Clinical imaging such as FDG-PET and SPECT has been well established in the diagnosis of Alzheimer's disease (AD) and other neurological disorders, but the diagnostic value of arterial spin labeling (ASL) MRI, a relatively new noninvasive imaging technique, has not been validated or confirmed. Comparative studies that compared ASL with FDG-PET, 15O-water-PET, SPECT, dynamic susceptibility contrast-enhanced (DSC), or dynamic contrast-enhanced (DCE) MRI are important to reveal the concordance and discordance between ASL and these clinical imaging tests. This paper reviews such studies in healthy subjects and patients with AD or other neurological disorders. These comparative studies have demonstrated that ASL and FDG-PET/15O-water-PET had overall concordance and regional variability in healthy subjects, and the regional hypoperfusion that ASL depicted in diseases such as AD was largely concordant with the abnormalities identified by FDG-PET/SPECT (the diagnostic performance was comparable), which suggests that ASL may have a similar diagnostic value as FDG-PET/SPECT. In addition, there are mixed findings in ASL cerebral blood flow (CBF) measurements compared with 15O-water-PET, and ASL may be less sensitive than DSC (or DCE) in the diagnosis of neurological disorders such as stroke. Studies with large samples are needed to further validate the diagnostic value of ASL and its CBF measurement. Furthermore, it is necessary to optimize and standardize ASL parameters and explore new techniques to overcome the limitations of ASL and make it a clinical imaging alternative to invasive FDG-PET/SPECT/DSC/DCE in the diagnosis of AD and other neurological disorders. IT IS OFTEN difficult to differentiate early-stage Alzheimer's disease (AD) from other neurodegenerative dementias or mild cognitive impairment (MCI).1 MRI, FDG-PET, and SPECT have been the major clinical imaging tests used for the diagnosis of dementia. FDG-PET or SPECT uses radioactive tracers to image glucose metabolism or brain perfusion. Since reductions in cerebral glucose uptake and brain perfusion often precede brain atrophy, measures of FDG-PET/SPECT can serve as early biomarkers for preclinical or mild AD.2 FDG-PET/SPECT imaging in neurodegenerative disorders is based on the coupling of neural activity and glucose metabolism to reduced regional cerebral blood flow (CBF)3 due to the synchronization of cerebral metabolic demands to regional blood supply. Thus, spatial patterns of regional CBF in perfusion imaging tend to mirror FDG-PET glucose metabolism results unless neurovascular coupling is compromised.4 In addition, CBF measurements are important in the assessment of AD and other neurological disorders such as stroke. 15O-water-PET (PET imaging with 15O-water tracer) is considered a gold standard for quantifying CBF.5 The diagnostic value of PET and SPECT imaging has been well demonstrated and validated,1, 3 but they are invasive and expensive, and need exposure to radiation. Although relatively new, arterial spin labeling (ASL) MRI has emerged as a perfusion imaging technique of growing popularity due to its recent technical advancements and use of magnetically labeled arterial blood water as an intrinsic tracer. It measures CBF by computing the difference between the labeled and nonlabeled images. ASL is noninvasive, less expensive, convenient for acquisition (can be acquired in the same section of structural MRI) and allows multiple repeated measurements. Thus, it might be an alternative to invasive imaging tests such as FDG-PET and SPECT. There are mainly three types of ASL: continuous ASL (CASL), pulsed ASL (PASL), and pseudo-continuous ASL (pCASL). They are different in the way they label arterial blood water: CASL uses a single long pulse, PASL uses one or several short pulses, while pCASL applies over 1000 shaped radiofrequency pulses at around one per millisecond. Among the three, pCASL has the highest signal-to-noise ratio and superior labeling efficiency. Therefore, pCASL is recommended for clinical imaging.6 ASL studies have found that areas of hypoperfusion in dementia such as AD7-13 and frontotemporal dementia (FTD)10-15 are similar to those identified by FDG-PET or SPECT.7, 11, 16-21 It is of clinical interest to assess the diagnostic value of ASL due to its ease of access, noninvasiveness, cost-effectiveness, and free of radiation exposure. In addition, dynamic susceptibility contrast-enhanced (DSC) MRI is widely used for detecting perfusion deficits in neurological disorders such as stroke and brain tumors. It has high signal-to-noise ratio (SNR) and short scan time (1 min, due to T2*-weighted fast EPI sequences), but it is invasive and requires injection of contrast materials. The contrast material gadolinium could induce nephrogenic systemic fibrosis in patients with renovascular disease22 and DSC is sensitive to susceptibility artifacts (such as hemorrhages and calcifications), which limits its applicability. Another perfusion MR imaging technique, T1-weighted dynamic contrast-enhanced (DCE) MRI is more robust to susceptibility artifacts and has higher spatial resolution, but also needs injection of contrast materials. In contrast, ASL is noninvasive and insensitive to susceptibility artifacts (such as hemorrhages), and thus it might be an alternative to DSC/DCE MRI for detecting perfusion deficits in neurological disorders such as stroke and brain tumors. Over a decade, ASL has been used to study AD and several other neurological conditions such as cerebrovascular disorders and brain tumors.23 For a comparative overview of PET, SPECT, DSC, ASL and other brain perfusion imaging techniques (including detailed description and imaging parameters or features such as spatial resolution, reproducibility, accuracy, and scan time for each imaging technique), see the comprehensive review by Wintermark et al.23 While FDG-PET, SPECT, and DSC/DCE are well established clinical imaging tests, ASL is not, mainly due to its unconfirmed or invalidated diagnostic value. In recent years, an initiative has started to address the final steps to make ASL a clinical reality,24 and recommendations of ASL implementation for clinical applications have been made.6 However, how far is ASL from a clinical reality? Studies that compared ASL with 15O-water-PET, FDG-PET, SPECT, DSC, or DCE MRI are important to reveal the concordance and discordance between ASL and these clinical imaging tests, and the diagnostic value of ASL. This paper reviews comparative studies between ASL and 15O-water-PET/FDG-PET/SPECT/DSC/DCE in healthy subjects and patients with AD or other neurological disorders to assess the diagnostic value of ASL and understand how far ASL is from a clinical reality. This section is organized as follows: (1) Validation of ASL against other imaging methods in the healthy brain, and (2) ASL comparative studies in the disease states. The disease states in the latter mainly include neurodegenerative disorders (e.g., AD), cerebrovascular disorders, and brain tumors. ASL has been compared with 15O-water-PET, FDG-PET, and DSC MRI in the healthy brain, and several studies have attempted to validate ASL against the gold-standard 15O-water-PET for CBF measurements.25-32 Findings of validation against 15O-water-PET indicate either insignificant difference in (average whole brain or gray matter) CBF measurements using the two imaging methods,25, 27, 30 or significantly higher ASL-CBF values than those of PET.29, 31 Table 1 presents the details of these studies. Briefly, using 15O-water-PET as the gold standard for CBF quantification, Ye et al conducted the first ASL comparative study in 12 healthy subjects and found insignificant difference between ASL- or PET-measured CBF values in the cortical strips, but significantly lower ASL-measured CBF value in a central white matter region which may be due to longer arterial transit time (ATT) in regions of white matter.25 Later, Qiu et al assessed ATT of ASL in healthy subjects (n = 14) and showed changes of ATT could lead to regional CBF difference between ASL and 15O-water PET.26 Henriksen et al further evaluated PASL, 15O-water PET, DCE MRI and phase contrast mapping (PCM) imaging in healthy subjects (n = 17), and reported insignificant difference in the average global CBF values measured by ASL, PET, and DCE (e.g., ASL-CBF slightly lower than PET-CBF) (Fig. 1).27 In addition, Arbelaez et al examined healthy subjects (n = 9) during hypoglycemia and euglycemia with PASL and 15O-water PET, and reported similar increases in regional CBF on ASL and PET in response to hypoglycemia.28 Van Golen et al further found correlated global CBF values between pCASL and 15O-water PET in healthy subjects (n = 11) and type 1 diabetic patients (n = but significantly higher ASL-CBF values than In a recent et al demonstrated that pCASL CBF imaging had CBF as 15O-water PET in healthy subjects (n = during and there areas with a CBF such as the (e.g., cortical and (e.g., the regions on ASL (Fig. Furthermore, et al compared acquired 15O-water PET and pCASL in healthy subjects (n = and found overall = between ASL and PET with in of regions of interest They also found significantly higher ASL-CBF values than and regional and between the two imaging (e.g., higher CBF in the and regions on In study using acquired PASL and 15O-water PET, et al found that global ASL CBF and PET CBF concordant at but not during in (n = blood flow by CBF from three different subjects are and the T1-weighted CBF are global CBF is each CBF CBF = cerebral blood DCE = dynamic contrast T1-weighted perfusion ASL = arterial spin PET = et of with from the of Henriksen et The average CBF for PET pCASL and during and with results between and et of with from the of et the overall between ASL and 15O-water PET the CBF values measured by ASL from slightly lower than to significantly higher than 31 ASL-CBF values may be by the of flow which can be by using while lower ASL-measured CBF values may be due to longer ATT in brain regions which can be by ASL parameters such as the time or and concordance has also been reported in ASL studies against FDG-PET in the healthy et al measured changes of CBF and glucose metabolism during a in healthy subjects (n = and found an concordance between regional CBF and regional cerebral metabolism et al further compared cerebral perfusion and glucose metabolism at in healthy subjects (n = using pCASL and FDG-PET, and reported overall between ASL and FDG-PET, as well as regional variability and discordance (e.g., in the regions such as the and The overall between ASL and FDG-PET measurements with regional in regions such as the and has been in patients had neurological disorders the subjects had (n = by et al using acquired ASL and FDG-PET DSC MRI is considered the clinical standard for perfusion MR imaging in neurological disorders such as stroke and brain and CBF values measured by DSC are to those by 15O-water PET or et al and et al found that CBF values by ASL and DSC in brain of these studies are in Table the validation studies that compared ASL with 15O-water-PET, FDG-PET, or DSC MRI indicate that ASL and these clinical imaging tests had overall and regional in the healthy However, there are mixed findings in the CBF measurements using ASL and 27, Studies with samples are needed to further validate ASL CBF and Comparative studies between ASL and 15O-water have abnormalities in neurodegenerative disorders such as AD and 11, CBF measurements using ASL and 15O-water-PET have been reported in AD and et al examined patients with 1 with and healthy subjects with ASL and 15O-water-PET, and found global and regional in the gray matter and = et al conducted a study for patients with (n = and AD (n = using EPI ASL, ASL, and 15O-water PET, and reported that ASL was more correlated with PET = and more than EPI Table the details of these studies. patterns of regional abnormalities and diagnostic performance between ASL and FDG-PET/SPECT have been found in patients with AD or 11, a region of interest et al compared pCASL and FDG-PET in patients with AD (n = and reported concordance between the patterns of hypoperfusion and in patients and diagnostic areas the of for ASL and for In addition, et al compared acquired pCASL and FDG-PET in patients with AD (n = and demonstrated that ASL and FDG-PET identified similar regional deficits and had diagnostic performance of for ASL and for artifacts on Furthermore, et al examined AD patients and 12 patients with pCASL and FDG-PET, and found similar patterns of and and diagnostic performance of metabolism and perfusion in regions to AD and (Fig. In et al found that ASL and FDG-PET identified similar regions such as the and the in patients (n = In addition, et al examined patients with AD (n = of with with pCASL and SPECT, and demonstrated high concordance between the two imaging by two They reported higher of of SPECT than that of ASL ASL: mainly due to the on ASL, and that compared with SPECT, the diagnostic performance of ASL was slightly lower in the diagnosis of AD and and ASL of an and and an AD and with abnormalities in and abnormalities in metabolism and perfusion. et of with from the of et the concordance and between hypoperfusion and measurements by the two imaging techniques in AD and other neurodegenerative disorders, there are For in the regions has been found on but in these regions on FDG-PET in AD Another ASL regional in areas such as and in which has not been found on between ASL and 15O-water-PET measures has been found in patients with AD or Studies also found that ASL and FDG-PET largely and diagnostic performance in patients with neurodegenerative dementias such as AD and However, ASL is more by such as ATT than FDG-PET or SPECT which to artifacts on and its diagnostic these artifacts the diagnostic of ASL and make it a alternative to clinical PET or SPECT ASL has been compared with the gold standard 15O-water-PET imaging in cerebrovascular diseases and it has been found that CBF values measured by ASL and 15O-water-PET are but ASL-CBF values are to the long ATT in patients with such disorders, of ASL parameters such as time or is necessary to arterial transit artifacts on ASL images. multiple et al significantly CBF in the cerebral to the on ASL and 15O-water-PET correlated gray matter ASL-CBF and values = and higher average gray matter ASL-CBF than that of PET in patients with (n = In addition, between CBF values measured by PASL and 15O-water-PET = slightly higher average than and between and transit found in patients with diseases (n = The between ASL and DSC measurements in cerebrovascular diseases has from to et al found between the two imaging techniques in of patients with and that PASL could perfusion abnormalities in stroke similar to DSC et al also found that the ATT difference between the CBF measurements using CASL and DSC MRI correlated in patients with cerebrovascular disease (n = and that CASL and DSC MRI might be for perfusion in cerebrovascular Later, et al PASL with multiple to in patients with stroke and reported = between ASL perfusion and DSC perfusion imaging (Fig. stroke (n = et al found that CBF values from ASL and DSC in brain but in with CBF values from the two imaging techniques significantly due to et al further that pCASL and DSC MRI could regions of hypoperfusion in patients with stroke (n = with = between ASL and and pCASL was at regions of than DSC For perfusion et al found that in patients with stroke perfusion deficits by DSC (n = pCASL concordance and compared with DSC could perfusion pCASL could large perfusion deficits and of perfusion than et al compared the imaging and in patients with stroke (n = and found that ASL and DSC but ASL to perfusion In addition, et al reported that the concordance of pCASL and DSC in detecting perfusion abnormalities found in of the to perfusion in of and pCASL was less sensitive than DSC in detecting regional CBF changes in (n = Furthermore, et al found that pCASL the hypoperfusion in (n = and the and such as arterial transit flow and changes could the performance of However, recent studies that ASL with multiple can the of regions of ATT and reduced with stroke of the and of the and DSC a of contrast on an transit time and a of the regional cerebral blood flow (CBF) ASL imaging a et of and with from the of et Studies of ASL and DCE MRI in cerebrovascular diseases are and the findings of ASL and DCE CBF measurements are results from = to = studies are needed to understand the concordance and discordance between the two imaging In addition, ASL has been compared with SPECT in cerebrovascular and correlated ASL and SPECT CBF measurements have been et al reported between regional ASL-CBF and in patients with (n = 9) and using SPECT as the of ASL-CBF was Later, et al found significantly correlated regional CBF and cerebral values measured by PASL and SPECT in patients with (Fig. (n = and regional perfusion deficits by ASL to SPECT, ASL might CBF in Furthermore, concordance and discordance of ASL and SPECT in patients with (n = In et al reported = between ASL-CBF and (n = that ASL could regions of as In a recent et al found that ASL was to SPECT = in mapping cerebrovascular in patients with disease (n = Furthermore, ASL has been used for to and between ASL-CBF and measurements = was found in patients with disease (n = CBF by SPECT and ASL in patients with with and are and in the region can be in SPECT and ASL. et of and with from the of et between CBF measurements using ASL and 15O-water-PET, DSC, DCE or SPECT has been found in patients with cerebrovascular These comparative studies have demonstrated that ASL may have a similar diagnostic value as SPECT, but it may be less sensitive than DSC or DCE MRI in detecting regional CBF changes in cerebrovascular disorders such as stroke. such as multiple can ASL imaging and regional CBF or of The findings of between the measurements using ASL and other imaging techniques (such as 15O-water PET, DSC, and DCE) in brain are and the results from to et al found that perfusion values of ASL, 15O-water PET, DSC, and DCE in the brain and correlated = and ASL-CBF values higher than in patients with brain (n = et al reported that ASL-CBF and measurements correlated in = et al found between ASL and DSC = (n = and demonstrated DSC, ASL could between and et al reported that CASL and DSC measured values correlated = the two perfusion methods (n = either PASL or et (n = et (n = et (n = and et (n = that ASL and DSC had well correlated CBF measurements = which that ASL was an alternative to DSC MRI in CBF of brain Furthermore, et al found that average regional ASL and DSC CBF measurements correlated = was in of patients (n = the two imaging techniques but This may be due to such as the CBF of ASL in areas with arterial transit while DSC and the in the of DSC The diagnostic performance of ASL in brain has been et al compared PASL, FDG-PET, and blood in patients with (n = and found that ASL could from radiation with relatively high and FDG-PET MRI et al further evaluated the diagnostic performance of ASL, and FDG-PET in the diagnosis of brain and found in blood and uptake measurements that could differentiate central (n = from (n = with diagnostic In addition, et al examined patients with brain (n = and demonstrated that the CBF measurements by PASL and DSC could They also found that the of brain identified by PASL and DSC was around (n = The value of ASL to DSC has been evaluated in patients with (n = and et al reported that ASL had similar diagnostic as DSC and it the diagnostic of DSC by and ASL: in from et al also found similar diagnostic of ASL, DSC, and DCE in from diseases (n = ASL DSC DCE and the diagnostic performance the three perfusion imaging between CBF measurements using ASL and clinical imaging tests (such as 15O-water PET and and diagnostic performance between ASL and DSC have been found in patients with brain tumors. In addition, the value of ASL to DSC or DCE in the diagnosis of has been confirmed. There are ASL comparative studies in other neurological disorders such as It has been that ASL has a value in detecting perfusion deficits for or of In patients with (n = it was found that the CBF values in the of ASL and 15O-water PET not significantly ASL and FDG-PET correlated and they also correlated with the (n = In et al found that the was with regional hypoperfusion and in of et al further examined cerebral perfusion deficits in with cortical by of pCASL and FDG-PET and reported concordance in of et al evaluated ASL and DSC in detecting perfusion for of in (n = and found similar and similar with clinical using the two imaging of these studies are in Table In addition, ASL comparative studies have examined patients with other neurological disorders or such studies are compared ASL and DSC and in patients with neurological disorders such as brain and and reported of CBF between ASL and the two DSC et al used pCASL and FDG-PET to regional glucose metabolism and regional CBF in patients (n = and found with reduced and in regions on PET and ASL, between the two imaging Furthermore, imaging has been to patients with brain or or neurodegenerative disorders (n = which and allows between ASL and PET in these the comparative studies have demonstrated concordance between ASL and clinical imaging tests (e.g., in neurological disorders such as studies are needed to further validate the diagnostic value of ASL in these a alternative to invasive clinical imaging such as FDG-PET and SPECT, ASL has the to regional perfusion deficits and regional CBF The comparative studies in review the diagnostic value of ASL in AD and other neurological disorders, and the concordance and discordance between ASL and clinical imaging tests. important of the comparative studies is the limitations of ASL in the diagnosis of AD and other neurological disorders to clinical such as ATT and labeling the of ASL and on ASL different subjects or healthy due to different or For there are in the time of arterial blood to the brain in the have which results in arterial transit or artifacts on ASL. artifacts the diagnostic of ASL and its clinical limitations of ASL are as ASL is sensitive to ATT In the healthy brain, ATT may between and while in the brain, ATT can be or and a of is recommended for clinical This that the is longer than ATT for CBF but it may be at of the ASL or the ASL signal-to-noise in the may lead to in subjects have et al found the artifacts in the of ASL in of patients as have also been found in patients with stroke or which often arterial transit on There are mixed findings in dementia on there is ATT difference between AD patients and The used in ASL dementia studies is while for stroke ASL with multiple or multiple allows more ATT and which may CBF and the diagnostic value of ASL. In addition, ASL is less by ATT and can transit and it has been that ASL could regions with long arterial in patients with cerebrovascular Therefore, ASL with new techniques such as ASL may overcome the limitations of ASL. ASL is sensitive to ASL CBF imaging is from the difference between the labeled and nonlabeled and thus be to on ASL CBF In a recent et al found that the ASL in of patients due to Since ASL (such as and are to artifacts and these ASL can be used for clinical need to be in the clinical In addition, imaging techniques may ASL with reduced and ASL with high and there are other that artifacts on ASL or in CBF measurement. For an of ASL in cortical regions has been which to higher ASL-CBF values than those measured by 31 This can be by using Another is the et al reported that could not the on ASL which might be due to the image in the regions such as the are to or and have less which in such regions on However, has on the diagnosis of In addition, the between ASL from major MRI may CBF measurements and the of ASL et Thus, ASL parameters or (e.g., for labeling and in different need to be to make ASL ASL parameters (or such as resolution, scan and (or need to be for clinical use (e.g., optimize the between signal-to-noise and and of ASL and CBF methods are also important for or studies include ASL such as the Alzheimer's and the dementia or clinical such as imaging by ASL for clinical use in stroke In recent years, have been to standardize ASL imaging and CBF methods for clinical and more between ASL and MRI are In addition, time is in clinical applications such as it is necessary to not make ASL but also make ASL convenient (e.g., and robust to clinical In and of ASL parameters is needed to overcome the limitations of ASL ASL to be as a clinical imaging Furthermore, new ASL techniques such as ASL can transit of ASL and the that ASL may an alternative to in the clinical from the limitations of ASL, there are in the comparative studies in in of the studies is the relatively The diagnostic value of ASL needs to be further validated in studies. Another is that comparative studies acquired ASL and over time which could in regional cerebral perfusion or recent studies acquired the to of ASL with allows assessment of the diagnostic value of ASL, and more comparative studies with acquired ASL and clinical are needed to further validate the diagnostic value of ASL. In addition, there are mixed findings in the CBF measurements using ASL and 15O-water PET, and further studies are needed to make ASL CBF for clinical In the comparative studies in paper have demonstrated that ASL and FDG-PET/15O-water-PET had overall concordance and regional variability in healthy subjects, and regional hypoperfusion in AD and other neurological disorders identified by ASL was largely concordant with the on that ASL may have a similar diagnostic value as FDG-PET/SPECT. In addition, ASL may be less sensitive than DSC or DCE in the diagnosis of neurological disorders such as stroke. studies with large samples are needed to validate the diagnostic value of ASL, and its CBF For ASL to a clinical imaging alternative to invasive it is necessary to optimize and standardize ASL and explore new ASL techniques (such as to overcome the limitations of ASL and its diagnostic value in AD and other neurological disorders. This was by the of of The the and to review and for for in In 1 and are from the and at the the of the is is for the use to the
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