Alzheimer’s disease (AD) is a neurodegenerative disease that causes the brain to shrink, and neurons to die. AD is the most common cause of dementia, and currently is the 6th leading cause of death in the United States (Solis et al., 2020). AD is characterized by Amyloid-beta and Tau pathology, but also by changes in the cerebral blood flow (CBF). There is a decrease of CBF in AD subjects when compared with healthy controls and in the transition from MCI to AD (van der Kleij et al., 2018). Most patients with dementia suffer also from neuropsychiatric symptoms (NPSs) (anxiety, depression, apathy, and psychosis). MCI subjects could have an initial moderate NPS burden that becomes worse over the years or have an initial high NPS that decreases over 2 years (David ND et al.,2016). Nearly 40% of AD subjects suffer from depressive symptoms. Current pharmaceutical treatments for AD can only improve the symptoms and have modest or no effect for MCI (Tricco AC, et. Al, 2013). Some researchers have suggested that physical activity can attenuate the cognitive decline in MCI and AD (Fonte C, et al., 2019).
Arterial Spin Labeling (ASL) MRI is a completely noninvasive technique for measuring cerebral blood flow (CBF) (Detre et al., 1992). Using the magnetically labeled arterial blood as the endogenous tracer, the ASL perfusion signal is measured through the signal changes of the brain tissues after the labeled spins reached the imaging place. To control the background tissue signal, a paired image is acquired using the same radiofrequency (RF) pulses and imaging settings, but the spin labeling RF pulses are manipulated to not change the arterial blood signal. The perfusion-weighted signal is subsequently derived from the image intensity difference between the paired images, which are often dubbed as the label and control image (Detre et al., 2012). The quantitative CBF can be calculated from the ratio between the weighted perfusion signal and the MR signal at the fully relaxed condition – the M0, using the single-compartment model (Alsop et al., 2015). Over the past decades, a variety of ASL techniques have been proposed, which can be roughly divided into four classes: pulsed ASL, continuous ASL (CASL), pseudo-CASL (PCASL), and velocity-selective ASL (VS-ASL). PASL uses a short duration RF pulse to instantly invert the arterial spins, while CASL or PCASL uses a train of pulses with small flip angles to continuously drive the spins from the positive direction to the negative direction (Dai et al., 2008). PASL, CASL, and PCASL need a post-labeling delay time for the labeled spins to reach the imaging place. By contrast, VS-ASL uses velocity-selective RF pulses to label the spins right next to the imaging place so that the transit delay can be avoided (Wong et al.,2006). Nowadays, PASL and PCASL have been implemented in a commercial product by the major MR vendors and are widely available in the clinical MR machine.
The applications for ASL MRI in clinical research are diverse including the evaluation of cerebral vascular disease and neurodegeneration (Telischak et al.,2014). ASL MRI has been increasingly adopted in the study of cerebral blood flow in Alzheimer’s Disease (AD) mainly because of its non-invasiveness and relatively low cost (compared to PET) (Wolk and Detre, 2013). Based on cross-section studies, the most consistent CBF change patterns in AD are the hypoperfusion in the temporoparietal cortex (Hu at al., 2010; Wang et al., 2013; Wang et al., 2014). Two recent studies have reported the longitudinal CBF reduction in AD and patients with mild cognitive impairment (MCI) (Camargo and Wang, 2021; Duan et al., 2021).
While encouraging, a challenge in current ASL-based AD research is that ASL MRI has been acquired with different ASL MRI sequences, especially in the multi-site longitudinal study such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI)( http://adni.loni.usc.edu/). There is a need to investigate the potential effects of different ASL MRI acquisitions on the AD with normal elderly control (NC) CBF comparisons. Thus far, only one paper has been published assessing the effects of different ASL MRI sequences on CBF difference detection between MCI and NC (Sudipto et al., 2017). The purpose of this work was to compare three product ASL MRI sequences from two major MR vendors: 2D Gradient Echo-Planar Imaging-based PASL MRI sequence from Siemens Healthineers (abbreviated as 2D PASL), the 3D Turbo Gradient Spin Echo-based PASL MRI sequence from Siemens Healthineers (3D PASL), and the 3D Fast Spin Echo-based PCASL MRI sequence from GE Healthcare (3D PCASL) in NC, MCI, and AD subjects. 2D PASL and 3D PASL are both based on Cartesian readout and without background suppression; 3D PCASL is based on a stack of spiral readout and background suppression (BS) (Fernandez et al., 2008; Gunther et al., 2005). The second goal of this work was to examine the associations between regional CBF in NC, MCI, and AD subjects and memory as measured by the immediate recall total score (LIMM) (Wechsler et al., 1987).