Herukka Sanna-Kaisa, Rummukainen Jaana, Ihalainen Jouni, von Und Zu Fraunberg Mikael, Koivisto Anne M, Nerg Ossi, Puli Lakshman K, Seppälä Toni T, Zetterberg Henrik, Pyykkö Okko T, Helisalmi Seppo, Tanila Heikki, Alafuzoff Irina, Hiltunen Mikko, Rinne Jaakko, Soininen Hilkka, Jääskeläinen Juha E, Leinonen Ville
Unit of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
J Alzheimers Dis. 2015;46(1):261-9. doi: 10.3233/JAD-142862.
Amyloid-β (Aβ1 - 42), total tau (T-tau), and phosphorylated tau (P-tau181) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF.
To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF).
Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF.
ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1 - 42 and P-tau181 remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1 - 42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau181 (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1 - 42 levels than those six without amyloid pathology.
This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.
脑脊液（CSF）中的β淀粉样蛋白（Aβ1 - 42）、总tau蛋白（T-tau）和磷酸化tau蛋白（P-tau181）是阿尔茨海默病（AD）最有前景的生物标志物。然而，对于这些分子在活体大脑中的动态变化知之甚少。在转基因小鼠大脑中，可溶性Aβ随着年龄增长和Aβ病理进展而减少，脑脊液中情况类似。
评估人脑组织、脑室和腰椎脑脊液以及脑间质液（ISF）中与AD相关的病理变化之间的关系。
共11例疑似特发性正常压力脑积水患者接受了额叶皮质脑活检、24小时脑室内压力监测和微透析程序。对脑组织、脑脊液和脑间质液中的AD相关生物标志物进行分析。
脑间质液T-tau水平在最初12小时内大幅下降，然后趋于平稳直至实验结束。实验期间Aβ1 - 42和P-tau181保持稳定（n = 3）。脑间质液中的T-tau和P-tau高于脑室或腰椎脑脊液中的水平，而脑脊液和脑间质液样本中的Aβ1 - 42水平在相似范围内。脑间质液P-tau与脑室脑脊液T-tau（r = 0.70，p = 0.017）和P-tau181（r = 0.64，p = 0.034）相关。脑活检中有淀粉样蛋白病理改变的5例患者的脑间质液Aβ1 - 42水平往往低于无淀粉样蛋白病理改变的6例患者。
这是第一项在无明显脑损伤的人脑中报告脑间质液Aβ和tau水平的研究。所采用的设置能够从脑间质液中采样至少24小时，且不会因微透析程序而产生不良反应，从而在疾病的各个阶段跟踪活体大脑中AD发病机制关键分子的动态变化。
