Farr Laura M, Thorpe Naomi, Brinda Ethel M, Albalushi Naser, Sohail Mohammad, Rajkumar Anto P
Institute of Mental Health, Mental Health and Clinical Neurosciences Academic Unit, University of Nottingham, Nottingham, UK.
Nottinghamshire Healthcare NHS Foundation Trust, Nottingham, UK.
Acta Neuropsychiatr. 2025 Mar 27;37:e59. doi: 10.1017/neu.2025.15.
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are collectively called as Lewy body dementia (LBD). Despite the urgent clinical need, there is no reliable protein biomarker for LBD. Hence, we conducted the first comprehensive systematic review of all Differentially Abundant Proteins (DAP) in all tissues from people with LBD for advancing our understanding of LBD molecular pathology that is essential for facilitating discovery of novel diagnostic biomarkers and therapeutic targets for LBD.
We identified eligible studies by comprehensively searching five databases and grey literature (PROSPERO protocol:CRD42020218889). We completed quality assessment and extracted relevant data. We completed narrative synthesis and appropriate meta-analyses. We analysed functional implications of all reported DAP using tools.
We screened 11,006 articles and identified 193 eligible studies. 305 DAP were reported and 16 were replicated in DLB. 37 DAP were reported and three were replicated in PDD. Our meta-analyses confirmed six DAP (TAU, SYUA, NFL, CHI3L1, GFAP, CLAT) in DLB, and three DAP (TAU, SYUA, NFL) in PDD. There was no replicated blood-based DAP in DLB or PDD. The reported DAP may contribute to LBD pathology by impacting misfolded protein clearance, dopamine neurotransmission, apoptosis, neuroinflammation, synaptic plasticity and extracellular vesicles.
Our meta-analyses confirmed significantly lower CSF TAU levels in DLB and CSF SYUA levels in PDD, when compared to Alzheimer's disease. Our findings indicate promising diagnostic biomarkers for LBD and may help prioritising molecular pathways for therapeutic target discovery. We highlight ten future research priorities based on our findings.
路易体痴呆（DLB）和帕金森病痴呆（PDD）统称为路易体痴呆（LBD）。尽管临床需求迫切，但目前尚无可靠的LBD蛋白质生物标志物。因此，我们首次对LBD患者所有组织中的所有差异丰富蛋白（DAP）进行了全面系统的综述，以加深我们对LBD分子病理学的理解，这对于促进发现LBD的新型诊断生物标志物和治疗靶点至关重要。
我们通过全面检索五个数据库和灰色文献（PROSPERO协议：CRD42020218889）来确定符合条件的研究。我们完成了质量评估并提取了相关数据。我们完成了叙述性综合分析和适当的荟萃分析。我们使用工具分析了所有报告的DAP的功能影响。
我们筛选了11006篇文章，确定了193项符合条件的研究。报告了305种DAP，其中16种在DLB中得到重复验证。报告了37种DAP，其中3种在PDD中得到重复验证。我们的荟萃分析在DLB中确认了6种DAP（TAU、SYUA、NFL、CHI3L1、GFAP、CLAT），在PDD中确认了3种DAP（TAU、SYUA、NFL）。在DLB或PDD中没有基于血液的重复验证的DAP。报告的DAP可能通过影响错误折叠蛋白清除、多巴胺神经传递、细胞凋亡、神经炎症、突触可塑性和细胞外囊泡而导致LBD病理学改变。
我们的荟萃分析证实，与阿尔茨海默病相比，DLB患者脑脊液中TAU水平显著降低，PDD患者脑脊液中SYUA水平显著降低。我们的研究结果表明LBD有前景的诊断生物标志物，并可能有助于确定治疗靶点发现的分子途径优先级。我们根据研究结果突出了十个未来研究重点。
