特发性正常压力脑积水的脑脊液生物标志物和脑活检结果
Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus.
作者信息
Pyykkö Okko T, Lumela Miikka, Rummukainen Jaana, Nerg Ossi, Seppälä Toni T, Herukka Sanna-Kaisa, Koivisto Anne M, Alafuzoff Irina, Puli Lakshman, Savolainen Sakari, Soininen Hilkka, Jääskeläinen Juha E, Hiltunen Mikko, Zetterberg Henrik, Leinonen Ville
机构信息
Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
Department of Pathology, Kuopio University Hospital, Kuopio, Finland.
出版信息
PLoS One. 2014 Mar 17;9(3):e91974. doi: 10.1371/journal.pone.0091974. eCollection 2014.
BACKGROUND
The significance of amyloid precursor protein (APP) and neuroinflammation in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) is unknown.
OBJECTIVE
To investigate the role of soluble APP (sAPP) and amyloid beta (Aβ) isoforms, proinflammatory cytokines, and biomarkers of neuronal damage in the cerebrospinal fluid (CSF) in relation to brain biopsy Aβ and hyperphosphorylated tau (HPτ) findings.
METHODS
The study population comprised 102 patients with possible NPH with cortical brain biopsies, ventricular and lumbar CSF samples, and DNA available. The final clinical diagnoses were: 53 iNPH (91% shunt-responders), 26 AD (10 mixed iNPH+AD), and 23 others. Biopsy samples were immunostained against Aβ and HPτ. CSF levels of AD-related biomarkers (Aβ42, p-tau, total tau), non-AD-related Aβ isoforms (Aβ38, Aβ40), sAPP isoforms (sAPPα, sAPPβ), proinflammatory cytokines (several interleukins (IL), interferon-gamma, monocyte chemoattractant protein-1, tumor necrosis factor-alpha) and biomarkers of neuronal damage (neurofilament light and myelin basic protein) were measured. All patients were genotyped for APOE.
RESULTS
Lumbar CSF levels of sAPPα were lower (p<0.05) in patients with shunt-responsive iNPH compared to non-iNPH patients. sAPPβ showed a similar trend (p = 0.06). CSF sAPP isoform levels showed no association to Aβ or HPτ in the brain biopsy. Quantified Aβ load in the brain biopsy showed a negative correlation with CSF levels of Aβ42 in ventricular (r = -0.295, p = 0.003) and lumbar (r = -0.356, p = 0.01) samples, while the levels of Aβ38 and Aβ40 showed no correlation. CSF levels of proinflammatory cytokines and biomarkers of neuronal damage did not associate to the brain biopsy findings, diagnosis, or shunt response. Higher lumbar/ventricular CSF IL-8 ratios (p<0.001) were seen in lumbar samples collected after ventriculostomy compared to the samples collected before the procedure.
CONCLUSIONS
The role of sAPP isoforms in iNPH seems to be independent from the amyloid cascade. No neuroinflammatory background was observed in iNPH or AD.
背景
淀粉样前体蛋白（APP）和神经炎症在特发性正常压力脑积水（iNPH）和阿尔茨海默病（AD）中的意义尚不清楚。
目的
研究脑脊液（CSF）中可溶性APP（sAPP）和淀粉样β（Aβ）亚型、促炎细胞因子以及神经元损伤生物标志物与脑活检Aβ和高磷酸化tau（HPτ）结果的关系。
方法
研究人群包括102例可能患有NPH的患者，他们均进行了皮质脑活检、脑室和腰椎CSF样本采集，且有可用的DNA。最终临床诊断为：53例iNPH（91%分流反应者）、26例AD（10例混合性iNPH+AD）和23例其他疾病。活检样本进行Aβ和HPτ免疫染色。检测CSF中AD相关生物标志物（Aβ42、p-tau、总tau）、非AD相关Aβ亚型（Aβ38、Aβ40）、sAPP亚型（sAPPα、sAPPβ）、促炎细胞因子（几种白细胞介素（IL）、干扰素-γ、单核细胞趋化蛋白-1、肿瘤坏死因子-α）以及神经元损伤生物标志物（神经丝轻链和髓鞘碱性蛋白）的水平。所有患者均进行APOE基因分型。
结果
与非iNPH患者相比，分流反应性iNPH患者腰椎CSF中sAPPα水平较低（p<0.05）。sAPPβ呈现类似趋势（p = 0.06）。CSF中sAPP亚型水平与脑活检中的Aβ或HPτ无关联。脑活检中定量的Aβ负荷与脑室（r = -0.295，p = 0.003）和腰椎（r = -0.356，p = 0.01）样本中CSF的Aβ42水平呈负相关，而Aβ38和Aβ40水平无相关性。CSF中促炎细胞因子水平和神经元损伤生物标志物与脑活检结果、诊断或分流反应均无关联。与脑室造瘘术前采集的样本相比，脑室造瘘术后采集的腰椎样本中腰椎/脑室CSF的IL-8比值更高（p<0.001）。
结论
sAPP亚型在iNPH中的作用似乎独立于淀粉样蛋白级联反应。在iNPH或AD中未观察到神经炎症背景。
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