Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
Transl Psychiatry. 2024 Apr 4;14(1):178. doi: 10.1038/s41398-024-02878-z.
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 cohort: 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) tissues. 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 TIMP1. 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 associated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 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）的行为和心理症状的痴呆（BPSD）具有重大负担、成本和预后更差，但对于这些症状的分子原因知之甚少。我们使用 AD 中 BPSD 的生前评估，证明在我们的队列中，个体 BPSD 可以分为 4 个域因素：情感、淡漠、激越和精神病。然后，我们对每个域使用死后前扣带皮层（ACC）组织的批量 RNA-seq 进行了转录组范围分析。虽然所有 4 个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 是每个域特有的，只有 22 个 DEG 是所有 BPSD 域共有的，包括 TIMP1。加权基因共表达网络分析（WGCNA）产生了多个转录模块，这些模块在 BPSD 域之间共享或每个域特有，并且使用 NetDecoder 分析了通过生物网络的上下文相关信息流。对于激越域，我们发现所有 DEG 和高度相关的转录模块在功能上都富含与 TIMP1、TAGLN 和 FLNA 等 ECM 相关基因富集。另一个与激越域相关的独特转录模块也富含参与突触后信号转导的基因，包括 DRD1、PDE1B、CAMK4 和 GABRA4。通过比较病例和对照网络中 DEG 之间的上下文相关变化，ESR1 和 PARK2 被认为是与激越相关的两个具有高影响的基因，它们通过生物网络介导了显著的信息流。总的来说，我们的工作为未来研究 BPSD 的生物学机制和药物开发建立了独特的靶点。
