Zhang Yan, Huang Gan, Geng Jieli, Li Xia, Xin Mei, Yuan Peizhe, Wang Yue, Xu Qun, Wang Gang, Huang Gang, Liu Jianjun, Zhang Chenpeng
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Eur J Nucl Med Mol Imaging. 2025 Jul 18. doi: 10.1007/s00259-025-07445-2.
The role of glymphatic dysfunction in Alzheimer's disease (AD), as measured by diffusion tensor imaging along perivascular spaces (DTI-ALPS) indexing of perivascular function, its progression, and its interaction with amyloid-β (Aβ) and tau proteins, remains controversial. To investigate whether the DTI-ALPS index mediates AD-related cognitive decline through Aβ/tau-dependent pathways using tri-tracer PET/MRI.
This retrospective study (2021-2024) analyzed 140 participants (median age 69.00 [61.00, 74.00] years; 84 women), including 99 with AD (37 early-onset [EOAD], 62 late-onset [LOAD]), 35 with mild cognitive impairment (MCI), and 6 with subjective cognitive decline (SCD). All participants underwent simultaneous [⁸F] Florbetapir (Aβ), [⁸F] PI-2620(tau), and [⁸F] FDG PET/MRI with DTI-ALPS indexing for glymphatic function quantification. Causal mediation analysis was used to assess the relationships between biomarkers (P < 0.05).
The ALPS index progressively decreased across clinical stages (SCD: 1.51 ± 0.08 vs. MCI: 1.37 ± 0.13 vs. AD: 1.32 ± 0.14; P = 0.001), correlating with higher Aβ-PET (r = - 0.31, P < 0.001), tau-PET (ρ = - 0.18, P = 0.035), and FDG-PET scores (ρ = - 0.22, P = 0.008). Aβ-PET fully mediated the ALPS effects on FDG-PET (β = - 0.14, P = 0.002) and cognition (β = 0.12 ~ 0.14, P < 0.01), independent of tau (P > 0.05). The Aβ-negative subgroups showed correlations with ALPS-age (r = - 0.48, P = 0.007), ALPS-education (r = 0.39, P = 0.035), and ALPS-cognition (MoCA: r = 0.62, P < 0.001). The Aβ-positive subgroups revealed inverse ALPS-Aβ associations (ρ = - 0.27, P = 0.010; age/education-adjusted ρ = - 0.24, P = 0.022) alongside positive adjusted correlations with cognition (MMSE: ρ = 0.28, P = 0.009). EOAD exhibited distinct ALPS-cognition relationships compared to LOAD (MMSE: r = - 0.39, P = 0.016 vs. ρ = - 0.06, P = 0.620).
DTI-ALPS quantifies glymphatic dysfunction driving AD progression predominantly through Aβ-dependent pathways, with EOAD demonstrating distinct neuroimaging-cognition relationships compared to LOAD.
通过沿血管周围间隙的扩散张量成像（DTI-ALPS）对血管周围功能进行索引测量，研究淋巴系统功能障碍在阿尔茨海默病（AD）中的作用、其进展以及与淀粉样β蛋白（Aβ）和tau蛋白的相互作用，目前仍存在争议。本研究旨在使用三示踪剂PET/MRI，探讨DTI-ALPS指数是否通过Aβ/tau依赖途径介导AD相关的认知衰退。
这项回顾性研究（2021 - 2024年）分析了140名参与者（中位年龄69.00[61.00, 74.00]岁；84名女性），包括99名AD患者（37名早发型[EOAD]，62名晚发型[LOAD]）、35名轻度认知障碍（MCI）患者和6名主观认知衰退（SCD）患者。所有参与者均接受了同时进行的[⁸F]氟代贝他吡（Aβ）、[⁸F]PI - 2620（tau）和[⁸F]氟代脱氧葡萄糖（FDG）PET/MRI检查，并通过DTI-ALPS对淋巴系统功能进行量化索引。采用因果中介分析来评估生物标志物之间的关系（P < 0.05）。
ALPS指数在各临床阶段逐渐降低（SCD：1.51±0.08 vs. MCI：1.37±0.13 vs. AD：1.32±0.14；P = 0.001），与较高的Aβ-PET（r = - 0.31，P < 0.001）、tau-PET（ρ = - 0.18，P = 0.035）和FDG-PET评分（ρ = - 0.22，P = 0.008）相关。Aβ-PET完全介导了ALPS对FDG-PET（β = - 0.14，P = 0.002）和认知（β = 0.12 ~ 0.1４，P < 0.01）的影响，独立于tau（P > 0.05）。Aβ阴性亚组显示与ALPS-年龄（r = - 0.48，P = 0.007）、ALPS-教育程度（r = 0.39，P = 0.035）和ALPS-认知（蒙特利尔认知评估量表：r = 0.62，P < 0.00１）相关。Aβ阳性亚组显示ALPS与Aβ呈负相关（ρ = - 0.27，P = 0.010；年龄/教育程度调整后ρ = - 0.24，P = 0.022），同时与认知呈正相关（简易精神状态检查表：ρ = 0.28，P = 0.009）。与LOAD相比，EOAD表现出不同的ALPS-认知关系（简易精神状态检查表：r = - 0.39，P = 0.016 vs. ρ = - 0.06，P = 0.620）。
DTI-ALPS主要通过Aβ依赖途径量化驱动AD进展的淋巴系统功能障碍，与LOAD相比，EOAD表现出不同的神经影像学-认知关系。
