotkin, Vivianna M. Van Deerlin, Joseph Quinn, Kathryn (Kathy) Chung, Amie Peterson, Liana S. Rosenthal, Ted M. Dawson, Marilyn S. Albert, Jennifer G. Goldman, Glenn T. Stebbins, Bryan Bernard, Zbigniew K. Wszolek, Owen A. Ross, Dennis W. Dickson, David EidelbergPaul J. Mattis, Martin Niethammer, Dora Yearout, Shu Ching Hu, Brenna A. Cholerton, Megan Smith, Ignacio F. Mata, Thomas J. Montine, Karen L. Edwards, Cyrus P. Zabetian

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Importance Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. OBJECTIVE To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. DESIGN, SETTING, AND PARTICIPANTS The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. MAIN OUTCOMES AND MEASURES Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. RESULTS Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95% CI, 1.72-7.58; P =.002), E326K (β = 3.42; 95% CI, 0.66-6.17; P =.02), and GBA variants combined as a single group (β = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95% CI, 0.23-0.53; P =.01) and E326K (β = 0.64; 95% CI, 0.43-0.86; P =.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P =.01) and GBA variant carriers (15 of 39 [38.5%]; P =.04) progressed to mild cognitive impairment or dementia. CONCLUSIONS AND RELEVANCE GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

Original languageEnglish (US)
Pages (from-to)1217-1224
Number of pages8
JournalJAMA Neurology
Volume73
Issue number10
DOIs
StatePublished - Oct 1 2016

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Parkinson Disease
Mutation
Genotype
Tremor
Gait
Movement Disorders
Dementia
Disease Progression
Levodopa
Linear Models
Logistic Models
Outcome Assessment (Health Care)
Education
Cognitive Dysfunction

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Davis, M. Y., Johnson, C. O., Leverenz, J. B., Weintraub, D., Trojanowski, J. Q., Chen-Plotkin, A., ... Zabetian, C. P. (2016). Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in parkinson disease. JAMA Neurology, 73(10), 1217-1224. https://doi.org/10.1001/jamaneurol.2016.2245

Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in parkinson disease. / Davis, Marie Y.; Johnson, Catherine O.; Leverenz, James B.; Weintraub, Daniel; Trojanowski, John Q.; Chen-Plotkin, Alice; Van Deerlin, Vivianna M.; Quinn, Joseph; Chung, Kathryn (Kathy); Peterson, Amie; Rosenthal, Liana S.; Dawson, Ted M.; Albert, Marilyn S.; Goldman, Jennifer G.; Stebbins, Glenn T.; Bernard, Bryan; Wszolek, Zbigniew K.; Ross, Owen A.; Dickson, Dennis W.; Eidelberg, David; Mattis, Paul J.; Niethammer, Martin; Yearout, Dora; Hu, Shu Ching; Cholerton, Brenna A.; Smith, Megan; Mata, Ignacio F.; Montine, Thomas J.; Edwards, Karen L.; Zabetian, Cyrus P.

In: JAMA Neurology, Vol. 73, No. 10, 01.10.2016, p. 1217-1224.

Research output: Contribution to journalArticle

Davis, MY, Johnson, CO, Leverenz, JB, Weintraub, D, Trojanowski, JQ, Chen-Plotkin, A, Van Deerlin, VM, Quinn, J, Chung, KK, Peterson, A, Rosenthal, LS, Dawson, TM, Albert, MS, Goldman, JG, Stebbins, GT, Bernard, B, Wszolek, ZK, Ross, OA, Dickson, DW, Eidelberg, D, Mattis, PJ, Niethammer, M, Yearout, D, Hu, SC, Cholerton, BA, Smith, M, Mata, IF, Montine, TJ, Edwards, KL & Zabetian, CP 2016, 'Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in parkinson disease', JAMA Neurology, vol. 73, no. 10, pp. 1217-1224. https://doi.org/10.1001/jamaneurol.2016.2245
Davis MY, Johnson CO, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A et al. Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in parkinson disease. JAMA Neurology. 2016 Oct 1;73(10):1217-1224. https://doi.org/10.1001/jamaneurol.2016.2245
Davis, Marie Y. ; Johnson, Catherine O. ; Leverenz, James B. ; Weintraub, Daniel ; Trojanowski, John Q. ; Chen-Plotkin, Alice ; Van Deerlin, Vivianna M. ; Quinn, Joseph ; Chung, Kathryn (Kathy) ; Peterson, Amie ; Rosenthal, Liana S. ; Dawson, Ted M. ; Albert, Marilyn S. ; Goldman, Jennifer G. ; Stebbins, Glenn T. ; Bernard, Bryan ; Wszolek, Zbigniew K. ; Ross, Owen A. ; Dickson, Dennis W. ; Eidelberg, David ; Mattis, Paul J. ; Niethammer, Martin ; Yearout, Dora ; Hu, Shu Ching ; Cholerton, Brenna A. ; Smith, Megan ; Mata, Ignacio F. ; Montine, Thomas J. ; Edwards, Karen L. ; Zabetian, Cyrus P. / Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in parkinson disease. In: JAMA Neurology. 2016 ; Vol. 73, No. 10. pp. 1217-1224.
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abstract = "Importance Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. OBJECTIVE To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. DESIGN, SETTING, AND PARTICIPANTS The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. MAIN OUTCOMES AND MEASURES Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. RESULTS Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8{\%}) were women and 507 (69.2{\%}) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95{\%} CI, 1.72-7.58; P =.002), E326K (β = 3.42; 95{\%} CI, 0.66-6.17; P =.02), and GBA variants combined as a single group (β = 4.01; 95{\%} CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95{\%} CI, 0.23-0.53; P =.01) and E326K (β = 0.64; 95{\%} CI, 0.43-0.86; P =.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6{\%}]; P =.01) and GBA variant carriers (15 of 39 [38.5{\%}]; P =.04) progressed to mild cognitive impairment or dementia. CONCLUSIONS AND RELEVANCE GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.",
author = "Davis, {Marie Y.} and Johnson, {Catherine O.} and Leverenz, {James B.} and Daniel Weintraub and Trojanowski, {John Q.} and Alice Chen-Plotkin and {Van Deerlin}, {Vivianna M.} and Joseph Quinn and Chung, {Kathryn (Kathy)} and Amie Peterson and Rosenthal, {Liana S.} and Dawson, {Ted M.} and Albert, {Marilyn S.} and Goldman, {Jennifer G.} and Stebbins, {Glenn T.} and Bryan Bernard and Wszolek, {Zbigniew K.} and Ross, {Owen A.} and Dickson, {Dennis W.} and David Eidelberg and Mattis, {Paul J.} and Martin Niethammer and Dora Yearout and Hu, {Shu Ching} and Cholerton, {Brenna A.} and Megan Smith and Mata, {Ignacio F.} and Montine, {Thomas J.} and Edwards, {Karen L.} and Zabetian, {Cyrus P.}",
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T1 - Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in parkinson disease

AU - Davis, Marie Y.

AU - Johnson, Catherine O.

AU - Leverenz, James B.

AU - Weintraub, Daniel

AU - Trojanowski, John Q.

AU - Chen-Plotkin, Alice

AU - Van Deerlin, Vivianna M.

AU - Quinn, Joseph

AU - Chung, Kathryn (Kathy)

AU - Peterson, Amie

AU - Rosenthal, Liana S.

AU - Dawson, Ted M.

AU - Albert, Marilyn S.

AU - Goldman, Jennifer G.

AU - Stebbins, Glenn T.

AU - Bernard, Bryan

AU - Wszolek, Zbigniew K.

AU - Ross, Owen A.

AU - Dickson, Dennis W.

AU - Eidelberg, David

AU - Mattis, Paul J.

AU - Niethammer, Martin

AU - Yearout, Dora

AU - Hu, Shu Ching

AU - Cholerton, Brenna A.

AU - Smith, Megan

AU - Mata, Ignacio F.

AU - Montine, Thomas J.

AU - Edwards, Karen L.

AU - Zabetian, Cyrus P.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Importance Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. OBJECTIVE To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. DESIGN, SETTING, AND PARTICIPANTS The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. MAIN OUTCOMES AND MEASURES Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. RESULTS Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95% CI, 1.72-7.58; P =.002), E326K (β = 3.42; 95% CI, 0.66-6.17; P =.02), and GBA variants combined as a single group (β = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95% CI, 0.23-0.53; P =.01) and E326K (β = 0.64; 95% CI, 0.43-0.86; P =.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P =.01) and GBA variant carriers (15 of 39 [38.5%]; P =.04) progressed to mild cognitive impairment or dementia. CONCLUSIONS AND RELEVANCE GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

AB - Importance Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. OBJECTIVE To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. DESIGN, SETTING, AND PARTICIPANTS The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. MAIN OUTCOMES AND MEASURES Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. RESULTS Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β = 4.65; 95% CI, 1.72-7.58; P =.002), E326K (β = 3.42; 95% CI, 0.66-6.17; P =.02), and GBA variants combined as a single group (β = 4.01; 95% CI, 1.95-6.07; P = 1.5 × 10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β = 0.38; 95% CI, 0.23-0.53; P =.01) and E326K (β = 0.64; 95% CI, 0.43-0.86; P =.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P =.01) and GBA variant carriers (15 of 39 [38.5%]; P =.04) progressed to mild cognitive impairment or dementia. CONCLUSIONS AND RELEVANCE GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

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