Cerebrovascular Reactivity at Rest and Its Association With Cognitive Function in People With Genetic Frontotemporal Dementia

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.

Figure 1. Neurocognitively Meaningful Independent Components Based on Spatial ICA on RSFA Maps

Spatial distribution of 4 ICs within neurocognitively meaningful areas (i.e., GM regions) based on spatial ICA on RSFA maps across participants, where differences in IC loading values are found in association with genetic status, age, and genetic status × age interaction. Robust general linear model regression lines for each IC are presented in scatter plots with respective r values on the right side of each IC map. p Values are FDR-corrected at the 0.05 level across the whole sample. Group-level spatial maps are overlaid onto the Colin-27 (ch2.nii) structural template of the MNI brain, where intensity values correspond to z-values. FDR = false discovery rate; GM = gray matter; IC = independent component; ICA = IC analysis; MNI = Montreal Neurological Institute; RSFA = resting-state fluctuation amplitudes.

Figure 2. Differences in Global Cognitive Function in Association With Genetic Status, RSFA, and Genetic Status × RSFA Interaction Across Groups of Interest

Cognitive function is denoted by participants' loading values for PC 1 after PCA on 9 cognitive measures. Effects are illustrated for ICA-based components within GM areas (A) and several representative ROIs based on TFCE-corrected voxel-wise univariate analysis (B). Robust general linear model regression lines for each respective IC and ROI are presented in scatter plots with corresponding r values on the right side of a representative slice depicting each IC/ROI map. p Values are FDR-corrected at the 0.05 level across the whole sample. FDR = false discovery rate; GM = gray matter; IC = independent component; ICA = IC analysis; MFG = middle frontal gyrus; PC = principal component; PCA = PC analysis; PCC = posterior cingulate cortex; ROI = region of interest; RSFA = resting-state fluctuation amplitudes; TFCE = threshold-free cluster enhancement.

Figure 3. RSFA Effects Based on Voxel-Wise Univariate Analysis

(A) Regional distribution of RSFA effects based on voxel-level univariate analysis. Cold colors denote RSFA decreases as a function of genetic status and their interaction with age. Statistical parametric maps are displayed at an uncorrected level of p < 0.01 to better visualize regional CVR patterns. Images are overlaid onto the Colin-27 (ch2.nii) structural template of the MNI brain. (B) Differences in RSFA in association with genetic status, age, and genetic status × age interaction across groups of interest in several representative ROIs based on TFCE-corrected voxel-wise univariate analysis on RSFA maps. Robust general linear model regression lines for each ROI are presented in scatter plots with respective r values on the right side of each ROI map. p Values are FDR-corrected at the 0.05 level across the whole sample. CVR = cerebrovascular reactivity; FDR = false discovery rate; MFG = middle frontal gyrus; MNI = Montreal Neurological Institute; NC = noncarrier; PCC = posterior cingulate cortex; PSC = presymptomatic carrier; ROI = region of interest; RSFA = resting-state fluctuation amplitudes; SC = symptomatic carrier of a sequence variation; TFCE = threshold-free cluster enhancement.