评估血脑屏障功能障碍及其与阿尔茨海默病病理、认知障碍和神经炎症的关联。
Assessing blood-brain barrier dysfunction and its association with Alzheimer's pathology, cognitive impairment and neuroinflammation.
作者信息
Preis Lukas, Villringer Kersten, Brosseron Frederic, Düzel Emrah, Jessen Frank, Petzold Gabor C, Ramirez Alfredo, Spottke Annika, Fiebach Jochen B, Peters Oliver
机构信息
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin-Institute of Psychiatry and Psychotherapy, Berlin, Germany.
Centre for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12200, Berlin, Germany.
出版信息
Alzheimers Res Ther. 2024 Jul 31;16(1):172. doi: 10.1186/s13195-024-01529-1.
BACKGROUND
Blood-brain barrier (BBB) alterations may contribute to AD pathology through various mechanisms, including impaired amyloid-β (Aβ) clearance and neuroinflammation. Soluble platelet-derived growth factor receptor beta (sPDGFRβ) has emerged as a potential biomarker for BBB integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a direct assessment of BBB permeability. However, the relationship between BBB dysfunction, cognitive impairment, and AD pathology remains unclear, with inconsistent findings in the literature.
METHODS
We conducted a cross-sectional study using data from the DELCODE and DESCRIBE cohorts to investigate BBB dysfunction in participants with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia. BBB function was assessed using DCE-MRI and sPDGFRβ levels in cerebrospinal fluid and AD biomarkers Aβ and tau were measured. In a subset of patients, the CSF/plasma-ratio of albumin (QAlb) as a standard marker of BBB integrity and markers of neuroinflammation were analyzed.
RESULTS
91 participants (NC: 44, MCI: 21, AD: 26) were included in the analysis. The average age was 74.4 years, 42% were female. Increased hippocampal BBB disruption was observed in the AD-group (K: 0.55 × 10 min ± 0.74 × 10 min) but not the MCI-group (K: 0.177 × 10 min ± 0.22 × 10 min), compared to the NC group (K: 0.19 × 10 min ± 0.37 × 10 min, p < .01). sPDGFRβ was not significantly different between the cognitive groups. However, sPDGFRβ levels were significantly associated with age (r = .33, p < .01), independent of vascular risk factors. Further, sPDGFRβ showed significant positive associations with soluble Aβ levels (Aβ40: r = .57, p < .01; Aβ42: r = .39, p < .01) and YKL-40 (r = .53, p < .01), a marker of neuroinflammation. sPDGFRβ/DCE-MRI was not associated with overall AD biomarker positivity or APOE-status.
CONCLUSION
In dementia, but not MCI, hippocampal BBB disruption was observed. sPDGFRβ increased with age and was associated with neuroinflammation independent of cognitive impairment. The association between Aβ and sPDGFRβ may indicate a bidirectional relationship reflecting pericytes' clearance of soluble Aβ and/or vasculotoxic properties of Aβ.
背景
血脑屏障（BBB）改变可能通过多种机制导致阿尔茨海默病（AD）病理变化，包括淀粉样β蛋白（Aβ）清除受损和神经炎症。可溶性血小板衍生生长因子受体β（sPDGFRβ）已成为血脑屏障完整性的潜在生物标志物。动态对比增强磁共振成像（DCE-MRI）可直接评估血脑屏障通透性。然而，血脑屏障功能障碍、认知障碍和AD病理之间的关系仍不明确，文献中的研究结果并不一致。
方法
我们进行了一项横断面研究，使用来自DELCODE和DESCRIBE队列的数据，调查认知正常（NC）、轻度认知障碍（MCI）和AD痴呆患者的血脑屏障功能障碍情况。使用DCE-MRI评估血脑屏障功能，并测量脑脊液中的sPDGFRβ水平以及AD生物标志物Aβ和tau。在一部分患者中，分析了作为血脑屏障完整性标准标志物的脑脊液/血浆白蛋白比值（QAlb）和神经炎症标志物。
结果
91名参与者（NC：44名，MCI：21名，AD：26名）纳入分析。平均年龄为74.4岁，42%为女性。与NC组（K：0.19×10⁻³min⁻¹±0.37×10⁻³min⁻¹，p＜0.01）相比，AD组（K：0.55×10⁻³min⁻¹±0.74×10⁻³min⁻¹）海马区血脑屏障破坏增加，而MCI组（K：0.177×10⁻³min⁻¹±0.22×10⁻³min⁻¹）未观察到。认知组之间sPDGFRβ无显著差异。然而，sPDGFRβ水平与年龄显著相关（r = 0.33，p＜0.01），与血管危险因素无关。此外，sPDGFRβ与可溶性Aβ水平（Aβ40：r = 0.57，p＜0.01；Aβ42：r = 0.39，p＜0.01）和神经炎症标志物YKL-40（r = 0.53，p＜0.01）呈显著正相关。sPDGFRβ/DCE-MRI与总体AD生物标志物阳性或APOE状态无关。
结论
在痴呆患者中观察到海马区血脑屏障破坏，而MCI患者中未观察到。sPDGFRβ随年龄增加，且与认知障碍无关的神经炎症相关。Aβ与sPDGFRβ之间的关联可能表明一种双向关系，反映了周细胞对可溶性Aβ的清除和/或Aβ的血管毒性特性。
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