Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
JAMA Neurol. 2019 Feb 1;76(2):187-193. doi: 10.1001/jamaneurol.2018.3459.
Accumulating data suggest that elevated cerebrospinal fluid (CSF) neurofilament light (NfL) and neurogranin (Ng) levels are associated with cognitive decline and may be useful markers of neurodegeneration. However, to our knowledge, previous studies have not assessed these CSF markers in the community, evaluated them with regards to risk of mild cognitive impairment (MCI), or compared their prognostic value with CSF total tau (T-tau) or phosphorylated tau (P-tau).
To determine (1) whether CSF NfL and Ng levels were associated with risk of MCI, (2) the effect size of these markers compared with CSF T-tau or P-tau for risk of MCI, and (3) whether CSF amyloid-β (Aβ42) modified these associations.
DESIGN, SETTING AND PARTICIPANTS: The analyses included 648 participants without cognitive impairment who were enrolled into the prospective population-based Mayo Clinic Study of Aging between January 2004 and December 2015 with available CSF data and at least 1 follow-up visit. Participants were followed up for a median of 3.8 years (interquartile range, 2.6-5.4 years). The CSF NfL and Ng levels were measured using an in-house sandwich enzyme-linked immunosorbent assay. The CSF Aβ42, T-tau, and P-tau levels were measured with automated electrochemiluminescence immunoassays. Cox proportional hazards models, with age as the timescale, were used to assess the association between CSF NfL, Ng, Aβ42, T-tau, or P-tau with risk of MCI after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index. To examine CSF Aβ42 as an effect modifier, it was categorized into tertiles; the bottom tertile was defined as having elevated brain amyloid.
Risk of MCI.
At baseline, the median age of the 648 participants without cognitive impairment was 72.3 years (range, 50.7-95.3 years) and 366 (56.5%) were men; 96 (14.8%) developed incident MCI. Compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3.1-fold increased risk of MCI (hazard ratio, 3.13; 95% CI, 1.36-7.18) in multivariate models. Neither CSF T-tau, P-tau, nor Ng was associated with risk of MCI. There was no interaction between Aβ42 and CSF NfL for risk of MCI.
Elevated CSF NfL levels but not CSF T-tau, P-tau or Ng are a risk factor for MCI in a community population and are independent of brain amyloid.
越来越多的数据表明，脑脊液（CSF）神经丝轻链（NfL）和神经颗粒蛋白（Ng）水平升高与认知能力下降有关，并且可能是神经退行性变的有用标志物。然而，据我们所知，之前的研究并未在社区中评估这些 CSF 标志物，也未评估它们在轻度认知障碍（MCI）风险方面的作用，或者比较它们与 CSF 总 tau（T-tau）或磷酸化 tau（P-tau）的预后价值。
确定（1）CSF NfL 和 Ng 水平是否与 MCI 风险相关，（2）与 CSF T-tau 或 P-tau 相比，这些标志物的效应大小与 MCI 风险相关，以及（3）CSF 淀粉样蛋白-β（Aβ42）是否改变了这些关联。
设计、地点和参与者：分析纳入了 648 名无认知障碍的参与者，他们于 2004 年 1 月至 2015 年 12 月期间参加了前瞻性基于人群的梅奥诊所老龄化研究，并具有可用的 CSF 数据和至少 1 次随访。参与者的中位随访时间为 3.8 年（四分位距，2.6-5.4 年）。使用内部夹心酶联免疫吸附试验测量 CSF NfL 和 Ng 水平。使用自动化电化学发光免疫分析测量 CSF Aβ42、T-tau 和 P-tau 水平。使用 Cox 比例风险模型，以年龄为时间尺度，调整性别、教育、载脂蛋白 E 基因型和 Charlson 合并症指数后，评估 CSF NfL、Ng、Aβ42、T-tau 或 P-tau 与 MCI 风险之间的关联。为了检验 CSF Aβ42 作为效应修饰物，将其分为三分位；底部三分位定义为脑淀粉样蛋白升高。
MCI 风险。
在基线时，648 名无认知障碍的参与者的中位年龄为 72.3 岁（范围，50.7-95.3 岁），其中 366 名（56.5%）为男性；96 名（14.8%）发生了新发 MCI。与最低四分位数相比，CSF NfL 的最高四分位数与 MCI 的风险增加 3.1 倍相关（风险比，3.13；95%CI，1.36-7.18），在多变量模型中。CSF T-tau、P-tau 或 Ng 均与 MCI 风险无关。CSF Aβ42 与 CSF NfL 之间没有 MCI 风险的相互作用。
在社区人群中，升高的 CSF NfL 水平但不是 CSF T-tau、P-tau 或 Ng 是 MCI 的一个危险因素，并且独立于脑淀粉样蛋白。
