Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Ganqiang Liu, Brendon Boot, Joseph J. Locascio, Iris E. Jansen, Sophie Winder-Rhodes, Shirley Eberly, Alexis Elbaz, Alexis Brice, Bernard Ravina, Jacobus J. van Hilten, Florence Cormier-Dequaire, Jean Christophe Corvol, Roger A. Barker, Peter Heutink, Johan Marinus, Caroline H. Williams-Gray, Clemens R. Scherzer, C. Scherzer, B. T. Hyman, A. J. Ivinson & 67 others A. Trisini-Lipsanopoulos, D. Franco, K. Burke, L. R. Sudarsky, M. T. Hayes, C. C. Umeh, J. H. Growdon, M. A. Schwarzschild, A. Y. Hung, A. W. Flaherty, A. M. Wills, N. I. Mejia, S. N. Gomperts, V. Khurana, D. J. Selkoe, T. Yi, K. Page, Z. Liao, R. Barker, T. Foltynie, C. H. Williams-Gray, S. Mason, S. Winder-Rhodes, R. Barker, C. H. Williams-Gray, D. Breen, G. Cummins, J. Evans, S. Winder-Rhodes, J. C. Corvol, A. Brice, A. Elbaz, A. Mallet, M. Vidailhet, A. M. Bonnet, C. Bonnet, D. Grabli, A. Hartmann, S. Klebe, L. Lacomblez, G. Mangone, F. Bourdain, J. P. Brandel, P. Derkinderen, F. Durif, V. Mesnage, F. Pico, O. Rascol, S. Forlani, S. Lesage, K. Tahiri, J. J. van Hilten, J. Marinus, Z. Liao, K. Page, D. Franco, K. Duong, T. Yi, A. Trisini-Lipsanopoulos, X. Dong, L. R. Sudarsky, S. J. Hutten, S. S. Amr, I. Shoulson, C. M. Tanner, A. E. Lang, M. A. Nalls

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Objective: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. Methods: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. Results: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance. Interpretation: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685.

Original languageEnglish
Pages (from-to)674-685
Number of pages12
JournalAnnals of Neurology
Volume80
Issue number5
DOIs
Publication statusPublished - 1 Nov 2016

Cite this

Liu, G., Boot, B., Locascio, J. J., Jansen, I. E., Winder-Rhodes, S., Eberly, S., ... Nalls, M. A. (2016). Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. Annals of Neurology, 80(5), 674-685. https://doi.org/10.1002/ana.24781
Liu, Ganqiang ; Boot, Brendon ; Locascio, Joseph J. ; Jansen, Iris E. ; Winder-Rhodes, Sophie ; Eberly, Shirley ; Elbaz, Alexis ; Brice, Alexis ; Ravina, Bernard ; van Hilten, Jacobus J. ; Cormier-Dequaire, Florence ; Corvol, Jean Christophe ; Barker, Roger A. ; Heutink, Peter ; Marinus, Johan ; Williams-Gray, Caroline H. ; Scherzer, Clemens R. ; Scherzer, C. ; Hyman, B. T. ; Ivinson, A. J. ; Trisini-Lipsanopoulos, A. ; Franco, D. ; Burke, K. ; Sudarsky, L. R. ; Hayes, M. T. ; Umeh, C. C. ; Growdon, J. H. ; Schwarzschild, M. A. ; Hung, A. Y. ; Flaherty, A. W. ; Wills, A. M. ; Mejia, N. I. ; Gomperts, S. N. ; Khurana, V. ; Selkoe, D. J. ; Yi, T. ; Page, K. ; Liao, Z. ; Barker, R. ; Foltynie, T. ; Williams-Gray, C. H. ; Mason, S. ; Winder-Rhodes, S. ; Barker, R. ; Williams-Gray, C. H. ; Breen, D. ; Cummins, G. ; Evans, J. ; Winder-Rhodes, S. ; Corvol, J. C. ; Brice, A. ; Elbaz, A. ; Mallet, A. ; Vidailhet, M. ; Bonnet, A. M. ; Bonnet, C. ; Grabli, D. ; Hartmann, A. ; Klebe, S. ; Lacomblez, L. ; Mangone, G. ; Bourdain, F. ; Brandel, J. P. ; Derkinderen, P. ; Durif, F. ; Mesnage, V. ; Pico, F. ; Rascol, O. ; Forlani, S. ; Lesage, S. ; Tahiri, K. ; van Hilten, J. J. ; Marinus, J. ; Liao, Z. ; Page, K. ; Franco, D. ; Duong, K. ; Yi, T. ; Trisini-Lipsanopoulos, A. ; Dong, X. ; Sudarsky, L. R. ; Hutten, S. J. ; Amr, S. S. ; Shoulson, I. ; Tanner, C. M. ; Lang, A. E. ; Nalls, M. A. / Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. In: Annals of Neurology. 2016 ; Vol. 80, No. 5. pp. 674-685.
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title = "Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's",
abstract = "Objective: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. Methods: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. Results: Overall, 10.3{\%} of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4{\%} of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95{\%} confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7{\%}) had an HR of 3.22 (95{\%} CI, 1.18–8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5{\%} of patients; HR, 1.96; 95{\%} CI, 0.92–4.18) or nonpathogenic risk variants (6.6{\%} of patients; HR, 1.36; 95{\%} CI, 0.89–2.05) did not reach significance. Interpretation: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685.",
author = "Ganqiang Liu and Brendon Boot and Locascio, {Joseph J.} and Jansen, {Iris E.} and Sophie Winder-Rhodes and Shirley Eberly and Alexis Elbaz and Alexis Brice and Bernard Ravina and {van Hilten}, {Jacobus J.} and Florence Cormier-Dequaire and Corvol, {Jean Christophe} and Barker, {Roger A.} and Peter Heutink and Johan Marinus and Williams-Gray, {Caroline H.} and Scherzer, {Clemens R.} and C. Scherzer and Hyman, {B. T.} and Ivinson, {A. J.} and A. Trisini-Lipsanopoulos and D. Franco and K. Burke and Sudarsky, {L. R.} and Hayes, {M. T.} and Umeh, {C. C.} and Growdon, {J. H.} and Schwarzschild, {M. A.} and Hung, {A. Y.} and Flaherty, {A. W.} and Wills, {A. M.} and Mejia, {N. I.} and Gomperts, {S. N.} and V. Khurana and Selkoe, {D. J.} and T. Yi and K. Page and Z. Liao and R. Barker and T. Foltynie and Williams-Gray, {C. H.} and S. Mason and S. Winder-Rhodes and R. Barker and Williams-Gray, {C. H.} and D. Breen and G. Cummins and J. Evans and S. Winder-Rhodes and Corvol, {J. C.} and A. Brice and A. Elbaz and A. Mallet and M. Vidailhet and Bonnet, {A. M.} and C. Bonnet and D. Grabli and A. Hartmann and S. Klebe and L. Lacomblez and G. Mangone and F. Bourdain and Brandel, {J. P.} and P. Derkinderen and F. Durif and V. Mesnage and F. Pico and O. Rascol and S. Forlani and S. Lesage and K. Tahiri and {van Hilten}, {J. J.} and J. Marinus and Z. Liao and K. Page and D. Franco and K. Duong and T. Yi and A. Trisini-Lipsanopoulos and X. Dong and Sudarsky, {L. R.} and Hutten, {S. J.} and Amr, {S. S.} and I. Shoulson and Tanner, {C. M.} and Lang, {A. E.} and Nalls, {M. A.}",
year = "2016",
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doi = "10.1002/ana.24781",
language = "English",
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pages = "674--685",
journal = "Annals of Neurology",
issn = "0364-5134",
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Liu, G, Boot, B, Locascio, JJ, Jansen, IE, Winder-Rhodes, S, Eberly, S, Elbaz, A, Brice, A, Ravina, B, van Hilten, JJ, Cormier-Dequaire, F, Corvol, JC, Barker, RA, Heutink, P, Marinus, J, Williams-Gray, CH, Scherzer, CR, Scherzer, C, Hyman, BT, Ivinson, AJ, Trisini-Lipsanopoulos, A, Franco, D, Burke, K, Sudarsky, LR, Hayes, MT, Umeh, CC, Growdon, JH, Schwarzschild, MA, Hung, AY, Flaherty, AW, Wills, AM, Mejia, NI, Gomperts, SN, Khurana, V, Selkoe, DJ, Yi, T, Page, K, Liao, Z, Barker, R, Foltynie, T, Williams-Gray, CH, Mason, S, Winder-Rhodes, S, Barker, R, Williams-Gray, CH, Breen, D, Cummins, G, Evans, J, Winder-Rhodes, S, Corvol, JC, Brice, A, Elbaz, A, Mallet, A, Vidailhet, M, Bonnet, AM, Bonnet, C, Grabli, D, Hartmann, A, Klebe, S, Lacomblez, L, Mangone, G, Bourdain, F, Brandel, JP, Derkinderen, P, Durif, F, Mesnage, V, Pico, F, Rascol, O, Forlani, S, Lesage, S, Tahiri, K, van Hilten, JJ, Marinus, J, Liao, Z, Page, K, Franco, D, Duong, K, Yi, T, Trisini-Lipsanopoulos, A, Dong, X, Sudarsky, LR, Hutten, SJ, Amr, SS, Shoulson, I, Tanner, CM, Lang, AE & Nalls, MA 2016, 'Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's' Annals of Neurology, vol. 80, no. 5, pp. 674-685. https://doi.org/10.1002/ana.24781

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. / Liu, Ganqiang; Boot, Brendon; Locascio, Joseph J.; Jansen, Iris E.; Winder-Rhodes, Sophie; Eberly, Shirley; Elbaz, Alexis; Brice, Alexis; Ravina, Bernard; van Hilten, Jacobus J.; Cormier-Dequaire, Florence; Corvol, Jean Christophe; Barker, Roger A.; Heutink, Peter; Marinus, Johan; Williams-Gray, Caroline H.; Scherzer, Clemens R.; Scherzer, C.; Hyman, B. T.; Ivinson, A. J.; Trisini-Lipsanopoulos, A.; Franco, D.; Burke, K.; Sudarsky, L. R.; Hayes, M. T.; Umeh, C. C.; Growdon, J. H.; Schwarzschild, M. A.; Hung, A. Y.; Flaherty, A. W.; Wills, A. M.; Mejia, N. I.; Gomperts, S. N.; Khurana, V.; Selkoe, D. J.; Yi, T.; Page, K.; Liao, Z.; Barker, R.; Foltynie, T.; Williams-Gray, C. H.; Mason, S.; Winder-Rhodes, S.; Barker, R.; Williams-Gray, C. H.; Breen, D.; Cummins, G.; Evans, J.; Winder-Rhodes, S.; Corvol, J. C.; Brice, A.; Elbaz, A.; Mallet, A.; Vidailhet, M.; Bonnet, A. M.; Bonnet, C.; Grabli, D.; Hartmann, A.; Klebe, S.; Lacomblez, L.; Mangone, G.; Bourdain, F.; Brandel, J. P.; Derkinderen, P.; Durif, F.; Mesnage, V.; Pico, F.; Rascol, O.; Forlani, S.; Lesage, S.; Tahiri, K.; van Hilten, J. J.; Marinus, J.; Liao, Z.; Page, K.; Franco, D.; Duong, K.; Yi, T.; Trisini-Lipsanopoulos, A.; Dong, X.; Sudarsky, L. R.; Hutten, S. J.; Amr, S. S.; Shoulson, I.; Tanner, C. M.; Lang, A. E.; Nalls, M. A.

In: Annals of Neurology, Vol. 80, No. 5, 01.11.2016, p. 674-685.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

AU - Liu, Ganqiang

AU - Boot, Brendon

AU - Locascio, Joseph J.

AU - Jansen, Iris E.

AU - Winder-Rhodes, Sophie

AU - Eberly, Shirley

AU - Elbaz, Alexis

AU - Brice, Alexis

AU - Ravina, Bernard

AU - van Hilten, Jacobus J.

AU - Cormier-Dequaire, Florence

AU - Corvol, Jean Christophe

AU - Barker, Roger A.

AU - Heutink, Peter

AU - Marinus, Johan

AU - Williams-Gray, Caroline H.

AU - Scherzer, Clemens R.

AU - Scherzer, C.

AU - Hyman, B. T.

AU - Ivinson, A. J.

AU - Trisini-Lipsanopoulos, A.

AU - Franco, D.

AU - Burke, K.

AU - Sudarsky, L. R.

AU - Hayes, M. T.

AU - Umeh, C. C.

AU - Growdon, J. H.

AU - Schwarzschild, M. A.

AU - Hung, A. Y.

AU - Flaherty, A. W.

AU - Wills, A. M.

AU - Mejia, N. I.

AU - Gomperts, S. N.

AU - Khurana, V.

AU - Selkoe, D. J.

AU - Yi, T.

AU - Page, K.

AU - Liao, Z.

AU - Barker, R.

AU - Foltynie, T.

AU - Williams-Gray, C. H.

AU - Mason, S.

AU - Winder-Rhodes, S.

AU - Barker, R.

AU - Williams-Gray, C. H.

AU - Breen, D.

AU - Cummins, G.

AU - Evans, J.

AU - Winder-Rhodes, S.

AU - Corvol, J. C.

AU - Brice, A.

AU - Elbaz, A.

AU - Mallet, A.

AU - Vidailhet, M.

AU - Bonnet, A. M.

AU - Bonnet, C.

AU - Grabli, D.

AU - Hartmann, A.

AU - Klebe, S.

AU - Lacomblez, L.

AU - Mangone, G.

AU - Bourdain, F.

AU - Brandel, J. P.

AU - Derkinderen, P.

AU - Durif, F.

AU - Mesnage, V.

AU - Pico, F.

AU - Rascol, O.

AU - Forlani, S.

AU - Lesage, S.

AU - Tahiri, K.

AU - van Hilten, J. J.

AU - Marinus, J.

AU - Liao, Z.

AU - Page, K.

AU - Franco, D.

AU - Duong, K.

AU - Yi, T.

AU - Trisini-Lipsanopoulos, A.

AU - Dong, X.

AU - Sudarsky, L. R.

AU - Hutten, S. J.

AU - Amr, S. S.

AU - Shoulson, I.

AU - Tanner, C. M.

AU - Lang, A. E.

AU - Nalls, M. A.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Objective: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. Methods: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. Results: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance. Interpretation: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685.

AB - Objective: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. Methods: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. Results: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance. Interpretation: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685.

UR - http://www.scopus.com/inward/record.url?scp=84995745476&partnerID=8YFLogxK

U2 - 10.1002/ana.24781

DO - 10.1002/ana.24781

M3 - Article

VL - 80

SP - 674

EP - 685

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 5

ER -