Associations of CSF PDGFRβ With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes.
Associations of CSF PDGFRβ With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes.
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DOI：
10.1212/wnl.0000000000207358
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发表时间：
2023-07-04
期刊：
影响因子：
9.9
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中科院分区：
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神经血管单位中受损的周细胞将血小板衍生生长因子β（PDGFR β）释放到CSF中。然而，目前尚不清楚周细胞损伤如何导致阿尔茨海默病（AD）相关的变化和血脑屏障（BBB）损伤。我们的目的是测试CSF PDGFR β是否与导致痴呆的不同AD相关和年龄相关病理变化相关。在来自瑞典BioFINDER-2队列的771名认知未受损（CU，n = 408）、轻度认知障碍（MCI，n = 175）和痴呆（n = 188）参与者的CSF中测量PDGFR β。然后，我们检查了β-淀粉样蛋白（A β）-PET和tau-PET标准化摄取值比值、APOE ε 4基因型和皮质厚度、白色病变（WML）和脑血流量的MRI测量值之间的相关性。我们还分析了CSF PDGFR β在衰老、BBB功能障碍（通过CSF/血浆白蛋白比率，QAlb测量）和神经炎症（即，CSF水平的YKL-40和胶质细胞酸性蛋白[GFAP]，优先在反应性星形胶质细胞中表达）。该队列的平均年龄为67岁（CU = 62.8，MCI = 69.9，痴呆= 70.4），50.1%为男性（CU = 46.6%，MCI = 53.7%，痴呆= 54.3%）。脑脊液PDGFR β浓度与年龄相关（B = 19.1，β = 0.5，95% CI 16 - 22.2，p <0.001），神经胶质活化的CSF神经炎性标志物YKL-40增加（B = 3.4，β = 0.5，95% CI 2.8 - 3.9，p <0.001），GFAP（B = 27.4，β = 0.4，95%CI 20.9 - 33.9，p <0.001），以及通过QAl B测量的更差的BB B完整性（B = 37.4，β = 0.2，95%CI 24.9 - 49.9，p <0.001）。年龄也与更差的BBB完整性相关，这部分是由PDGFR β和神经炎症标志物介导的（总效应的16%-33%）。然而，PDGFR β与APOE ε 4基因型、A β和tau病理的PET成像、或脑萎缩和WML的MRI测量无相关性（p> 0.05）。总之，由CSF PDGFR β反映的周细胞损伤可能与年龄相关的BBB破坏以及神经炎症有关，但与阿尔茨海默病相关的病理变化无关。
Injured pericytes in the neurovascular unit release platelet-derived growth factor β (PDGFRβ) into the CSF. However, it is not clear how pericyte injury contributes to Alzheimer disease (AD)–related changes and blood-brain barrier (BBB) damage. We aimed to test whether CSF PDGFRβ was associated with different AD-associated and age-associated pathologic changes leading to dementia. PDGFRβ was measured in the CSF of 771 participants with cognitively unimpaired (CU, n = 408), mild cognitive impairment (MCI, n = 175), and dementia (n = 188) from the Swedish BioFINDER-2 cohort. We then checked association with β-amyloid (Aβ)-PET and tau-PET standardized uptake value ratio, APOE ε4 genotype and MRI measurements of cortical thickness, white matter lesions (WMLs), and cerebral blood flow. We also analyzed the role of CSF PDGFRβ in the relationship between aging, BBB dysfunction (measured by CSF/plasma albumin ratio, QAlb), and neuroinflammation (i.e., CSF levels of YKL-40 and glial fibrillary acidic protein [GFAP], preferentially expressed in reactive astrocytes). The cohort had a mean age of 67 years (CU = 62.8, MCI = 69.9, dementia = 70.4), and 50.1% were male (CU = 46.6%, MCI = 53.7%, dementia = 54.3%). Higher CSF PDGFRβ concentrations were related to higher age (b = 19.1, β = 0.5, 95% CI 16–22.2, p < 0.001), increased CSF neuroinflammatory markers of glial activation YKL-40 (b = 3.4, β = 0.5, 95% CI 2.8–3.9, p < 0.001), GFAP (b = 27.4, β = 0.4, 95% CI 20.9–33.9, p < 0.001), and worse BBB integrity measured by QAlb (b = 37.4, β = 0.2, 95% CI 24.9–49.9, p < 0.001). Age was also associated with worse BBB integrity, and this was partly mediated by PDGFRβ and neuroinflammatory markers (16%–33% of total effect). However, PDGFRβ showed no associations with APOE ε4 genotype, PET imaging of Aβ and tau pathology, or MRI measures of brain atrophy and WMLs (p > 0.05). In summary, pericyte damage, reflected by CSF PDGFRβ, may be involved in age-related BBB disruption together with neuroinflammation, but is not related to Alzheimer-related pathologic changes.