认知未受损个体血液生物标志物纵向变化与MRI神经退行性变的关联
在阿姆斯特丹主观认知下降队列中，167名认知未受损个体接受重复血液采样和MRI扫描，随访5±3年。基线及纵向升高的GFAP与几乎所有AD特征脑区的萎缩率相关，基线pTau217与内侧颞叶萎缩相关，pTau217变化估计早于海马萎缩19.8年。血液标志物捕获脑萎缩的不同方面，支持联合使用。
要点
- 基线及纵向升高的GFAP与广泛AD特征脑区萎缩率相关。
- 基线pTau217与内侧颞叶萎缩相关，其变化趋势早于海马萎缩约19.8年。
- 基线NfL与颞叶萎缩相关，但NfL变化无此关联。
核心结论
- 血液生物标志物反映脑萎缩的不同方面，pTau217主要提示内侧颞叶萎缩，GFAP提示更广泛的神经退行性变。
- 支持联合使用pTau217和GFAP用于预防试验和临床护理中的早期识别与监测。
研究设计与样本
- 前瞻性观察性主观认知障碍队列研究，位于阿姆斯特丹，从记忆门诊招募主观认知下降个体。
- 共纳入167名认知未受损个体（49名淀粉样蛋白阳性，118名淀粉样蛋白阴性），淀粉样蛋白阳性者年龄66±8岁（57.1%女性），阴性者61±8岁（33.9%女性）。
- 重复血液采样484份样本，随访5±3年；MRI扫描457次，随访5±3年；使用SIMOA平台测量血液生物标志物，FreeSurfer确定AD特征脑区体积。
- 采用线性混合模型分析基线或生物标志物斜率与脑体积变化的关联；探索性分析比较外推的pTau217轨迹与海马体积轨迹。
主要发现
- 基线水平和纵向升高的GFAP与几乎所有AD特征区域更高的萎缩率相关（β范围-0.02至-0.00，95%CI范围-0.04至-0.00，pFDR<0.05）。
- 基线pTau217与多个内侧颞叶区域萎缩相关（β范围-0.03至-0.01，95%CI范围-0.04至-0.00，pFDR<0.05）。
- pTau217升高主要与颞叶区域萎缩相关（β范围-0.02至-0.01，95%CI范围-0.02至-0.00），但FDR校正后仅为趋势水平（pFDR=0.077）。
- 基线NfL浓度（而非其升高）与颞叶区域萎缩相关（β范围-0.02至-0.01，95%CI范围-0.04至-0.00，pFDR<0.05）。
- 基线Aβ42/40仅与海马萎缩相关（0.01 [0.00-0.03]），但FDR校正后不显著。
关键数值与推荐
- GFAP基线及纵向升高与AD特征区域萎缩率关联的β范围-0.02至-0.00，95%CI范围-0.04至-0.00，pFDR<0.05。
- 基线pTau217与内侧颞叶萎缩关联的β范围-0.03至-0.01，95%CI范围-0.04至-0.00，pFDR<0.05。
- pTau217升高与颞叶萎缩关联的β范围-0.02至-0.01，95%CI范围-0.02至-0.00，pFDR=0.077。
- 基线NfL与颞叶萎缩关联的β范围-0.02至-0.01，95%CI范围-0.04至-0.00，pFDR<0.05。
- 基线Aβ42/40与海马萎缩关联的值为0.01（0.00-0.03），FDR校正后不显著。
临床怎么用
- 在认知未受损个体中，可联合检测血液pTau217和GFAP以评估内侧颞叶及广泛脑区神经退行性变风险。
- 血液GFAP和pTau217的纵向变化可用于监测早期脑萎缩进程，辅助预防试验和临床护理中的风险分层。
局限性
- 探索性分析中pTau217变化与颞叶萎缩的关联经FDR校正后仅为趋势水平（pFDR=0.077）。
- 基线Aβ42/40与海马萎缩的关联经FDR校正后不显著。
以上解读依据论文摘要（全文未开放获取或许可不允许翻译转载）。
原文
BACKGROUND AND OBJECTIVES: Blood-based biomarkers are reliable indicators of Alzheimer disease (AD)-related pathology in cognitively normal individuals. However, it remains unclear how changes in these biomarkers relate to emerging brain atrophy. We aimed to investigate longitudinal associations between blood-based biomarkers and brain atrophy, and the temporal sequence of these processes. METHODS: In the prospective observational Subjective Cognitive Impairment Cohort based in Amsterdam, individuals with subjective cognitive decline recruited from a memory clinic underwent repeated blood sampling (484 samples, follow-up 5 ± 3 years) and MRI scans (457 scans, follow-up 5 ± 3 years). We measured blood-based biomarkers (Aβ42/40 ratio [Aβ42/40], phosphorylated tau [pTau217], glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) using the SIMOA platform. AD-signature brain volumes (5 temporal, 4 parietal, and 2 frontal regions) were determined using the FreeSurfer pipeline. We used linear mixed models to examine associations between baseline or slope of biomarker and brain volume changes. In an exploratory analysis, extrapolated pTau217 trajectories were compared with hippocampal volume trajectories to estimate the temporal gap between these changes. RESULTS: A total of 167 individuals were included (49 amyloid-positive and 118 amyloid-negative), with amyloid-positive individuals being older (age: 66 ± 8 years, 57.1% female) than amyloid-negative individuals (61 ± 8 years, 33.9% female). Baseline levels and longitudinal increases in GFAP showed associations with higher rates of atrophy across nearly all AD-signature regions (β range -0.02 to -0.00, 95% CI range -0.04 to -0.00, pFDR < 0.05). Baseline pTau217 was associated with atrophy across several medial temporal regions (β range -0.03 to -0.01, 95% CI range -0.04 to -0.00, pFDR < 0.05), whereas increases in pTau217 were only associated with atrophy primarily in temporal regions (β range -0.02 to -0.01, 95% CI range -0.02 to -0.00), although the latter associations were only trend-level after FDR correction (pFDR = 0.077). Baseline concentrations, but not increases in NfL, showed associations with temporal regions (β range -0.02 to -0.01, 95% CI range -0.04 to -0.00, pFDR < 0.05). By contrast, baseline Aβ42/40 showed only associations with hippocampal atrophy (0.01 [0.00-0.03]), but not after FDR correction. Using baseline and (extrapolated) trajectories over time, we estimated that changes in pTau217 preceded hippocampal atrophy by 19.8 (10.7-43.7) years. DISCUSSION: Blood-based biomarkers capture distinct aspects of brain atrophy, with pTau217 primarily indicating atrophy in medial temporal regions and GFAP more widespread neurodegeneration. This supports the complementary use of both markers for early identification and monitoring in preventive trials and clinical care.
引用
- Trieu C, Dicks E, de Leeuw D, et al. Longitudinal Change in Blood-Based Biomarkers and the Association With MRI-Measured Neurodegeneration in Cognitively Unimpaired Individuals. Neurology. 2026. PMID: 42224636. doi:10.1212/WNL.0000000000218119
供执业医师工作参考，不替代临床判断；数值与分级以指南原文为准。