Imaging Multiple Sclerosis Lesions Using Magnevist and Gadavist

Rationale/Goal: The use of contrast agents in magnetic resonance imaging (MRI) has been a
gold standard in diagnosing multiple sclerosis (MS). One active lesion (i.e. enhanced after
the injection of contrast agent) is one of the major McDonald criteria in diagnosis patients
with MS and request further follow up. Therefore, it is of great importance to study the
characteristics of contrast agents and their ability to cross the blood brain barrier and
enhance lesions, and thus understand the mechanism underlying this debilitating disease. It
is the aim of this proposal to compare lesion load visualization in MS patients using
Magnevist and Gadavist contrast agents and show reduced whole brain perfusion of MS patients
compared to healthy subjects. This proposal will allow us to investigate the increase in
angiogenic sensitivity to contrast agent (Gadavist), in addition to testing the ability to
differentiate the breakdown of blood brain barrier.

METHODS

-Study Design: Fifty-four (54) subjects will be enrolled in this study including 36 MS
patients and 18 healthy subjects as age and gender-matched controls over a one year period.
Approval from Wayne State University Institutional Review Board (IRB) will be obtained
before the beginning of this study. All the participants will sign an informed consent form
after being told about the study and its possible associated risks. We propose to study 18
relapsing remitting MS (RRMS) patients and 18 clinically isolated syndrome (CIS) patients
and 18 normal controls. The subjects will be scanned at entry and a second time (scan 2) -
no sooner than 8 days after the first scan but no later than 30 days after the first scan.
Every effort will be made to scan them as close as possible to the 8 day period.

Nine RRMS and nine CIS patients will undergo an MR scan using Magnevist first (scan 1 at
entry) then Gadavist (scan 2) while the other nine in each category will undergo an MR scan
using Gadavist first (scan 1 at entry) then Magnevist (scan 2). Eighteen normal subjects
will undergo the same protocol described above for MS patients, 9 with one order (Magnevist
then Gadavist) and 9 with the other (Gadavist then Magnevist), to be used as age and gender
matched controls for data analysis. Patients will be recruited by physicians affiliated with
the Detroit Medical Center (DMC) and surrounding areas.

MR Protocol

The investigators have prepared an MR imaging protocol that will allow this information to
be assessed quantitatively in both the MS and normal populations. This protocol will include
the usual conventional T2, fluid attenuated inversion recovery (FLAIR), susceptibility
weighted imaging (SWI), pre and post T1 scans (both volumetric interpolated breath-hold
(VIBE) and magnetization-prepared rapid acquisition with gradient echo (MP-RAGE)) at early
and later time points as well as dynamic susceptibility contrast enhanced perfusion weighted
imaging (DSC-PWI), flow and average perfusion using phase contrast (PC), MR angiography
(MRA) and double inversion recovery (DIR). For DSC-PWI, the investigators have developed the
perfusion software necessary to analyze this data quantitatively including a new processing
approach referred to as Tissue Similarity Mapping (TSM). This technique uses all time points
in the PWI data to yield a new means to study similarities between blood flow patterns in
tissue of the brain. It may help in better diagnosing vascular differences between tissues
(specifically MS lesions), in addition to the conventional processing to measure relative
cerebral blood flow, relative cerebral blood volume, mean transit time, and several other
measures in the white matter and gray matter areas of the brain. If Magnevist was used in
the initial scan, this protocol will be repeated on the same subject after a period of 8 to
30 days using Gadavist.

- Image acquisition The investigators have designed this protocol to assess the
pathophysiology of MS lesions in space and in time. SWI will be used as a means to
visualize iron deposition in lesions, possibly resulting from myelin breakdown or
microhemorrhages. FLAIR, T2 and DIR will be used to assess any inflammation or edema in
lesions. Contrast enhanced sequences including PWI, SWI and T1, in that order, will be
used to dynamically assess the vascular characteristics of the different structures of
the brain including white matter, gray matter and lesions. PC will be used to
investigate the blood supply and drainage to and from the brain and any correlation
with identified perfusion deficit. This will add 4 to 6 minutes to the original
protocol. MRA, on the other hand, will be used to visualize and assess the blood supply
system integrity. Finally, the investigators will acquire T1 and SWI sequences at
different time points post contrast (please refer Sequence_Order.pdf) to compare the
mechanism of work Magnevist and Gadavist have in terms of relaxivity and permeability
and their ability to show more lesions.

- Data analysis Perfusion Weighted Imaging PWI is a well established MRI method for
studying cerebral hemodynamics and has found various applications in tumor,
angiogenesis and stroke imaging. The hemodynamic characteristics are determined by
creating maps of various parameters, such as: cerebral blood flow (CBF), cerebral blood
volume (CBV), mean transit time (MTT) and time to bolus peak (TTP), and these parameter
maps are derived from the evolution of the intensity of T2*-weighted gradient- or
spin-echo, echo-planar images as a gadolinium contrast agent bolus passes through the
blood vessels. Through the use of these maps, it is possible to visualize the passage
of blood throughout the brain and to identify any regions of abnormal behavior.
Quantification of these hemodynamic parameters is possible, utilizing the central
volume theorem and a subsequent deconvolution technique. the investigators developed
software SPIN (signal processing in Nuclear magnetic resonance), Detroit, Michigan,
USA) to process the PWI source data to create perfusion maps. The position of the
arterial input function (AIF), which is needed for deconvolution, is automatically
determined by using the maximum concentration (Cmax), time to peak (TTP) and first
moment MTT (fMTT). The concentration-time curve for arteries has short fMTT, short TTP
and high Cmax. Twenty voxels, which best fit these properties, are selected. Then, the
concentration-time curves of these voxels are averaged, smoothed and truncated to avoid
the signal from the second pass of the tracer. Singular value decomposition (SVD) was
used to determine the hemodynamic parameters such as CBV, CBF and MTT. The parametric
maps will be derived from the PWI data using the investigators' in-house software SPIN.
These maps include relative cerebral blood flow and cerebral blood volume in white
matter, gray matter and MS lesions. This will reveal any changes/ abnormalities related
to the vascular system such as ischemia, infarcts or any abnormal blood flow to any
specific region that might be involved in MS pathogenesis. Finally, color-coded maps of
CBV and CBF with the application of threshold were computed and generated
pixel-by-pixel for better visualizing the differences between tissues.

- Susceptibility Weighted Imaging A 64x64 (or equivalent) low spatial frequency kernel
matrix was used to complex-divide the original k-space data to create an effective high
pass filtered phase image (check reference 12). The resulting SWI filtered phase image
is used as a means to visualize lesions and their iron content.

- Conventional MR sequences including T1, T2 and FLAIR Two blinded radiologists will
review the conventional MR data sets to determine the presence of chronic and active MS
lesions over time and compare the results with non-conventional MR quantitative results
(SWI and PWI).

Study Organization: This study will be performed at Wayne State University, Detroit, MI. MRI
data will be obtained using a 3 Tesla Siemens system (Siemens Medical Solutions, Erlangen,
Germany) with a state-of-the-art 32 channel head coil and the latest SWI software located at
the basement of Harper University Hospital (affiliated with Wayne State University).

Study Population: Fifty-four (54)subjects will be recruited in this study including 18 RRMS
patients, 18 CIS patients and 18 control subjects. Patients will be recruited by physicians
affiliated with the Detroit Medical Center (DMC), Oakland Hospital in Detroit, Michigan (MI)
and other local hospitals and physicians. Patients with prior known neurological disorders
other than MS or substances abuse, with contraindication to MRI such as pacemaker,
pregnancy, other non-MR compatible implanted device as well as with moderate to severe
kidney disease that have impaired ability to filter the contrast agents will be excluded
from the study. Brain MRI scans will be obtained once at entry as the investigators will be
running a cross sectional study. Controls will be recruited from the university environment
in Detroit and the surrounding areas.

- Assignment of subjects to study arms or groups - Randomization: The contrast agent used
will be randomly assigned to MS patients and controls while ensuring the coverage of
each type of agent for the two groups to be studied. The conventional dose (according
to the FDA guidelines) of 0.2 mL/kg (0.1mmol/kg) for Magnevist and 0.1 mL/kg
(0.1mmol/kg) for Gadavist.

- Blinding: Data processors as well as radiologists, will be blinded to what contrast
agent has been used to ensure objectivity in data analysis.

- Primary Efficacy Variable(s): Post contrast imaging sequences will be repeated after 5
and 20 minutes to monitor lesions visualization as a function of time and test the
efficacy of both contrast agents as diagnostic measures, revealed by crossing the blood
brain barrier into MS lesions.

- Secondary Efficacy Variable(s): SWI data will be collected after 10 minutes and 25
minutes.

- Safety Variables: Safety Monitoring All subjects will initially be screened for
inclusion and exclusion criteria by physician (MS patients) or key personnel involved
in this research (normal volunteers). After the consent/ Health Insurance Portability
and Accountability Act (HIPAA) is signed, a further MRI and MRI contrast safety
assessment will be conducted by the Research Nurse and/or the MRI Research Technologist
involved in this research. Only when all safety parameters are met, will the subject be
scanned. The research technologist will communicate with the subject as well as
visually observe them during the entire exam for their comfort and safety. Once the
scan is complete, the subject will be assessed one more time by the Research Nurse
and/or the MRI Research Technologist. In case of an unexpected problem during the MRI
scan or MRI contrast administration, the radiologist will be notified immediately to
assess the situation. The PI as well as the subjects physician (if known) will also be
notified about the event. The PI will be responsible to submit any or all source
documents and report forms to the IRB in less than 5 working days. In each case, the PI
will also provide a judgment in consultation with a radiologist as to whether or not
the adverse event is associated with or related to the study protocol.

- Sample Size Assumptions / Target Number of Valid Cases: Power analysis: With 18 RR
patients for both Magnevist and Gadavist, the power to differentiate between a p(n)=0.2
versus a p(MS) = 0.5 is above 80%. Here p refers to the probability that PWI flow
abnormalities exist in the normal versus MS population, respectively.

Inclusion Criteria:

MS Patients:

- Patients who suffer from clinically definite MS with a RR phenotype or CIS

- Age range from 20-59 years old

- Not pregnant or nursing

- Able to understand and sign a consent form

- No contraindication to MRI and contrast agent

Controls:

- Control is a healthy volunteer

- Aged from 20-59 years old

- Not pregnant or nursing

- Able to understand and sign a consent form

- No contraindication to MRI and contrast agent

Exclusion Criteria:

MS Patients:

- History of other major illness such as diabetes, chronic renal disease, a prior known
neurological disorder other than MS or substances abuse

- Currently receiving chemo therapy, on dialysis

- Known contraindication to MRI such as pacemaker, pregnancy, other non-MR compatible
implanted device

- Allergic to MRI contrast Patients with moderate to severe kidney disease that have
impaired ability to filter the contrast agents (serum creatinine > 1.8 mg/dL).

- Younger than 20 or older than 59

- Pregnancy or nursing

- Unable to understand and sign a consent form

Controls:

- History of other major illness such as diabetes, chronic renal disease, a prior known
neurological disorder or substances abuse

- Currently receiving chemo therapy, on dialysis

- Known contraindication to MRI such as pacemaker, pregnancy, other non-MR compatible
implanted device

- Allergic to MRI contrast Controls with moderate to severe kidney disease that have
impaired ability to filter the contrast agents (serum creatinine > 1.8 mg/dL).

- Younger than 20 or older than 59

- Pregnancy or nursing

- Unable to understand and sign a consent form