Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
Department of Clinical Neurosciences, Cambridge Centre for Frontotemporal Dementia and Related Disorders, University of Cambridge, Cambridge, UK.
J Neurol. 2024 Dec;271(12):7572-7582. doi: 10.1007/s00415-024-12700-x. Epub 2024 Oct 3.
Growing evidence supports the value of neurofilament light (NfL) as a prognostic biomarker in premanifest Huntington's disease (HD). To date, however, there has been no longitudinal study exceeding 3 years examining either its serial dynamics or predictive power in HD. We aimed to conduct the first such study.
Serum NfL was sampled using ultrasensitive immunoassay at four timepoints across a 14-year period in a cohort of HD gene carriers (n = 21) and controls (n = 14). Gene carriers were premanifest at baseline. Clinical features of HD were evaluated by Unified Huntington's Disease Rating Scale (UHDRS TMS), Montreal Cognitive Assessment (MoCA), Trail A/B task, Symbol Digit Modalities Task and semantic/phonemic fluency tasks.
14/21 HD gene carriers converted to prodromal or manifest disease by the final timepoint ("converters"). At baseline and each subsequent timepoint, NfL levels were higher in converters than in non-converters and controls (p = < 0.001-0.03, η = 0.25-0.66). The estimated rate of change in NfL was higher in converters than in non-converters (p = 0.03) and controls (p = 0.001). Baseline NfL was able to discriminate converters from non-converters (area under curve = 1.000, p = 0.003). A higher rate of change in NfL was predictive of more severe motor (UHDRS-TMS p = 0.007, β = 0.711, R = 0.468) and cognitive deficits (MoCA p = 0.007, β = - 0.798, R = 0.604; Trail B, p = 0.007, β = 0.772, R = 0.567; phonemic fluency p = 0.035, β = - 0.632, R = 0.345).
Our data suggest that (1) NfL longitudinal dynamics in premanifest/transitional HD are non-constant; rising faster in those closer to disease onset, and (2) NfL can identify individuals at risk of conversion to manifest disease and predict clinical trajectory, > 10 years from disease onset.
越来越多的证据支持神经丝轻链（NfL）作为前驱期亨廷顿病（HD）的预后生物标志物的价值。然而，迄今为止，尚无超过 3 年的纵向研究检查其在 HD 中的连续动态或预测能力。我们旨在进行首次此类研究。
使用超敏免疫测定法，在 14 年的时间内，在 HD 基因携带者（n=21）和对照组（n=14）的四个时间点采集血清 NfL。基因携带者在基线时处于前驱期。使用统一亨廷顿病评定量表（UHDRS TMS）、蒙特利尔认知评估（MoCA）、Trail A/B 任务、符号数字模态任务和语义/语音流畅性任务评估 HD 的临床特征。
14/21 名 HD 基因携带者在最后一个时间点转化为前驱期或显性疾病（“转化者”）。在基线和随后的每个时间点，转化者的 NfL 水平均高于非转化者和对照组（p<0.001-0.03，η=0.25-0.66）。转化者的 NfL 变化率高于非转化者（p=0.03）和对照组（p=0.001）。基线 NfL 能够区分转化者和非转化者（曲线下面积=1.000，p=0.003）。NfL 变化率较高可预测更严重的运动（UHDRS-TMS p=0.007，β=0.711，R=0.468）和认知缺陷（MoCA p=0.007，β=-0.798，R=0.604；Trail B，p=0.007，β=0.772，R=0.567；语音流畅性 p=0.035，β=-0.632，R=0.345）。
我们的数据表明：（1）前驱期/过渡期 HD 中 NfL 的纵向动态是非恒定的；在更接近疾病发作的患者中，其上升速度更快；（2）NfL 可以识别出有转化为显性疾病风险的个体，并预测临床轨迹，距疾病发作>10 年。
