Kancheva Ivana Kirilova, Bouzigues Arabella, Russell Lucy Louise, Foster Phoebe H, Ferry-Bolder Eve, Van Swieten John C, Jiskoot Lize Corrine, Seelaar Harro, Sánchez-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, Ducharme Simon, Butler Christopher, Le Ber Isabelle, Finger Elizabeth, Tartaglia Maria Carmela, Masellis Mario, Synofzik Matthis, Moreno Fermin, Borroni Barbara, Rohrer Jonathan Daniel, van der Weerd Louise, Rowe James B, Tsvetanov Kamen
Department of Radiology, Leiden University Medical Center, the Netherlands.
Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, University of Cambridge, United Kingdom.
Neurology. 2025 Sep 23;105(6):e213677. doi: 10.1212/WNL.0000000000213677. Epub 2025 Sep 4.
Cerebrovascular reactivity (CVR) is an indicator of cerebrovascular health, and its signature in familial frontotemporal dementia (FTD) remains unknown. The primary aim was to investigate CVR in genetic FTD using an fMRI index of vascular contractility termed resting-state fluctuation amplitudes (RSFAs) and to assess whether RSFA differences are moderated by age. A secondary aim was to study the relationship between RSFA and cognition.
Participants included presymptomatic and symptomatic , , and pathogenic variation carriers, along with noncarriers, from the prospective Genetic FTD Initiative cohort study. Cross-sectional differences in CVR were assessed using both component-based and voxel-level RSFA maps. To study disease progression-related effects, the moderating effect of age on differences between genetic status groups was analyzed using generalized linear models. The influence of RSFA, and its interaction with genetic status, on participants' cognitive function was also examined. All models were adjusted for sex, handedness, and scanning site and false discovery rate-corrected at < 0.05.
A total of 284 presymptomatic and 124 symptomatic sequence variation carriers, and 265 noncarriers, were included in the analysis (mean age 48.17 years, 55% female). Across the sample, symptomatic carriers exhibited lower RSFA and a greater age-related RSFA decline predominantly in the medial frontal (-0.07 standard units, = 0.046, 95% CI -0.13 to -0.01) and posterior parietal (-0.06 standard units, = 0.048, 95% CI -0.12 to 0.01) cortex, compared with presymptomatic carriers and noncarriers. RSFA was inversely correlated with age (-0.43 standard units, < 0.001, 95% CI -0.48 to -0.37) and positively associated with cognitive function (0.09 standard units, = 0.008, 95% CI 0.04-0.15), particularly in the prefrontal cortex, in sequence variation carriers across the sample, independent of disease stage.
CVR impairment in genetic FTD has a predilection for the middle frontal and posterior cortex, and its preservation may yield a cognitive benefit for at-risk individuals. Although findings do not provide causality and warrant replication, they support the notion that vascular dysfunction in familial FTD may be a target for biomarker identification and disease-modifying efforts.
脑血管反应性（CVR）是脑血管健康的一项指标，其在家族性额颞叶痴呆（FTD）中的特征尚不清楚。主要目的是使用一种称为静息态波动幅度（RSFAs）的功能磁共振成像血管收缩性指标来研究遗传性FTD中的CVR，并评估RSFA差异是否受年龄影响。次要目的是研究RSFA与认知之间的关系。
参与者包括来自前瞻性遗传性FTD倡议队列研究的症状前和有症状的 、 和 致病变异携带者以及非携带者。使用基于成分和体素水平的RSFA图谱评估CVR的横断面差异。为了研究与疾病进展相关的影响，使用广义线性模型分析年龄对遗传状态组之间差异的调节作用。还检查了RSFA及其与遗传状态的相互作用对参与者认知功能的影响。所有模型均针对性别、利手和扫描部位进行了调整，并在 < 0.05时进行了错误发现率校正。
分析共纳入284名症状前和124名有症状的序列变异携带者以及265名非携带者（平均年龄48.17岁，55%为女性）。在整个样本中，有症状的携带者表现出较低的RSFA，且与年龄相关的RSFA下降幅度更大，主要集中在内侧额叶（-0.07标准单位， = 0.046，95%可信区间-0.13至-0.01）和顶叶后部（-0.06标准单位， = 0.048，95%可信区间-0.12至0.01）皮质，与症状前携带者和非携带者相比。RSFA与年龄呈负相关（-0.43标准单位， < 0.001，95%可信区间-0.48至-0.37），与认知功能呈正相关（0.09标准单位， = 0.008，95%可信区间0.04 - 0.15），特别是在整个样本的序列变异携带者的前额叶皮质中，与疾病阶段无关。
遗传性FTD中的CVR损伤易发生于额中回和后皮质，其保持可能对高危个体产生认知益处。尽管研究结果未提供因果关系且需要重复验证，但它们支持这样一种观点，即家族性FTD中的血管功能障碍可能是生物标志物识别和疾病修饰研究的一个靶点。
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