Cardiovascular brain impulses in Alzheimer's disease

Abstract

Accumulation of amyloid-β is a key neuropathological feature in brain of Alzheimer's disease patients. Alterations in cerebral haemodynamics, such as arterial impulse propagation driving the (peri)vascular CSF flux, predict future Alzheimer's disease progression. We now present a non-invasive method to quantify the three-dimensional propagation of cardiovascular impulses in human brain using ultrafast 10 Hz magnetic resonance encephalography. This technique revealed spatio-temporal abnormalities in impulse propagation in Alzheimer's disease. The arrival latency and propagation speed both differed in patients with Alzheimer's disease. Our mapping of arterial territories revealed Alzheimer's disease-specific modifications, including reversed impulse propagation around the hippocampi and in parietal cortical areas. The findings imply that pervasive abnormality in (peri)vascular CSF impulse propagation compromises vascular impulse propagation and subsequently glymphatic brain clearance of amyloid-β in Alzheimer's disease.

Keywords: Alzheimer’s disease; amyloid beta; cardiovascular pulses; glymphatic system.

Figure 1

The cardiovascular pulse propagation vector and voxel-wise pulse arrival times relative to the ACA. (A) Schematic overview of cardiovascular pulse propagation in human brain as functions of time and spatial location. The cardiovascular impulse induces a sharp drop in the MREG signal that moves through the brain as a wave. Optical flow algorithm follows this drop to calculate the local propagation speed (see ‘Materials and methods’ section’. (B) Mean cardiac pulse arrival times with ACA reference [MNI (0, 30, 3)] in seconds for Alzheimer’s disease (AD) and control groups. The bottom row shows their difference (P < 0.05, FDR-corrected), where lower pulse arrival latency is shown in purple (AD early) and greater latency is shown in turquoise (AD late).

Figure 2

Examples of the MREG signal shape. (A) Physiological MREG signals at the ACA in QRS synchronization with simulated ECG plots. From top to bottom: simulated ECG signal matching measured QRS timing, wide band cardiac MREG signal used in this study (0.6–5.0 Hz), narrow band MREG cardiac signal (0.7–1.5 Hz), and respiratory MREG signal (0.15–0.5 Hz). Vertical axes are in arbitrary units, and only MREG signals are comparable. (B) Cardiovascular MREG signal examples of the 0.9 s cardiac cycle used in this work at several representative locations in the brain midline. Average signals are separately shown for control and Alzheimer’s disease group with 95% CI in the background. Vertical axes are MREG signals in arbitrary units.

Figure 3

Speed (v_rms) differences in Alzheimer’s disease and control groups, the distribution of cardiac cycle length, and the whole brain average of propagation speed. (A) The 3D time lapse video of the differences (background colour) and significant differences (P < 0.05, FDR-corrected) between Alzheimer’s disease and control groups in speed magnitude (v_rms) of the cardiovascular impulse propagation in a dynamic 3D plot (see Supplementary Video 1 and Supplementary Fig. 4 for full brain coverage). (B) Median 0.9 s cycles were chosen for optical flow analysis based on the similar heart rate distributions from Alzheimer’s disease subjects and controls. (C) Distribution of mean cardiovascular impulse propagation speed (v_rms) across the whole brain data. Background colours separate the three zones; low (0–14 mm/s, P < 3.0 × 10⁻⁴) and high speeds (44–100 mm/s, P < 1.7 × 10⁻¹⁹) predominate in Alzheimer’s disease, while mid-range speeds (15–43 mm/s, P < 5.1 × 10⁻⁸) speeds predominate in controls.

Figure 4

Time-lapse image over the entire brain at 0.1 s time resolution indicating the direction u of maximal difference in cardiovascular impulse propagation speed (v_u) between control and Alzheimer’s disease groups. The directions are marked by unit sticks and colour, and P < 0.05 differences are indicated with beige voxel background. The maximum area coverage of impulse abnormality in Alzheimer’s disease coincides with the cardiovascular impulse arrival to the brain at 0.6 s, i.e. some 0.3 s after the ECG R-peak. The maximal v_u change follows the general flow directions in the main arterial territories the brain: note the hand drawn cerebral vascular territory map on the bottom for comparison. During brain impulse diastole the most Alzheimer’s disease differences are localized in central thalamic structures.

Figure 5

Faster and slower pulse propagation speed (v_u) in Alzheimer’s disease. Selected 3D planes [MNI: (0, −25, −11)] showing (A) the directions of maximal v_u difference as in Fig. 4, and (B) types of difference and their coverage (P < 0.05, FDR-corrected) in those directions. Zones: Alzheimer’s disease (AD) propagation faster (red–yellow), Alzheimer’s disease propagation slower (blue–light blue). The colour intensities in B represent the amount of difference in propagation speed along directions in A on the same scale as in Fig. 6A (4–80 mm/s). The two transparent glass brain projections indicate the wide area coverage of v_u changes detected. The complete cardiac cycle is presented in Supplementary Video 2 and Supplementary Fig. 5.

Figure 6

Reversed pulse propagation direction in Alzheimer’s disease. (A) Zone of opposite propagation direction in Alzheimer’s disease brain where the difference is significant (in green, P < 0.05, FDR-corrected). In this volume, maximal v_u differences have opposite signs (direction). The volume is shown in selected 3D planes [intersecting at MNI: (30, −25, −11)] and in a glass brain to demonstrate its spatial extent. The colour intensities represent the magnitude of the group difference in propagation speed along the same directions as in Figs 4 and 5A and of the same scale as in Fig. 5B (4–80 mm/s). The complete cardiac cycle and u directions are presented in Supplementary Video 2 and Supplementary Fig. 6. (B and C) Multi-level statistical analysis for hippocampal regions. Distribution of subject-wise mean propagation speed (v_u) in the left and right hippocampi differ significantly for (B) the left hippocampus (P = 3.34 × 10⁻³) and (C) the right hippocampus (P = 3.95 × 10⁻⁴) to Welch’s t-test. Hippocampi are marked with pink circles on the axial images in A.

Figure 7

Spatial overlap of grey matter atrophy and most correlating results. Grey matter atrophy group differences (P < 0.05) are presented in red–yellow, and combined optical flow (v_u) result at t = 0.0 s (group differences, P < 0.05) in blue–light blue colours. Combined v_u results are the spatial combination of areas with significantly increased, decreased, or reversed cardiovascular impulse propagation in Alzheimer’s disease (Figs 5 and 6A). Spatial correlation is at the maximum of 0.16 at presented t = 0.0 s (Supplementary Table 2).