Franzmeier Nicolai, Ren Jinyi, Damm Alexander, Monté-Rubio Gemma, Boada Mercè, Ruiz Agustín, Ramirez Alfredo, Jessen Frank, Düzel Emrah, Rodríguez Gómez Octavio, Benzinger Tammie, Goate Alison, Karch Celeste M, Fagan Anne M, McDade Eric, Buerger Katharina, Levin Johannes, Duering Marco, Dichgans Martin, Suárez-Calvet Marc, Haass Christian, Gordon Brian A, Lim Yen Ying, Masters Colin L, Janowitz Daniel, Catak Cihan, Wolfsgruber Steffen, Wagner Michael, Milz Esther, Moreno-Grau Sonia, Teipel Stefan, Grothe Michel J, Kilimann Ingo, Rossor Martin, Fox Nick, Laske Christoph, Chhatwal Jasmeer, Falkai Peter, Perneczky Robert, Lee Jae-Hong, Spottke Annika, Boecker Henning, Brosseron Frederic, Fliessbach Klaus, Heneka Michael T, Nestor Peter, Peters Oliver, Fuentes Manuel, Menne Felix, Priller Josef, Spruth Eike J, Franke Christiana, Schneider Anja, Westerteicher Christine, Speck Oliver, Wiltfang Jens, Bartels Claudia, Araque Caballero Miguel Ángel, Metzger Coraline, Bittner Daniel, Salloway Stephen, Danek Adrian, Hassenstab Jason, Yakushev Igor, Schofield Peter R, Morris John C, Bateman Randall J, Ewers Michael
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany.
Fundació ACE, Alzheimer Treatment and Research Center, Barcelona, Spain.
Mol Psychiatry. 2021 Feb;26(2):614-628. doi: 10.1038/s41380-019-0404-6. Epub 2019 Mar 21.
In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNF an important modulating factor of cognitive impairment in AD. However, the effect of BDNF on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNF on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNF carriers compared to BDNF homozogytes. BDNF was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNF could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNF was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNF is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.
在阿尔茨海默病（AD）中，编码脑源性神经营养因子（BDNF）的基因中的单核苷酸多态性与原发性AD病理（β-淀粉样蛋白，Aβ）对神经退行性变和认知衰退的更严重影响相关，这使得BDNF成为AD认知障碍的一个重要调节因子。然而，BDNF对可能是AD认知障碍基础的功能网络的影响却知之甚少。我们采用交叉验证方法，首先在来自显性遗传阿尔茨海默病网络（DIAN）的常染色体显性AD（ADAD）受试者中，探究BDNF对静息态功能磁共振成像（fMRI）评估的功能网络的影响。在六个主要大规模网络的基于种子点的连通性分析中，我们发现与BDNF纯合子相比，BDNF携带者中海马体（种子点）与内侧前额叶之间的连通性下降更为明显。BDNF与其他任何网络的连通性均无关联。接下来，我们测试了在散发性出现Aβ的老年受试者中，是否也能发现BDNF导致海马体与内侧前额叶连通性更明显下降这一现象，这些受试者包括一组主观认知衰退者（N = 149，FACEHBI研究）和一组从临床前到AD痴呆阶段的受试者（N = 114，DELCODE研究）。在这两个独立招募的组中，在控制海马体体积和其他混杂因素后，BDNF与更异常的Aβ水平（通过生物流体检测或淀粉样蛋白PET评估）对海马体与内侧前额叶连通性下降的更强影响相关。在DIAN和DELCODE研究中，较低的海马体与内侧前额叶连通性与较低的整体认知表现相关。这些结果共同表明，BDNF与海马体 - 前额叶连通性对原发性AD病理的更高易损性选择性相关，从而导致更严重的AD相关认知障碍。
