Abstract
BACKGROUND AND OBJECTIVES: 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. METHODS: Participants included presymptomatic and symptomatic C9orf72, GRN, and MAPT 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 p < 0.05. RESULTS: 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, p = 0.046, 95% CI -0.13 to -0.01) and posterior parietal (-0.06 standard units, p = 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, p < 0.001, 95% CI -0.48 to -0.37) and positively associated with cognitive function (0.09 standard units, p = 0.008, 95% CI 0.04-0.15), particularly in the prefrontal cortex, in sequence variation carriers across the sample, independent of disease stage. DISCUSSION: 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.