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Original Investigation |

Clinical and Biochemical Differences in Patients Having Parkinson Disease With vs Without GBA Mutations

Lama M. Chahine, MD1; Judy Qiang, BA1; Emily Ashbridge1; James Minger, BA1; Dora Yearout, BS6,7; Stacy Horn, DO1,3; Amy Colcher, MD1,3; Howard I. Hurtig, MD1,3; Virginia M-Y. Lee, PhD2,3,4; Vivianna M. Van Deerlin, MD, PhD2,3,4; James B. Leverenz, MD6,7,8; Andrew D. Siderowf, MD, MSCE5; John Q. Trojanowski, MD, PhD2,3,4; Cyrus P. Zabetian, MD, MS6,7; Alice Chen-Plotkin, MD1,3,4
[+] Author Affiliations
1Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
2Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
3Morris K. Udall Center of Excellence for Parkinson’s Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
4Institute on Aging, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
5Avid Radiopharmaceuticals, Philadelphia, Pennsylvania
6Veterans Affairs Puget Sound Health Care System, University of Washington School of Medicine, Seattle
7Department of Neurology, University of Washington School of Medicine, Seattle
8Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle
JAMA Neurol. 2013;70(7):852-858. doi:10.1001/jamaneurol.2013.1274.
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Importance  Biochemical abnormalities present in GBA (mut/wt) carriers may offer new pathogenetic insights to and potential therapeutic targets in Parkinson disease (PD).

Objective  To determine whether patients having PD with vs without GBA mutations differ in clinical phenotype or plasma protein expression.

Design and Setting  Case-control study of patients having PD with vs without GBA mutations. Clinical characteristics were compared between groups, and biochemical profiling of 40 plasma proteins was performed to identify proteins that differed in expression between groups.

Participants  The discovery cohort included 20 patients having PD with GBA mutations. Clinical characteristics of GBA-associated PD cases were compared with those of 242 patients having PD in whom GBA mutations were excluded by full gene sequencing.

Main Outcome Measures  Biochemical profiling was available for all 20 GBA-associated PD cases, as well as a subset (87 of 242) of the GBA-negative PD cases. The replication cohort included 19 patients having PD with GBA mutations and 41 patients having PD without GBA mutations.

Results  Compared with patients having PD without GBA mutations, patients having PD with GBA mutations were younger at disease onset (P = .04) and were more likely to demonstrate cognitive dysfunction (P = .001). In a multiple regression model that included age, sex, and assay batch as covariates, GBA mutation status was significantly associated with plasma levels of interleukin 8 (P = .001), monocyte chemotactic protein 1 (P = .008), and macrophage inflammatory protein 1α (P = .005). The association between interleukin 8 and GBA mutation status was replicated (P = .03) in a separate cohort of patients having PD with vs without GBA mutations.

Conclusions and Relevance  Patients having PD with GBA mutations have earlier age at disease onset and are more likely to demonstrate cognitive dysfunction. Monocyte-associated inflammatory mediators may be elevated in patients having PD with GBA mutations.

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Figure 1.
Clinical Characteristics in GBA Mutation Carriers Compared With Those Without GBA Mutations

A, Age at onset was significantly younger in patients having Parkinson disease (PD) with heterozygous or homozygous GBA mutations compared with patients having PD without GBA mutations (P = .04, log-rank test). B, Age at diagnosis was also younger in GBA mutation carriers compared with those without GBA mutations (P = .01, log-rank test).

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Figure 2.
Biochemical Differences in GBA Mutation Carriers Compared With Those Without GBA Mutation

A, Mean levels of interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP1), macrophage inflammatory protein 1α (MIP1α), stem cell factor (SCF), and PARC were significantly higher in GBA (mut/wt) and GBA (mut/mut) compared to GBA (wt/wt) in univariate analysis. B, In a multivariate model adjusting for age at plasma draw, sex, and assay batch, IL8, MCP-1, and MIP-1α remained significantly elevated in carriers of GBA mutations with Parkinson disease (PD), but only IL-8 and MCP1 were significantly elevated in GBA (mut/wt) patients with PD compared with GBA (wt/wt) patients with PD. *P < .05; †P < .01.

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Figure 3.
Comparison of Interleukin 8 (IL-8) and Monocyte Chemotactic Protein 1 (MCP1) Levels in Those With vs Without GBA Mutations in the Replication Cohort

The observation that GBA mutation carriers have higher levels of IL-8 was replicated. In contrast, no significant difference in MCP1 levels was observed. Raw values are shown in A, and age-adjusted and sex-adjusted regression models are summarized in B. *P < .05.

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