Our results demonstrate that pcASL sequence could provide CBF measurement with high reliability in both young controls and older subjects. The normalized CBF images measured by pcASL were comparable to those obtained with 15
O-water PET scans on the same subjects including AD, MCI patients and elderly controls. A previous ASL study revealed that random noise contributed to the fluctuations in ASL perfusion signal more than the physiological variations within each subject (13
). This finding indicated that the low SNR in ASL signal could potentially limit the measurement’s reliability. Furthermore, a recent study showed that voxels in deep WM measured by ASL had a perfusion SNR less than one and ASL applicability became problematic (12
). In order to improve perfusion SNR, the current pcASL technique in this study adapted a combination of several technical advances including a 3.0 Tesla scanner, a multi-channel receiver coil, pseudo-continuous ASL labeling, background static signal suppression and 3D segmented spiral acquisition.
First, the ASL perfusion signal is largely enhanced on 3.0T compared to 1.5T since both the blood T1 relaxation time and spin magnetization are increased with the magnetic field strength. Second, the pseudo-continuous tagging method achieves a high labeling efficacy with a standard coil setting by applying thousands of millisecond-long pulses to create the blood flow driven adiabatic inversion condition with minimized MT effect (17
). Third, the static background signal is suppressed with null pulses to reduce the MT effect and improve the perfusion SNR (21
). Fourth, a segmented multi-shot 3D spiral acquisition allows a very short TE and leads to less signal dropout and imaging distortion, especially in the frontal and temporal lobes where the susceptibility-induced problems are severe in typical echo planar images. With a combination of all the above technical improvements, the pcASL sequence used only ~5 minutes to collect the perfusion maps with a similar SNR to a recent ASL study with a 10 minute long scan (12
From the current ICC result, there is no difference in reliability of the ASL measurements between young and elderly subjects. However, the older subjects only had two pcASL scans while the young controls had three. The number of repeated measurements could directly affect the reliability outcome since ICC is a ratio outcome related to variance. When we randomly removed one pcASL scan result from the reliability analysis, the CBF reliability from the young subjects would increase and show slightly higher reliability than those ICC values from the older subjects. Increased reliability in young controls is consistent with the slightly higher perfusion SNR in young controls’ CBF images in comparison to those in elderly subjects.
Cerebral blood flow is believed to be tightly coupled to brain neuronal activity and could be affected by various factors (33
). A previous study with 15
O-water PET has reported 8% variation in white matter and 10% in gray matter for 2-day intervals (34
). The current experiment was designed to study the instrumental error of pcASL CBF measurement, therefore the time frame of repeated measurements was within one hour. We expected that most of the variance in CBF value would arise from the measurement instead of physiological changes. In terms of ICC values, our pcASL reliability result is better than the previously reported CBF variation in both GM and WM with pulsed ASL technique (13
). One important issue of perfusion measurement is the CBF variation across subjects. Roughly 20–25% percent variation across-subjects was observed for the pcASL CBF mean values. Compared to young controls, elderly subjects showed greater variation overall. Besides the physiological CBF variation across subjects, one major concern about ASL signal is its labeling efficacy variation between subjects. Recent studies have shown high variation in pcASL inversion pulse labeling efficacy due to its sensitivity to the blood velocity (17
). Before making conclusion of the high sensitivity of pcASL technique, a careful evaluation of ASL CBF signal with other absolute flow quantification methods is necessary.
Since we did not record the radioactivity of an arterial blood sample during the PET scan, the absolute value of CBF could not be quantified in the current 15
O-water PET experiment. However, the relative CBF (rCBF) values from PET scans showed a tight correlation to the quantitative ASL CBF values in the older subjects who received both scans. Using the Bland-Altman plot, the rCBF value difference between two methods was within the 95% CI range. This converging perfusion result in elderly subjects is consistent with the previous ASL-PET comparison in young controls (10
). However, in the Bland-Altman plots of both GM and PCC ROIs, the agreement of two measurements remained lowest on the AD patient, whose perfusion was also lowest among all participants. This could suggest the perfusion variation depends strongly on the magnitude of measurement. Although the pcASL technique used a similar flow quantification mechanism as 15
O-water PET, the ASL model suffers from the fast decay of magnetization. Our current single compartment ASL model assumes that water of blood is instantaneously exchanged into tissue as soon as it reaches brain. Compared to the 15
O-water 2-minute half-life, the magnetically labeled water in ASL only has a 1–2 second half-life. The assumptions regarding exchange rate between blood/tissue compartments and the decay of the tag could bring error into the flow quantification and possibly over-estimate the derived CBF values. The heterogeneity of arterial transit time between subjects and different brain regions may further affect the precision of the flow quantification. Under the current 3.0 T field strength and 1.5 second post-labeling delay time, these above errors in the single compartment flow quantification model is likely to be limited to GM (11
One interesting finding of the current study is that the GM to WM perfusion ratio decreases when the subject’s age increases and such GM/WM ratios were especially lower among the MCI and AD patients. Although cerebral perfusion was previously reported to decrease with age at a rate of 0.45 – 0.7% per year, this pattern of age dependent CBF reduction may be nonlinear across stages of the lifespan (35
). For example, by using ASL on 1.5 T MR system, a recent study found aging-related perfusion reductions in the frontal lobe (14
) while another group reported a significant gap in CBF only between children and adult subjects, but much less CBF difference between adults and elderly subjects (38
). Meanwhile, white matter perfusion rate changes remained stable against aging (39
). In our current result, neither GM nor WM CBF is significantly different between the young and elderly controls. The correlations between age and GM or WM perfusion rates were not significant.
Several previous studies have reported hypo-perfusion in AD and MCI patients with ASL techniques (4
) while other more recent studies found regional hyper-perfusion in the dementia patients (41
) that is indicative of brain compensation. Recent AD research has been focused on the elderly people who are at risk for developing AD. For example, it was reported that people at risk for AD exhibit compensatory increased perfusion in the mesial temporal lobes during resting ASL imaging (41
). The test-retest of ASL technique has not been tested before with an at-risk cohort or AD patients. When there is a conflicting finding of increased and decreased perfusion during the early stage of AD, the reliability test becomes even more important. Our interpretation and hypothesis of the CBF change related to early AD brain adjustment for the loss of synapses and neurons certainly relies on the reliability and validity of the measurement itself. One encouraging finding from the current data is that the high ICC value of repeated pcASL CBF measures indicated good reliability among elderly subjects, including AD and MCI patients. An overall trend of slight CBF decrease with aging is found across all ROIs when comparing young and elderly subjects. However, none of these ROIs’ CBF comparison yielded a statistically significant difference. A larger sample size and more sophisticated model such as multivariate analysis of different brain ROIs (40
) would further help to depict the age-perfusion relationship. Interestingly, while MCI patients show similar perfusion rates compared to cognitively normal elderly subjects, their GM/WM ratios were close to values of the AD subjects and much lower than most controls. Due to the small patient number included in our current study, limited interpretation could be made to link this GM and WM perfusion change mismatch to early AD pathophysiological processes at this point.
Several limitations remain in this study. First, we did not sample the arterial blood radiation dosage during the 15
O-water PET scan. A quantitative CBF comparison from both ASL and PET methods would be more desirable to study the potential problems in the ASL quantification model. Fortunately, similar comparison work has been previously performed within the same group of adults and discrepancies between two CBF methods has been addressed (10
). Second, we did not include arterial blood transit time or capillary permeability (exchange ratio between compartments) into the flow quantification. In order to measure the transit time, the protocol would require varying post-labeling delay, which would prohibitively increase the scan time. The precise measurement of the capillary permeability surface area product for the two-compartment flow model is also problematic under current MR capabilities (44
). The overall effect of these factors on CBF values remains unclear and needs further investigation. Future longitudinal repeated CBF measurement would be very important to evaluate its usefulness in clinical environment.