Clinical and biochemical differences in patients having Parkinson disease with vs without GBA mutations

Abstract

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.

Figure 1

Clinical characteristics in GBA mutation carriers compared to those without mutation. (A) Age at onset was significantly younger in PD patients with heterozygous or homozygous GBA mutation, compared with PD patients without GBA mutation (log rank p-value=0.041). (B) Age at diagnosis was also younger in GBA mutation carriers compared to those without GBA mutations (log rank p-value=0.013). (C) Consensus clinician determination of cognitive status was more likely to be MCI or dementia in PD patients with GBA mutation (Chi² p-value=0.022). These differences persisted in a multivariate linear regression model adjusting for age at cognitive testing and gender.

Figure 2

Biochemical differences in GBA mutation carriers compared to those without GBA mutation. (A) Mean levels of IL8, MCP1, MIP1α, 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 PD, but only IL8 and MCP-1 were significantly elevated in GBA(mut/wt) PD patients compared to GBA(wt/wt) PD patients. *p<0.05; **p<0.01

Figure 3

Comparison of IL8 and MCP1 levels in those with and without GBA mutation in the replication cohort. The observation that GBA mutation carriers have higher levels of IL8 was replicated. In contrast, no significant difference in MCP1 levels was observed. IL8 and MCP1 levels are expressed in pg/mL, with raw values shown in Panel A and age- and gender-adjusted regression models shown in Panel B.