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Contribution of Five Functional Loci of Dopamine Metabolism-Related Genes to Parkinson's Disease and Multiple System Atrophy in a Chinese Population.

ABSTRACT: Background: Impaired dopamine metabolism is associated with Parkinson's disease (PD). Considering the overlap in the clinical and pathological characteristics between PD and multiple system atrophy (MSA), we investigated the effect of five potential functional polymorphisms in dopamine metabolism-related genes on disease susceptibility, phenotypes, and responses to dopamine in a large sample of PD and MSA patients. Methods: A total of 1506 PD patients, 496 MSA patients, and 894 healthy controls were included in this study. Five variants (rs6356 in TH, rs921451 in DDC, rs4680 in COMT, rs1799836 in MAOB, and rs1611115 in DBH) were genotyped in all cases using Sequenom iPLEX Assay technology. Results: After adjusting for gender and age at onset, except for DDC rs921451, which was associated with an increased risk of MSA (p = 0.001, OR = 1.21), no significant differences were found in genotype distribution or minor allele frequencies for the other four variants between PD and MSA patients and healthy controls. In the subgroup analysis, DDC rs921451 was associated with an increased risk for late-onset PD as well as for PD onset in males (p = 0.002 [OR = 1.13] p = 0.003 [OR = 1.15], respectively). In addition, patients harboring the risk allele DDC rs921451 required lower levodopa equivalent daily doses of dopaminergic medication than those without the risk allele (52.00 ± 21.31 mg/day, p = 0.015). Conclusion: None of the five candidate functional variants is a major determinant of the risk for PD or MSA. The modified PD phenotypes associated with these variants requires further confirmation.

SUBMITTER: Chen Y

PROVIDER: S-EPMC7497786 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Contribution of Five Functional Loci of Dopamine Metabolism-Related Genes to Parkinson's Disease and Multiple System Atrophy in a Chinese Population.

Chen Yongping Y Ou Ruwei R Zhang Lingyu L Gu Xiaojing X Yuan Xiaoqin X Wei Qian-Qian QQ Cao Bei B Zhao Bi B Wu Ying Y Shang Huifang H

Frontiers in neuroscience 20200903

<b>Background:</b> Impaired dopamine metabolism is associated with Parkinson's disease (PD). Considering the overlap in the clinical and pathological characteristics between PD and multiple system atrophy (MSA), we investigated the effect of five potential functional polymorphisms in dopamine metabolism-related genes on disease susceptibility, phenotypes, and responses to dopamine in a large sample of PD and MSA patients. <b>Methods:</b> A total of 1506 PD patients, 496 MSA patients, and 894 hea ...[more]

PMID: 33013295

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Project description:BackgroundBoth Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized.ObjectivesTo use serotonin transporter [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD.MethodsWe performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest.ResultsPatients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD.ConclusionsBrainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Project description:Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy1. Clinically, it is challenging to differentiate Parkinson's disease and multiple system atrophy, especially at the early stages of disease2. Aggregates of α-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of α-synuclein that can self-propagate and spread from cell to cell3-6. Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect α-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity7,8. Here we show that the α-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson's disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of α-synuclein-PMCA, and found that the characteristics of the α-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson's disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that α-synuclein aggregates that are associated with Parkinson's disease and multiple system atrophy correspond to different conformational strains of α-synuclein, which can be amplified and detected by α-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of α-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinson's disease and multiple system atrophy.

Project description:Multiple system atrophy (MSA) and Parkinson's disease (PD) belong to alpha-synucleinopathy, but they have very different clinical courses and prognoses. An imaging biomarker that can differentiate between the two diseases early in the disease course is desirable for appropriate treatment. Neuroimaging-based brain age paradigm provides an individualized marker to differentiate aberrant brain aging patterns in neurodegenerative diseases. In this study, patients with MSA (N = 23), PD (N = 33), and healthy controls (N = 34; HC) were recruited. A deep learning approach was used to estimate brain-predicted age difference (PAD) of gray matter (GM) and white matter (WM) based on image features extracted from T1-weighted and diffusion-weighted magnetic resonance images, respectively. Spatial normative models of image features were utilized to quantify neuroanatomical impairments in patients, which were then used to estimate the contributions of image features to brain age measures. For PAD of GM (GM-PAD), patients with MSA had significantly older brain age (9.33 years) than those with PD (0.75 years; P = 0.002) and HC (-1.47 years; P < 0.001), and no significant difference was found between PD and HC (P = 1.000). For PAD of WM (WM-PAD), it was significantly greater in MSA (9.27 years) than that in PD (1.90 years; P = 0.037) and HC (-0.74 years; P < 0.001); there was no significant difference between PD and HC (P = 0.087). The most salient image features that contributed to PAD in MSA and PD were different. For GM, they were the orbitofrontal regions and the cuneus in MSA and PD, respectively, and for WM, they were the central corpus callosum and the uncinate fasciculus in MSA and PD, respectively. Our results demonstrated that MSA revealed significantly greater PAD than PD, which might be related to markedly different neuroanatomical contributions to brain aging. The image features with distinct contributions to brain aging might be of value in the differential diagnosis of MSA and PD.

Dataset Information

Contribution of Five Functional Loci of Dopamine Metabolism-Related Genes to Parkinson's Disease and Multiple System Atrophy in a Chinese Population.

Publications

Contribution of Five Functional Loci of Dopamine Metabolism-Related Genes to Parkinson's Disease and Multiple System Atrophy in a Chinese Population.

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