A Study On Cerebellar White Matter Integrity And MiRNA Characteristics In At-Risk Population For Bipolar Disorder

Background:Bipolar Disorder(BD)is a common psychiatric disorder with a global prevalence of around 1%to 3%,typically presenting its first episode during adolescence or early adulthood.Offspring of BD patients have a higher likelihood to develop BD compared to the general population,but effective biological markers are currently lacking to predict when and how these at-risk individuals may convert to BD.The aim of this study is to explore potential early biological markers in BD highrisk individuals from two distinct perspectives:1.We first investigate whether changes in the integrity of cerebellar white matter tracts could serve as a predictive biological marker for the risk of BD development by comparing this feature among BD high-risk individuals,healthy controls,and BD patients.2.Secondly,we explore differences in Micro RNA between BD high-risk individuals and healthy controls from a transcriptomics perspective,and whether changes in Micro RNA can serve as a predictive biomarker for conversion to BD in this high-risk population.Method:The study is divided into two parts:Part One:We recruited 221 offspring of BD patients from the Affiliated Brain Hospital of Guangzhou Medical University and the community.They were classified into four groups based on a series of well-defined criteria:Healthy Control(NC)(n=77),High-Risk(HR)(n=32),Ultra-High-Risk(UHR)(n=38),and Bipolar Disorder(BD)(n=64).Part Two:We selected 45 adolescents with Subthreshold Mood Syndromes(SMS)from the offspring of BD patients,and 35 healthy adolescents aged 8-28 as control(HC).We prepared a transcriptome sequencing library after RNA extraction from whole blood samples of some participants,then assessed the quality of the library on an Agilent BioAnalyst 2100 system.Finally,we performed clustering and sorting,differential expression analysis,CeRNA network analysis,and Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis.performed.Results:Part One:The results of the ANCOVA analysis showed that,compared with the BD group,the Mean Diffusivity(MD)(p=0.043)and Radial Diffusivity(RD)(p=0.039)of the left corticopontine-cerebellar tract in the HR group were significantly reduced.Moreover,logistic regression results,after controlling for covariates,revealed that measurements of specific diffusion rates(such as RD and MD)in the cerebellar tract(e.g.,corticopontine-cerebellar tract),reflect significant differences between the groups at different stages of BD.Part Two:We found that compared with healthy controls,adolescents with Subthreshold Mood Syndromes(SMS)had 96 lncRNAs,14 miRNAs,and 537 proteincoding mRNAs upregulated,and 17 lncRNAs,6 miRNAs,and 112 protein-coding mRNAs downregulated.We established a BD lncRNA-miRNA-mRNA ceRNA network consisting of 20 differentially expressed(DE)miRNAs,294 DE lncRNAs,and 214 DE mRNAs.We performed GO and KEGG pathway enrichment analyses to determine the biological functions of significantly dysregulated genes.We found that changes in the functions of protein digestion and absorption,and extracellular matrixreceptor interaction pathways,may be associated with the occurrence of SMS.Conclusion:This study found that specific diffusion rates(RD and MD)of the cerebellar tract(such as the corticopontine-cerebellar tract)showed significant differences between groups at different stages of BD.This can help detect the trajectory changes of early BD syndromes,especially when BD syndromes start from the HR stage.The regulation of gene expression included in GO and KEGG may be involved in the pathogenesis of BD,and these genes could serve as biological markers and therapeutic targets for BD.GO analysis showed that extracellular matrix components,protein acetylation of the extracellular matrix,and extracellular matrix are the most important biological processes related to mood disorders.KEGG pathway analysis revealed several pathways related to mood disorders,such as protein digestion and absorption,tyrosine metabolism,and long-term potentiation.The results of GO and KEGG analysis in this study suggest that extracellular matrix proteins and synaptic plasticity play a key role in the development of BD.