The relative brain signal variability increases in the behavioral variant of frontotemporal dementia and Alzheimer's disease but not in schizophrenia

Abstract

Overlapping symptoms between Alzheimer's disease (AD), behavioral variant of frontotemporal dementia (bvFTD), and schizophrenia (SZ) can lead to misdiagnosis and delays in appropriate treatment, especially in cases of early-onset dementia. To determine the potential of brain signal variability as a diagnostic tool, we assessed the coefficient of variation of the BOLD signal (CV_BOLD) in 234 participants spanning bvFTD (n = 53), AD (n = 17), SZ (n = 23), and controls (n = 141). All underwent functional and structural MRI scans. Data unveiled a notable increase in CV_BOLD in bvFTD patients across both datasets (local and international, p < 0.05), revealing an association with clinical scores (CDR and MMSE, r = 0.46 and r = -0.48, p < 0.0001). While SZ and control group demonstrated no significant differences, a comparative analysis between AD and bvFTD patients spotlighted elevated CV_BOLD in the frontopolar cortices for the latter (p < 0.05). Furthermore, CV_BOLD not only presented excellent diagnostic accuracy for bvFTD (AUC 0.78-0.95) but also showcased longitudinal repeatability. During a one-year follow-up, the CV_BOLD levels increased by an average of 35% in the bvFTD group, compared to a 2% increase in the control group (p < 0.05). Our findings suggest that CV_BOLD holds promise as a biomarker for bvFTD, offering potential for monitoring disease progression and differentiating bvFTD from AD and SZ.

Keywords: Alzheimer’s disease; brain signal variability; frontotemporal dementia; functional MRI; schizophrenia.

Figure 1.

(a) Examples of random single voxel BOLD signal time series and formation of relative brain signal variability maps (CV_BOLD) based on each voxel’s time series standard deviation (σ) and mean (μ). (b) Group mean CV_BOLD maps on axial view and (c) whole-brain average CV_BOLD values (mean ± 95% confidence interval). Note that CV_BOLD values are dependent on imaging parameters. t-test values: ****p < 0.0001; ns not significant.

Figure 2.

Relative brain signal variability (CV_BOLD) in patients compared with controls. Differences in CV_BOLD were examined using whole-brain voxel-wise analyses. (a) The maps depict group-level differences where CV_BOLD is higher in bvFTD patients in both datasets 1 and 2, and where bvFTD patients exhibit higher CV_BOLD levels in the frontal areas than AD patients (p < 0.05, family-wise error corrected). Importantly, there were no statistically significant differences observed between schizophrenia patients and controls. (b) Common voxels between datasets 1 and 2, used as the region-of-interest (ROI_FTD) for further analysis. The sizes of these regions/ROIs were reported in both voxels and cubic centimeters. The 3 D map is available in NIFTI format as a supplementary file. (c–f) Area under the ROC curves (AUC) values were calculated. (c,d) AUC for bvFTD and controls using the ROI_FTD. (e) AUC for bvFTD vs. AD and (f) AUC for SZ vs. controls. Higher AUC values indicate better discrimination. The 95% confidence intervals (CI) are presented in brackets.

Figure 3.

Accuracy, repeatability, and correlation with clinical parameters in dataset 1. (a) Within-individual changes in the average whole-brain CV_BOLD over time after baseline imaging (0 months) in bvFTD patients and controls. The data represents the mean ± 95% confidence intervals. Mixed-effects analysis: **** p < 0.0001. (b) Voxel-wise statistically significant difference where CV_BOLD increased over 6 months (paired t-test, TFCE-corrected). (c) Voxels displaying group-level differences where CV_BOLD is higher in bvFTD patients at baseline (0 months) (same as in Figure 2(a)). This area was used as the region of interest (ROI_dataset1) in (d–e). (d) Negative correlation between CV_BOLD values in this area and Mini-Mental State Examination (MMSE). MMSE scores range from 0 to 30, with a score of 10 to 26 indicating moderate-to-mild cognitive impairment and (e) correlation between CV_BOLD in this area and Clinical Dementia Rating (CDR). CDR Sum of boxes (CDR_SOB) scores range from 0 to 18, with a score above 0.5 indicating cognitive impairment, 4.5–9.0 mild dementia, 9.5–15.5 moderate dementia, and 16–18 severe dementia.

Figure 4.

Group-level differences in CV_BOLD and voxel-based morphometry results. a-b shows the area where CV_BOLD is statistically significantly higher in bvFTD patients compared to controls (marked with yellow). Correspondingly, gray matter volume is lower in bvFTD patients compared to controls, indicated in blue. Panels a and b present p-value maps (family-wise error corrected, p < 0.05). Panels c and d depict the correlation between gray matter volume and whole-brain mean CV_BOLD values.