Association Of CR1 Polymorphism With Brain Function In Amnestic-Type Mild Cognitive Impairment

BackgroundAmnestic mild cognitive impairment (aMCI) patients, who declined at a rate ten times greater than normal aging (1%-2%) to Alzheimer's disease (AD), have made a great contribution to the incidence of AD. Complement receptor 1 (CR1) has been identified as one of the most important susceptible genes of AD in several Genome Wide Association Studies (GWAS) based on large samples. It has been found that CR1 rs3818361 is associated with increasing risk of AD in several ethnic groups. Resting-state functional magnetic resonance imaging (rs-fMRI) technology could detect our brain's blood oxygenation level dependent (BOLD) signals generated by its spontaneous activity. Based on the intensity of BOLD signals, amplitude of low frequency fluctuation (ALFF) has been used to investigate the level of spontaneous neuronal activity and become one of the most important methods in rs-fMRI-associated study. With exploring the association of CR1 polymorphism with brain function in aMCI patients, we hope to provide more evidence to the study of imaging genetics of dementia.Chapter One:Literature reviewReview 1:CRl in Alzheimer's diseaseAbstract:Study of CR1 and the neuroinflammation hypothesis in the development of AD have been popular worldwide, after several GWAS identify CR1 as a susceptible gene in AD. As an opsonic receptor and regulator of complement system, CR1-F is neuroprotective in AD. Genetic variation of CR1 is always associated with CR1-S, which increases the risk of AD by decreasing the clearance of C3b-opsonized A?. CR1 assists in erythrocytes-mediated immune clearance of A? in circulatory system and microglial-mediated clearance of A? in brain. In conclusion, CR1 plays a double-edged function in neuroinflammation of AD:protect the brain by promoting the clearance of A? and inhibiting exaggerated inflammatory response; damage and kill neurons after over activation.Review 2:An insight into tauopathy of Alzheimer's diseaseAbstract:As a complex, progressive, irreversible neurodegenerative disease, Alzheimer's disease is characterized by decreased cognition, and the pathological hallmarks:amyloid plaques and neurofibrillary tangles (NFTs). To determine the physiopathologic mechanism of AD for effective prevention and treatment, several modeling hypotheses have emerged. Amyloid hypothesis and tau protein hypothesis are most widely accepted. However, many ?-amyloid-based drugs which were promising have declared failure in recent year. The tau hypothesis as an alternative pathway is now attracting increasing attention. It has been recognized that current and future trends in AD research increasingly focus on the discovery and understanding of complex functional systems. Thorough understanding of the molecular, genetic and epigenetic mechanisms underlying the intricate pathogenesis of AD give us a novel insight into therapeutics. We will have an insight into tauopathy and review related mechanisms that may lead to tauopathy.Chapter two:Exploring association of CR1 polymorphism with regional brain function in aMCI patientsObjectives:Exploring association of CR1 rs3818361 polymorphism with brain resting-state function in aMCI patients.Method:In this study,85 aMCI patients and 135 healthy controls (HC) grouped by their CR1 rs3818361 genotypes underwent resting-state functional magnetic resonance and a clinical interview which focuses on neurological and mental status exam. Then, gene-brain-behavior relationships were examined to determine the effect of the risk variant on regional brain activity in these subjects.Results:1. The difference of neurological and mental status exams between aMCI and HC subjects is significant (p<0.05).2. Regions of "groups×genotypes" ANOVA interaction are located in right superior frontal gyrus (rSFG) and anterior cingulate (AC).3. Negative relation of regional brain activity of rSFG and AC with mini-mental state examination (MMSE), positive relation of regional brain activity of rSFG and AC with seconds consumed in trail making test B (TMT-B) were observed in GG carriers of aMCI patients (p< 0.00238).Conclusion:Our findings are the first to show that CRl rs3818361 polymorphism has a significant influence on overall cognitive function impairment and executive function. CR1 rs3818361 GG genotype in aMCI patients is related with aberrant activation of rSFG.Chapter three:Summary and prospectsFeaturesBased on the gene-brain-behavior frame, with taking advantage of the combination of CR1 SNP rs3818361 genetic polymorphism, rs-fMRI technology and multi-dimension neuropsychological tests, we hope to map the altered pattern of neuroimaging of cognitive dysfunction in aMCI patients.InnovationCR1, which plays a pivotal role in neuroinflammation in central nervous system, has been proved to be associated with increased risk of AD. The study exploring spatial patterns of the progress from aMCI to AD by integrating genetic polymorphism of CR1 rs3818361 and rs-fMRI technology is rare in China. We hope to map the altered pattern of neuroimaging of cognitive dysfunction in aMCI patients and provide more evidence for early diagnosis of AD. Conclusion Our findings are the first to show that CR1 rs3818361 polymorphism has a significant influence on overall cognitive function impairment and executive function. CR1 rs3818361 GG genotype in aMCI patients is related with aberrant activation of rSFG.Prospects1. Launch multi-center, multi-subtypes longitudinal follow-up study and strengthen the representativeness of study.2. Combine multi-modality fMRI technology and multi-analytic methods and improve the reliability of the result.3. Promote genetic pathway-based study and multidisciplinary cooperation and enhance early diagnosis and treatment of AD.