Premi Enrico, Diano Matteo, Mattioli Irene, Altomare Daniele, Cantoni Valentina, Bocchetta Martina, Gasparotti Roberto, Buratti Emanuele, Pengo Marta, Bouzigues Arabella, Russell Lucy L, Foster Phoebe H, Ferry-Bolder Eve, Heller Carolin, van Swieten John C, Jiskoot Lize C, Seelaar Harro, Moreno Fermin, Sanchez-Valle Raquel, Galimberti Daniela, Laforce Robert, Graff Caroline, Masellis Mario, Tartaglia Maria Carmela, Rowe James B, Finger Elizabeth, Vandenberghe Rik, de Mendonça Alexandre, Butler Chris R, Gerhard Alexander, Ducharme Simon, Le Ber Isabelle, Tiraboschi Pietro, Santana Isabel, Pasquier Florence, Synofzik Matthis, Levin Johannes, Otto Markus, Sorbi Sandro, Rohrer Jonathan D, Borroni Barbara
Stroke Unit, ASST Spedali Civili Brescia, Brescia, 25123, Italy.
Department of Psychology, University of Torino, Turin, 10124, Italy.
Brain Commun. 2024 Jun 14;6(4):fcae185. doi: 10.1093/braincomms/fcae185. eCollection 2024.
The glymphatic system is an emerging target in neurodegenerative disorders. Here, we investigated the activity of the glymphatic system in genetic frontotemporal dementia with a diffusion-based technique called diffusion tensor image analysis along the perivascular space. We investigated 291 subjects with symptomatic or presymptomatic frontotemporal dementia (112 with [] expansion, 119 with [] mutations and 60 with [] mutations) and 83 non-carriers (including 50 young and 33 old non-carriers). We computed the diffusion tensor image analysis along the perivascular space index by calculating diffusivities in the -, - and -axes of the plane of the lateral ventricle body. Clinical stage and blood-based markers were considered. A subset of 180 participants underwent cognitive follow-ups for a total of 640 evaluations. The diffusion tensor image analysis along the perivascular space index was lower in symptomatic frontotemporal dementia (estimated marginal mean ± standard error, 1.21 ± 0.02) than in old non-carriers (1.29 ± 0.03, = 0.009) and presymptomatic mutation carriers (1.30 ± 0.01, < 0.001). In mutation carriers, lower diffusion tensor image analysis along the perivascular space was associated with worse disease severity ( = -1.16, < 0.001), and a trend towards a significant association between lower diffusion tensor image analysis along the perivascular space and higher plasma neurofilament light chain was reported ( = -0.28, = 0.063). Analysis of longitudinal data demonstrated that worsening of disease severity was faster in patients with low diffusion tensor image analysis along the perivascular space at baseline than in those with average ( = 0.009) or high ( = 0.006) diffusion tensor image analysis along the perivascular space index. Using a non-invasive imaging approach as a proxy for glymphatic system function, we demonstrated glymphatic system abnormalities in the symptomatic stages of genetic frontotemporal dementia. Such measures of the glymphatic system may elucidate pathophysiological processes in human frontotemporal dementia and facilitate early phase trials of genetic frontotemporal dementia.
胶质淋巴系统是神经退行性疾病中一个新兴的研究靶点。在此，我们采用一种基于扩散的技术——沿血管周围间隙的扩散张量图像分析，来研究遗传性额颞叶痴呆中胶质淋巴系统的活性。我们调查了291名有症状或无症状的额颞叶痴呆患者（112名携带[]扩增，119名携带[]突变，60名携带[]突变）以及83名非携带者（包括50名年轻非携带者和33名老年非携带者）。我们通过计算侧脑室体平面的x、y和z轴上的扩散率，来计算沿血管周围间隙指数的扩散张量图像分析。同时考虑了临床分期和血液标志物。180名参与者的一个子集接受了认知随访，共计640次评估。有症状的额颞叶痴呆患者的沿血管周围间隙指数的扩散张量图像分析（估计边际均值±标准误，1.21±0.02）低于老年非携带者（1.29±0.03，P = 0.009）和无症状突变携带者（1.30±0.01，P < 0.001）。在突变携带者中，较低的沿血管周围间隙的扩散张量图像分析与更严重的疾病严重程度相关（β = -1.16，P < 0.001），并且有报道称较低的沿血管周围间隙的扩散张量图像分析与较高的血浆神经丝轻链之间存在显著关联的趋势（β = -0.28，P = 0.063）。纵向数据分析表明，基线时沿血管周围间隙的扩散张量图像分析较低的患者，其疾病严重程度的恶化速度比沿血管周围间隙指数的扩散张量图像分析为平均水平（P = 0.009）或高水平（P = 0.006）的患者更快。通过使用一种非侵入性成像方法作为胶质淋巴系统功能的替代指标，我们在遗传性额颞叶痴呆的有症状阶段证实了胶质淋巴系统异常。这种胶质淋巴系统的测量方法可能有助于阐明人类额颞叶痴呆的病理生理过程，并促进遗传性额颞叶痴呆的早期试验。
