Studies Of Snca Gene Polymorphisms And Brain Analysis Using Voxel Based Mri Morphometry In Patients With Parkinson’s Disease With Mild Cognitive Impairment

Parkinson’s disease (PD) is one common movement disorder characterized by degeneration and loss of dopaminergic neurons in substantia nigra and the appearance of cytoplasmic inclusions named the Lewy bodies. The most common symptoms include slowness of movement, tremor, muscle stiffness and postural instability.Although best known for its characteristic movement disorder, PD is now appreciated to cause cognitive impairment, autonomic dysfunction, sensory disturbances, sleep difficulties and neuropsychiatric symptoms. Mild cognitive impairment (MCI) and dementia are now recognized as a common feature of PD. MCI and dementia not only affect quality of life but also increase the burdens of the caregivers, accelerate the progress of the disease, even be a risk factor of long-term death of the PD patients.Although the mechanism of disease contributing to impairment cognitive in patients with PD is largely unknown, there is a relationship between the etiology and pathogenesis with an abnormality of complicated neuropathology. Mutations alpha-synuclein (SNCA) gene have been shown to be responsible for a familial Parkinson disease. The appearance of cytoplasmic inclusions named the Lewy bodies is the characteristic pathological hallmark of all PD, in which protein encoded by SNCA gene is identified as major component of Lewy body. However, the great majority of cases of this disorder are sporadic, resulting from complex interactions among genes, and between genes and environmental factors. Early association studies have shown that polymorphic variants in SNCA gene may add the risk of developing commom, idiopathic PD by increasing the gene expression level. Maraganore team performed a Meta analysis of association betweens allele-length variability in the mixed dinucleotide repeat in the promoter (D4S3481; Rep1) and proning to sporadic PD susceptibility, the study showed that the longer of allele-length variability, the highter risk of developing parkionson disease. In a human a-synuclein in transgenic mouse study, Cronin et al have found human SNCA mRNA and protein levels were increased1.7-and1.25-fold, respectively, in the expanded, PD allele compared with the shorter allele and demonstrated that Rep1regulates human SNCA expression by increasing its transcription in the adult nervous system. A lot of study found that the polymorphic variants of SNCA gene may increase the risk of developing PD, for example rs356165, rs3733449, rs11931074and rs3857059. So SNCA gene polymorphism plays a critical role in the susceptibility of PD.Moreover, SNCA protein is not only associated with PD, but also with PD cognitive impairment. Three missense mutations (A53T, A30P, and E64K) and duplications or triplications of the locus containing SNCA have been identified previously in families with autosomal dominant PD, all or some patients can appear clinical manifestation of Parkinson’s disease dementia (PDD). A study of88pathologically confirmed PD cases, Braak found that only9cases had intact or marginally impaired cognition, the rest developed mildly to moderate cognitive impairment and there existed a correlate between MMSE score and Lewy body. One recent pathologic study demonstrated that α-synuclein-positive Lewy bodies rather than AD pathologies played an important role in dementia patients with PD. In another study, the researchers investigated the effects of risk and protective SNCA haplotypes associated with Parkinson’s disease on cognitive sequence learning in204healthy volunteers. Four of these haplotypes which were associated with decreased risk of Parkinson’s disease, and two of the six haplotypesare associated with increasedrisk of Parkinson’s disease were including. The study found the risk SNCA haplotypes was associated with Parkinson’s disease on cognitive sequence learning namely SNCA gene affecttde memory systems.In our previoue study, we have investigated the association between single nucleotide polymorphism rs1372525in SNCA gene with cognitive impairment in PD. We found the SNP rs1372525of the a-synuclein gene was not associated with susceptibility of Parkinson’s disease; there was not a correlation beween rsl372525with cognitive impairment in Han Chinese population. But the sample size was very small (PD; n=90, normal controls; n=96) and PD patient was divided into cognitive impairment and cognitively normal group only according to MoCA scores in the study. Recent Genome Wide Association Studies (GWAS) found that SNP rs2736990, rs356219of the alpha-synuclein gene was associated with PD. We intend to do some further works based on previoue study, including enlarging the sample size and completing neuropsychological battery, and carry out a analysis of association betweens SNP rs2736990, rs356219, rs1372525of SNCA gene and sporadic PD and mild impairment cognitive susceptibility in Han Chinese population.Alpha-synuclein is a small14-KD protein; its physiological function does not fully understand but may play a certain role in regulation of cell differentiation, signal transmission and neural plasticity. Because alpha-synuclein anormal aggregation leads to degeneration and loss of neurons, then autopsy can manifest morphological changes. Pathological study is a useful method for mechanism but still exist considerable difficulties on the central nervous system diseases, especially in the early stage.Voxel Based Morphometry (VBM) technology is one of the commom methods based on the MRI brain structure analysis. It can reveal the changes of tissue shapes and more sensitive to discover subtle variations than common Magnetic Resonance Imaging (MRI) and appropriate to examine the structural brain changes. It is excessively sensitive for early morphological changes in the neurodegenerative diseases and can provide critical information in the early diagnosis.VBM technology was extensive applications in analysis of the difference of brain structure in all kinds of patients including dementia, Schizophrenia, headache, sleep apnea, multiple sclerosis, PDD and so on. Many morphologic studies showed that PDD patients have significant widespread cerebral atrophy incluing frontal, temporal parietal, occipital lobe and hippocampi. But the anatomy changes of MCI are still limited.So, the aim of our work is to investigate the pattern of cortical atrophy in PD-MCI using VBM who underwent a complete neuropsychological battery that includes evaluation of memory, attention, visuo-spatial abilities, executive functions, and provide neuroimaging biomarkers for the early diagnosis in the PD-MCI and guidelines for clinical interfere.This paper includes two parts:Ⅰ. the study between the polymorphisms analysis of SNCA gene with mild cognitive impairment in Parkinson’s disease.Ⅱ. A whole brain analysis using voxel base morphometry in patients with Parkinson’s pisease with mild cognitive impairment.Part Ⅰ:the polymorphisms analysis of SNCA gene in Patients with Parkinson’s Disease With Mild Cognitive ImpairmentObjective:To analyze the SNCA gene polymorphisms and investigate the relationship between the SNCA gene polymorphisms and PD-MCI susceptibility.Methods:189PD cases and189normal controls were included for research. The PD patients will be divided into PD-MCI and PD-CN groups in accordance with neuropsychological battery socres. The genotype of the three SNPs (rs1372525, rs356219, and rs2736990) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) combined with DNA sequencing were difined, and a statistical analysis of the data was made. Genotype and allele frequencies were tested for significance using a95%two-sided χ2test between the groups. Results:The genotype frequencies were consistent with Hardy-Weinberg equilibrium distribution in PD and control groups.PD compared with control group:1. There were no significant differences in the genotypes(A/A、A/G、G/G) and alleles (A、G) frequencies of rs1372525between PD and control group(P>0.05).2. There were no significant differences in the genotypes (C/C. C/T、T/T) and alleles (C、T) frequencies of rs2736990between PD and control group (P>0.05)3. We found a significant difference in the allele (A、G) frequencies of rs356219(P<0.05), but no significant difference in the genotype (A/A、A/G、G/G) frequencies between the two groups (P>0.05)PD-MCI compared with PD-CN group: Make comparisons of genotypes and alleles frequencies among the PD-MCI and PD-CN groups, the results show that there was no significant difference in rs1372525, rs2736990and rs356219, sugestting that three polymorphisms may not be associated with PD mild cognitive impairment. Conclusions:1. The polymorphism of rs356219of SNCA gene may be associated with PD; the "G" allele of rs356219may be an important susceptibility factor to PD patients;2. The development of PD-MCI is lack of associated with rs1372525, rs356219, and rs2736990polymorphisms of SNCA in Chinese Han population. Parts Ⅱ:A whole brain analysis using Voxel Based Morphometry in Patients with Parkinson’s Disease With Mild Cognitive Impairment PD using voxel based morphometry and provide theoretical support for early diagnosis and clinical interference.Method:55PD patients and36normal controls were included. The PD patients were underwent the Unified Parkinson disease rating scale (UPDRS-Ⅲ), Hoehn-Yahr (H-Y), Mini-mental state examination (MMSE), Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC), Wechsler Memory Scale (WMS-R). PD patients would be divided into with and without mild cognitive impairment group. Along with concept of MCI suggested by Peterson and colleagues, Patients were considered MCI if at least one of four cognitive domains was abnormal.The subjects were examined by using T1W three-dimensional Spoiled gradient recalled echo sequence.The data were analyzed by using VBM based on SPM5to generate gray matter density map.Results:①Patients with mild cognitive impairment had reductions in grey matter concentration in the frontal, parietal lobes, right caudate and cuneus compared with the controls. On the left side, there was also reduced grey matter density in the middle frontal lobe, postcentral. On the right side, there was reduced grey matter density in the superior and middle frontal gurus, postcentral, caudate nucleus and cuneus.②Patients with PD-MCI had a cluster of reduced grey matter in the both parietal lobes and right lingual gurus compared with PD-CN.③PDND did not have any areas of more grey matter atrophy than normal controls.Conclusions:①Gray matter atrophy in brain region can exist in PD-MCI patients, involving bilateral frontal, parietal, right caudate nucleus and cuneus.②PDND did not have any areas of grey matter atrophy. With occurrence of mild cognitive impairment, abnormal brain regions were gradually extended.③VBM can evaluate the early structural changes of full brain in vivo.