Table_1_Alzheimer's disease pathology: pathways between chronic vascular risk factors and blood-brain barrier dysfunction in a cohort of patients with different types of dementia.XLSX

BackgroundBlood brain barrier (BBB) breakdown is considered a potential mechanism of dementia. The Alzheimer's disease (AD) biomarkers and vascular factors are also associated with BBB permeability.
ObjectiveIn the present study, the combination effects of neuropathological biomarkers of AD and chronic vascular risk factors for BBB were investigated.
MethodsThe cerebrospinal fluid (CSF)/serum albumin ratio (Qalb), an indicator of BBB permeability, was measured in a total of 95 hospitalized dementia patients. The demographics, clinical information, and laboratory tests were collected from the inpatient records. The CSF neuropathological biomarkers of AD and apolipoprotein E (APOE) genotype were also collected. The mediation analysis model was used to calculate the associations among neuropathological biomarkers of AD (mediator), the Qalb, and chronic vascular risk factors.
ResultsThree types of dementia, AD (n = 52), Lewy body dementia (LBD, n = 19), and frontotemporal lobar degeneration (n = 24), were included with a mean Qalb of 7.18 (± 4.36). The Qalb was significantly higher in dementia patients with type 2 diabetes mellitus (T2DM, p = 0.004) but did not differ based on the presence of APOE ε4 allele, CMBs, or amyloid/tau/neurodegeneration (ATN) framework. The Qalb was negatively associated with the levels of Aβ1-42 (B = −20.775, p = 0.009) and Aβ1-40 (B = −305.417, p = 0.005) and positively associated with the presence of T2DM (B = 3.382, p < 0.001) and the levels of glycosylated hemoglobin (GHb, B = 1.163, p < 0.001) and fasting blood glucose (FBG, B = 1.443, p < 0.001). GHb is a direct chronic vascular risk factor for higher Qalb (total effect B = 1.135, 95% CI: 0.611–1.659, p < 0.001). Ratios of Aβ1-42/Aβ1-40 or t-tau/Aβ1-42 were mediators of the association between the Qalb and GHb; the direct effect of GHb on the Qalb was 1.178 (95% CI: 0.662–1.694, p < 0.001).
ConclusionGlucose exposure can directly or indirectly affect BBB integrity through Aβ and tau, indicating glucose affects BBB breakdown and glucose stability plays an important role in dementia protection and management.

背景 血脑屏障（blood brain barrier, BBB）功能受损被认为是痴呆的潜在发病机制。阿尔茨海默病（Alzheimer's disease, AD）相关生物标志物与血管因素均与血脑屏障通透性相关。
目的 本研究旨在探讨阿尔茨海默病神经病理生物标志物与慢性血管危险因素对血脑屏障的联合影响。
方法 本研究共纳入95名住院痴呆患者，检测其脑脊液（cerebrospinal fluid, CSF）/血清白蛋白比值（Qalb，血脑屏障通透性的指示指标）。从住院病历中收集受试者的人口学资料、临床信息及实验室检测结果，同时采集其脑脊液中阿尔茨海默病神经病理生物标志物数据与载脂蛋白E（apolipoprotein E, APOE）基因型信息。采用中介分析模型计算阿尔茨海默病神经病理生物标志物（中介变量）、Qalb与慢性血管危险因素之间的关联。
结果 本研究纳入三类痴呆患者：阿尔茨海默病（n=52）、路易体痴呆（Lewy body dementia, LBD, n=19）与额颞叶变性（frontotemporal lobar degeneration, n=24），受试者平均Qalb为7.18（±4.36）。合并2型糖尿病（type 2 diabetes mellitus, T2DM）的痴呆患者Qalb显著升高（p=0.004），但Qalb与APOE ε4等位基因携带情况、脑微出血（cerebral microbleeds, CMBs）或淀粉样蛋白/tau/神经退行性变（amyloid/tau/neurodegeneration, ATN）框架分型无显著差异。Qalb与Aβ1-42水平呈负相关（B=-20.775，p=0.009），与Aβ1-40水平亦呈负相关（B=-305.417，p=0.005）；同时Qalb与2型糖尿病患病情况（B=3.382，p<0.001）、糖化血红蛋白（glycosylated hemoglobin, GHb）水平（B=1.163，p<0.001）及空腹血糖（fasting blood glucose, FBG）水平（B=1.443，p<0.001）呈正相关。糖化血红蛋白是导致Qalb升高的直接慢性血管危险因素（总效应B=1.135，95%置信区间：0.611–1.659，p<0.001）。Aβ1-42/Aβ1-40比值或t-tau/Aβ1-42比值可介导Qalb与糖化血红蛋白之间的关联；糖化血红蛋白对Qalb的直接效应为1.178（95%置信区间：0.662–1.694，p<0.001）。
结论 血糖暴露可通过淀粉样蛋白与tau蛋白直接或间接影响血脑屏障完整性，提示血糖可影响血脑屏障受损，而血糖稳态在痴呆的防治与管理中具有重要作用。