Background

Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome.

Methods

We did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses.

Findings

Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3·6 years (SD 1·6, range 0·6–9·2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0·83 (95% CI 0·76–0·91) in the prodromal group and 0·94 (0·90–0·97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1·04-fold risk of clinical progression (95% CI 1·01–1·07; p=0·0034). Plasma NfL concentrations showed an annual increase of 3·0% (95% CI 0·4–5·8) per year in the asymptomatic non-progressors group, 11·5% (4·9–18·5) per year in the asymptomatic progressors group, and 16·0% (8·4–24·0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24·3% (15·3–34·1).

Interpretation

Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials.

Funding

AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, National Institute for Health Research, EU Joint Programme–Neurodegenerative Disease Research, Alzheimer's society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit, and NHS National Institute of Health Research Applied Research Collaborations East of England, UK.

中文翻译：

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唐氏综合症成人的诊断和预后表现以及血浆神经丝轻链浓度的纵向变化：一项队列研究

背景

患有唐氏综合症的成年人患阿尔茨海默病的风险极高，但在这一人群中诊断阿尔茨海默病具有挑战性。我们的目的是验证血浆神经丝轻链 (NfL) 在诊断唐氏综合症症状性阿尔茨海默病中的临床效用，评估其预后价值，并确定成人唐氏综合症患者的纵向变化。

方法

我们进行了一项多中心队列研究，包括从法国、德国、西班牙、英国和美国的六家医院和大学医疗中心招募的患有唐氏综合症的成年人（≥18岁），对他们进行了评估、随访和提供至少两个血浆样本。当地临床医生将参与者分类为无症状（即临床上不怀疑阿尔茨海默病）、前驱阿尔茨海默病或阿尔茨海默病痴呆。我们将随访期间沿着阿尔茨海默病连续体进展的个体分类为进展者。对血浆样本进行回顾性分析；使用用于生物标志物检测的商业试剂盒集中测量 NfL 浓度。我们使用方差分析来评估基线 NfL 浓度的差异，使用 Cox 回归来研究其预后价值，并使用线性混合模型来估计纵向变化。为了解释潜在的混杂因素，我们将年龄、性别和智力障碍作为协变量纳入分析。

发现

2010年8月2日至2019年7月16日期间，我们分析了236名唐氏综合症患者的608份样本：165人（70%）无症状，32人（14%）患有前驱阿尔茨海默病，29人（12%）患有阿尔茨海默病痴呆; 十 [4%] 参与者被排除，因为他们的分类不确定。平均随访时间为 3·6 年（SD 1·6，范围 0·6–9·2）。基线血浆 NfL 浓度显示前驱组受试者工作特征曲线下面积为 0·83 (95% CI 0·76–0·91)，痴呆组受试者工作特征曲线下面积为 0·94 (0·90–0·97)用于区分无症状的参与者。基线 NfL 浓度增加 1 pg/mL 与临床进展风险增加 1·04 倍相关（95% CI 1·01–1·07；p=0·0034）。血浆 NfL 浓度在无症状非进展组中每年增加 3·0% (95% CI 0·4–5·8)，在无症状非进展组中每年增加 11·5% (4·9–18·5)。无症状进展者组，前驱阿尔茨海默病进展者组每年有 16·0% (8·4–24·0)。在患有阿尔茨海默病痴呆的参与者中，NfL 浓度平均增加了 24·3% (15·3–34·1)。

解释

血浆 NfL 浓度对于唐氏综合症中的症状性阿尔茨海默氏病具有出色的诊断和预后性能。血浆 NfL 的纵向轨迹支持其在临床试验中用作治疗诊断标记。

资金

AC Immune、La Caixa 基金会、Instituto de Salud Carlos III、国家老龄化研究所、Wellcome Trust、Jérôme Lejeune 基金会、医学研究委员会、国家健康研究所、欧盟神经退行性疾病研究联合计划、阿尔茨海默病协会、Deutsche Forschungsgemeinschaft、Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit 和英国东英格兰 NHS 国家卫生研究院应用研究合作机构。