Selnes Per, Blennow Kaj, Zetterberg Henrik, Grambaite Ramune, Rosengren Lars, Johnsen Lisbeth, Stenset Vidar, Fladby Tormod
Department of Neurology, Akershus University Hospital, Norway.
Cerebrospinal Fluid Res. 2010 Jul 30;7:10. doi: 10.1186/1743-8454-7-10.
Alzheimer's disease (AD) and cerebrovascular disease (CVD) including chronic small vessel disease of the brain (SVD) are the most frequent causes of dementia. AD is associated with metabolism of amyloid precursor protein (APP) and low levels of amyloid-beta peptide (Abeta) X-42 in the cerebrospinal fluid (CSF). CVD and SVD are established risk factors for AD, brain white matter lesions (WML) are established surrogate markers for SVD and are also associated with reduced CSF AbetaX-42.A cohort survey was performed to examine whether SVD or acute CVD affects APP metabolism and to explore a potential association between WML and APP metabolism in two groups; cognitively impaired patients, subjective and mild (SCI and MCI) and stroke patients. Through measurements of CSF APP metabolite levels in patients with a wide range of WML volumes, this study aimed to determine how SVD influences APP metabolism.
Sixty-three patients were included: 37 with subjective cognitive impairment (SCI) or mild cognitive impairment (MCI) without stroke, and 26 after acute stroke. Chronic and acute WML volume and infarct volume were determined by magnetic resonance imaging (MRI) post-scan processing, and CSF levels of alpha- and beta-cleaved soluble APP (sAPP-alpha and sAPP-beta, AbetaX-38, AbetaX-40 and AbetaX-42) were determined. The Mann-Whitney test was used to compare the patient groups. Chronic and acute WML volumes, infarct volume, age, and sex were used as predictors for CSF biomarker levels in linear regression analysis.
CSF levels of sAPP-alpha and sAPP-beta were strongly correlated (r = 0.95, p < 0.001) and lower levels of these biomarkers were found in the stroke group than in the SCI/MCI group; median sAPP-alpha 499.5 vs. 698.0 ng/mL (p < 0.001), sAPP-beta 258.0 vs. 329.0 ng/mL (p < 0.005). CSF levels of sAPP-alpha, sAPP-beta, AbetaX-38, AbetaX-40 and AbetaX-42 were inversely correlated with chronic WML volume (p </= 0.005; p </= 0.01; p </= 0.01; p </= 0.05; p </= 0.05 respectively), but not with acute WML or infarct volumes.
Lower CSF levels of sAPP-alpha and sAPP-beta in the stroke group than in the SCI/MCI group and an inverse correlation with chronic WML indicate that ischemia lowers the levels of CSF sAPP metabolites and suggests that APP axonal transport or metabolism may be affected in SVD of the brain.
阿尔茨海默病（AD）和脑血管疾病（CVD），包括脑慢性小血管疾病（SVD），是痴呆最常见的病因。AD与淀粉样前体蛋白（APP）的代谢以及脑脊液（CSF）中淀粉样β肽（Aβ）X - 42水平降低有关。CVD和SVD是AD的既定风险因素，脑白质病变（WML）是SVD的既定替代标志物，也与CSF AβX - 42降低有关。进行了一项队列研究，以检查SVD或急性CVD是否影响APP代谢，并探讨两组中WML与APP代谢之间的潜在关联；认知受损患者，主观和轻度（SCI和MCI）以及中风患者。通过测量广泛WML体积患者的CSF APP代谢物水平，本研究旨在确定SVD如何影响APP代谢。
纳入63例患者：37例有主观认知障碍（SCI）或轻度认知障碍（MCI）且无中风，26例急性中风后患者。通过磁共振成像（MRI）扫描后处理确定慢性和急性WML体积以及梗死体积，并测定CSF中α - 和β - 裂解可溶性APP（sAPP - α和sAPP - β，AβX - 38，AβX - 40和AβX - 42）的水平。采用曼 - 惠特尼检验比较患者组。在线性回归分析中，慢性和急性WML体积、梗死体积、年龄和性别用作CSF生物标志物水平的预测因子。
sAPP - α和sAPP - β的CSF水平高度相关（r = 0.95，p < 0.001），中风组中这些生物标志物的水平低于SCI/MCI组；sAPP - α中位数为499.5 vs. 698.0 ng/mL（p < 0.001），sAPP - β为258.0 vs. 329.0 ng/mL（p < 0.005）。sAPP - α、sAPP - β、AβX - 38、AβX - 40和AβX - 42的CSF水平与慢性WML体积呈负相关（分别为p≤0.005；p≤0.01；p≤0.01；p≤0.05；p≤0.05），但与急性WML或梗死体积无关。
中风组中sAPP - α和sAPP - β的CSF水平低于SCI/MCI组，且与慢性WML呈负相关，表明缺血会降低CSF sAPP代谢物水平，并提示APP轴突运输或代谢可能在脑SVD中受到影响。
