Bouzigues Arabella, Du Vincent Le, Joulot Matthieu, Peysson Ninon, Houot Marion, Béranger Benoît, Russell Lucy L, Foster Phoebe H, Ferry-Bolder Eve, van Swieten John C, Jiskoot Lize, Seelaar Harro, Sanchez-Valle Raquel, Laforce Robert, Graff Caroline, Galimberti Daniela, Vandenberghe Rik, de Mendonça Alexandre, Tiraboschi Pietro, Santana Isabel, Gerhard Alexander, Levin Johannes, Sorbi Sandro, Otto Markus, Bertoux Maxime, Lebouvier Thibaud, Ducharme Simon, Butler Chris R, Ber Isabelle Le, Finger Elizabeth, Tartaglia Maria Carmela, Masellis Mario, Rowe James B, Synofzik Matthis, Moreno Fermin, Borroni Barbara, Rohrer Jonathan D, Migliaccio Raffaella
Paris Brain Institute, Sorbonne Université, INSERM U1127, Hôpital Pitié-Salpêtrière, Paris, France.
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Alzheimers Dement. 2025 Jul;21(7):e70367. doi: 10.1002/alz.70367.
Microtubule-associated protein tau (MAPT) mutations cause frontotemporal dementia (FTD), characterised by behavioural, language, and motor impairments due to brain connectivity disruptions. We investigated structural and functional connectivity in 86 mutation carriers and 272 controls to map connectivity changes at different disease stages.
The CDR Dementia Staging Instrument plus National Alzheimer's Coordinating Center (NACC) Behaviour and Language domains (CDR plus NACC FTLD) stratified carriers into three groups: asymptomatic, prodromal, and symptomatic. We extracted measures of cortical thickness, white matter integrity, and functional connectivity, which were compared between each carrier group and controls using linear mixed models.
Early isolated functional disruptions in salience/visual networks were present in asymptomatic carriers, along with anterior cingulate gray matter reductions. In prodromal carriers, functional changes extended to other networks, with additional structural damage in temporal poles/cingulate.
This study shows that functional networks likely drive lifelong compensation for a genetically determined disease, manifesting clinically when structural damage reaches a critical threshold. This supports connectivity measures as potential biomarkers for MAPT-related neurodegeneration.
Our findings reveal the progressive and staged nature of structural and functional connectivity alterations in MAPT mutation carriers, with distinct patterns at each disease stage. In asymptomatic carriers, we identified early functional connectivity alterations in salience and visual networks, despite preserved white matter and only subtle gray matter atrophy. These appear to represent both response to pathology and possible compensatory mechanisms. In prodromal carriers, functional connectivity alterations were accompanied by structural damage, including cortical atrophy and white matter tract disruptions, in regions directly connected to early-affected networks. The sequential progression, from functional connectivity changes to structural degeneration, aligns with the hypothesis that tau propagates along axonal connections, disrupting neural network integrity before measurable atrophy occurs. We propose a theoretical data-driven model of biomarker evolution in MAPT mutation carriers, highlighting functional disruptions as early indicators and structural damage as a later-stage hallmark. These connectivity biomarkers have the potential to inform therapeutic strategies and clinical trial design.
微管相关蛋白tau（MAPT）突变会导致额颞叶痴呆（FTD），其特征是由于脑连接中断而出现行为、语言和运动障碍。我们对86名突变携带者和272名对照者的结构和功能连接性进行了研究，以绘制不同疾病阶段的连接性变化图谱。
使用CDR痴呆分期工具加上国家阿尔茨海默病协调中心（NACC）行为和语言领域（CDR加NACC FTLD）将携带者分为三组：无症状组、前驱组和有症状组。我们提取了皮质厚度、白质完整性和功能连接性的测量值，并使用线性混合模型对每个携带者组与对照组进行比较。
无症状携带者的显著/视觉网络中存在早期孤立的功能破坏，同时前扣带回灰质减少。在前驱携带者中，功能变化扩展到其他网络，颞极/扣带回出现额外的结构损伤。
本研究表明，功能网络可能驱动对遗传性疾病的终身代偿，当结构损伤达到临界阈值时在临床上表现出来。这支持将连接性测量作为MAPT相关神经退行性变的潜在生物标志物。
我们的研究结果揭示了MAPT突变携带者结构和功能连接性改变的渐进性和阶段性本质，每个疾病阶段都有不同的模式。在无症状携带者中，尽管白质保留且灰质萎缩轻微，但我们在显著和视觉网络中发现了早期功能连接性改变。这些似乎既代表了对病理的反应，也代表了可能的代偿机制。在前驱携带者中，功能连接性改变伴随着结构损伤，包括与早期受影响网络直接相连区域的皮质萎缩和白质束中断。从功能连接性变化到结构退化的顺序进展与tau沿轴突连接传播、在可测量的萎缩发生之前破坏神经网络完整性的假设一致。我们提出了一个MAPT突变携带者生物标志物演变的理论数据驱动模型，强调功能破坏是早期指标，结构损伤是后期标志。这些连接性生物标志物有可能为治疗策略和临床试验设计提供信息。
