Fisher Daniel W, Dunn Jeffrey T, Keszycki Rachel, Rodriguez Guadalupe, Bennett David A, Wilson Robert S, Dong Hongxin
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine.
Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine.
Res Sq. 2023 Jan 11:rs.3.rs-2444391. doi: 10.21203/rs.3.rs-2444391/v1.
Despite the significant burden, cost, and worse prognosis of Alzheimer's disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our sample: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissue. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of differentially expressed genes (DEGs), most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including . Weighted gene co-expression network analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly correlated transcriptional module were functionally enriched for ECM-related genes including , and . Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including , and . By comparing context-dependent changes in DEGs between cases and control networks, and were implicated as two high impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.
尽管阿尔茨海默病（AD）伴发痴呆行为和心理症状（BPSD）带来了巨大负担、成本且预后较差，但对于这些症状的分子成因却知之甚少。通过对AD患者BPSD的生前评估，我们证明在我们的样本中，个体BPSD可分为4个领域因素：情感、冷漠、激越和精神病性症状。然后，我们利用死后前扣带回皮质（ACC）组织的批量RNA测序对每个领域进行了全转录组分析。尽管所有4个领域都与数百个差异表达基因（DEG）的主要下调模式相关，但大多数DEG在每个领域都是独特的，所有BPSD领域仅有22个DEG是共有的，包括 。加权基因共表达网络分析（WGCNA）产生了多个在BPSD领域之间共享或每个领域独有的转录模块，并且使用NetDecoder分析通过生物网络的上下文相关信息流。对于激越领域，我们发现所有DEG和一个高度相关的转录模块在功能上富集了包括 、 和 在内的细胞外基质（ECM）相关基因。另一个也与激越领域相关的独特转录模块富含参与突触后信号传导的基因，包括 、 和 。通过比较病例和对照网络之间DEG的上下文相关变化， 和 被认为是与激越相关的两个高影响基因，它们介导了通过生物网络的显著信息流。总体而言，我们的工作为未来研究BPSD的生物学机制及由此产生的药物开发确立了独特的靶点。
