From the Department of Neurology (R.S., E.W.P., B.M.A., N.A.D., S.L., J.H.K., K.B.C.), Memory and Aging CenterWeill Institute for Neurosciences, University of California, San Francisco; Helen Wills Neuroscience Institute (C.F.), University of California, Berkeley; Department of Psychiatry and Neurochemistry (J.N., A.B., K.B., H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory (A.B., K.B., H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL (H.Z.), London; and Hong Kong Center for Neurodegenerative Diseases (H.Z.), China.
Neurology. 2022 Nov 14;99(20):e2285-e2293. doi: 10.1212/WNL.0000000000201165.
Synaptic dysfunction and degeneration is a predominant feature of brain aging, and synaptic preservation buffers against Alzheimer disease (AD) protein-related brain atrophy. We tested whether CSF synaptic protein concentrations similarly moderate the effects of axonal injury, indexed by CSF neurofilament light [NfL]), on brain atrophy in clinically normal adults.
Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (mean scan [follow-up] = 2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 25 [SNAP-25], neurogranin, growth-associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau/Aβ ratio reflecting AD proteinopathy). Ten bilateral temporoparietal gray matter region of interest (ROIs) shown to be sensitive to clinical AD were summed to generate a composite temporoparietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporoparietal trajectories, controlling for ptau/Aβ ratios.
Forty-six clinically normal older adults (mean age = 70 years; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL ( range: 0.10-0.36). Higher baseline NfL, but not ptau/Aβ ratios, predicted steeper temporoparietal atrophy (NfL × time: β = -0.08, < 0.001; ptau/Aβ × time: β = -0.02, = 0.31). SNAP-25, neurogranin, and GAP-43 significantly moderated NfL-related atrophy trajectories (-0.07 ≤ β's ≥ -0.06, s < 0.05) such that NfL was associated with temporoparietal atrophy at high (more abnormal) but not low (more normal) synaptic protein concentrations. At high NfL concentrations, atrophy trajectories were 1.5-4.5 times weaker when synaptic protein concentrations were low (β range: -0.21 to -0.07) than high (β range: -0.33 to -0.30).
The association between baseline CSF NfL and longitudinal temporoparietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions.
突触功能障碍和退化是大脑衰老的主要特征，而突触的保存可以缓冲与阿尔茨海默病（AD）相关的蛋白质引起的脑萎缩。我们测试了脑脊液（CSF）中的突触蛋白浓度是否同样可以调节轴突损伤的影响，轴突损伤由 CSF 神经丝轻链[NfL]来衡量），在临床正常的成年人中对脑萎缩的影响。
在 UCSF 记忆与衰老中心的 Hillblom 老龄化网络观察性研究中，临床正常的老年人完成了基线腰椎穿刺和纵向脑 MRI（平均扫描[随访]=2.6[3.7 年]）。CSF 中突触蛋白（突触结合蛋白-1、突触小体相关蛋白 25[SNAP-25]、神经颗粒蛋白、生长相关蛋白 43[GAP-43]）、轴突损伤（NfL）和核心 AD 生物标志物（ptau/Aβ 比值反映 AD 蛋白病）进行了检测。选择了 10 个双侧颞顶叶灰质感兴趣区（ROI），这些 ROI 对临床 AD 敏感，加起来生成一个颞顶叶 ROI 复合区。线性混合效应模型测试了基线突触蛋白对基线 NfL 相关颞顶叶轨迹的统计学调节，同时控制了 ptau/Aβ 比值。
共纳入 46 名临床正常的老年人（平均年龄 70 岁；43%为女性）。突触蛋白与 NfL 呈小到中度相关（范围：0.10-0.36）。较高的基线 NfL，但不是 ptau/Aβ 比值，预示着颞顶叶萎缩更陡峭（NfL×时间：β=-0.08，<0.001；ptau/Aβ×时间：β=-0.02，=0.31）。SNAP-25、神经颗粒蛋白和 GAP-43 显著调节了 NfL 相关的萎缩轨迹（-0.07≤β'≥-0.06，s<0.05），使得 NfL 在高（更异常）而不是低（更正常）的突触蛋白浓度时与颞顶叶萎缩相关。在高 NfL 浓度下，当突触蛋白浓度较低（β范围：-0.21 至-0.07）时，与高 NfL 浓度（β范围：-0.33 至-0.30）相比，萎缩轨迹减弱了 1.5-4.5 倍。
基线 CSF NfL 与纵向颞顶叶萎缩之间的关联是由突触功能障碍加速的，并通过突触完整性得到缓冲。除了 AD 蛋白外，同时检查体内的轴突和突触生物标志物，可能会提高对 AD 敏感脑区出现明显结构变化之前神经改变的检测能力。
