期刊
ANNALS OF NEUROLOGY
卷 80, 期 5, 页码 674-685出版社
WILEY-BLACKWELL
DOI: 10.1002/ana.24781
关键词
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资金
- Michael J. Fox Foundation
- NIH [PDBP U01 NS082157, NS050095, NS24778]
- Harvard NeuroDiscovery Center
- U.S. Department of Defense
- M.E.M.O. Hoffman Foundation
- Parkinson's Disease Foundation
- Wellcome Trust
- MRC
- Parkinson's UK
- Cure-PD
- Patrick Berthoud Trust
- Van Geest Foundation
- NIHR
- Assistance Publique Hopitaux de Paris
- French clinical research hospital program-PHRC [AOR08010]
- 0Investissements d'Avenir [ANR-10-IAIHU-06]
- Prinses Beatrix Fonds [WAR05-0120]
- Stichting Alkemade-Keuls
- Stichting ParkinsonFonds
- MRC [G0001067] Funding Source: UKRI
- Medical Research Council [G0001067] Funding Source: researchfish
ObjectiveWe hypothesized that specific mutations in the -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. MethodsA 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. ResultsOverall, 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. InterpretationMutations 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
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