Memory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant Pau, 08025, Barcelona, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain.
Mol Neurodegener. 2020 Aug 17;15(1):46. doi: 10.1186/s13024-020-00398-0.
Alzheimer's disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging).
This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ, CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([F]-fluorodeoxyglucose positron emission tomography).
Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r = 0.2, p = 0.003), adults with DS (r = 0.4, p < 0.0001) and sporadic AD (r = 0.4, p < 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aβ (r > 0.3, p < 0.006), low CSF t-tau (r > 0.3, p < 0.001), increased cortical atrophy (p < 0.05) and reduced glucose metabolism (p < 0.05).
Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.
阿尔茨海默病（AD）是唐氏综合征（DS）患者死亡的主要原因。DS 人群中迫切需要 AD 的客观标志物，以改善早期诊断和监测疾病进展。NPTX2 最近作为散发性 AD 患者阿尔茨海默病相关抑制回路功能障碍的有前途的脑脊液（CSF）生物标志物出现。本研究的目的是评估 NPTX2 在 DS 成人的 CSF 中的水平，并探讨 NPTX2 与 CSF 中 PV 中间神经元受体 GluA4 以及现有的 AD 生物标志物（CSF 和神经影像学）之间的关系。
这是一项横断面、回顾性研究，纳入了无症状 AD（aDS，n=49）、前驱 AD（pDS，n=18）和 AD 痴呆（dDS，n=27）的 DS 成人患者。还纳入了非三体型对照者（n=34）和散发性 AD 痴呆患者（sAD，n=40）作为对照。我们根据临床诊断和智力障碍程度比较了 CSF NPTX2 的组间差异。我们确定了 CSF NPTX2 水平与年龄、认知表现（CAMCOG、自由和线索选择性提醒、语义口头流畅性）、CSF 中 PV 中间神经元标志物（GluA4）和核心 AD 生物标志物（CSF Aβ、CSF t-tau、皮质萎缩（磁共振成像）和葡萄糖代谢[F]-氟脱氧葡萄糖正电子发射断层扫描）之间的关系。
与对照组相比，所有 AD 阶段的 DS 患者的平均 CSF NPTX2 水平均降低；aDS（0.6 倍，adj.p<0.0001）、pDS（0.5 倍，adj.p<0.0001）和 dDS（0.3 倍，adj.p<0.0001）。这种降低与散发性 AD 观察到的降低相似（0.5 倍，adj.p<0.0001）。CSF NPTX2 水平与年龄（p=0.6）、智力障碍（p=0.7）或认知表现（均 p>0.07）无关。在所有临床组中，低 CSF NPTX2 水平与低 GluA4 相关；对照组（r=0.2，p=0.003）、DS 成人（r=0.4，p<0.0001）和散发性 AD（r=0.4，p<0.0001）。在 DS 成人中，低 CSF NPTX2 水平与低 CSF Aβ（r>0.3，p<0.006）、低 CSF t-tau（r>0.3，p<0.001）、皮质萎缩增加（p<0.05）和葡萄糖代谢减少（p<0.05）相关。
脑脊液 NPTX2 水平降低，一种与抑制回路功能相关的蛋白质，在散发性和遗传性 AD 中都很常见。CSF NPTX2 是 DS 成人中早期 AD 相关变化的有前途的 CSF 替代标志物。
