138892 20240321220522.0 10.1002/ana.24781 doi pmid:27717005 pmid pmc:PMC5244667 pmc 0364-5134 ISSN 1531-8249 ISSN altmetric:12138885 altmetric DZNE-2020-05214 English 610 Liu, Ganqiang 0 Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. Hoboken, NJ 2016 Wiley-Blackwell online Crossref Wiley 2016-11-18 print Crossref Wiley 2016-11-01 article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1586181625_18620 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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.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.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.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. 345 - Population Studies and Genetics (POF3-345) G:(DE-HGF)POF3-345 POF3-345 POF III 0 2015-09-01 Crossref http://doi.wiley.com/10.1002/tdm_license_1.1 Dataset connected to CrossRef, PubMed, Glucosylceramidase EC 3.2.1.45 NLM Chemicals Aged MeSH Aged, 80 and over MeSH Cognitive Dysfunction: etiology MeSH Cognitive Dysfunction: genetics MeSH Disease Progression MeSH Female MeSH Gaucher Disease: complications MeSH Gaucher Disease: genetics MeSH Glucosylceramidase: genetics MeSH Humans MeSH Longitudinal Studies MeSH Male MeSH Middle Aged MeSH Parkinson Disease: complications MeSH Parkinson Disease: genetics MeSH Boot, Brendon 1 Locascio, Joseph J 2 Jansen, Iris E P:(DE-2719)2813349 3 dzne Winder-Rhodes, Sophie 4 Eberly, Shirley 5 Elbaz, Alexis 6 Brice, Alexis 7 Ravina, Bernard 8 van Hilten, Jacobus J 9 Cormier-Dequaire, Florence 10 Corvol, Jean-Christophe 11 Barker, Roger A 12 Heutink, Peter P:(DE-2719)2810728 13 dzne Marinus, Johan 14 Williams-Gray, Caroline H 15 Scherzer, Clemens R P:(DE-HGF)0 16 Corresponding author Progression, International Genetics of Parkinson Disease 17 Scherzer, C. 18 Hyman, B. T. 19 Ivinson, A. J. 20 Trisini-Lipsanopoulos, A. 21 Franco, D. 22 Burke, K. 23 Sudarsky, L. R. 24 Hayes, M. T. 25 Umeh, C. C. 26 Growdon, J. H. 27 Schwarzschild, M. A. 28 Hung, A. Y. 29 Flaherty, A. W. 30 Wills, A-M 31 Mejia, N. I. 32 Gomperts, S. N. 33 Khurana, V. 34 Selkoe, D. J. 35 Yi, T. 36 Page, K. 37 Liao, Z. 38 Barker, R. 39 Foltynie, T. 40 Williams-Gray, C. H. 41 Mason, S. 42 Winder-Rhodes, S. 43 Barker, R. 44 Williams-Gray, C. H. 45 Breen, D. 46 Cummins, G. 47 Evans, J. 48 Winder-Rhodes, S. 49 Corvol, J-C 50 Brice, A. 51 Elbaz, A. 52 Mallet, A. 53 Vidailhet, M. 54 Bonnet, A-M 55 Bonnet, C. 56 Grabli, D. 57 Hartmann, A. P:(DE-HGF)0 58 Klebe, S. 59 Lacomblez, L. 60 Mangone, G. 61 Bourdain, F. 62 Brandel, J-P 63 Derkinderen, P. 64 Durif, F. 65 Mesnage, V. 66 Pico, F. 67 Rascol, O. 68 Forlani, S. 69 Lesage, S. 70 Tahiri, K. 71 van Hilten, J. J. 72 Marinus, J. 73 Liao, Z. 74 Page, K. 75 Franco, D. 76 Duong, K. 77 Yi, T. 78 Trisini-Lipsanopoulos, A. 79 Dong, X. 80 Sudarsky, L. R. 81 Hutten, S. J. 82 Amr, S. S. 83 Shoulson, I. 84 Tanner, C. M. 85 Lang, A. E. P:(DE-HGF)0 86 Nalls, M. 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