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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA.|Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA.
authors.forename: Ganqiang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA.|Department of Neurology, Brigham and Women's Hospital, Boston, MA.
authors.forename: Brendon
authors.initials: B
authors.lastname: Boot
authors.affiliation: Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Locascio
authors.affiliation: Department of Medical Genomics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, HZ, The Netherlands.|German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Jansen
authors.affiliation: John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sophie
authors.initials: S
authors.lastname: Winder-Rhodes
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY.
authors.forename: Shirley
authors.initials: S
authors.lastname: Eberly
authors.affiliation: INSERM, Centre for Research in Epidemiology and Population Health, U1018, Epidemiology of ageing and age related diseases, Villejuif, France.|University Paris-Sud, UMRS 1018, Villejuif, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Elbaz
authors.affiliation: Sorbonne Université, Université Pierre et Marie Curie Paris 06 UMR S 1127, Institut National de Santé et en Recherche Médicale U 1127 and Centre d'Investigation Clinique 1422, Centre National de Recherche Scientifique U 7225, Institut du Cerveau et de la Moelle Epinière, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Voyager Therapeutics, Clinical Development, Cambridge, MA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ravina
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jacobus J
authors.initials: JJ
authors.lastname: van Hilten
authors.affiliation: Sorbonne Université, Université Pierre et Marie Curie Paris 06 UMR S 1127, Institut National de Santé et en Recherche Médicale U 1127 and Centre d'Investigation Clinique 1422, Centre National de Recherche Scientifique U 7225, Institut du Cerveau et de la Moelle Epinière, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Cormier-Dequaire
authors.affiliation: Sorbonne Université, Université Pierre et Marie Curie Paris 06 UMR S 1127, Institut National de Santé et en Recherche Médicale U 1127 and Centre d'Investigation Clinique 1422, Centre National de Recherche Scientifique U 7225, Institut du Cerveau et de la Moelle Epinière, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.affiliation: John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: Department of Medical Genomics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, HZ, The Netherlands.|German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Marinus
authors.affiliation: John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Williams-Gray
authors.affiliation: Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA.|Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA.|Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA.|Department of Neurology, Brigham and Women's Hospital, Boston, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Scherzer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D060825:Cognitive Dysfunction / Q000209:etiology / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005776:Gaucher Disease / Q000150:complications / Q000235:genetics*; D005962:Glucosylceramidase / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics*
chemical_list: D005962:Glucosylceramidase