Casaletto Kaitlin B, Zetterberg Henrik, Blennow Kaj, Brinkmalm Ann, Honer William, Schneider Julie A, Bennett David A, Djukic Nina, You Michelle, Weiner-Light Sophia, Fonseca Corrina, Miller Bruce L, Kramer Joel
From the Memory and Aging Center (K.B.C., N.D., M.Y., S.W.-L., C.F., B.L.M., J.K.), Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco; Department of Psychiatry and Neurochemistry (H.Z., K.B., A.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z., K.B., A.B.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z., K.B., A.B.), UCL Institute of Neurology, Queen ; UK Dementia Research Institute at UCL (H.Z.), London, UK; Department of Psychiatry (W.H.), University of British Columbia, Vancouver, Canada; and Department of Neurological Sciences (J.A.S., D.A.B.), Rush Medical College, Chicago, IL.
Neurology. 2021 Jul 19;97(3):e284-e297. doi: 10.1212/WNL.0000000000012145.
To test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults in vivo and postmortem.
The 2 independent observational, cross-sectional cohorts included (1) in vivo community-dwelling, clinically normal adults from the University of California, San Francisco Memory and Aging Center who completed lumbar puncture and MRI (exclusion criteria, Clinical Dementia Rating score >0) and (2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In vivo measures included CSF synaptic proteins (synaptotagmin-1, synaptosome associated protein-25, neurogranin, and growth associated protein-43), β-amyloid (Aβ), tau phosphorylated at amino acid 181 (ptau), and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, vesicle associated membrane protein (VAMP), and SNARE complex) and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins × amyloid on tau, and synaptic proteins × tau on GMV).
Sixty-eight in vivo older adults (age 71 years, 43% female) and 633 decedents (age 90 years, 68% female, 34% clinically normal) were included. Each in vivo CSF synaptic protein moderated the relationship between Aβ and ptau (-0.23 < < -0.12, < 0.05) and the relationship between ptau and GMV (-0.49 < < -0.32, < 0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aβ-ptau and ptau-brain volume, effects that were absent or reversed in those with more normal CSF synaptic protein. Postmortem analyses recapitulated CSF models. More normal brain tissue levels of complexin-I, VAMP, and SNARE moderated the adverse relationship between neuritic plaque and NFT counts (-0.10 < < -0.08, < 0.05).
Pathogenic relationships of Aβ and tau may depend on synaptic state. Synaptic markers may help identify risk or resilience to AD proteinopathy.
检验以下假设，即在体内和死后的老年人中，淀粉样蛋白、tau蛋白和神经退行性变（A/T/N）级联反应中的基本关系取决于突触完整性。
2个独立的观察性横断面队列包括：（1）来自加利福尼亚大学旧金山分校记忆与衰老中心的社区居住、临床正常的成年人，他们完成了腰椎穿刺和MRI检查（排除标准：临床痴呆评定量表评分>0）；（2）拉什记忆与衰老项目的死后受试者（排除标准：无法签署知情同意书）。体内测量指标包括脑脊液突触蛋白（突触结合蛋白-1、突触体相关蛋白-25、神经颗粒素和生长相关蛋白-43）、β淀粉样蛋白（Aβ）、氨基酸181位点磷酸化的tau蛋白（ptau）以及MRI灰质体积（GMV）。死后测量指标包括脑组织中突触前蛋白（复合体蛋白-I、复合体蛋白-II、囊泡相关膜蛋白（VAMP）和SNARE复合体）的水平以及神经炎性斑块和神经原纤维缠结（NFT）的计数。回归模型检验了突触蛋白水平在A/T/N级联反应中的统计学调节作用（突触蛋白×淀粉样蛋白对tau蛋白的影响，以及突触蛋白×tau蛋白对GMV的影响）。
纳入了68名体内的老年人（年龄71岁，43%为女性）和633名受试者（年龄90岁，68%为女性，34%临床正常）。每种体内脑脊液突触蛋白都调节了Aβ与ptau之间的关系（-0.23 << -0.12，<0.05）以及ptau与GMV之间的关系（-0.49 << -0.32，<0.05）。脑脊液突触蛋白异常程度越高的个体，Aβ-ptau和ptau-脑体积之间呈现出预期的关系，而在脑脊液突触蛋白较正常的个体中，这种关系不存在或相反。死后分析重现了脑脊液模型。复合体蛋白-I、VAMP和SNARE在脑组织中的水平越正常，对神经炎性斑块和NFT计数之间的不良关系的调节作用越明显（-0.10 << -0.08，<0.05）。
Aβ和tau蛋白的致病关系可能取决于突触状态。突触标志物可能有助于识别对AD蛋白病的风险或恢复能力。
