Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, USA.
Ann Neurol. 2024 Feb;95(2):299-313. doi: 10.1002/ana.26822. Epub 2023 Nov 10.
This study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment-responsive causes of RPD.
Biomarkers of Alzheimer disease neuropathology (amyloid-β 42/40 ratio, phosphorylated tau [p-tau181, p-tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin-like protein-1 [VILIP-1], total tau), neuroinflammation (chitinase-3-like protein [YKL-40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein-1 [MCP-1]), and synaptic dysfunction (synaptosomal-associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age- and sex-matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease.
Alzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL-40 and low VILIP-1 identified patients with autoimmune/inflammatory diseases. MCP-1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP-1, p-tau181, and sTREM2 identified the 44 patients with treatment-responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease.
Selected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross-sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2024;95:299-313.
本研究旨在应用已确立和新兴的脑脊液（CSF）生物标志物来提高快速进展性痴呆（RPD）患者的诊断准确性。重叠的临床特征和诊断测试结果使得 RPD 患者的病因诊断变得复杂。需要客观的指标来提高诊断的准确性，并识别出具有潜在治疗反应原因的 RPD 患者。
测量了 78 例前瞻性收集的 RPD 患者（由于神经退行性、血管和自身免疫/炎症性疾病引起）、35 例年龄和性别匹配的具有典型进行性神经退行性疾病的患者和 72 例认知正常对照者的 CSF 中阿尔茨海默病神经病理学的生物标志物（β淀粉样蛋白 42/40 比值、磷酸化 tau [p-tau181、p-tau231]）、神经轴索/神经元损伤（神经丝轻链 [NfL]、视黄醇结合蛋白-1 [VILIP-1]、总 tau）、神经炎症（几丁质酶 3 样蛋白 [YKL-40]、可溶性髓系细胞触发受体 2 [sTREM2]、胶质纤维酸性蛋白 [GFAP]、单核细胞趋化蛋白 1 [MCP-1]）和突触功能障碍（突触相关蛋白 25kDa、神经颗粒蛋白）。比较了不同病因诊断、潜在治疗反应和具有典型和快速进展性神经退行性疾病表现的患者之间的生物标志物水平。
阿尔茨海默病生物标志物与 RPD 的神经退行性病因有关。高 NfL、sTREM2 和 YKL-40 以及低 VILIP-1 可识别出自身免疫/炎症性疾病患者。RPD 血管性病因患者的 MCP-1 水平最高。包含 GFAP、MCP-1、p-tau181 和 sTREM2 的多变量模型可以准确识别出 89%的具有治疗反应性病因的 44 例 RPD 患者。神经退行性疾病的典型和快速进展性表现之间观察到的差异很小。
在具有异质性 RPD 病因的患者中，在发病时选择 CSF 生物标志物与病因诊断和治疗反应性相关。横断面生物标志物告知驱动快速进行性神经退行性疾病的机制的能力尚不清楚。
