Assessing blood-brain barrier dysfunction and its association with Alzheimer's pathology, cognitive impairment and neuroinflammation.

IF 7.9 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's Research & Therapy Pub Date : 2024-07-31 DOI:10.1186/s13195-024-01529-1

Lukas Preis, Kersten Villringer, Frederic Brosseron, Emrah Düzel, Frank Jessen, Gabor C Petzold, Alfredo Ramirez, Annika Spottke, Jochen B Fiebach, Oliver Peters

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Abstract

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^trans: 0.55 × 10^- 3 min^- 1 ± 0.74 × 10^- 3 min^- 1) but not the MCI-group (K^trans: 0.177 × 10^- 3 min^- 1 ± 0.22 × 10^- 3 min^- 1), compared to the NC group (K^trans: 0.19 × 10^- 3 min^- 1 ± 0.37 × 10^- 3 min^- 1, 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.

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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。

背景：血脑屏障（BBB）的改变可能会通过各种机制导致注意力缺失症的病理变化，包括淀粉样蛋白-β（Aβ）清除障碍和神经炎症。可溶性血小板衍生生长因子受体β（sPDGFRβ）已成为BBB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 BBB 的通透性。然而，BBB功能障碍、认知障碍和AD病理学之间的关系仍不清楚，文献中的研究结果也不一致：我们利用 DELCODE 和 DESCRIBE 队列的数据开展了一项横断面研究，调查认知正常（NC）、轻度认知障碍（MCI）和 AD 痴呆参与者的 BBB 功能障碍。使用 DCE-MRI 评估了 BBB 功能，并测量了脑脊液中的 sPDGFRβ 水平和 AD 生物标志物 Aβ 和 tau。在一部分患者中，还分析了脑脊液/血浆白蛋白比率（QAlb）（BBB完整性的标准标志物）和神经炎症标志物：91名参与者（NC：44人，MCI：21人，AD：26人）参与了分析。平均年龄为 74.4 岁，42% 为女性。与 NC 组（Ktrans：0.19 × 10- 3 min- 1 ± 0.37 × 10- 3 min- 1，P 结论：与 MCI 组（Ktrans：0.177 × 10- 3 min- 1 ± 0.22 × 10- 3 min-1）相比，AD 组（Ktrans：0.55 × 10- 3 min- 1 ± 0.74 × 10- 3 min-1）观察到海马 BBB 破坏增加，而 MCI 组（Ktrans：0.177 × 10- 3 min- 1 ± 0.22 × 10- 3 min-1）没有观察到：sPDGFRβ随年龄增长而增加，并与神经炎症相关，与认知障碍无关。Aβ和sPDGFRβ之间的关联可能表明了一种双向关系，反映了周细胞清除可溶性Aβ和/或Aβ的血管毒性特性。

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来源期刊

Alzheimer's Research & Therapy 医学-神经病学

CiteScore

13.10

自引率

3.30%

发文量

172

审稿时长

>12 weeks

期刊介绍： Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.