The brain is cleaned from waste by glymphatic clearance serving a similar purpose as the lymphatic system in the rest of the body. Impairment of the glymphatic brain clearance precedes protein accumulation and reduced cognitive function in Alzheimer's disease (AD). Cardiovascular pulsations are a primary driving force of the glymphatic brain clearance. We developed a method to quantify cardiovascular pulse propagation in the human brain with magnetic resonance encephalography (MREG). We extended a standard optical flow estimation method to three spatial dimensions, with a multi-resolution processing scheme. We added application-specific criteria for discarding inaccurate results. With the proposed method, it is now possible to estimate the propagation of cardiovascular pulse wavefronts from the whole brain MREG data sampled at 10 Hz. The results show that on average the cardiovascular pulse propagates from major arteries via cerebral spinal fluid spaces into all tissue compartments in the brain. We present an example, that cardiovascular pulsations are significantly altered in AD: coefficient of variation and sample entropy of the pulse propagation speed in the lateral ventricles change in AD. These changes are in line with the theory of glymphatic clearance impairment in AD. The proposed noninvasive method can assess a performance indicator related to the glymphatic clearance in the human brain. Index Terms-Brain, FMRI, heart, MREG, optical flow. I. INTRODUCTION R ECENTLY emerged glymphatic brain clearance mechanisms have been shown to use physiological pulsations to clear the brain tissue from metabolic waste materials such as beta-amyloid protein aggregates [1]-[3]. Glymphatic clearance pushes waste to dural lymphatic vessels and finally to cercical lymph nodes. Abnormal glymphatic clearance has been shown in [1] and [2] to cause beta-amyloid aggregation preceding the Alzheimer's disease.

Biomarkers sensitive to prodromal or early pathophysiological changes in Alzheimer’s disease (AD) symptoms could improve disease detection and enable timely interventions. Changes in brain hemodynamics may be associated with the main clinical AD symptoms. To test this possibility, we measured the variability of blood oxygen level-dependent (BOLD) signal in individuals from three independent datasets (totaling 80 AD patients and 90 controls). We detected a replicable increase in brain BOLD signal variability in the AD populations, which constituted a robust biomarker for clearly differentiating AD cases from controls. Fast BOLD scans showed that the elevated BOLD signal variability in AD arises mainly from cardiovascular brain pulsations. Manifesting in abnormal cerebral perfusion and cerebrospinal fluid convection, present observation presents a mechanism explaining earlier observations of impaired glymphatic clearance associated with AD in humans.

Accumulation of amyloid-β is a key neuropathological feature in brain of Alzheimer's disease patients. Alterations in cerebral hemodynamics, such as arterial impulse propagation driving the (peri)vascular cerebrospinal fluid 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 Alzheimer's disease patients. 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 cerebrospinal fluid impulse propagation compromises vascular impulse propagation and subsequently glymphatic brain clearance of amyloid-β in Alzheimer's disease.

Resting state functional MRI has shown potential for detecting changes in cerebral blood oxygen level-dependent signal in patients with epilepsy, even in the absence of epileptiform activity. Furthermore, it has been suggested that coefficient of variation mapping of fast functional MRI signal may provide a powerful tool for identification of intrinsic brain pulsations in neurological diseases such as dementia, stroke, and epilepsy. In this study, we used fast functional MRI sequence (magnetic resonance encephalography) to acquire ten whole brain images per second. We used the functional MRI data to compare physiological brain pulsations between healthy controls (n = 102) and patients with epilepsy (n = 33), and furthermore to drug-naïve seizure patients (n = 9). Analyses were performed by calculating coefficient of variation and spectral power in full-band and filtered sub-bands. Brain pulsations in the respiratory-related frequency sub-band (0.11–0.51 Hz) were significantly (p<0.05) increased in patients with epilepsy, with an increase in both signal variance and power. At the individual level, over 80% of medicated and drug-naïve seizure patients exhibited areas of abnormal brain signal power that correlated well with the known clinical diagnosis, while none of the controls showed signs of abnormality with the same threshold. The differences were most apparent in the basal brain structures, respiratory centers of brain stem, midbrain, and temporal lobes. Notably, full-band, very low frequency (0.01-0.1 Hz) and cardiovascular (0.8-1.76 Hz) brain pulses showed no differences between groups. This study extends and confirms our previous results of abnormal fast functional MRI signal variance in epilepsy patients. Only respiratory-related brain pulsations were clearly increased with no changes in either physiological cardiorespiratory rates or head motion between the subjects. The regional alterations in brain pulsations suggest that mechanisms driving the cerebrospinal fluid homeostasis may be altered in epilepsy. Magnetic resonance encephalography has both increased sensitivity and high specificity for detecting the increased brain pulsations, particularly in times when other tools for locating epileptogenic areas remain inconclusive.