Department of Neurology, University Medical Centre Ljubljana, Ljubljana 1000, Slovenia; Faculty of Pharmacy, University of Ljubljana, Ljubljana 1000, Slovenia.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg 413 45, Sweden; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15215, USA.
Mult Scler Relat Disord. 2024 Oct;90:105801. doi: 10.1016/j.msard.2024.105801. Epub 2024 Aug 5.
Mechanisms underlying neurodegeneration in multiple sclerosis (MS) remain poorly understood but mostly implicate molecular pathways that are not unique to MS. Recently detected tau seeding activity in MS brain tissues corroborates previous neuropathological reports of hyperphosphorylated tau (p-tau) accumulation in secondary and primary progressive MS (PPMS). We aimed to investigate whether aberrant tau phosphorylation can be detected in the cerebrospinal fluid (CSF) of MS patients by using novel ultrasensitive immunoassays for different p-tau biomarkers.
CSF samples of patients with MS (n = 55) and non-inflammatory neurological disorders (NIND, n = 31) were analysed with in-house Single molecule array (Simoa) assays targeting different tau phosphorylation sites (p-tau181, p-tau212, p-tau217 and p-tau231). Additionally, neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were measured with a multiplexed Simoa assay. Patients were diagnosed with clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS, n = 21) and PPMS (n = 24) according to the 2017 McDonald criteria and had MRI, EDSS and basic CSF analysis performed at the time of diagnosis.
Patients with progressive disease course had between 1.4-fold (p-tau217) and 2.2-fold (p-tau212) higher p-tau levels than relapsing MS patients (PPMS compared with CIS + RRMS, p < 0.001 for p-tau181, p-tau212, p-tau231 and p = 0.042 for p-tau217). P-tau biomarkers were associated with disease duration (ρ=0.466-0.622, p < 0.0001), age (ρ=0.318-0.485, p < 0.02, all but p-tau217) and EDSS at diagnosis and follow-up (ρ=0.309-0.440, p < 0.02). In addition, p-tau biomarkers correlated with GFAP (ρ=0.517-0.719, p ≤ 0.0001) but not with the albumin quotient, CSF cell count or NFL. Patients with higher MRI lesion load also had higher p-tau levels p ≤ 0.01 (<10 vs. ≥ 10 lesions, all p ≤ 0.01).
CSF concentrations of novel p-tau biomarkers point to a higher degree of tau phosphorylation in PPMS than in RRMS. Associations with age, disease duration and EDSS suggest this process increases with disease severity; however, replication of these results in larger cohorts is needed to further clarify the relevance of altered tau phosphorylation throughout the disease course in MS.
多发性硬化症（MS）中神经退行性变的机制仍知之甚少，但大多涉及并非 MS 所特有的分子途径。最近在 MS 脑组织中检测到的 tau 种籽活性证实了先前关于继发性和原发性进行性 MS（PPMS）中过度磷酸化 tau（p-tau）积累的神经病理学报告。我们旨在通过使用针对不同 p-tau 生物标志物的新型超敏免疫分析来检测 MS 患者脑脊液（CSF）中是否存在异常 tau 磷酸化。
对 55 例 MS 患者（n = 55）和非炎症性神经疾病（NIND，n = 31）的 CSF 样本进行了分析，采用了针对不同 tau 磷酸化位点（p-tau181、p-tau212、p-tau217 和 p-tau231）的内部单分子阵列（Simoa）分析。此外，还使用多重 Simoa 分析测量了神经丝轻链（NFL）和神经胶质纤维酸性蛋白（GFAP）。根据 2017 年 McDonald 标准，患者被诊断为临床孤立综合征（CIS，n = 10）、复发缓解型 MS（RRMS，n = 21）和 PPMS（n = 24），并在诊断时进行了 MRI、EDSS 和基本 CSF 分析。
与复发型 MS 患者相比（PPMS 与 CIS + RRMS 相比，p < 0.001 用于 p-tau181、p-tau212、p-tau231 和 p = 0.042 用于 p-tau217），进展性疾病患者的 p-tau 水平高 1.4 倍（p-tau217）至 2.2 倍（p-tau212）。p-tau 生物标志物与疾病持续时间（ρ=0.466-0.622，p < 0.0001）、年龄（ρ=0.318-0.485，p < 0.02，均除了 p-tau217）和诊断时及随访时的 EDSS 相关（ρ=0.309-0.440，p < 0.02）。此外，p-tau 生物标志物与 GFAP 相关（ρ=0.517-0.719，p ≤ 0.0001），但与白蛋白商数、CSF 细胞计数或 NFL 无关。MRI 病变负荷较高的患者 p-tau 水平也较高（p ≤ 0.01（<10 与≥10 个病变相比，均 p ≤ 0.01）。
新型 p-tau 生物标志物的 CSF 浓度表明，PPMS 中 tau 的磷酸化程度高于 RRMS。与年龄、疾病持续时间和 EDSS 的相关性表明，这一过程随着疾病严重程度的增加而增加；然而，需要在更大的队列中复制这些结果，以进一步阐明 MS 病程中改变的 tau 磷酸化的相关性。
