Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer disease (AD) comes primarily from rodent models. However, unlike rodents, in which predominant extracranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Dynamic PET with 18F-THK5117, a tracer for tau pathology, was used to estimate the ventricular CSF time-activity as a biomarker for CSF clearance. We tested 3 hypotheses: extracranial CSF is detected at the superior turbinates; CSF clearance is reduced in AD; and CSF clearance is inversely associated with amyloid deposition. Methods: Fifteen subjects, 8 with AD and 7 normal control volunteers, were examined with 18F-THK5117. Ten subjects additionally underwent 11C-Pittsburgh compound B (11C-PiB) PET scanning, and 8 were 11C-PiB-positive. Ventricular time-activity curves of 18F-THK5117 were used to identify highly correlated time-activity curves from extracranial voxels. Results: For all subjects, the greatest density of CSF-positive extracranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinate CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET-measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.

中文翻译：

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用动态PET测量阿尔茨海默病中的脑脊液清除率。

支持减少脑脊液（CSF）清除率参与阿尔茨海默病（AD）病理生理的假说的证据主要来自啮齿动物模型。但是，与啮齿动物不同，在颅内，主要的颅外CSF散发是通过嗅觉神经穿过筛状板，而人类CSF清除途径却没有得到很好的表征。具有18F-THK5117（tau病理示踪剂）的动态PET用于评估心室CSF时间活性，作为CSF清除的生物标志物。我们测试了3个假设：在上鼻甲中检测到颅外CSF；AD中的CSF清除率降低；脑脊液清除率与淀粉样蛋白沉积成反比。方法：用18F-THK5117检查15名受试者，其中8名AD患者和7名正常对照志愿者。十名受试者另外接受了11C-匹兹堡化合物B（11C-PiB）PET扫描，其中8名11C-PiB阳性。18F-THK5117的心室时间活动曲线用于从颅外体素中识别高度相关的时间活动曲线。结果：对于所有受试者，CSF阳性颅外体素的最大密度在鼻甲中。示踪剂浓度分析证实了上鼻甲CSF信号强度较高。AD患者的心室示踪剂清除率降低了23％，而上鼻甲CSF出口部位减少了66％。心室脑脊液清除率与淀粉样蛋白沉积呈负相关。结论：人鼻甲是脑脊液清除系统的一部分。在AD中发现侧脑室和上鼻甲CSF清除异常。心室CSF清除率降低与脑淀粉样蛋白沉积增加有关。这些数据表明，PET测量的CSF清除率是AD和其他神经退行性疾病潜在兴趣的生物标记。