BOLD fMRI in the white matter as a marker of aging and small vessel disease

Abstract

Purpose: Determine whether white matter signal fluctuation on T2* weighted BOLD contrast images are associated with aging and cerebral small vessel disease (SVD).

Methodology: Resting state BOLD data were collected with a 250 ms repetition time (TR) to achieve unaliased, ungated cardiac sampled BOLD (cs-BOLD) images on 11 young adult controls, 10 healthy older adult controls and 7 adults with extensive white matter hyperintensities (WMH) from SVD. Tissue classes (WM and GM) were segmented on T1 images. WMH were identified on FLAIR images in the SVD group. Raw physiological noise (σphysio) and cardiac pulsatility (i.e. fluctuations at the cardiac frequency) were calculated voxel wise and group differences were tested by ANOVA. It was also possible to calculate σphysio in 2s TR cardiac aliased whole-brain BOLD (wb-BOLD) data (N = 84) obtained from the International Consortium for Brain Mapping.

Results: CS-BOLD metrics showed an aging and SVD effects (p<0.0005). Covariates such as thermal noise, WM volume and partial volume did not influence the significant aging effect seen on the cardiac pulsatility metric (p<0.017) but did influence the σphysio (p = 0.184). As a verification of the cs-BOLD findings, the wb-BOLD also showed a linear aging effect of σphysio in WM. In the SVD adults, cardiac pulsatility and σphysio were lower in WMH regions compared to normal appearing white matter (NAWM) regions (p<0.0013 and p<0.002, respectively). Cardiac pulsatility was better able to distinguish WMH regions from NAWM than σphysio as measured by effect size (Cohen's d 2.2 and 0.88, respectively).

Conclusion: NAWM was found to have graded increases in cardiac pulsations due to age and SVD, independently. Within SVD participants, WMH lesions had reduced physiological noise compared to NAWM. Cardiac pulsatility in resting BOLD data may provide a complementary dynamic measure of WM integrity to add to static FLAIR anatomical images.

Figure 1. Fluid attenuated inversion recovery (FLAIR) images of SVD participants.

Figure 2. Overview of cs-BOLD imaging and the cardiac pulsatility metric.

A) Axial positioning of the critically-sampled BOLD slices; B) Representative cs-BOLD axial slice from an elderly control at time point 1 (maximum tissue type contrast, non steady-state); C) smoothed mean tissue class power spectrum (each bin contains the integrated power within ±0.02 Hz of the central frequency). NB: non-brain voxels (pulsatility present because of EPI ghosting); CSF: cerebrospinal fluid; GM: grey matter; WM: white matter.

Figure 3. cs-BOLD physiological noise and cardiac pulsatility results.

(A) Mean physiological noise (σ_physio) in the NAWM of young controls (YC), elderly controls (EC), and patients with small vessel disease (SVD); (B) mean cardiac pulsatility in the NAWM of YC, EC, and SVD. *: significant after Bonferroni correction for multiple comparisons.

Figure 4. Illustrative cardiac pulsatility slices.

Top: cardiac pulsatility in three cs-BOLD participants representative of the YC, EC, and SVD cohorts; bottom: NAWM masks (yellow) overlaid on cs-BOLD images for the same participants, WMH mask (red).

Figure 5. Comparison between white matter hyperintensities (WMH) and normal appearing white matter (NAWM) using (A) physiological noise and (B) cardiac pulsatility metrics.

Figure 6. Significant age effect on physiological noise in WM in wb-BOLD data (TR = 2s, n = 84, r = 0.27, p<0.01).