Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40139, Bologna, Italy.
Department of Neurology, Ulm University Hospital, 89073, Ulm, Germany.
Alzheimers Res Ther. 2019 Dec 31;12(1):2. doi: 10.1186/s13195-019-0562-4.
In neurodegenerative dementias (NDs) such as prion disease, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD), protein misfolding leads to the tissue deposition of protein aggregates which, in turn, trigger neuroinflammation and neurodegeneration. Cerebrospinal fluid (CSF) biomarkers have the potential to reflect different aspects of these phenomena across distinct clinicopathological subtypes and disease stages.
We investigated CSF glial markers, namely chitotriosidase 1 (CHIT1), chitinase-3-like protein 1 (YKL-40) and glial fibrillary acidic protein (GFAP) in prion disease subtypes (n = 101), AD (n = 40), clinicopathological subgroups of FTLD (n = 72), and controls (n = 40) using validated, commercially available ELISA assays. We explored glial biomarker levels' associations with disease variables and neurodegenerative CSF biomarkers and evaluated their diagnostic accuracy. The genotype of the CHIT1 rs3831317 polymorphic site was also analyzed.
Each ND group showed increased levels of CHIT1, YKL-40, and GFAP compared to controls with a difference between prion disease and AD or FTLD limited to YKL-40, which showed higher values in the former group. CHIT1 levels were reduced in both heterozygotes and homozygotes for the CHIT1 24-bp duplication (rs3831317) in FTLD and controls, but this effect was less significant in AD and prion disease. After stratification according to molecular subgroups, we demonstrated (i) an upregulation of all glial markers in Creutzfeldt-Jakob disease VV2 compared to other disease subtypes, (ii) a difference in CHIT1 levels between FTLD with TAU and TDP43 pathology, and (iii) a marked increase of YKL-40 in FTLD with amyotrophic lateral sclerosis (ALS) in comparison with FTLD without ALS. In prion disease, glial markers correlated with disease stage and were already elevated in one pre-symptomatic case of Gerstmann-Sträussler-Scheinker disease. Regarding the diagnostic value, YKL-40 was the only glial marker that showed a moderate accuracy in the distinction between controls and NDs.
NDs share a CSF profile characterized by increased levels of CSF CHIT1, YKL-40, and GFAP, which likely reflects a common neuroinflammatory response to protein misfolding and aggregation. CSF glial markers of neuroinflammation demonstrate limited diagnostic value but have some potential for monitoring the clinical and, possibly, preclinical phases of NDs.
在神经退行性痴呆（NDs）中，如朊病毒病、阿尔茨海默病（AD）和额颞叶变性（FTLD），蛋白质错误折叠导致蛋白质聚集体在组织中沉积，进而引发神经炎症和神经退行性变。脑脊液（CSF）生物标志物有可能反映不同临床病理亚型和疾病阶段的这些现象的不同方面。
我们使用经过验证的商业 ELISA 检测试剂盒，研究了朊病毒病亚型（n=101）、AD（n=40）、FTLD 的临床病理亚组（n=72）和对照组（n=40）的 CSF 神经胶质标志物，即壳三糖苷酶 1（CHIT1）、壳多糖酶 3 样蛋白 1（YKL-40）和神经胶质纤维酸性蛋白（GFAP）。我们探讨了神经胶质生物标志物水平与疾病变量和神经退行性 CSF 生物标志物的相关性，并评估了它们的诊断准确性。还分析了 CHIT1 rs3831317 多态性位点的基因型。
与对照组相比，每个 NDs 组的 CHIT1、YKL-40 和 GFAP 水平均升高，朊病毒病与 AD 或 FTLD 之间的差异仅限于 YKL-40，前者组的 YKL-40 水平更高。在 FTLD 和对照组中，CHIT1 水平在 24 碱基对重复（rs3831317）的 CHIT1 杂合子和纯合子中均降低，但在 AD 和朊病毒病中这种效应不明显。根据分子亚组进行分层后，我们证明了（i）与其他疾病亚型相比，Creutzfeldt-Jakob 病 VV2 中所有神经胶质标志物均上调，（ii）FTLD 中 TAU 和 TDP43 病理之间的 CHIT1 水平差异，以及（iii）与无肌萎缩侧索硬化症（ALS）的 FTLD 相比，FTLD 中 YKL-40 的显著增加。在朊病毒病中，神经胶质标志物与疾病阶段相关，并且在格斯特曼-施特劳斯勒-谢因克病的一个前症状病例中已经升高。关于诊断价值，YKL-40 是唯一一种在区分对照组和 NDs 方面具有中等准确性的神经胶质标志物。
NDs 具有相似的 CSF 特征，其特征为 CSF CHIT1、YKL-40 和 GFAP 水平升高，这可能反映了对蛋白质错误折叠和聚集的共同神经炎症反应。神经炎症 CSF 神经胶质标志物具有有限的诊断价值，但具有监测 NDs 的临床和可能的临床前阶段的一些潜力。
