Strauss Alexandra, Swann Peter, Kigar Stacey L, Christou Rafailia, Savinykh Yarkoni Natalia, Turner Lorinda, Murley Alexander G, Chouliaras Leonidas, Shapiro Noah, Ashton Nicholas J, Savulich George, Bevan-Jones W Richard, Surendranthan Ajenthan, Blennow Kaj, Zetterberg Henrik, O'Brien John T, Rowe James B, Malpetti Maura
University of Cambridge Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, UK.
Department of Psychiatry, University of Cambridge, Cambridge, UK.
Mol Psychiatry. 2025 May;30(5):1985-1994. doi: 10.1038/s41380-024-02809-w. Epub 2024 Oct 29.
The innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g., microglia), peripheral innate immune cells (e.g., blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate immune cell types across different neurodegenerative diseases remains incomplete. This study aimed to characterize peripheral innate immune profiles using flow cytometry for immunophenotyping of peripheral blood mononuclear cells in n = 148 people with Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), Lewy body dementia (LBD) as compared to n = 37 healthy controls. To compare groups, we used multivariate dissimilarity analysis and principal component analysis across 19 innate immune cell types. We identified pro-inflammatory profiles that significantly differ between patients with all-cause dementia and healthy controls, with some significant differences between patient groups. Regression analysis confirmed that time to death following the blood test correlated with the individuals' immune profile weighting, positively to TREM2+ and non-classical monocytes and negatively to classical monocytes. Taken together, these results describe transdiagnostic peripheral immune profiles and highlight the link between prognosis and the monocyte cellular subdivision and function (as measured by surface protein expression). The results suggest that blood-derived innate immune profiles can inform sub-populations of cells relevant for specific neurodegenerative diseases that are significantly linked to accelerated disease progression and worse survival outcomes across diagnoses. Blood-based innate immune profiles may contribute to enhanced precision medicine approaches in dementia, helping to identify and monitor therapeutic targets and stratify patients for candidate immunotherapies.
先天免疫系统在许多神经退行性疾病的进展中起着不可或缺的作用。除了中枢先天免疫细胞（如小胶质细胞）外，外周先天免疫细胞（如血液单核细胞、自然杀伤细胞和树突状细胞）在这些疾病状态下也可能有所不同。然而，不同神经退行性疾病中外周先天免疫细胞类型的特征描述仍不完整。本研究旨在使用流式细胞术对n = 148例阿尔茨海默病（AD）、额颞叶痴呆（FTD）、皮质基底节综合征（CBS）、进行性核上性麻痹（PSP）、路易体痴呆（LBD）患者以及n = 37名健康对照者的外周血单核细胞进行免疫表型分析，以表征外周先天免疫特征。为了比较各组，我们对19种先天免疫细胞类型进行了多变量差异分析和主成分分析。我们确定了全因痴呆患者与健康对照者之间存在显著差异的促炎特征，患者组之间也存在一些显著差异。回归分析证实，血液检测后的死亡时间与个体的免疫特征权重相关，与TREM2 +和非经典单核细胞呈正相关，与经典单核细胞呈负相关。综上所述，这些结果描述了跨诊断的外周免疫特征，并突出了预后与单核细胞细胞亚群和功能（通过表面蛋白表达测量）之间的联系。结果表明，血液来源的先天免疫特征可以为与特定神经退行性疾病相关的细胞亚群提供信息，这些疾病与加速疾病进展和更差的生存结果显著相关。基于血液的先天免疫特征可能有助于提高痴呆症的精准医学方法，有助于识别和监测治疗靶点，并为候选免疫疗法对患者进行分层。
