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Ann Neurol. 2016 Nov;80(5):674-685. doi: 10.1002/ana.24781.

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

Author information

1
Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA.
2
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA.
3
Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA.
4
Department of Neurology, Brigham and Women's Hospital, Boston, MA.
5
Department of Neurology, Massachusetts General Hospital, Boston, MA.
6
Department of Medical Genomics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, HZ, The Netherlands.
7
German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany.
8
John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
9
Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY.
10
INSERM, Centre for Research in Epidemiology and Population Health, U1018, Epidemiology of ageing and age related diseases, Villejuif, France.
11
University Paris-Sud, UMRS 1018, Villejuif, France.
12
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.
13
Voyager Therapeutics, Clinical Development, Cambridge, MA.
14
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.

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.

PMID:
27717005
PMCID:
PMC5244667
DOI:
10.1002/ana.24781
[Indexed for MEDLINE]
Free PMC Article

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