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. Author manuscript; available in PMC: 2014 Jul 1.
Published in final edited form as: JAMA Neurol. 2013 Jul;70(7):852–858. doi: 10.1001/jamaneurol.2013.1274

Clinical and Biochemical Differences in Parkinson’s Patients With and Without GBA Mutations

LM Chahine 1, JK Qiang 1, E Ashbridge 1, J Minger 1, D Yearout 2,3, S Horn 1,4, A Colcher 1,4, H Hurtig 1,4, VM Lee 4,5, VM Van Deerlin 4,5,6, JB Leverenz 3,7, A Siderowf 3,4, JQ Trojanowski 4,5,6, CP Zabetian 2,3, A Chen-Plotkin 1,4
PMCID: PMC3762458  NIHMSID: NIHMS487654  PMID: 23699752

Abstract

Objective

To determine whether Parkinson’s Disease (PD) patients with and without glucocerebrosidase gene (GBA) mutations differ in clinical phenotype or plasma protein expression.

Design

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

Subjects

The discovery cohort included 20 PD patients with GBA mutations. Clinical characteristics for GBA-associated PD cases were compared to those of 242 PD patients in whom GBA mutations were excluded by full gene sequencing; biochemical profiling was available for all 20 GBA-associated PD cases as well as a subset (n=87/242) of the GBA-negative PD cases. The replication cohort included 19 PD patients with and 41 PD patients without GBA mutation.

Results

PD patients with GBA mutations were younger at disease onset (p=0.041) and were more likely to demonstrate cognitive dysfunction compared to those without mutations (p=0.001). In a multiple regression model including age, gender, and assay batch as covariates, GBA mutation status was significantly associated with plasma levels of interleukin-8 (IL8, p=0.001), monocyte chemotactic protein-1 (p=0.008), and macrophage inflammatory protein-1-alpha (p=0.005). The association between IL8 and GBA mutation status was replicated (p=0.025) in a separate cohort of PD patients with and without GBA mutations.

Conclusions

PD patients 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 PD patients with GBA mutations.

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by clinical features of parkinsonism and the pathological finding of neuronal α-synuclein-positive Lewy bodies. A strong association has been established between PD and mutations in the GBA gene1–3, encoding the lysosomal enzyme glucocerebrosidase. Pathogenetic mutations in both alleles of GBA (GBA (mut/mut)) cause the lysosomal storage disorder Gaucher’s disease. Carriers of a single mutant GBA allele (GBA (mut/wt)) are unaffected by Gaucher
s disease. However, recently, heterozygous GBA mutations have been demonstrated to be the most common single gene mutation associated with sporadic PD, occurring 5 times more often in PD patients than in the general population2.

While the underlying reason for the association between GBA mutations and PD is unknown4, a direct mechanistic link between glucocerebrosidase and α-synuclein may exist, since abnormal glucocerebrosidase activity has been shown to impair α-synuclein processing both in vitro and in vivo5,6. Accordingly, biochemical abnormalities present in GBA (mut/wt) carriers may offer new pathophysiological insights and potential therapeutic targets in PD.

In this study, we compared clinical characteristics and levels of 40 plasma proteins in a group of PD patients with and without GBA mutations.

Materials and Methods

Patient Cohorts

This was a case-control study of a group of PD patients with GBA mutations (GBA (mut/wt) and GBA (mut/mut)) and a comparator group of PD patients without GBA mutations (GBA (wt/wt)). Institutional review board approval at all involved institutions was obtained.

The discovery cohort included individuals evaluated at the University of Pennsylvania (UPenn) with a clinical diagnosis of PD based on United Kingdom Brain Bank criteria7. For comparison of clinical characteristics, the discovery cohort consisted of 20 PD patients with GBA mutations and 242 PD patients in which GBA mutations were excluded (see below for mutation screening methodology). For comparison of biochemical characteristics, a convenience subset of these PD patients including 20 PD patients with GBA mutations and 87 GBA (wt/wt) PD patients was used. For both the full discovery cohort, and the subset of 107 patients for whom biochemical profiling was performed, patients were recruited without bias for specific characteristics or prior knowledge of genetic status.

To replicate significant biochemical findings in an independent cohort, plasma samples were obtained from 60 PD patients at the University of Washington (UW), recruited as previously described8. The replication cohort consisted of 17 GBA (mut/wt) PD patients, 2 GBA (mut/mut) PD patients, and 41 GBA (wt/wt) PD patients.

Genetic Screening for GBA mutations

In the UPenn discovery cohort of PD patients, GBA mutations were identified by one of two approaches. For 254 PD patients, long range PCR amplification followed by sequencing of all 11 exons of the GBA gene was conducted as described9 (see supplementary methods). All PD patients with GBA mutations identified in this manner were included as GBA mutation carriers; those without an identified mutation were included in the comparator non-mutation group. For an additional 231 PD patients, screening was performed for only the two most common GBA mutations, N370S and L444P2 (see supplementary methods3,10). All PD patients with GBA mutations identified through the abbreviated-screening technique were included as cases. Because other GBA mutations were not assessed in these 231 individuals, no subjects from this group were included in the comparator group of PD patients without GBA mutation.

In the UW replication cohort of PD patients, GBA mutation status was ascertained by long range PCR amplification followed by sequencing of all 11 exons of the GBA gene9 (see supplementary methods).

Clinical Characterization (Discovery Cohort)

Demographic information, age at time of PD symptom onset (reported by the patient), age at time of diagnosis of PD by a physician, and modified Hoehn and Yahr (H&Y) staging11, 12 of PD were obtained. Cognition was classified as normal cognition, mild cognitive impairment (MCI), or dementia, as determined by consensus clinical determination (see supplementary methods)13, 14.

Biochemical Characterization by Multiplex Immunoassay (Discovery Cohort)

Simultaneous screening of plasma samples from PD patients with and without GBA mutation was initially performed for a commercially available panel of 71 plasma proteins on a multiplex bead-based immunoassay by Rules Based Medicine (RBM, Austin, TX) as previously described15; 40/71 plasma analytes met quality control measures and were included in the analysis (see supplementary methods for sample handling/processing and quality control).

Enzyme-Linked Immunosorbent Assay (Replication Cohort)

Enzyme-linked immunosorbent assay (ELISA) was used to replicate biochemical findings. MCP1 was measured by ELISA (R&D Systems, MN), and IL-8 was measured by ELISA (BD Biosciences, CA), following standard manufacturer instructions. For further details, see supplementary methods.

Statistical Analyses

Survival curve analyses using log rank tests were used to compare age at disease onset and age at PD diagnosis for PD patients with and without GBA mutations. Binomial logistic regression was used to examine the effect of GBA status on cognition, using consensus clinical determination of normal or abnormal cognition (MCI or dementia) as ordinal outcomes. For analyses pertaining to plasma protein levels, levels of the 40 measured plasma proteins were compared in PD patients with and without GBA mutations by Mann-Whitney testing (cutoff for initial screening = two-tailed p≤0.05). Markers identified as nominally significant in this initial screening were then entered into a multivariate linear regression model designating age at plasma draw, sex, and assay batch as covariates.

In the replication cohort, candidate plasma protein levels were compared between PD patients with and without GBA mutations in univariate analysis and with a multivariate model adjusting for age at plasma draw and sex (no adjustment for assay batch, as all samples were assayed simultaneously). Significance was set as a one-tailed p-value≤0.05, since expected directionality was known.

The association between levels of replicated plasma analytes and cognitive function (clinician consensus) was examined through linear regression with age at consensus clinical determination and sex as covariates; an association with motor impairment (modified (H&Y) stage) was assessed using a linear regression model including sex and age at plasma as covariates.

All statistical analyses were performed using the statistical package R, version 2.14.0. R-scripts are available on request.

Results

PD patients with GBA mutations demonstrate earlier age at disease onset and more cognitive impairment

Discovery cohort characteristics are shown in Table 1. Mean age at onset of PD symptoms was younger in PD patients with GBA mutations (n=20; eTable 2), compared with those without GBA mutations (n=242) (59.0 (standard error of the mean (SEM) 2 years) vs. 63.14 (SEM 0.57) years, log rank p=0.041) (Figure 1A). Mean age at PD diagnosis was also younger in patients with GBA mutations, compared with those without GBA mutations (59.39 (SEM 2.1) years vs. 64.68 (SEM 0.55) years, log rank p=0.013, Figure 1B).

Table 1.

Demographic and clinical characteristics of discovery cohort

Entire Discovery Cohort (n=262)
GBA(wt/wt):
GBA(mut/wt) &
GBA(mut/mut) 		242:20
GBA(mut/wt):
GBA(mut/mut) 		17:3
Male:Female Overall
182:80
GBA(wt/wt)
168:74		 GBA(mut/wt)
14:3		 GBA(mut/mut)
0:3
Modified Hoehn and
Yahr Mean Stage 		Overall
2.6
GBA(wt/wt)
2.7		 GBA(mut/wt)
2.3		 GBA(mut/mut)
2.3
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Figure 1.

Figure 1

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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.

Cognitive performance differed between PD patients with and without GBA mutations. Specifically, 15/20 (75%) GBA mutation carriers had a clinical consensus determination of MCI or dementia compared to 105/242 (43%) mutation-negative PD patients (Chi2=7.61; p=0.022, Figure 1C). In a multivariate model adjusting for age at consensus determination and sex, GBA mutation carriers were still more likely to show MCI or dementia (OR=7.65, 95% CI 2.34–25.05, p=0.001); this relationship persisted after adjusting for disease duration at consensus determination and degree of motoric impairment (modified (H&Y) stage) (OR=9.95, 95% CI 2.69–36.87, p=0.001).

PD patients with GBA mutations have higher plasma levels of monocyte-associated inflammatory mediators

In univariate analyses, 6 plasma analytes were associated with presence of GBA mutation, with higher analyte levels among mutation carriers (Figure 2A). These included interleukin-8 (IL8; p=0.008), monocyte chemotactic protein 1/ Chemokine (C-C motif) ligand 2 (MCP-1; p=0.004), macrophage inflammatory protein-1α (MIP1α; p=0.003), macrophage inflammatory protein-1β (MIP1β; p=0.003), stem cell factor (SCF; p=0.021) and Pulmonary and Activation-Regulated Chemokine (PARC; p=0.005). Notably, 5 of these 6 plasma proteins (IL8, MCP-1, MIP1α, SCF, and PARC) were elevated even in GBA (mut/wt) PD patients. Furthermore, plasma analytes differing between PD patients with and without GBA mutations in this initial analysis were highly enriched for monocyte-associated inflammatory mediators. Specifically, of the 40 analytes screened, only 8 are monocyte-associated inflammatory mediators, but 5/6 plasma proteins differentiating GBA-associated PD (IL8, MCP-1, MIP1α, MIP1β, and PARC) fell within this group (Fisher exact test p-value for enrichment = 0.0005). Markers identified as significant in screening were entered into a multivariate model adjusting for age at plasma draw, sex, and assay batch. IL8, MCP-1, and MIP-1α, again enriched for monocyte-associated inflammatory mediators (Fisher exact test p-value = 0.006) remained elevated in carriers of GBA mutations (Figure 2B).

Figure 2.

Figure 2

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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

We next sought to determine whether, in the multivariate model, these differences between GBA mutation carriers and GBA (wt/wt) PD were driven by the 3 GBA (mut/mut) PD patients. Confining our analysis to GBA (mut/wt) (n=17) vs. GBA (wt/wt) (n=87) PD patients only, we found that increases in IL8 (p=0.004) and MCP-1 (p=0.010) persisted in GBA heterozygote mutation carriers, while the apparent increase in MIP-1α levels was primarily due to very high levels in the 3 GBA (mut/mut) PD patients (Figure 2B).

GBA mutation carriers demonstrate increased plasma levels of IL8 in an independent cohort of PD patients

To test the robustness of the finding of elevated IL8 and MCP-1 plasma levels among GBA (mut/wt) PD patients, we evaluated an independent replication cohort (n=19 PD patients with GBA mutations vs. 41 PD patients without GBA mutations) using ELISA as an alternative measurement method.

Despite differences in clinical characteristics between the discovery and replication cohorts (eTable 3), the correlation between GBA mutation status and IL8 levels persisted (p=0.025), with the same directionality, in a multivariate model adjusting for age at plasma draw and gender. Removing the two GBA (mut/mut) individuals and comparing only 17 GBA (mut/wt) to 41 GBA (wt/wt) PD patients, the increase in IL8 levels in GBA (mut/wt) subjects remained significant in univariate analysis (p=0.043, Figure 3A), but lost strict statistical significance in multivariate analysis (p=0.10).

Figure 3.

Figure 3

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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.

We endeavored to determine whether the loss of a significant difference in IL8 levels when analysis was confined to comparing just GBA (mut/wt) to GBA (wt/wt) PD patients was due to loss of power from decreased sample size or from particularly high IL8 plasma levels in GBA (mut/mut) patients. Thus, we randomly sampled 17 of the 19 mutation carriers in the replication cohort 100 times; ∼30% of the time, we obtained a p-value >0.05, suggesting that loss of sample size may account for the observed result.

In contrast to our IL8 findings, we observed no association between GBA mutation status and plasma MCP-1 levels in the replication cohort (Figure 3B). However, this finding is complicated by the fact that MCP-1 levels measured by multiplex immunoassay differed from MCP-1 levels measured by ELISA, despite internal consistency (low coefficient of variation) within each technical platform (eFigure 1).

Elevated interleukin-8 levels are associated with poorer cognition

For the cohort as a whole, higher IL8 levels predicted worse cognitive function in a multivariate model including age and sex as covariates (β=0.04, p=0.012). Subgroup analyses suggested that this relationship between higher IL8 levels and consensus clinical determination of MCI or dementia is more prominent in the subgroup of GBA-associated PD (β=0.04, p=0.060) than the PD patients without GBA mutation (p=0.76).

There was no association between IL8 levels and modified (H&Y) stage in either cohort-wide analysis or in the GBA-associated subgroup analysis.

Discussion

Three key findings arose from our assessment of differences between PD patients with and without GBA mutations. PD patients with GBA mutation had a younger age at onset and were more likely to have clinical evidence of MCI or dementia. Biochemically, elevated plasma levels of several monocyte-associated inflammatory mediators were found in PD patients with GBA mutations, compared to those without GBA mutations. Elevated plasma levels of IL8 among PD patients with GBA mutations were then confirmed in an independent replication cohort.

Our findings agree with previous reports that PD patients with mutations in the GBA gene have a younger age at PD onset2,16. PD patients who are heterozygous for a GBA mutation have also been reported to have more subjective cognitive dysfunction2,17–19. In early onset PD (onset <50 years), cognitive impairment among GBA mutation carriers has been substantiated by neuropsychological tests17, and otherwise asymptomatic GBA mutation carriers may also have impaired performance on cognitive tests compared to non-carriers20. Consistent with these reports, we found GBA mutation carriers more likely to have MCI or dementia in a large cohort of PD patients with typical age at PD onset.

In this study, we also report on biochemical differences between PD patients with and without GBA mutations. While it is has long been known that Gaucher's disease patients, carrying two mutant copies of the GBA gene (GBA (mut/mut)), show elevated levels of a number of blood-based markers21–23, heterozygous GBA mutation carriers have not been previously evaluated in a systematic way. In our screening analysis, we found elevated levels of MCP-1, MIP1α, IL8, and PARC, all previously shown to be increased in GBA (mut/mut) individuals21,24,25, in the GBA (mut/wt) carriers with PD in our cohort as well. For most of these proteins, differences between PD patients with and without GBA mutations did not survive adjustment for potential confounders or replication efforts, suggesting that they are either false positive signals or that our study was underpowered to detect true differences. However, the cytokine IL8 did emerge from our screen of 40 plasma proteins as robustly elevated in GBA-associated PD, replicating in an independent cohort of patients assayed by a different method.

It is worth noting the preponderance of monocyte-lineage associated inflammatory mediators found to be elevated in our GBA mutation carriers26–28. In Gaucher's disease, a state of systemic and, in the case of the neuronopathic form, central nervous system inflammation has long been recognized29–31, attributed to glucocerebroside deposition in monocyte-lineage cells. Thus, it is not entirely surprising that individuals with one mutated GBA allele should demonstrate signs of inflammation as well, although this has not been previously demonstrated.

In addition, an emerging literature increasingly suggests connections between PD, glucocerebrosidase, and inflammation relevant to our current findings. Specifically, a bidirectional loop has been demonstrated between glucocerebrosidase and α-synuclein: accumulated glucocerebroside leads to accumulation of insoluble α-synuclein amyloid fibrils which block intracellular trafficking and further reduce glucocerebrosidase activity in neuronal lysosomes5. Moreover, in neonatal rat glial cells, exposure to α-synuclein can induce release of multiple inflammatory mediators -- including MCP-1 and MIP1α --with a potentially greater response for PD-mutation-associated forms of α-synuclein32. Finally, the introduction of an inflammatory stimulator into the substantia nigra of mice induces a neuroinflammatory response that appears to be dependent on α-synuclein, since mice null for α-synuclein do not mount this response33. Thus, it is hypothetically possible that glucocerebrosidase, α-synuclein, and monocyte-lineage-mediated inflammation all participate in a pathogenic cascade. If so, the fact that heterozygous GBA mutations may be sufficient to induce some degree of inflammation -- as suggested by our current data -- is relevant to understanding the predisposition of GBA mutation carriers, including GBA (mut/wt) individuals, to develop PD at an earlier age and with more risk for cognitive dysfunction. Indeed, our finding that higher IL8 levels correlate with poorer cognitive performance in both the full cohort and in the GBA-associated PD cases is consistent with this interpretation.

Several limitations to our study warrant mention. We used a case-control design to compare PD with GBA mutations vs. PD without GBA mutations. Thus, our sample may not be representative of the general PD population. However, both clinical characterization and plasma profile screening were conducted blinded to GBA mutation status, so it is unlikely that the differences found were related to bias in mutation carriers selected. In addition, in 231 subjects, screening was performed for only the 2 most common GBA mutations (N370S and L444P). It is therefore very possible that in this second group several more PD patients carried rarer GBA mutations. However, we guarded against the possibility that those individuals undetected by our screening method had dramatically different clinical characteristics or plasma profiles from the ones analyzed in this study by covering both severe GBA mutations (L444P) and less severe mutations (N370S) with our approach. Of note, for our comparison GBA (wt/wt) group, we only used individuals in which GBA mutations had been excluded by complete sequencing.

While the number of GBA mutation-associated PD cases in this study is relatively large, our study may not have had adequate statistical power to detect all differences. For instance, in the replication cohort, the difference in IL8 values between PD with and without GBA mutations achieved statistical significance when all 19 GBA mutation carriers were considered, but fell to non-significance when the 2 GBA (mut/mut) individuals were excluded. Subsequent analyses randomly omitting 2 cases demonstrated that statistical significance was lost a substantial proportion (30%) of the time, suggesting that our study may have been underpowered to detect a true difference. Thus, replication of our results in other cohorts or larger numbers of patients would be a valuable addition to the data presented here. Furthermore, regarding MCP-1 measurements, ELISA and multiplex immunoassay values for duplicate plasma samples were poorly correlated, despite internal consistency within each technical platform, suggesting that technical limitations may have resulted in our failure to replicate higher MCP-1 levels in the second cohort.

Finally, while we used an unbiased screening approach with a commercially available multiplex immunoassay to find biochemical markers differentiating PD patients with and without GBA mutations, our 40-protein panel is certainly not comprehensive, and there may be many other plasma proteins that differentiate these groups. We note, however, that even within the 40 proteins evaluated here, a very significant enrichment for monocyte-lineage inflammatory mediators was observed and may be biologically meaningful.

In conclusion, in this study, we extend previous reports that PD patients with GBA mutations have distinctive features, compared to PD without GBA mutations. Clinically, these include an earlier age at onset and worse cognitive function. In addition, we show for the first time that PD patients with GBA mutations, including heterozygous GBA mutations, may also have biochemical differences detectable in plasma, namely elevated levels of monocyte-associated inflammatory mediators. Taken together, our findings suggest that GBA mutations, even in a heterozygous state, may be sufficient to cause some systemic inflammation, which may, in turn, contribute to PD pathophysiology.

Supplementary Material

01

Acknowledgments

Acknowledgements and Funding

The biomarker data in this project was obtained through a partnership grant between the University of Pennsylvania and Pfizer (Penn Pfizer). The clinical data in this project were collected through the support of a Morris K. Udall Parkinson's Disease Research Center of Excellence grant from NINDS (NS-053488 and P50 NS062684). Alice Chen-Plotkin is also supported by the NIH (AG-033101), the Burroughs Wellcome Fund Career Award for Medical Scientists, a Doris Duke Clinician Scientist Development Award, and the Benaroya Fund. Cyrus Zabetian is supported by the NIH (R01 NS065070) and the Department of Veterans Affairs (Merit Award 1I01BX000531). We thank Travis Unger for technical assistance and our patients and their families for their participation in this research.

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