主动脉僵硬与神经炎症、突触功能障碍和神经退行性变生物标志物的关联。
Association of Aortic Stiffness With Biomarkers of Neuroinflammation, Synaptic Dysfunction, and Neurodegeneration.
机构信息
From the Vanderbilt Memory & Alzheimer's Center (E.E.M., D.L., J.L., S.J.S., F.E.C., K.R.P., M.E.M., K.A.G., T.J.H., A.L.J.), Department of Biostatistics (D.L.), Radiology & Radiological Sciences (J.G.T., S.N., J.J.C.), Department of Neurology (K.R.P., M.E.M., K.A.G., T.J.H., A.L.J.), Division of Cardiovascular Medicine (S.P.B., J.A.B., A.L.J.), Department of Medicine, and Vanderbilt Genetics Institute (T.J.H.), Vanderbilt University Medical Center, Nashville, TN; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Molndal, Sweden; Department of Neurodegenerative Disease (H.Z.), University College London Institute of Neurology, Queen Square; and United Kingdom Dementia Research Institute at University College London (H.Z.), UK.
出版信息
Neurology. 2021 Jul 27;97(4):e329-e340. doi: 10.1212/WNL.0000000000012257. Epub 2021 May 24.
OBJECTIVES
To test the hypothesis that increased aortic stiffening is associated with greater CSF evidence of core Alzheimer disease pathology (β-amyloid [Aβ], phosphorylated tau [p-tau]), neurodegeneration (total tau [t-tau]), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light [NFL]), and neuroinflammation (YKL-40, soluble triggering receptor expressed on myeloid cells 2 [sTREM2]), we analyzed pulse wave velocity (PWV) data and CSF data among older adults.
METHODS
Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic PWV (meters per second) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations after adjustment for age, race/ethnicity, education, apolipoprotein (APOE) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis, ε4, and hypertension on each biomarker.
RESULTS
One hundred forty-six participants were examined (age 72 ± 6 years). Aortic PWV interacted with age on p-tau (β = 0.31, = 0.04), t-tau, (β = 2.67, = 0.05), neurogranin (β = 0.94, = 0.04), and sTREM2 (β = 20.4, = 0.05). Among participants >73 years of age, higher aortic PWV related to higher p-tau (β = 2.4, = 0.03), t-tau (β = 19.3, = 0.05), neurogranin (β = 8.4, = 0.01), and YKL-40 concentrations (β = 7,880, = 0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (β = -10.76, = 0.03) and hypertension status on YKL-40 (β = 18,020, < 0.001).
CONCLUSIONS
Among our oldest participants, ≥74 years of age, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and reduced blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age.
目的
为验证主动脉僵硬度增加与脑脊髓液（CSF）中核心阿尔茨海默病病理（β-淀粉样蛋白[Aβ]、磷酸化tau[p-tau]）、神经退行性变（总 tau[t-tau]）、突触功能障碍（神经颗粒蛋白）、神经轴突损伤（神经丝轻链[NFL]）和神经炎症（YKL-40、髓系细胞触发受体 2 可溶性[sTREM2]）标志物更多证据相关的假设，我们分析了老年参与者的脉搏波速度（PWV）数据和 CSF 数据。
方法
无卒中和痴呆的范德比尔特记忆与衰老项目参与者为观察性社区研究，他们接受了心脏磁共振评估主动脉 PWV（米/秒）和腰椎穿刺以获得 CSF。在调整年龄、种族/民族、教育程度、载脂蛋白（APOE）ε4 状态、弗雷明汉卒中风险评分和认知诊断后，线性回归将主动脉 PWV 与 CSF Aβ、p-tau、t-tau、神经颗粒蛋白、NFL、YKL-40 和 sTREM2 浓度相关联。重复模型检验 PWV 与年龄、诊断、ε4 和高血压对每种生物标志物的相互作用。
结果
146 名参与者接受了检查（年龄 72±6 岁）。主动脉 PWV 与 p-tau（β=0.31， =0.04）、t-tau（β=2.67， =0.05）、神经颗粒蛋白（β=0.94， =0.04）和 sTREM2（β=20.4， =0.05）的年龄存在交互作用。在年龄＞73 岁的参与者中，较高的主动脉 PWV 与较高的 p-tau（β=2.4， =0.03）、t-tau（β=19.3， =0.05）、神经颗粒蛋白（β=8.4， =0.01）和 YKL-40 浓度相关（β=7880， =0.005）。主动脉 PWV 与神经颗粒蛋白的诊断存在中度交互作用（β=-10.76， =0.03），与 YKL-40 的高血压状态存在中度交互作用（β=18020， ＜0.001）。
结论
在我们年龄最大的参与者中（≥74 岁），更大的主动脉僵硬度与体内生物标志物证据表明神经炎症、tau 磷酸化、突触功能障碍和神经退行性变有关，但与淀粉样变性无关。中央动脉僵硬可能导致大脑微循环逐渐受损，组织血流输送减少，导致更晚期的神经炎症和神经退行性变。
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