Dataset Information

Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.

ABSTRACT: Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression.The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state.Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site.Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (??=?4.65; 95% CI, 1.72-7.58; P?=?.002), E326K (??=?3.42; 95% CI, 0.66-6.17; P?=?.02), and GBA variants combined as a single group (??=?4.01; 95% CI, 1.95-6.07; P?=?1.5?×?10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (??=?0.38; 95% CI, 0.23-0.53; P?=?.01) and E326K (??=?0.64; 95% CI, 0.43-0.86; P?=?.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P?=?.01) and GBA variant carriers (15 of 39 [38.5%]; P?=?.04) progressed to mild cognitive impairment or dementia.GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

SUBMITTER: Davis MY

PROVIDER: S-EPMC5056861 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.

Davis Marie Y MY Johnson Catherine O CO Leverenz James B JB Weintraub Daniel D Trojanowski John Q JQ Chen-Plotkin Alice A Van Deerlin Vivianna M VM Quinn Joseph F JF Chung Kathryn A KA Peterson-Hiller Amie L AL Rosenthal Liana S LS Dawson Ted M TM Albert Marilyn S MS Goldman Jennifer G JG Stebbins Glenn T GT Bernard Bryan B Wszolek Zbigniew K ZK Ross Owen A OA Dickson Dennis W DW Eidelberg David D Mattis Paul J PJ Niethammer Martin M Yearout Dora D Hu Shu-Ching SC Cholerton Brenna A BA Smith Megan M Mata Ignacio F IF Montine Thomas J TJ Edwards Karen L KL Zabetian Cyrus P CP

JAMA neurology 20161001 10

<h4>Importance</h4>Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets.<h4>Objective</h4>To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression.<h4>Design, setting, and participants</h4>The entire GBA coding region was screened for mutations and E326K in 740 patient ...[more]

PMID: 27571329

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Project description:ImportanceDespite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual LRRK2 and GBA variations Parkinson disease (PD) than in GBA variation PD alone.ObjectiveTo evaluate the association of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in PD.Design, setting, and participantsThis longitudinal cohort study of continuous measures in LRRK2 PD, GBA PD, LRRK2/GBA PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-LRRK2-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for GBA and LRRK2 variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020.Main outcomes and measuresThe associations of LRRK2 G2019S and GBA genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale-Part III scores were examined using linear mixed effects models with PD duration as the time scale.ResultsAmong 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had GBA PD, 155 (13.0%) had LRRK2 PD, 21 (1.8%) had LRRK2/GBA PD, and 889 (74.5%) had idiopathic PD. Patients with GBA PD had faster decline in MoCA than those with LRRK2/GBA PD (B [SE], -0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], -0.33 [0.09] points/y; P < .001), or idiopathic PD (B [SE], -0.23 [0.08] points/y; P = .005). There was a LRRK2 G2019S × GBA interaction in MoCA decline (B [SE], 0.22 [0.11] points/y; P = .04), but not after excluding severe GBA variations (B [SE], 0.12 [0.11] points/y; P = .28). Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004).Conclusions and relevanceThese findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD. This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe GBA variation is warranted.

Project description:ImportanceGenetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance.ObjectiveTo assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD.Design, setting, and participantsThis longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression.Main outcomes measuresThe combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring.ResultsOf the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson's Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01).Conclusions and relevanceSusceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.

Dataset Information

Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.

Publications

Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease.

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