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?-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease.

ABSTRACT: Currently, there are no reported genetic predictors of motor symptom progression in Parkinson's disease (PD). In familial PD, disease severity is associated with higher ?-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson's patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson's Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57-10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96-2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.

SUBMITTER: Ritz B

PROVIDER: S-EPMC3352914 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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α-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease.

Ritz Beate B Rhodes Shannon L SL Bordelon Yvette Y Bronstein Jeff J

PloS one 20120515 5

Currently, there are no reported genetic predictors of motor symptom progression in Parkinson's disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson's patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor s ...[more]

PMID: 22615757

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Project description:Background: Asymmetry of motor signs is a cardinal feature of Parkinson disease which may impact phenotypic expression. Objective: To investigate the relationship between lateralization of motor signs and symptom progression and severity during longitudinal observation for up to 4 years in a naturalistic study. Methods: We analyzed data prospectively collected during the NINDS Parkinson Disease Biomarker Project (PDBP). We defined the Movement Disorder Society Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II as the primary measure of symptom progression. Left side predominant subjects were those whose lateralized motor scores on the MDS-UPDRS part III were ≥2 points higher on the left side than on the right side of the body. Multiple regression models (controlled for age, gender, education years, ethnicity, levodopa equivalent daily dose (LEDD) at baseline, and years with PD) were used to estimate the rate of symptom progression comparing left predominant (LPD) with non-left predominant (NLPD) subjects. A sensitivity analysis was performed using the same multiple regression models in the subgroups of low (0-26) or high (>27) MDS-UPDRS II score at baseline to determine if PD severity influenced the results. Results: We included 390 participants, 177 LPD and 213 NLPD. We found that MDS-UPDRS part II progression from baseline to 48 months was faster in LPD compared to NLPD (0.6 points per year faster in LPD, p = 0.05). Additionally, the LPD group was statistically significantly worse at baseline and at 48 months in several subparts of the MDS-UPDRS and the Parkinson's Disease Questionnaire-39 (PDQ-39) mobility score. Significantly slower progression (difference of -0.8, p = 0.01) and lower score at 48 months (difference of -3.8, p = 0.003) was seen for NLPD vs. LPD in the group with lower baseline MDS-UPDRS part II score. Conclusion: Left side lateralization was associated with faster symptom progression and worse outcomes in multiple clinical domains in our cohort. Clinicians should consider using motor predominance in their counseling regarding prognosis.

Project description:BackgroundThe accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.MethodsPrimary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.ResultsThe number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877.ConclusionsPathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.

Dataset Information

?-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease.

Publications

α-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease.

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