Measuring Cerebral Blood Flow Using Pseudo-continuous Arterial Spin Labeling Perfusion Magnetic Resonance Imaging
Phase: NA
Conditions: Traumatic Brain Injury, Multiple Sclerosis, Alzheimer's Disease, Tumor
Sponsor: Loma Linda University

 
Measuring Cerebral Blood Flow Using Pseudo-Continuous Arterial Spin Labeling 
Perfusion Magnetic Resonance Imaging 
 
NCT02767609 
 
April 28, 2014 

Measuring Cerebral Blood Flow Using Pseudo-Continuous Arterial Spin Labeling 
Perfusion Magnetic Resonance Imaging. 
 
Principal Investigator:  Brenda Bartnik Olson, PhD 
 
Assistant Professor, Department of Radiology, MRI 
 
Room B623, MRI 
 
Loma Linda University Medical Center 
 
Phone: 558-4000 x85216 
 
Fax: 558-0335 
 
bbartnik@llu.edu 
 
Study Personnel: 
Barbara Holshouser, PhD 
 
Professor, Department of Radiology, MRI 
 
Study Location:            MRI Department 
                                      Loma Linda University Medical Center 
 
 
 
 
Study Information:       Expected start date: April 14th, 2014 
 
Expected stop date: April 30th, 2016 
 
Type of research: biomedical 
 
 
 
Inclusion/Exclusion criteria:  
Inclusion Criteria: 
 Any person between the ages of 0-90 years, who is undergoing routine magnetic 
resonance imaging (MRI) of the head with or without contrast at LLUMC.  
 Must be eligible for MRI (no electronic or metal implants that are not MR 
compatible) 
 
Exclusion Criteria: 
 Electronic or metal implant that is not MRI safe, pregnancy or claustrophobia 
 
Subject recruitment and screening: 
 English speaking patient populations of LLUMC with an order for a Head MRI 
with or without contrast between the ages of 0-90 years will be recruited. We plan 
to recruit 300 subjects. 
 Healthy volunteers between the ages of 12-90 years will be recruited from the 
local population using word of mouth. We plan to recruit 50 subjects. 
 
Informed Consent Process: 
 
 Before participating in the study, each subject will sign an informed consent form.  
 Each subject will have the right to refuse the addition of the pseudo-continuous 
arterial spin label (pCASL) sequence and still have their MRI as ordered.  
 Consent will take place in the MRI Department, LLUMC prior to the MRI study 
and the consent process will be completed by the study PI or study personnel. 
 

 All findings and documents are considered confidential. The resultant MR 
pCASL images will be archived as part of the patients medical record on the 
Radiology PACS server.  
 
Study Design 
Background 
Cerebral blood flow (CBF) represents an important physiological parameter for the diagnosis and 
management of multiple brain disorders. The clinical need for CBF measurements is further 
complicated by the desire to have a non-invasive method with high temporal resolution that can 
measure CBF over a wide range of blood flows and in a wide range of patients. Numerous 
techniques are available to measure CBF. Nuclear medicine approaches, such as single positron 
emission computed tomography (SPECT) and positron emission tomography (PET) rely on 
radioisotopes which can be problematic in the pediatric population. In contrast, MRI-based 
methods are non-invasiveness and the CBF information can be obtained in conjunction with 
other MRI techniques (i.e. diffusion weighted imaging or spectroscopy) which allows for a 
combined longitudinal assessment of CBF, morphology, and metabolism, to provide a more 
complete understanding of the developing pathophysiological mechanisms.  
 
Two distinct MRI techniques have been developed, which differ with regard to their use of 
contrast agents. With dynamic susceptibility contrast perfusion imaging (DSC-PWI), an injection 
of a gadolinium-based contrast agent is required. The use of DSC-PWI is complicated by 
technical difficulties in administering intravenous contrast in the neonatal and pediatric 
populations and by the risk of developing nephrogenic systemic fibrosis (NSF), which is 
increased in high-risk patients, such as those with impaired kidney function, diabetes, or over the 
age of 60 years (reviewed in Tepel et al 2006). In contrast, in arterial spin labeling (ASL) 
perfusion imaging arterial blood water is used as an endogenous diffusible tracer where 
radiofrequency (RF) pulses magnetically label the moving spins in flowing blood without the use 
of a contrast agent. After a time delay allowing for the magnetically labeled blow to flow into the 
brain, “labeled” images are acquired. Separate control images are also acquired, without labeling 
and the difference between the two sets of imaged provides a measure of perfusion. Since 
gadolinium-based contrast agents are not required, the ASL perfusion technique is completely 
non-invasive (Calamante et al., 1999). In addition, ASL techniques are insensitive to blood-brain 
barrier permeability changes, which can occur after strokes or with tumors (reviewed in Wang et 
al., 2012).  
 
Because gadolinium-based contrast is not used, the ASL technique has an inherently lower 
sensitivity than DSC-PWI.  Recent advances in MRI technology, specifically the clinical use of 
higher field strength MRI systems (3 Tesla), which increase the inherent signal to noise of 
tissues, has made this technique potentially more feasible. ASL imaging is also limited by the 
short tracer (labeled blood water) half-life (1-2 seconds) resulting in limited sensitivity (reviewed 
in Wang et al., 2012). To date, there are a number of commercially available ASL techniques 
that differ in their labeling schemes, which has contributed to the difficulty in obtaining 
consistent results across different patient populations (pediatric, elderly, stroke, tumors).  The 
two most common labeling strategies are 1) continuous (CASL) labeling where a single, long 
label (1-3 seconds) is applied and 2) pulsed (pASL) labeling, where a single or a small number of 
pulses are applied over a shorter duration (10-20 milliseconds). More recently, pseudo-

continuous ASL (pCASL) labeling strategies, where 1000 or more pulses are applied over a long 
duration (1 -3 seconds) have been developed.  Compared to continuous labeling (CASL), pCASL 
labeling strategies provide superior labeling efficiency and thus increased sensitivity (Alsop et 
al., 2014). A number of recent reports using pseudo-continuous ASL (pCASL) have been 
published and show increased reliability across different patient populations (Wang et al., 2012; 
Tancredi et al., 2012; White et al., 2014).  Moreover, a recent consensus statement published by 
the International Society of Magnetic Resonance in Medicine Perfusion Study Group 
recommends the use of pCASL labeling strategies for clinical applications (Alsop et al., 2014). 
However, to date this pCASL sequence is not commercially available on the MRI systems 
currently used at LLUMC (Siemens Medical Solutions), while it is routinely available on 
General Electric and Philips Healthcare MR systems. 
 
Objectives  
The objectives of this investigator-initiated study is to determine the accuracy and reliability of a 
newly developed pCASL sequence and post-processing software (provided by Dr. J.J. Wang, 
University of California Los Angeles) across multiple patient populations (neonate to elderly) 
and pathological processes. 
 
Study Procedure 
Overview: Each subject will undergo a MRI study of the head with or with contrast including the 
pCASL sequence for a total of ~35 minutes in the MRI scanner.  
 
Imaging: Following consent, subjects will be imaged at LLUMC using the 3T MRI scanner 
(Siemens Medical Solutions, Malvern, PA) after MRI safety screening questionnaire is complete. 
Subjects will be asked to lie on or be positioned on their backs in the MRI scanner. The coil will 
be placed around their head and the subject will be provided with headphones (with music) 
during the scan. Imaging will consist of LLUMC’s routine diagnostic MR protocol for brain 
imaging (anatomic T1 and T2 weighted sequences, FLAIR, diffusion weighted imaging, 
susceptibility weighted imaging, and dynamic susceptibility contrast perfusion imaging) and the 
addition of the pCASL sequence to evaluate cerebral perfusion.  
 
 
Data Collection and Analysis 
The relative CBF in frontal, parietal, occipital gray matter and white matter regions, basal 
ganglia, thalami, and cerebellum will be measured using region of interest analysis obtained 
from both the DSC-PWI and pCASL sequences. The resultant regional CBF values will be 
compared between the two methods using a Mann Whitney test (SPSS, version 21). A resulting 
data base of institutional control values for these regional CBF will be created.  
 
Risks 
MRI related risks: 
The pCASL sequence being tested is a modification of current FDA-approved and commercially 
available pASL sequence whose development is supported by Siemens Medical Inc. under a 
Master Research agreement with UCLA. The specific absorption rate (SAR, a measure of heat 
deposition in tissue) of pCASL is lower than with CASL sequences (Chen et al., 2011; Alsop et 
al., 2014); both which are within FDA specified parameters. Importantly, SAR limits are hard 

coded into the MRI scanner software and cannot be overridden. In addition, before an acquisition 
starts, the SAR level is calculated by the scanner software using the parameters specified and if 
the SAR is calculated to exceed the FDA limit, a warning is generated and the acquisition will 
not run. Moreover, this sequence does not require the use of gadolinium contrast, thereby 
eliminating the risk associated with its use. All safety precautions normally used for patient 
scanning will be used and include the use of  the standard LLUMC safety screening 
questionnaire to determine if the subject has MR incompatible devices or objects in the body that 
might cause harm such as a pacemaker, defibrillator, stents, coils, pumps, stimulators, etc.  prior 
to having the MRI scan to determine if it is safe to scan.  This form will be reviewed by MRI 
staff (MR Technologist and/or study Investigator) before the subject is allowed in the MRI suite. 
 
Confidentiality or Privacy Issues 
Each participant’s imaging data will be archived in their medical record (Radiology PACS image 
archive server). To protect against a breach of confidentiality or privacy, prior to data analysis 
subject identifiers will be removed and replaced by a unique research identifier. The key to the 
research ID will be kept in a computer file on CD and locked in a file cabinet in the PI’s office.  
 
Benefits 
It is not anticipated that there will be any direct benefit to most participants at the time of the 
study. However, should this study show that the pCASL sequence can provide an accurate and 
reliable measure of CBF, future use could provide additional information to Physicians in 
vulnerable (neonate and pediatric, elderly, diabetic, and renal-compromised) patients that would 
not routinely get this information.  
 
References 
 
Calamante F, Thomas DL, Pell GS, Wiersma J, Turner R. (1999) Measuring cerebral blood flow 
using magnetic resonance imaging techniques. J Cereb Blood Flow Metab. 19(7):701-35.  
 
Tepel M, Aspelin P, Lameire N. (2006) Contrast-induced nephropathy: a clinical and 
evidence-based approach. Circulation. 113(14):1799-806. 
 
Wang DJ, Alger JR, Qiao JX, Hao Q, Hou S, Fiaz R, Gunther M, Pope WB, Saver 
JL, Salamon N, Liebeskind DS, UCLA Stroke Investigators. (2012) The value of arterial spin-
labeled perfusion imaging in acute ischemic stroke: comparison with dynamic susceptibility 
contrast-enhanced MRI. Stroke. 43(4):1018-24. 
 
Tancredi FB, Gauthier CJ, Madjar C, Bolar DS, Fisher JA, Wang DJ, Hoge RD. (2012) 
Comparison of pulsed and pseudocontinuous arterial spin-labeling for measuring CO2 -induced 
cerebrovascular reactivity. J Magn Reson Imaging. 36(2):312-21.  
 
White CM, Pope WB, Zaw T, Qiao J, Naeini KM, Lai A, Nghiemphu PL, Wang JJ, 
Cloughesy TF, Ellingson BM. (2014) Regional and voxel-wise comparisons of blood flow 
measurements between dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) 
and arterial spin labeling (ASL) in brain tumors. J Neuroimaging. 24(1):23-30.  
 

Alsop DC, Detre JA, Golay X, Günther M, Hendrikse J, Hernandez-Garcia L, Lu H, Macintosh 
BJ, Parkes LM, Smits M, van Osch MJ, Wang DJ, Wong EC, Zaharchuk G. (2014) 
Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A 
consensus of the ISMRM perfusion study group and the European consortium for ASL in 
dementia. Magn Reson Med. 2014 doi: 10.1002/mrm.25197.  
 
Chen Y, Wang DJ, Detre JA. (2011) Test-retest reliability of arterial spin labeling with common 
labeling strategies. J Magn Reson Imaging. 33(4):940-9.